Genetics

Study 1 Overview (Cortés et al)

Objective: To compare the efficacy and safety of trastuzumab deruxtecan with those of trastuzumab emtansine in patients with HER2-positive metastatic breast cancer previously treated with trastuzumab and taxane.

Design: Phase 3, multicenter, open-label randomized trial conducted at 169 centers and 15 countries.

Setting and participants: Eligible patients had to have unresectable or metastatic HER2-positive breast cancer that had progressed during or after treatment with trastuzumab and a taxane or had disease that progressed within 6 months after neoadjuvant or adjuvant treatment involving trastuzumab or taxane. Patients with stable or previously treated brain metastases were eligible. Patients were not eligible for the study if they had symptomatic brain metastases, prior exposure to trastuzumab emtansine, or a history of interstitial lung disease.

Intervention: Patients were randomized in a 1-to-1 fashion to receive either trastuzumab deruxtecan 5.4 mg/kg every 3 weeks or trastuzumab emtansine 3.6 mg/kg every 3 weeks. Patients were stratified according to hormone-receptor status, prior treatment with epratuzumab, and the presence or absence of visceral disease.

Main outcome measures: The primary endpoint of the study was progression-free survival as determined by an independent central review. Secondary endpoints included overall survival, overall response, and safety.

Main results: A total of 524 patients were enrolled in the study, with 261 patients randomized to trastuzumab deruxtecan and 263 patients randomized to trastuzumab emtansine. The demographic and baseline characteristics were similar between the 2 cohorts, and 60% of patients in both groups received prior epratuzumab therapy. Stable brain metastases were present in around 20% of patients in each group, and 70% of patients in each group had visceral disease. The median duration of follow-up was 16.2 months with trastuzumab deruxtecan and 15.3 months with trastuzumab emtansine.

The median progression-free survival was not reached in the trastuzumab deruxtecan group and was 6.8 months in the trastuzumab emtansine group (95% CI, 5.6-8.2). At 12 months the percentage of patients alive without disease progression was significantly larger in the trastuzumab deruxtecan group compared with the trastuzumab emtansine group. The hazard ratio for disease progression or death from any cause was 0.28 (95% CI, 0.22-0.37; P < .001). Subgroup analyses showed a benefit in progression-free survival with trastuzumab deruxtecan across all subgroups.

At the time of this analysis, the percentage of patients who were alive at 12 months was 94% with trastuzumab deruxtecan and 85.9% with trastuzumab emtansine. The response rates were significantly higher with trastuzumab deruxtecan compared with trastuzumab emtansine (79.7% vs 34.2%). A complete response was seen in 16% of patients in the trastuzumab deruxtecan arm, compared with 8.7% of patients in the trastuzumab emtansine group. The disease control rate (complete response, partial response, or stable disease) was higher in the trastuzumab deruxtecan group compared with the trastuzumab emtansine group (96.6% vs 76.8%).

Serious adverse events were reported in 19% of patients in the trastuzumab deruxtecan group and 18% of patients in the trastuzumab emtansine group. Discontinuation due to adverse events was higher in the trastuzumab deruxtecan group, with 13.6% of patients discontinuing trastuzumab deruxtecan. Grade 3 or higher adverse events were seen in 52% of patients treated with trastuzumab deruxtecan and 48% of patients treated with trastuzumab emtansine. The most commonly reported adverse event with trastuzumab deruxtecan was nausea/vomiting and fatigue. These adverse events were seen more in the trastuzumab deruxtecan group compared with the trastuzumab emtansine group. No drug-related grade 5 adverse events were reported.

In the trastuzumab deruxtecan group, 10.5% of patients receiving trastuzumab deruxtecan developed interstitial lung disease or pneumonitis. Seven patients had grade 1 events, 18 patients had grade 2 events, and 2 patients had grade 3 events. No grade 4 or 5 events were noted in either treatment group. The median time to onset of interstitial lung disease or pneumonitis in those receiving trastuzumab deruxtecan was 168 days (range, 33-507). Discontinuation of therapy due to interstitial lung disease or pneumonitis occurred in 8% of patients receiving trastuzumab deruxtecan and 1% of patients receiving trastuzumab emtansine.

Conclusion: Trastuzumab deruxtecan significantly decreases the risk of disease progression or death compared to trastuzumab emtansine in patients with HER2-positive metastatic breast cancer who have progressed on prior trastuzumab and taxane-based therapy.

Study 2 Overview (Modi et al)

Objective: To assess the efficacy of trastuzumab deruxtecan in patients with unresectable or metastatic breast cancer with low levels of HER2 expression.

Design: This was a randomized, 2-group, open-label, phase 3 trial.

Setting and participants: The trial was designed with a planned enrollment of 480 patients with hormone receptor–positive disease and 60 patients with hormone receptor–negative disease. Patients were randomized in a 2:1 ratio. Randomization was stratified according to HER2 status (immunohistochemical [IHC] 1+ vs IHC 2+/in situ hybridization [ISH] negative), number of prior lines of therapy, and hormone-receptor status. IHC scores for HER2 expression were determined through central testing. Specimens that had HER2 IHC scores of 2+ were reflexed to ISH. Specimens were considered HER2-low-expressing if they had an IHC score of 1+ or if they had an IHC score of 2+ and were ISH negative.

Eligible patients had to have received chemotherapy for metastatic disease or had disease recurrence during or within 6 months after completing adjuvant chemotherapy. Patients with hormone receptor–positive disease must have had at least 1 line of endocrine therapy. Patients were eligible if they had stable brain metastases. Patients with interstitial lung disease were excluded.

Intervention: Patients were randomized to receive trastuzumab deruxtecan 5.4 mg/kg every 3 weeks or physician’s choice of chemotherapy (capecitabine, eribulin, gemcitabine, paclitaxel, or nab-paclitaxel).

Main outcome measures: The primary endpoint was progression-free survival in patients with hormone receptor–positive disease. Secondary endpoints were progression-free survival among all patients, overall survival in hormone receptor–positive patients, and overall survival in all patients. Additional secondary endpoints included objective response rates, duration of response, and efficacy in hormone receptor–negative patients.

Main results: A total of 373 patients were assigned to the trastuzumab deruxtecan group and 184 patients were assigned to the physician’s choice chemotherapy group; 88% of patients in each cohort were hormone receptor–positive. In the physician’s choice chemotherapy group, 51% received eribulin, 20% received capecitabine, 10% received nab-paclitaxel, 10% received gemcitabine, and 8% received paclitaxel. The demographic and baseline characteristics were similar between both cohorts. The median duration of follow-up was 18.4 months.

The median progression-free survival in the hormone receptor–positive cohort was 10.1 months in the trastuzumab deruxtecan group and 5.4 months in the physician’s choice chemotherapy group (HR, 0.51; 95% CI, 0.4-0.64). Subgroup analyses revealed a benefit across all subgroups. The median progression-free survival among patients with a HER2 IHC score of 1+ and those with a HER2 IHC score of 2+/negative ISH were identical. In patients who received a prior CDK 4/6 inhibitor, the median progression-free survival was also 10 months in the trastuzumab deruxtecan group. In those who were CDK 4/6- naïve, the progression-free survival was 11.7 months. The progression-free survival in all patients was 9.9 months in the trastuzumab deruxtecan group and 5.1 months in the physician’s choice chemotherapy group (HR, 0.46; 95% CI, 0.24-0.89).

The median overall survival in the hormone receptor–positive cohort was 23.9 months in the trastuzumab deruxtecan group compared with 17.5 months in the physician’s choice chemotherapy group (HR, 0.64; 95% CI, 0.48-0.86; P = .003). The median overall survival in the entire population was 23.4 months in the trastuzumab deruxtecan group vs 16.8 months in the physician’s choice chemotherapy group. In the hormone receptor–negative cohort, the median overall survival was 18.2 months in the trastuzumab deruxtecan group and 8.3 months in the physician’s choice chemotherapy group. Complete responses were seen in 3.6% in the trastuzumab deruxtecan group and 0.6% and the physician’s choice chemotherapy group. The median duration of response was 10.7 months in the trastuzumab deruxtecan group and 6.8 months in the physician’s choice chemotherapy group.

Incidence of serious adverse events was 27% in the trastuzumab deruxtecan group and 25% in the physician’s choice chemotherapy group. Grade 3 or higher events occurred in 52% of the trastuzumab deruxtecan group and 67% of the physician’s choice chemotherapy group. Discontinuation due to adverse events occurred in 16% in the trastuzumab deruxtecan group and 18% in the physician’s choice chemotherapy group; 14 patients in the trastuzumab deruxtecan group and 5 patients in the physician’s choice chemotherapy group had an adverse event that was associated with death. Death due to pneumonitis in the trastuzumab deruxtecan group occurred in 2 patients. Drug-related interstitial lung disease or pneumonitis occurred in 45 patients who received trastuzumab deruxtecan. The majority of these events were grade 1 and grade 2. However, 3 patients had grade 5 interstitial lung disease or pneumonitis.

Conclusion: Treatment with trastuzumab deruxtecan led to a significant improvement in progression-free survival compared to physician’s choice chemotherapy in patients with HER2-low metastatic breast cancer.

Commentary

Trastuzumab deruxtecan is an antibody drug conjugate that consists of a humanized anti-HER2 monoclonal antibody linked to a topoisomerase 1 inhibitor. This antibody drug conjugate is unique compared with prior antibody drug conjugates such as trastuzumab emtansine in that it has a high drug-to-antibody ratio (~8). Furthermore, there appears to be a unique bystander effect resulting in off-target cytotoxicity to neighboring tumor cells, enhancing the efficacy of this novel therapy. Prior studies of trastuzumab deruxtecan have shown durable activity in heavily pretreated patients with metastatic HER2-positive breast cancer.¹

HER2-positive breast cancer represents approximately 20% of breast cancer cases in women.² Historically, HER2 positivity has been defined by strong HER2 expression with IHC staining (ie, score 3+) or HER2 amplification through ISH. Conversely, HER2-negative disease has historically been defined as those with IHC scores of 0 or 1+. This group represents approximately 60% of HER2-negative metastatic breast cancer patients.³ These patients have limited targeted treatment options after progressing on primary therapy. Prior data has shown that patients with low HER2 expression represent a heterogeneous population and thus, the historic categorization of HER2 status as positive or negative may in fact not adequately characterize the proportion of patients who may derive clinical benefit from HER2-directed therapies. Nevertheless, there have been no data to date that have shown improved outcomes in low HER2 expressers with anti-HER2 therapies.

The current studies add to the rapidly growing body of literature outlining the efficacy of the novel antibody drug conjugate trastuzumab deruxtecan. The implications of the data presented in these 2 studies are immediately practice changing.

In the DESTINY-Breast03 trial, Cortéz and colleagues show that trastuzumab deruxtecan therapy significantly prolongs progression-free survival compared with trastuzumab emtansine in patients with HER2-positive metastatic breast cancer who have progressed on first-line trastuzumab and taxane-based therapy. With a hazard ratio of 0.28 for disease progression or death, the efficacy of trastuzumab deruxtecan highlighted in this trial clearly makes this the standard of care in the second-line setting for patients with metastatic HER2-positive breast cancer. The overall survival in this trial was immature at the time of this analysis, and thus continued follow-up to validate the results noted here are warranted.

The DESTINY-Breast04 trial by Modi et al expands the cohort of patients who benefit from trastuzumab deruxtecan profoundly. This study defines a population of patients with HER2-low metastatic breast cancer who will now be eligible for HER2-directed therapies. These data show that therapy with trastuzumab deruxtecan leads to a significant and clinically meaningful improvement in both progression-free survival and overall survival compared with chemotherapy in patients with metastatic breast cancer with low expression of HER2. This benefit was seen in both the estrogen receptor–positive cohort as well as the entire population, including pre-treated triple-negative disease. Furthermore, this study does not define a threshold of HER2 expression by IHC that predicts benefit with trastuzumab deruxtecan. Patients with an IHC score of 1+ as well as those with a score of 2+/ISH negative both benefit to a similar extent from trastuzumab deruxtecan. Interestingly, in the DAISY trial, antitumor activity was noted with trastuzumab deruxtecan even in those without any detectable HER2 expression on IHC.⁴ Given the inconsistency and potential false negatives of IHC along with heterogeneous HER2 expression, further work is needed to better identify patients with low levels of HER2 expression who may benefit from this novel antibody drug conjugate. Thus, a reliable test to quantitatively assess the level of HER2 expression is needed in order to determine more accurately which patients will benefit from trastuzumab deruxtecan.

Last, trastuzumab deruxtecan has been associated with interstitial lung disease and pneumonitis. Interstitial lung disease and pneumonitis occurred in approximately 10% of patients who received trastuzumab deruxtecan in the DESTINY-Breast03 trial and about 12% of patients in the DESTINY-Breast04 trial. Most of these events were grade 1 and grade 2. Nevertheless, clinicians must be aware of this risk and monitor patients frequently for the development of pneumonitis or interstitial lung disease.

Application for Clinical Practice and System Implementation

The results of the current studies show a longer progression-free survival with trastuzumab deruxtecan in both HER2-low expressing metastatic breast cancer and HER2-positive metastatic breast cancer following taxane and trastuzumab-based therapy. These results are clearly practice changing and represent a new standard of care in these patient populations. It is incumbent upon treating oncologists to work with our pathology colleagues to assess HER2 IHC thoroughly in order to identify all potential patients who may benefit from trastuzumab deruxtecan in the metastatic setting. The continued advancement of anti-HER2 therapy will undoubtedly have a significant impact on patient outcomes going forward.

Practice Points

• With a hazard ratio of 0.28 for disease progression or death, the efficacy of trastuzumab deruxtecan highlighted in the DESTINY-Breast03 trial clearly makes this the standard of care in the second-line setting for patients with metastatic HER2-positive breast cancer.
• In the DESTINY-Breast04 trial, a significant and clinically meaningful improvement in both progression-free survival and overall survival compared with chemotherapy was seen in patients with metastatic breast cancer with low expression of HER2, including both the estrogen receptor–positive cohort as well as the entire population, including those with pre-treated triple-negative disease.

­—Daniel Isaac, DO, MS

Study 1 Overview (Cortés et al)

Objective: To compare the efficacy and safety of trastuzumab deruxtecan with those of trastuzumab emtansine in patients with HER2-positive metastatic breast cancer previously treated with trastuzumab and taxane.

Design: Phase 3, multicenter, open-label randomized trial conducted at 169 centers and 15 countries.

Setting and participants: Eligible patients had to have unresectable or metastatic HER2-positive breast cancer that had progressed during or after treatment with trastuzumab and a taxane or had disease that progressed within 6 months after neoadjuvant or adjuvant treatment involving trastuzumab or taxane. Patients with stable or previously treated brain metastases were eligible. Patients were not eligible for the study if they had symptomatic brain metastases, prior exposure to trastuzumab emtansine, or a history of interstitial lung disease.

Intervention: Patients were randomized in a 1-to-1 fashion to receive either trastuzumab deruxtecan 5.4 mg/kg every 3 weeks or trastuzumab emtansine 3.6 mg/kg every 3 weeks. Patients were stratified according to hormone-receptor status, prior treatment with epratuzumab, and the presence or absence of visceral disease.

Main outcome measures: The primary endpoint of the study was progression-free survival as determined by an independent central review. Secondary endpoints included overall survival, overall response, and safety.

Main results: A total of 524 patients were enrolled in the study, with 261 patients randomized to trastuzumab deruxtecan and 263 patients randomized to trastuzumab emtansine. The demographic and baseline characteristics were similar between the 2 cohorts, and 60% of patients in both groups received prior epratuzumab therapy. Stable brain metastases were present in around 20% of patients in each group, and 70% of patients in each group had visceral disease. The median duration of follow-up was 16.2 months with trastuzumab deruxtecan and 15.3 months with trastuzumab emtansine.

The median progression-free survival was not reached in the trastuzumab deruxtecan group and was 6.8 months in the trastuzumab emtansine group (95% CI, 5.6-8.2). At 12 months the percentage of patients alive without disease progression was significantly larger in the trastuzumab deruxtecan group compared with the trastuzumab emtansine group. The hazard ratio for disease progression or death from any cause was 0.28 (95% CI, 0.22-0.37; P < .001). Subgroup analyses showed a benefit in progression-free survival with trastuzumab deruxtecan across all subgroups.

At the time of this analysis, the percentage of patients who were alive at 12 months was 94% with trastuzumab deruxtecan and 85.9% with trastuzumab emtansine. The response rates were significantly higher with trastuzumab deruxtecan compared with trastuzumab emtansine (79.7% vs 34.2%). A complete response was seen in 16% of patients in the trastuzumab deruxtecan arm, compared with 8.7% of patients in the trastuzumab emtansine group. The disease control rate (complete response, partial response, or stable disease) was higher in the trastuzumab deruxtecan group compared with the trastuzumab emtansine group (96.6% vs 76.8%).

Serious adverse events were reported in 19% of patients in the trastuzumab deruxtecan group and 18% of patients in the trastuzumab emtansine group. Discontinuation due to adverse events was higher in the trastuzumab deruxtecan group, with 13.6% of patients discontinuing trastuzumab deruxtecan. Grade 3 or higher adverse events were seen in 52% of patients treated with trastuzumab deruxtecan and 48% of patients treated with trastuzumab emtansine. The most commonly reported adverse event with trastuzumab deruxtecan was nausea/vomiting and fatigue. These adverse events were seen more in the trastuzumab deruxtecan group compared with the trastuzumab emtansine group. No drug-related grade 5 adverse events were reported.

In the trastuzumab deruxtecan group, 10.5% of patients receiving trastuzumab deruxtecan developed interstitial lung disease or pneumonitis. Seven patients had grade 1 events, 18 patients had grade 2 events, and 2 patients had grade 3 events. No grade 4 or 5 events were noted in either treatment group. The median time to onset of interstitial lung disease or pneumonitis in those receiving trastuzumab deruxtecan was 168 days (range, 33-507). Discontinuation of therapy due to interstitial lung disease or pneumonitis occurred in 8% of patients receiving trastuzumab deruxtecan and 1% of patients receiving trastuzumab emtansine.

Conclusion: Trastuzumab deruxtecan significantly decreases the risk of disease progression or death compared to trastuzumab emtansine in patients with HER2-positive metastatic breast cancer who have progressed on prior trastuzumab and taxane-based therapy.

Study 2 Overview (Modi et al)

Objective: To assess the efficacy of trastuzumab deruxtecan in patients with unresectable or metastatic breast cancer with low levels of HER2 expression.

Design: This was a randomized, 2-group, open-label, phase 3 trial.

Setting and participants: The trial was designed with a planned enrollment of 480 patients with hormone receptor–positive disease and 60 patients with hormone receptor–negative disease. Patients were randomized in a 2:1 ratio. Randomization was stratified according to HER2 status (immunohistochemical [IHC] 1+ vs IHC 2+/in situ hybridization [ISH] negative), number of prior lines of therapy, and hormone-receptor status. IHC scores for HER2 expression were determined through central testing. Specimens that had HER2 IHC scores of 2+ were reflexed to ISH. Specimens were considered HER2-low-expressing if they had an IHC score of 1+ or if they had an IHC score of 2+ and were ISH negative.

Eligible patients had to have received chemotherapy for metastatic disease or had disease recurrence during or within 6 months after completing adjuvant chemotherapy. Patients with hormone receptor–positive disease must have had at least 1 line of endocrine therapy. Patients were eligible if they had stable brain metastases. Patients with interstitial lung disease were excluded.

Intervention: Patients were randomized to receive trastuzumab deruxtecan 5.4 mg/kg every 3 weeks or physician’s choice of chemotherapy (capecitabine, eribulin, gemcitabine, paclitaxel, or nab-paclitaxel).

Main outcome measures: The primary endpoint was progression-free survival in patients with hormone receptor–positive disease. Secondary endpoints were progression-free survival among all patients, overall survival in hormone receptor–positive patients, and overall survival in all patients. Additional secondary endpoints included objective response rates, duration of response, and efficacy in hormone receptor–negative patients.

Main results: A total of 373 patients were assigned to the trastuzumab deruxtecan group and 184 patients were assigned to the physician’s choice chemotherapy group; 88% of patients in each cohort were hormone receptor–positive. In the physician’s choice chemotherapy group, 51% received eribulin, 20% received capecitabine, 10% received nab-paclitaxel, 10% received gemcitabine, and 8% received paclitaxel. The demographic and baseline characteristics were similar between both cohorts. The median duration of follow-up was 18.4 months.

The median progression-free survival in the hormone receptor–positive cohort was 10.1 months in the trastuzumab deruxtecan group and 5.4 months in the physician’s choice chemotherapy group (HR, 0.51; 95% CI, 0.4-0.64). Subgroup analyses revealed a benefit across all subgroups. The median progression-free survival among patients with a HER2 IHC score of 1+ and those with a HER2 IHC score of 2+/negative ISH were identical. In patients who received a prior CDK 4/6 inhibitor, the median progression-free survival was also 10 months in the trastuzumab deruxtecan group. In those who were CDK 4/6- naïve, the progression-free survival was 11.7 months. The progression-free survival in all patients was 9.9 months in the trastuzumab deruxtecan group and 5.1 months in the physician’s choice chemotherapy group (HR, 0.46; 95% CI, 0.24-0.89).

The median overall survival in the hormone receptor–positive cohort was 23.9 months in the trastuzumab deruxtecan group compared with 17.5 months in the physician’s choice chemotherapy group (HR, 0.64; 95% CI, 0.48-0.86; P = .003). The median overall survival in the entire population was 23.4 months in the trastuzumab deruxtecan group vs 16.8 months in the physician’s choice chemotherapy group. In the hormone receptor–negative cohort, the median overall survival was 18.2 months in the trastuzumab deruxtecan group and 8.3 months in the physician’s choice chemotherapy group. Complete responses were seen in 3.6% in the trastuzumab deruxtecan group and 0.6% and the physician’s choice chemotherapy group. The median duration of response was 10.7 months in the trastuzumab deruxtecan group and 6.8 months in the physician’s choice chemotherapy group.

Incidence of serious adverse events was 27% in the trastuzumab deruxtecan group and 25% in the physician’s choice chemotherapy group. Grade 3 or higher events occurred in 52% of the trastuzumab deruxtecan group and 67% of the physician’s choice chemotherapy group. Discontinuation due to adverse events occurred in 16% in the trastuzumab deruxtecan group and 18% in the physician’s choice chemotherapy group; 14 patients in the trastuzumab deruxtecan group and 5 patients in the physician’s choice chemotherapy group had an adverse event that was associated with death. Death due to pneumonitis in the trastuzumab deruxtecan group occurred in 2 patients. Drug-related interstitial lung disease or pneumonitis occurred in 45 patients who received trastuzumab deruxtecan. The majority of these events were grade 1 and grade 2. However, 3 patients had grade 5 interstitial lung disease or pneumonitis.

Conclusion: Treatment with trastuzumab deruxtecan led to a significant improvement in progression-free survival compared to physician’s choice chemotherapy in patients with HER2-low metastatic breast cancer.

Commentary

Trastuzumab deruxtecan is an antibody drug conjugate that consists of a humanized anti-HER2 monoclonal antibody linked to a topoisomerase 1 inhibitor. This antibody drug conjugate is unique compared with prior antibody drug conjugates such as trastuzumab emtansine in that it has a high drug-to-antibody ratio (~8). Furthermore, there appears to be a unique bystander effect resulting in off-target cytotoxicity to neighboring tumor cells, enhancing the efficacy of this novel therapy. Prior studies of trastuzumab deruxtecan have shown durable activity in heavily pretreated patients with metastatic HER2-positive breast cancer.¹

HER2-positive breast cancer represents approximately 20% of breast cancer cases in women.² Historically, HER2 positivity has been defined by strong HER2 expression with IHC staining (ie, score 3+) or HER2 amplification through ISH. Conversely, HER2-negative disease has historically been defined as those with IHC scores of 0 or 1+. This group represents approximately 60% of HER2-negative metastatic breast cancer patients.³ These patients have limited targeted treatment options after progressing on primary therapy. Prior data has shown that patients with low HER2 expression represent a heterogeneous population and thus, the historic categorization of HER2 status as positive or negative may in fact not adequately characterize the proportion of patients who may derive clinical benefit from HER2-directed therapies. Nevertheless, there have been no data to date that have shown improved outcomes in low HER2 expressers with anti-HER2 therapies.

The current studies add to the rapidly growing body of literature outlining the efficacy of the novel antibody drug conjugate trastuzumab deruxtecan. The implications of the data presented in these 2 studies are immediately practice changing.

In the DESTINY-Breast03 trial, Cortéz and colleagues show that trastuzumab deruxtecan therapy significantly prolongs progression-free survival compared with trastuzumab emtansine in patients with HER2-positive metastatic breast cancer who have progressed on first-line trastuzumab and taxane-based therapy. With a hazard ratio of 0.28 for disease progression or death, the efficacy of trastuzumab deruxtecan highlighted in this trial clearly makes this the standard of care in the second-line setting for patients with metastatic HER2-positive breast cancer. The overall survival in this trial was immature at the time of this analysis, and thus continued follow-up to validate the results noted here are warranted.

The DESTINY-Breast04 trial by Modi et al expands the cohort of patients who benefit from trastuzumab deruxtecan profoundly. This study defines a population of patients with HER2-low metastatic breast cancer who will now be eligible for HER2-directed therapies. These data show that therapy with trastuzumab deruxtecan leads to a significant and clinically meaningful improvement in both progression-free survival and overall survival compared with chemotherapy in patients with metastatic breast cancer with low expression of HER2. This benefit was seen in both the estrogen receptor–positive cohort as well as the entire population, including pre-treated triple-negative disease. Furthermore, this study does not define a threshold of HER2 expression by IHC that predicts benefit with trastuzumab deruxtecan. Patients with an IHC score of 1+ as well as those with a score of 2+/ISH negative both benefit to a similar extent from trastuzumab deruxtecan. Interestingly, in the DAISY trial, antitumor activity was noted with trastuzumab deruxtecan even in those without any detectable HER2 expression on IHC.⁴ Given the inconsistency and potential false negatives of IHC along with heterogeneous HER2 expression, further work is needed to better identify patients with low levels of HER2 expression who may benefit from this novel antibody drug conjugate. Thus, a reliable test to quantitatively assess the level of HER2 expression is needed in order to determine more accurately which patients will benefit from trastuzumab deruxtecan.

Last, trastuzumab deruxtecan has been associated with interstitial lung disease and pneumonitis. Interstitial lung disease and pneumonitis occurred in approximately 10% of patients who received trastuzumab deruxtecan in the DESTINY-Breast03 trial and about 12% of patients in the DESTINY-Breast04 trial. Most of these events were grade 1 and grade 2. Nevertheless, clinicians must be aware of this risk and monitor patients frequently for the development of pneumonitis or interstitial lung disease.

Application for Clinical Practice and System Implementation

The results of the current studies show a longer progression-free survival with trastuzumab deruxtecan in both HER2-low expressing metastatic breast cancer and HER2-positive metastatic breast cancer following taxane and trastuzumab-based therapy. These results are clearly practice changing and represent a new standard of care in these patient populations. It is incumbent upon treating oncologists to work with our pathology colleagues to assess HER2 IHC thoroughly in order to identify all potential patients who may benefit from trastuzumab deruxtecan in the metastatic setting. The continued advancement of anti-HER2 therapy will undoubtedly have a significant impact on patient outcomes going forward.

Practice Points

• With a hazard ratio of 0.28 for disease progression or death, the efficacy of trastuzumab deruxtecan highlighted in the DESTINY-Breast03 trial clearly makes this the standard of care in the second-line setting for patients with metastatic HER2-positive breast cancer.
• In the DESTINY-Breast04 trial, a significant and clinically meaningful improvement in both progression-free survival and overall survival compared with chemotherapy was seen in patients with metastatic breast cancer with low expression of HER2, including both the estrogen receptor–positive cohort as well as the entire population, including those with pre-treated triple-negative disease.

­—Daniel Isaac, DO, MS

Study 1 Overview (Cortés et al)

Objective: To compare the efficacy and safety of trastuzumab deruxtecan with those of trastuzumab emtansine in patients with HER2-positive metastatic breast cancer previously treated with trastuzumab and taxane.

Design: Phase 3, multicenter, open-label randomized trial conducted at 169 centers and 15 countries.

Setting and participants: Eligible patients had to have unresectable or metastatic HER2-positive breast cancer that had progressed during or after treatment with trastuzumab and a taxane or had disease that progressed within 6 months after neoadjuvant or adjuvant treatment involving trastuzumab or taxane. Patients with stable or previously treated brain metastases were eligible. Patients were not eligible for the study if they had symptomatic brain metastases, prior exposure to trastuzumab emtansine, or a history of interstitial lung disease.

Intervention: Patients were randomized in a 1-to-1 fashion to receive either trastuzumab deruxtecan 5.4 mg/kg every 3 weeks or trastuzumab emtansine 3.6 mg/kg every 3 weeks. Patients were stratified according to hormone-receptor status, prior treatment with epratuzumab, and the presence or absence of visceral disease.

Main outcome measures: The primary endpoint of the study was progression-free survival as determined by an independent central review. Secondary endpoints included overall survival, overall response, and safety.

Main results: A total of 524 patients were enrolled in the study, with 261 patients randomized to trastuzumab deruxtecan and 263 patients randomized to trastuzumab emtansine. The demographic and baseline characteristics were similar between the 2 cohorts, and 60% of patients in both groups received prior epratuzumab therapy. Stable brain metastases were present in around 20% of patients in each group, and 70% of patients in each group had visceral disease. The median duration of follow-up was 16.2 months with trastuzumab deruxtecan and 15.3 months with trastuzumab emtansine.

The median progression-free survival was not reached in the trastuzumab deruxtecan group and was 6.8 months in the trastuzumab emtansine group (95% CI, 5.6-8.2). At 12 months the percentage of patients alive without disease progression was significantly larger in the trastuzumab deruxtecan group compared with the trastuzumab emtansine group. The hazard ratio for disease progression or death from any cause was 0.28 (95% CI, 0.22-0.37; P < .001). Subgroup analyses showed a benefit in progression-free survival with trastuzumab deruxtecan across all subgroups.

At the time of this analysis, the percentage of patients who were alive at 12 months was 94% with trastuzumab deruxtecan and 85.9% with trastuzumab emtansine. The response rates were significantly higher with trastuzumab deruxtecan compared with trastuzumab emtansine (79.7% vs 34.2%). A complete response was seen in 16% of patients in the trastuzumab deruxtecan arm, compared with 8.7% of patients in the trastuzumab emtansine group. The disease control rate (complete response, partial response, or stable disease) was higher in the trastuzumab deruxtecan group compared with the trastuzumab emtansine group (96.6% vs 76.8%).

Serious adverse events were reported in 19% of patients in the trastuzumab deruxtecan group and 18% of patients in the trastuzumab emtansine group. Discontinuation due to adverse events was higher in the trastuzumab deruxtecan group, with 13.6% of patients discontinuing trastuzumab deruxtecan. Grade 3 or higher adverse events were seen in 52% of patients treated with trastuzumab deruxtecan and 48% of patients treated with trastuzumab emtansine. The most commonly reported adverse event with trastuzumab deruxtecan was nausea/vomiting and fatigue. These adverse events were seen more in the trastuzumab deruxtecan group compared with the trastuzumab emtansine group. No drug-related grade 5 adverse events were reported.

In the trastuzumab deruxtecan group, 10.5% of patients receiving trastuzumab deruxtecan developed interstitial lung disease or pneumonitis. Seven patients had grade 1 events, 18 patients had grade 2 events, and 2 patients had grade 3 events. No grade 4 or 5 events were noted in either treatment group. The median time to onset of interstitial lung disease or pneumonitis in those receiving trastuzumab deruxtecan was 168 days (range, 33-507). Discontinuation of therapy due to interstitial lung disease or pneumonitis occurred in 8% of patients receiving trastuzumab deruxtecan and 1% of patients receiving trastuzumab emtansine.

Conclusion: Trastuzumab deruxtecan significantly decreases the risk of disease progression or death compared to trastuzumab emtansine in patients with HER2-positive metastatic breast cancer who have progressed on prior trastuzumab and taxane-based therapy.

Study 2 Overview (Modi et al)

Objective: To assess the efficacy of trastuzumab deruxtecan in patients with unresectable or metastatic breast cancer with low levels of HER2 expression.

Design: This was a randomized, 2-group, open-label, phase 3 trial.

Setting and participants: The trial was designed with a planned enrollment of 480 patients with hormone receptor–positive disease and 60 patients with hormone receptor–negative disease. Patients were randomized in a 2:1 ratio. Randomization was stratified according to HER2 status (immunohistochemical [IHC] 1+ vs IHC 2+/in situ hybridization [ISH] negative), number of prior lines of therapy, and hormone-receptor status. IHC scores for HER2 expression were determined through central testing. Specimens that had HER2 IHC scores of 2+ were reflexed to ISH. Specimens were considered HER2-low-expressing if they had an IHC score of 1+ or if they had an IHC score of 2+ and were ISH negative.

Eligible patients had to have received chemotherapy for metastatic disease or had disease recurrence during or within 6 months after completing adjuvant chemotherapy. Patients with hormone receptor–positive disease must have had at least 1 line of endocrine therapy. Patients were eligible if they had stable brain metastases. Patients with interstitial lung disease were excluded.

Intervention: Patients were randomized to receive trastuzumab deruxtecan 5.4 mg/kg every 3 weeks or physician’s choice of chemotherapy (capecitabine, eribulin, gemcitabine, paclitaxel, or nab-paclitaxel).

Main outcome measures: The primary endpoint was progression-free survival in patients with hormone receptor–positive disease. Secondary endpoints were progression-free survival among all patients, overall survival in hormone receptor–positive patients, and overall survival in all patients. Additional secondary endpoints included objective response rates, duration of response, and efficacy in hormone receptor–negative patients.

Main results: A total of 373 patients were assigned to the trastuzumab deruxtecan group and 184 patients were assigned to the physician’s choice chemotherapy group; 88% of patients in each cohort were hormone receptor–positive. In the physician’s choice chemotherapy group, 51% received eribulin, 20% received capecitabine, 10% received nab-paclitaxel, 10% received gemcitabine, and 8% received paclitaxel. The demographic and baseline characteristics were similar between both cohorts. The median duration of follow-up was 18.4 months.

The median progression-free survival in the hormone receptor–positive cohort was 10.1 months in the trastuzumab deruxtecan group and 5.4 months in the physician’s choice chemotherapy group (HR, 0.51; 95% CI, 0.4-0.64). Subgroup analyses revealed a benefit across all subgroups. The median progression-free survival among patients with a HER2 IHC score of 1+ and those with a HER2 IHC score of 2+/negative ISH were identical. In patients who received a prior CDK 4/6 inhibitor, the median progression-free survival was also 10 months in the trastuzumab deruxtecan group. In those who were CDK 4/6- naïve, the progression-free survival was 11.7 months. The progression-free survival in all patients was 9.9 months in the trastuzumab deruxtecan group and 5.1 months in the physician’s choice chemotherapy group (HR, 0.46; 95% CI, 0.24-0.89).

The median overall survival in the hormone receptor–positive cohort was 23.9 months in the trastuzumab deruxtecan group compared with 17.5 months in the physician’s choice chemotherapy group (HR, 0.64; 95% CI, 0.48-0.86; P = .003). The median overall survival in the entire population was 23.4 months in the trastuzumab deruxtecan group vs 16.8 months in the physician’s choice chemotherapy group. In the hormone receptor–negative cohort, the median overall survival was 18.2 months in the trastuzumab deruxtecan group and 8.3 months in the physician’s choice chemotherapy group. Complete responses were seen in 3.6% in the trastuzumab deruxtecan group and 0.6% and the physician’s choice chemotherapy group. The median duration of response was 10.7 months in the trastuzumab deruxtecan group and 6.8 months in the physician’s choice chemotherapy group.

Incidence of serious adverse events was 27% in the trastuzumab deruxtecan group and 25% in the physician’s choice chemotherapy group. Grade 3 or higher events occurred in 52% of the trastuzumab deruxtecan group and 67% of the physician’s choice chemotherapy group. Discontinuation due to adverse events occurred in 16% in the trastuzumab deruxtecan group and 18% in the physician’s choice chemotherapy group; 14 patients in the trastuzumab deruxtecan group and 5 patients in the physician’s choice chemotherapy group had an adverse event that was associated with death. Death due to pneumonitis in the trastuzumab deruxtecan group occurred in 2 patients. Drug-related interstitial lung disease or pneumonitis occurred in 45 patients who received trastuzumab deruxtecan. The majority of these events were grade 1 and grade 2. However, 3 patients had grade 5 interstitial lung disease or pneumonitis.

Conclusion: Treatment with trastuzumab deruxtecan led to a significant improvement in progression-free survival compared to physician’s choice chemotherapy in patients with HER2-low metastatic breast cancer.

Commentary

Trastuzumab deruxtecan is an antibody drug conjugate that consists of a humanized anti-HER2 monoclonal antibody linked to a topoisomerase 1 inhibitor. This antibody drug conjugate is unique compared with prior antibody drug conjugates such as trastuzumab emtansine in that it has a high drug-to-antibody ratio (~8). Furthermore, there appears to be a unique bystander effect resulting in off-target cytotoxicity to neighboring tumor cells, enhancing the efficacy of this novel therapy. Prior studies of trastuzumab deruxtecan have shown durable activity in heavily pretreated patients with metastatic HER2-positive breast cancer.¹

HER2-positive breast cancer represents approximately 20% of breast cancer cases in women.² Historically, HER2 positivity has been defined by strong HER2 expression with IHC staining (ie, score 3+) or HER2 amplification through ISH. Conversely, HER2-negative disease has historically been defined as those with IHC scores of 0 or 1+. This group represents approximately 60% of HER2-negative metastatic breast cancer patients.³ These patients have limited targeted treatment options after progressing on primary therapy. Prior data has shown that patients with low HER2 expression represent a heterogeneous population and thus, the historic categorization of HER2 status as positive or negative may in fact not adequately characterize the proportion of patients who may derive clinical benefit from HER2-directed therapies. Nevertheless, there have been no data to date that have shown improved outcomes in low HER2 expressers with anti-HER2 therapies.

The current studies add to the rapidly growing body of literature outlining the efficacy of the novel antibody drug conjugate trastuzumab deruxtecan. The implications of the data presented in these 2 studies are immediately practice changing.

In the DESTINY-Breast03 trial, Cortéz and colleagues show that trastuzumab deruxtecan therapy significantly prolongs progression-free survival compared with trastuzumab emtansine in patients with HER2-positive metastatic breast cancer who have progressed on first-line trastuzumab and taxane-based therapy. With a hazard ratio of 0.28 for disease progression or death, the efficacy of trastuzumab deruxtecan highlighted in this trial clearly makes this the standard of care in the second-line setting for patients with metastatic HER2-positive breast cancer. The overall survival in this trial was immature at the time of this analysis, and thus continued follow-up to validate the results noted here are warranted.

The DESTINY-Breast04 trial by Modi et al expands the cohort of patients who benefit from trastuzumab deruxtecan profoundly. This study defines a population of patients with HER2-low metastatic breast cancer who will now be eligible for HER2-directed therapies. These data show that therapy with trastuzumab deruxtecan leads to a significant and clinically meaningful improvement in both progression-free survival and overall survival compared with chemotherapy in patients with metastatic breast cancer with low expression of HER2. This benefit was seen in both the estrogen receptor–positive cohort as well as the entire population, including pre-treated triple-negative disease. Furthermore, this study does not define a threshold of HER2 expression by IHC that predicts benefit with trastuzumab deruxtecan. Patients with an IHC score of 1+ as well as those with a score of 2+/ISH negative both benefit to a similar extent from trastuzumab deruxtecan. Interestingly, in the DAISY trial, antitumor activity was noted with trastuzumab deruxtecan even in those without any detectable HER2 expression on IHC.⁴ Given the inconsistency and potential false negatives of IHC along with heterogeneous HER2 expression, further work is needed to better identify patients with low levels of HER2 expression who may benefit from this novel antibody drug conjugate. Thus, a reliable test to quantitatively assess the level of HER2 expression is needed in order to determine more accurately which patients will benefit from trastuzumab deruxtecan.

Last, trastuzumab deruxtecan has been associated with interstitial lung disease and pneumonitis. Interstitial lung disease and pneumonitis occurred in approximately 10% of patients who received trastuzumab deruxtecan in the DESTINY-Breast03 trial and about 12% of patients in the DESTINY-Breast04 trial. Most of these events were grade 1 and grade 2. Nevertheless, clinicians must be aware of this risk and monitor patients frequently for the development of pneumonitis or interstitial lung disease.

Application for Clinical Practice and System Implementation

The results of the current studies show a longer progression-free survival with trastuzumab deruxtecan in both HER2-low expressing metastatic breast cancer and HER2-positive metastatic breast cancer following taxane and trastuzumab-based therapy. These results are clearly practice changing and represent a new standard of care in these patient populations. It is incumbent upon treating oncologists to work with our pathology colleagues to assess HER2 IHC thoroughly in order to identify all potential patients who may benefit from trastuzumab deruxtecan in the metastatic setting. The continued advancement of anti-HER2 therapy will undoubtedly have a significant impact on patient outcomes going forward.

Practice Points

• With a hazard ratio of 0.28 for disease progression or death, the efficacy of trastuzumab deruxtecan highlighted in the DESTINY-Breast03 trial clearly makes this the standard of care in the second-line setting for patients with metastatic HER2-positive breast cancer.
• In the DESTINY-Breast04 trial, a significant and clinically meaningful improvement in both progression-free survival and overall survival compared with chemotherapy was seen in patients with metastatic breast cancer with low expression of HER2, including both the estrogen receptor–positive cohort as well as the entire population, including those with pre-treated triple-negative disease.

­—Daniel Isaac, DO, MS

Breast cancer is the most common invasive cancer in women in the United States; it is estimated that there will be 287,850 new cases of breast cancer in the United States during 2022 with 43,250 deaths.¹ Lives are extended and saved every day because of a robust arsenal of treatments and interventions available to those who have been given a diagnosis of breast cancer. And, of course, lives are also extended and saved when we identify women at risk and provide early interventions. But in busy offices where time is short and there are competing demands on our time, proper assessment of a woman’s risk of breast cancer does not always happen. As a result, women with a higher risk of breast cancer may not be getting appropriate management.^2,3

Familiarizing yourself with several risk-assessment tools and knowing when genetic testing is needed can make a big difference. Knowing the timing of mammograms and magnetic resonance imaging (MRI) for women deemed to be at high risk is also key. The following review employs a case-based approach (with an accompanying ALGORITHM) to illustrate how best to identify women who are at heightened risk of breast cancer and maximize their care. We also discuss the chemoprophylaxis regimens that may be used for those at increased risk.

CASE

Rachel P, age 37, presents to establish care. She has an Ashkenazi Jewish background and wonders if she should start doing breast cancer screening before age 40. She has 2 children, ages 4 years and 2 years. Her maternal aunt had unilateral breast cancer at age 54, and her maternal grandmother died of ovarian cancer at age 65.

Risk assessment

The risk assessment process (see ALGORITHM) must start with either the clinician or the patient initiating the discussion about breast cancer risk. The clinician may initiate the discussion with a new patient or at an annual physical examination. The patient may start the discussion because they are experiencing new breast symptoms, have anxiety about developing breast cancer, or have a family member with a new cancer diagnosis.

Risk factors. There are single factors that convey enough risk to automatically designate the patient as high risk (see TABLE 1^4-9). These factors include having a history of chest radiation between the ages of 10 and 30, a history of breast biopsy with either lobular carcinoma in situ (LCIS) or atypical ductal hyperplasia (ADH), past breast and/or ovarian cancer, and either a family or personal history of a high penetrant genetic variant for breast cancer.^4-9

In women with previous chest radiation, breast cancer risk correlates with the total dose of radiation.⁵ For women with a personal history of breast cancer, the younger the age at diagnosis, the higher the risk of contralateral breast cancer.⁵ Precancerous changes such as ADH, LCIS, and ductal carcinoma in situ (DCIS) also confer moderate increases in risk. Women with these diagnoses will commonly have follow-up with specialists.

Risk assessment tools. There are several models available to assess a woman’s breast cancer risk (see TABLE 2^10-12). The Gail model (https://bcrisktool.cancer.gov/) is the oldest, quickest, and most widely known. However, the Gail model only accounts for first-degree relatives diagnosed with breast cancer, may underpredict risk in women with a more extensive family history, and has not been studied in women younger than 35. The International Breast Cancer Intervention Study (IBIS) Risk Evaluation Tool (https://ibis-risk-calculator.magview.com/), commonly referred to as the Tyrer-Cuzick model, incorporates second-degree relatives into the prediction model—although women may not know their full family history. Both the IBIS and the Breast Cancer Surveillance Consortium (BCSC) model (https://tools.bcsc-scc.org/BC5yearRisk/intro.htm) include breast density in the prediction algorithm. The choice of tool depends on clinician comfort and individual patient risk factors. There is no evidence that one model is better than another.^10-12

Continue to: CASE

CASE

Ms. P’s clinician starts with an assessment using the Gail model. However, when the result comes back with average risk, the clinician decides to follow up with the Tyrer-Cuzick model in order to incorporate Ms. P’s multiple ­second-degree relatives with breast and ovarian cancer. (The BCSC model was not used because it only includes first-degree relatives.)

Genetic testing

The National Comprehensive Cancer Network (NCCN) guidelines recommend genetic testing if a woman has a first- or ­second-degree relative with pancreatic cancer, metastatic prostate cancer, male breast cancer, breast cancer at age 45 or younger, 2 or more breast cancers in a single person, 2 or more people on the same side of the family with at least 1 diagnosed at age 50 or younger, or any relative with ovarian cancer (see TABLE 3).⁷ Before ordering genetic testing, it is useful to refer the patient to a genetic counselor for a thorough discussion of options.

Results of genetic testing may include high-risk variants, moderate-risk variants, and variants of unknown significance (VUS), or be negative for any variants. High-risk variants for breast cancer include BRCA1, BRCA2, PALB2, and cancer syndrome variants such as TP53, PTEN, STK11, and CDH1.^5,6,9,13-15 These high-risk variants confer sufficient risk that women with these mutations are automatically categorized in the high-risk group. It is estimated that high-risk variants account for only 25% of the genetic risk for breast cancer.¹⁶

BRCA1/2 and PTEN mutations confer greater than 80% lifetime risk, while other high-risk variants such as TP53, CDH1, and STK11 confer risks between 25% and 40%. These variants are also associated with cancers of other organs, depending on the mutation.¹⁷

Moderate-risk variants—ATM and CHEK2—do not confer sufficient risk to elevate women into the high-risk group. However, they do qualify these intermediate-risk women to participate in a specialized management strategy.^5,9,13,18

VUS are those for which the associated risk is unclear, but more research may be done to categorize the risk.⁹ The clinical management of women with VUS usually entails close monitoring.

In an effort to better characterize breast cancer risk using a combination of pathogenic variants found in broad multi-gene cancer predisposition panels, researchers have developed a method to combine risks in a “polygenic risk score” (PRS) that can be used to counsel women (see “What is a polygenic risk score for breast cancer?” on page 203).^19-21PRS predicts an additional 18% of genetic risk in women of European descent.²¹

Continue to: CASE

CASE

Using the assessment results, the clinician talks to Ms. P about her lifetime risk for breast cancer. The Gail model indicates her lifetime risk is 13.3%, just slightly higher than the average (12.5%), and her 5-year risk is 0.5% (average, 0.4%). The IBIS or Tyrer-­Cuzick model, which takes into account her second-degree relatives with breast and ovarian cancer and her Ashkenazi ethnicity (which confers increased risk due to elevated risk of BRCA mutations), predicts her lifetime risk of breast cancer to be 20.4%. This categorizes Ms. P as high risk.

Enhanced screening recommendations for women at high risk

TABLE 4^8,13,22 summarizes screening recommendations for women deemed to be at high risk for breast cancer. The American Cancer Society (ACS), NCCN, and the American College of Radiology (ACR) recommend that women with at least a 20% lifetime risk have yearly magnetic resonance imaging (MRI) and mammography (staggered so that the patient has 1 test every 6 months) starting 10 years before the age of onset for the youngest affected relative but not before age 30.⁸ For carriers of high-risk (as well as intermediate-risk) genes, NCCN recommends annual MRI screening starting at age 40.¹³BRCA1/2 screening includes annual MRI starting at age 25 and annual mammography every 6 months starting at age 30.²² Clinicians should counsel women with moderate risk factors (elevated breast density; personal history of ADH, LCIS, or DCIS) about the potential risks and benefits of enhanced screening and chemoprophylaxis.

Risk-reduction strategies

Chemoprophylaxis

The US Preventive Services Task Force (USPSTF) recommends that all women at increased risk for breast cancer consider chemoprophylaxis (B recommendation)²³ based on convincing evidence that 5 years of treatment with either a synthetic estrogen reuptake modulator (SERM) or an aromatase inhibitor (AI) decreases the incidence of estrogen receptor positive breast cancers. (See TABLE 5^7,23,24 for absolute risk reduction.) There is no benefit for chemoprophylaxis in women at average risk (D recommendation).²³ It is unclear whether chemoprophylaxis is indicated in women with moderate increased risk (ie, who do not meet the 20% lifetime risk criteria). Chemoprophylaxis may not be effective in women with BRCA1 mutations, as they often develop triple-negative breast cancers.

Accurate risk assessment and shared decision-making enable the clinician and patient to discuss the potential risks and benefits of chemoprophylaxis.^7,24 The USPSTF did not find that any 1 risk prediction tool was better than another to identify women who should be counseled about chemoprophylaxis. Clinicians should counsel all women taking AIs about optimizing bone health with adequate calcium and vitamin D intake and routine bone density tests.

Surgical risk reduction

The NCCN guidelines state that risk-reducing bilateral mastectomy is reserved for individuals with high-risk gene variants and individuals with prior chest radiation between ages 10 and 30.²⁵ NCCN also recommends discussing risk-reducing mastectomy with all women with BRCA mutations.²²

Risk-reducing oophorectomy is the standard of care for women with BRCA mutations to reduce the risk of ovarian cancer.

Bilateral mastectomy is the most effective method to reduce breast cancer risk and should be discussed after age 25 in women with BRCA mutations and at least 8 years after chest radiation is completed.²⁶ There is a reduction in breast cancer incidence of 90%.²⁵ Breast imaging for screening (mammography or MRI) is not indicated after risk-reducing mastectomy. However, clinical breast examinations of the surgical site are important, because there is a small risk of developing breast cancer in that area.²⁶

Risk-reducing oophorectomy is the standard of care for women with BRCA mutations to reduce the risk of ovarian cancer. It can also reduce the risk of breast cancer in women with BRCA mutations.²⁷

Continue to: CASE

CASE

Based on her risk assessment results, family history, and genetic heritage, Ms. P qualifies for referral to a genetic counselor for discussion of BRCA testing. The clinician discusses adding annual MRI to Ms. P’s breast cancer screening regimen, based on ACS, NCCN, and ACR recommendations, due to her 20.4% lifetime risk. Discussion of whether and when to start chemoprophylaxis is typically based on breast cancer risk, projected benefit, and the potential impact of medication adverse effects. A high-risk woman is eligible for 5 years of chemoprophylaxis (tamoxifen if premenopausal) based on her lifetime risk. The clinician discusses timing with Ms. P, and even though she is finished with childbearing, she would like to wait until she is age 45, which is before the age at which her aunt was given a diagnosis of breast cancer.

Conclusion

Primary care clinicians are well positioned to identify women with an elevated risk of breast cancer and refer them for enhanced screening and chemoprophylaxis (see ALGORITHM). Shared decision-making with the inclusion of patient decision aids (https://decisionaid.ohri.ca/AZsearch.php?criteria=breast+cancer) about genetic testing, chemoprophylaxis, and prophylactic mastectomy or oophorectomy may help women at intermediate or high risk of breast cancer feel empowered to make decisions about their breast—and overall—health.

CORRESPONDENCE
Sarina Schrager, MD, MS, Professor, Department of Family Medicine and Community Health, University of Wisconsin, 1100 Delaplaine Court, Madison, WI 53715; sbschrag@wisc.edu

Breast cancer is the most common invasive cancer in women in the United States; it is estimated that there will be 287,850 new cases of breast cancer in the United States during 2022 with 43,250 deaths.¹ Lives are extended and saved every day because of a robust arsenal of treatments and interventions available to those who have been given a diagnosis of breast cancer. And, of course, lives are also extended and saved when we identify women at risk and provide early interventions. But in busy offices where time is short and there are competing demands on our time, proper assessment of a woman’s risk of breast cancer does not always happen. As a result, women with a higher risk of breast cancer may not be getting appropriate management.^2,3

Familiarizing yourself with several risk-assessment tools and knowing when genetic testing is needed can make a big difference. Knowing the timing of mammograms and magnetic resonance imaging (MRI) for women deemed to be at high risk is also key. The following review employs a case-based approach (with an accompanying ALGORITHM) to illustrate how best to identify women who are at heightened risk of breast cancer and maximize their care. We also discuss the chemoprophylaxis regimens that may be used for those at increased risk.

CASE

Rachel P, age 37, presents to establish care. She has an Ashkenazi Jewish background and wonders if she should start doing breast cancer screening before age 40. She has 2 children, ages 4 years and 2 years. Her maternal aunt had unilateral breast cancer at age 54, and her maternal grandmother died of ovarian cancer at age 65.

Risk assessment

The risk assessment process (see ALGORITHM) must start with either the clinician or the patient initiating the discussion about breast cancer risk. The clinician may initiate the discussion with a new patient or at an annual physical examination. The patient may start the discussion because they are experiencing new breast symptoms, have anxiety about developing breast cancer, or have a family member with a new cancer diagnosis.

Risk factors. There are single factors that convey enough risk to automatically designate the patient as high risk (see TABLE 1^4-9). These factors include having a history of chest radiation between the ages of 10 and 30, a history of breast biopsy with either lobular carcinoma in situ (LCIS) or atypical ductal hyperplasia (ADH), past breast and/or ovarian cancer, and either a family or personal history of a high penetrant genetic variant for breast cancer.^4-9

In women with previous chest radiation, breast cancer risk correlates with the total dose of radiation.⁵ For women with a personal history of breast cancer, the younger the age at diagnosis, the higher the risk of contralateral breast cancer.⁵ Precancerous changes such as ADH, LCIS, and ductal carcinoma in situ (DCIS) also confer moderate increases in risk. Women with these diagnoses will commonly have follow-up with specialists.

Risk assessment tools. There are several models available to assess a woman’s breast cancer risk (see TABLE 2^10-12). The Gail model (https://bcrisktool.cancer.gov/) is the oldest, quickest, and most widely known. However, the Gail model only accounts for first-degree relatives diagnosed with breast cancer, may underpredict risk in women with a more extensive family history, and has not been studied in women younger than 35. The International Breast Cancer Intervention Study (IBIS) Risk Evaluation Tool (https://ibis-risk-calculator.magview.com/), commonly referred to as the Tyrer-Cuzick model, incorporates second-degree relatives into the prediction model—although women may not know their full family history. Both the IBIS and the Breast Cancer Surveillance Consortium (BCSC) model (https://tools.bcsc-scc.org/BC5yearRisk/intro.htm) include breast density in the prediction algorithm. The choice of tool depends on clinician comfort and individual patient risk factors. There is no evidence that one model is better than another.^10-12

Continue to: CASE

CASE

Ms. P’s clinician starts with an assessment using the Gail model. However, when the result comes back with average risk, the clinician decides to follow up with the Tyrer-Cuzick model in order to incorporate Ms. P’s multiple ­second-degree relatives with breast and ovarian cancer. (The BCSC model was not used because it only includes first-degree relatives.)

Genetic testing

The National Comprehensive Cancer Network (NCCN) guidelines recommend genetic testing if a woman has a first- or ­second-degree relative with pancreatic cancer, metastatic prostate cancer, male breast cancer, breast cancer at age 45 or younger, 2 or more breast cancers in a single person, 2 or more people on the same side of the family with at least 1 diagnosed at age 50 or younger, or any relative with ovarian cancer (see TABLE 3).⁷ Before ordering genetic testing, it is useful to refer the patient to a genetic counselor for a thorough discussion of options.

Results of genetic testing may include high-risk variants, moderate-risk variants, and variants of unknown significance (VUS), or be negative for any variants. High-risk variants for breast cancer include BRCA1, BRCA2, PALB2, and cancer syndrome variants such as TP53, PTEN, STK11, and CDH1.^5,6,9,13-15 These high-risk variants confer sufficient risk that women with these mutations are automatically categorized in the high-risk group. It is estimated that high-risk variants account for only 25% of the genetic risk for breast cancer.¹⁶

BRCA1/2 and PTEN mutations confer greater than 80% lifetime risk, while other high-risk variants such as TP53, CDH1, and STK11 confer risks between 25% and 40%. These variants are also associated with cancers of other organs, depending on the mutation.¹⁷

Moderate-risk variants—ATM and CHEK2—do not confer sufficient risk to elevate women into the high-risk group. However, they do qualify these intermediate-risk women to participate in a specialized management strategy.^5,9,13,18

VUS are those for which the associated risk is unclear, but more research may be done to categorize the risk.⁹ The clinical management of women with VUS usually entails close monitoring.

In an effort to better characterize breast cancer risk using a combination of pathogenic variants found in broad multi-gene cancer predisposition panels, researchers have developed a method to combine risks in a “polygenic risk score” (PRS) that can be used to counsel women (see “What is a polygenic risk score for breast cancer?” on page 203).^19-21PRS predicts an additional 18% of genetic risk in women of European descent.²¹

Continue to: CASE

CASE

Using the assessment results, the clinician talks to Ms. P about her lifetime risk for breast cancer. The Gail model indicates her lifetime risk is 13.3%, just slightly higher than the average (12.5%), and her 5-year risk is 0.5% (average, 0.4%). The IBIS or Tyrer-­Cuzick model, which takes into account her second-degree relatives with breast and ovarian cancer and her Ashkenazi ethnicity (which confers increased risk due to elevated risk of BRCA mutations), predicts her lifetime risk of breast cancer to be 20.4%. This categorizes Ms. P as high risk.

Enhanced screening recommendations for women at high risk

TABLE 4^8,13,22 summarizes screening recommendations for women deemed to be at high risk for breast cancer. The American Cancer Society (ACS), NCCN, and the American College of Radiology (ACR) recommend that women with at least a 20% lifetime risk have yearly magnetic resonance imaging (MRI) and mammography (staggered so that the patient has 1 test every 6 months) starting 10 years before the age of onset for the youngest affected relative but not before age 30.⁸ For carriers of high-risk (as well as intermediate-risk) genes, NCCN recommends annual MRI screening starting at age 40.¹³BRCA1/2 screening includes annual MRI starting at age 25 and annual mammography every 6 months starting at age 30.²² Clinicians should counsel women with moderate risk factors (elevated breast density; personal history of ADH, LCIS, or DCIS) about the potential risks and benefits of enhanced screening and chemoprophylaxis.

Risk-reduction strategies

Chemoprophylaxis

The US Preventive Services Task Force (USPSTF) recommends that all women at increased risk for breast cancer consider chemoprophylaxis (B recommendation)²³ based on convincing evidence that 5 years of treatment with either a synthetic estrogen reuptake modulator (SERM) or an aromatase inhibitor (AI) decreases the incidence of estrogen receptor positive breast cancers. (See TABLE 5^7,23,24 for absolute risk reduction.) There is no benefit for chemoprophylaxis in women at average risk (D recommendation).²³ It is unclear whether chemoprophylaxis is indicated in women with moderate increased risk (ie, who do not meet the 20% lifetime risk criteria). Chemoprophylaxis may not be effective in women with BRCA1 mutations, as they often develop triple-negative breast cancers.

Accurate risk assessment and shared decision-making enable the clinician and patient to discuss the potential risks and benefits of chemoprophylaxis.^7,24 The USPSTF did not find that any 1 risk prediction tool was better than another to identify women who should be counseled about chemoprophylaxis. Clinicians should counsel all women taking AIs about optimizing bone health with adequate calcium and vitamin D intake and routine bone density tests.

Surgical risk reduction

The NCCN guidelines state that risk-reducing bilateral mastectomy is reserved for individuals with high-risk gene variants and individuals with prior chest radiation between ages 10 and 30.²⁵ NCCN also recommends discussing risk-reducing mastectomy with all women with BRCA mutations.²²

Risk-reducing oophorectomy is the standard of care for women with BRCA mutations to reduce the risk of ovarian cancer.

Bilateral mastectomy is the most effective method to reduce breast cancer risk and should be discussed after age 25 in women with BRCA mutations and at least 8 years after chest radiation is completed.²⁶ There is a reduction in breast cancer incidence of 90%.²⁵ Breast imaging for screening (mammography or MRI) is not indicated after risk-reducing mastectomy. However, clinical breast examinations of the surgical site are important, because there is a small risk of developing breast cancer in that area.²⁶

Risk-reducing oophorectomy is the standard of care for women with BRCA mutations to reduce the risk of ovarian cancer. It can also reduce the risk of breast cancer in women with BRCA mutations.²⁷

Continue to: CASE

CASE

Based on her risk assessment results, family history, and genetic heritage, Ms. P qualifies for referral to a genetic counselor for discussion of BRCA testing. The clinician discusses adding annual MRI to Ms. P’s breast cancer screening regimen, based on ACS, NCCN, and ACR recommendations, due to her 20.4% lifetime risk. Discussion of whether and when to start chemoprophylaxis is typically based on breast cancer risk, projected benefit, and the potential impact of medication adverse effects. A high-risk woman is eligible for 5 years of chemoprophylaxis (tamoxifen if premenopausal) based on her lifetime risk. The clinician discusses timing with Ms. P, and even though she is finished with childbearing, she would like to wait until she is age 45, which is before the age at which her aunt was given a diagnosis of breast cancer.

Conclusion

Primary care clinicians are well positioned to identify women with an elevated risk of breast cancer and refer them for enhanced screening and chemoprophylaxis (see ALGORITHM). Shared decision-making with the inclusion of patient decision aids (https://decisionaid.ohri.ca/AZsearch.php?criteria=breast+cancer) about genetic testing, chemoprophylaxis, and prophylactic mastectomy or oophorectomy may help women at intermediate or high risk of breast cancer feel empowered to make decisions about their breast—and overall—health.

CORRESPONDENCE
Sarina Schrager, MD, MS, Professor, Department of Family Medicine and Community Health, University of Wisconsin, 1100 Delaplaine Court, Madison, WI 53715; sbschrag@wisc.edu

Breast cancer is the most common invasive cancer in women in the United States; it is estimated that there will be 287,850 new cases of breast cancer in the United States during 2022 with 43,250 deaths.¹ Lives are extended and saved every day because of a robust arsenal of treatments and interventions available to those who have been given a diagnosis of breast cancer. And, of course, lives are also extended and saved when we identify women at risk and provide early interventions. But in busy offices where time is short and there are competing demands on our time, proper assessment of a woman’s risk of breast cancer does not always happen. As a result, women with a higher risk of breast cancer may not be getting appropriate management.^2,3

Familiarizing yourself with several risk-assessment tools and knowing when genetic testing is needed can make a big difference. Knowing the timing of mammograms and magnetic resonance imaging (MRI) for women deemed to be at high risk is also key. The following review employs a case-based approach (with an accompanying ALGORITHM) to illustrate how best to identify women who are at heightened risk of breast cancer and maximize their care. We also discuss the chemoprophylaxis regimens that may be used for those at increased risk.

CASE

Rachel P, age 37, presents to establish care. She has an Ashkenazi Jewish background and wonders if she should start doing breast cancer screening before age 40. She has 2 children, ages 4 years and 2 years. Her maternal aunt had unilateral breast cancer at age 54, and her maternal grandmother died of ovarian cancer at age 65.

Risk assessment

The risk assessment process (see ALGORITHM) must start with either the clinician or the patient initiating the discussion about breast cancer risk. The clinician may initiate the discussion with a new patient or at an annual physical examination. The patient may start the discussion because they are experiencing new breast symptoms, have anxiety about developing breast cancer, or have a family member with a new cancer diagnosis.

Risk factors. There are single factors that convey enough risk to automatically designate the patient as high risk (see TABLE 1^4-9). These factors include having a history of chest radiation between the ages of 10 and 30, a history of breast biopsy with either lobular carcinoma in situ (LCIS) or atypical ductal hyperplasia (ADH), past breast and/or ovarian cancer, and either a family or personal history of a high penetrant genetic variant for breast cancer.^4-9

In women with previous chest radiation, breast cancer risk correlates with the total dose of radiation.⁵ For women with a personal history of breast cancer, the younger the age at diagnosis, the higher the risk of contralateral breast cancer.⁵ Precancerous changes such as ADH, LCIS, and ductal carcinoma in situ (DCIS) also confer moderate increases in risk. Women with these diagnoses will commonly have follow-up with specialists.

Risk assessment tools. There are several models available to assess a woman’s breast cancer risk (see TABLE 2^10-12). The Gail model (https://bcrisktool.cancer.gov/) is the oldest, quickest, and most widely known. However, the Gail model only accounts for first-degree relatives diagnosed with breast cancer, may underpredict risk in women with a more extensive family history, and has not been studied in women younger than 35. The International Breast Cancer Intervention Study (IBIS) Risk Evaluation Tool (https://ibis-risk-calculator.magview.com/), commonly referred to as the Tyrer-Cuzick model, incorporates second-degree relatives into the prediction model—although women may not know their full family history. Both the IBIS and the Breast Cancer Surveillance Consortium (BCSC) model (https://tools.bcsc-scc.org/BC5yearRisk/intro.htm) include breast density in the prediction algorithm. The choice of tool depends on clinician comfort and individual patient risk factors. There is no evidence that one model is better than another.^10-12

Continue to: CASE

CASE

Ms. P’s clinician starts with an assessment using the Gail model. However, when the result comes back with average risk, the clinician decides to follow up with the Tyrer-Cuzick model in order to incorporate Ms. P’s multiple ­second-degree relatives with breast and ovarian cancer. (The BCSC model was not used because it only includes first-degree relatives.)

Genetic testing

The National Comprehensive Cancer Network (NCCN) guidelines recommend genetic testing if a woman has a first- or ­second-degree relative with pancreatic cancer, metastatic prostate cancer, male breast cancer, breast cancer at age 45 or younger, 2 or more breast cancers in a single person, 2 or more people on the same side of the family with at least 1 diagnosed at age 50 or younger, or any relative with ovarian cancer (see TABLE 3).⁷ Before ordering genetic testing, it is useful to refer the patient to a genetic counselor for a thorough discussion of options.

Results of genetic testing may include high-risk variants, moderate-risk variants, and variants of unknown significance (VUS), or be negative for any variants. High-risk variants for breast cancer include BRCA1, BRCA2, PALB2, and cancer syndrome variants such as TP53, PTEN, STK11, and CDH1.^5,6,9,13-15 These high-risk variants confer sufficient risk that women with these mutations are automatically categorized in the high-risk group. It is estimated that high-risk variants account for only 25% of the genetic risk for breast cancer.¹⁶

BRCA1/2 and PTEN mutations confer greater than 80% lifetime risk, while other high-risk variants such as TP53, CDH1, and STK11 confer risks between 25% and 40%. These variants are also associated with cancers of other organs, depending on the mutation.¹⁷

Moderate-risk variants—ATM and CHEK2—do not confer sufficient risk to elevate women into the high-risk group. However, they do qualify these intermediate-risk women to participate in a specialized management strategy.^5,9,13,18

VUS are those for which the associated risk is unclear, but more research may be done to categorize the risk.⁹ The clinical management of women with VUS usually entails close monitoring.

In an effort to better characterize breast cancer risk using a combination of pathogenic variants found in broad multi-gene cancer predisposition panels, researchers have developed a method to combine risks in a “polygenic risk score” (PRS) that can be used to counsel women (see “What is a polygenic risk score for breast cancer?” on page 203).^19-21PRS predicts an additional 18% of genetic risk in women of European descent.²¹

Continue to: CASE

CASE

Using the assessment results, the clinician talks to Ms. P about her lifetime risk for breast cancer. The Gail model indicates her lifetime risk is 13.3%, just slightly higher than the average (12.5%), and her 5-year risk is 0.5% (average, 0.4%). The IBIS or Tyrer-­Cuzick model, which takes into account her second-degree relatives with breast and ovarian cancer and her Ashkenazi ethnicity (which confers increased risk due to elevated risk of BRCA mutations), predicts her lifetime risk of breast cancer to be 20.4%. This categorizes Ms. P as high risk.

Enhanced screening recommendations for women at high risk

TABLE 4^8,13,22 summarizes screening recommendations for women deemed to be at high risk for breast cancer. The American Cancer Society (ACS), NCCN, and the American College of Radiology (ACR) recommend that women with at least a 20% lifetime risk have yearly magnetic resonance imaging (MRI) and mammography (staggered so that the patient has 1 test every 6 months) starting 10 years before the age of onset for the youngest affected relative but not before age 30.⁸ For carriers of high-risk (as well as intermediate-risk) genes, NCCN recommends annual MRI screening starting at age 40.¹³BRCA1/2 screening includes annual MRI starting at age 25 and annual mammography every 6 months starting at age 30.²² Clinicians should counsel women with moderate risk factors (elevated breast density; personal history of ADH, LCIS, or DCIS) about the potential risks and benefits of enhanced screening and chemoprophylaxis.

Risk-reduction strategies

Chemoprophylaxis

The US Preventive Services Task Force (USPSTF) recommends that all women at increased risk for breast cancer consider chemoprophylaxis (B recommendation)²³ based on convincing evidence that 5 years of treatment with either a synthetic estrogen reuptake modulator (SERM) or an aromatase inhibitor (AI) decreases the incidence of estrogen receptor positive breast cancers. (See TABLE 5^7,23,24 for absolute risk reduction.) There is no benefit for chemoprophylaxis in women at average risk (D recommendation).²³ It is unclear whether chemoprophylaxis is indicated in women with moderate increased risk (ie, who do not meet the 20% lifetime risk criteria). Chemoprophylaxis may not be effective in women with BRCA1 mutations, as they often develop triple-negative breast cancers.

Accurate risk assessment and shared decision-making enable the clinician and patient to discuss the potential risks and benefits of chemoprophylaxis.^7,24 The USPSTF did not find that any 1 risk prediction tool was better than another to identify women who should be counseled about chemoprophylaxis. Clinicians should counsel all women taking AIs about optimizing bone health with adequate calcium and vitamin D intake and routine bone density tests.

Surgical risk reduction

The NCCN guidelines state that risk-reducing bilateral mastectomy is reserved for individuals with high-risk gene variants and individuals with prior chest radiation between ages 10 and 30.²⁵ NCCN also recommends discussing risk-reducing mastectomy with all women with BRCA mutations.²²

Risk-reducing oophorectomy is the standard of care for women with BRCA mutations to reduce the risk of ovarian cancer.

Bilateral mastectomy is the most effective method to reduce breast cancer risk and should be discussed after age 25 in women with BRCA mutations and at least 8 years after chest radiation is completed.²⁶ There is a reduction in breast cancer incidence of 90%.²⁵ Breast imaging for screening (mammography or MRI) is not indicated after risk-reducing mastectomy. However, clinical breast examinations of the surgical site are important, because there is a small risk of developing breast cancer in that area.²⁶

Risk-reducing oophorectomy is the standard of care for women with BRCA mutations to reduce the risk of ovarian cancer. It can also reduce the risk of breast cancer in women with BRCA mutations.²⁷

Continue to: CASE

CASE

Based on her risk assessment results, family history, and genetic heritage, Ms. P qualifies for referral to a genetic counselor for discussion of BRCA testing. The clinician discusses adding annual MRI to Ms. P’s breast cancer screening regimen, based on ACS, NCCN, and ACR recommendations, due to her 20.4% lifetime risk. Discussion of whether and when to start chemoprophylaxis is typically based on breast cancer risk, projected benefit, and the potential impact of medication adverse effects. A high-risk woman is eligible for 5 years of chemoprophylaxis (tamoxifen if premenopausal) based on her lifetime risk. The clinician discusses timing with Ms. P, and even though she is finished with childbearing, she would like to wait until she is age 45, which is before the age at which her aunt was given a diagnosis of breast cancer.

Conclusion

Primary care clinicians are well positioned to identify women with an elevated risk of breast cancer and refer them for enhanced screening and chemoprophylaxis (see ALGORITHM). Shared decision-making with the inclusion of patient decision aids (https://decisionaid.ohri.ca/AZsearch.php?criteria=breast+cancer) about genetic testing, chemoprophylaxis, and prophylactic mastectomy or oophorectomy may help women at intermediate or high risk of breast cancer feel empowered to make decisions about their breast—and overall—health.

CORRESPONDENCE
Sarina Schrager, MD, MS, Professor, Department of Family Medicine and Community Health, University of Wisconsin, 1100 Delaplaine Court, Madison, WI 53715; sbschrag@wisc.edu

Advances in Alzheimer disease (AD) genes and biomarkers now allow older adults to undergo testing and learn about their risk for AD.¹ Current routes for doing so include testing in cardiology, screening for enrollment in secondary prevention trials (which use these tests to determine trial eligibility),² and direct-to-consumer (DTC) services that provide these results as part of large panels.³ Patients may also obtain apolipoprotein (APOE) genotype information as part of an assessment of the risks and benefits of treatment with aducanumab (Aduhelm) or other anti-amyloid therapies that have been developed to stop or slow the progression of AD pathologies.

Expanded access to testing, in combination with limited guidance from DTC companies, suggests more older adults may consult their primary care physicians about this testing. In this narrative review, we use a vignette-driven approach to summarize the current scientific knowledge of the topic and to offer guidance on provider-patient discussions and follow-up.

First, a look at APOE genotyping

In cognitively unimpaired older adults, the APOE gene is a known risk factor for mild cognitive impairment (MCI) or AD.³ A person has 2 alleles of the APOE gene, which has 3 variants: ε2, ε3, and ε4. The combination of alleles conveys varying levels of risk for developing clinical symptoms (TABLE 1⁴), with ε4 increasing risk and ε2 decreasing risk compared to the more common ε3; thus the ε4/ε4 genotype conveys the most risk and the ε2/ε2 the least.

The APOE gene differs from other genes that have been identified in early-onset familial AD. These other genes, which include APP, PSEN1, and PSEN2, are deterministic genes that are fully penetrant. The APOE gene is not deterministic, meaning there is no combination of APOE alleles that are necessary or sufficient to cause late-onset AD dementia.

In clinical trials of amyloid-modifying therapies, the APOE gene has been shown to convey a risk of amyloid-related imaging abnormalities (ARIA).⁵ That is, in addition to conveying a risk for AD, the gene also conveys a risk for adverse effects of emerging treatments that can result in serious injury or death. This includes the drug aducanumab that was recently approved by the US Food and Drug Administration (FDA).⁶ In this review, we focus primarily on common clinical scenarios related to APOE. However, in light of the recent controversy over aducanumab and whether the drug should be offered to patients,^7-9 we also describe how a patient’s APOE genotype may factor into drug candidacy decisions.

Testing, in clinic and “at home.” To date, practice guidelines have consistently recommended against APOE genetic testing in routine clinical practice. This is primarily due to low clinical prognostic utility and the lack of actionable results. Furthermore, no lifestyle or pharmaceutical interventions based on APOE genotype currently exist (although trials are underway¹⁰).

In 2017, the FDA approved marketing of DTC testing for the APOE gene.¹¹ While DTC companies tend to issue standardized test result reports, the content and quality can vary widely. In fact, some provide risk estimates that are too high and too definitive and may not reflect the most recent science.¹²

Continue to: 7 clinical scenarios and how to approach them

7 clinical scenarios and how to approach them

Six of the following vignettes describe common clinical scenarios in which patients seek medical advice regarding APOE test results. The seventh vignette describes a patient whose APOE genotype may play a role in possible disease-modifying treatments down the road. Each vignette is designed to guide your approach to patient discussions and follow-up. Recommendations and considerations are also summarized in TABLE 2^13-16.

Vignette 1

Janet W, age 65, comes to the clinic for a new patient visit. She has no concerns about her memory but recently purchased DTC genetic testing to learn about her genetic health risks. Her results showed an APOE ε4/ε4 genotype. She is now concerned about developing AD. Her mother was diagnosed with AD in her 70s.

Several important pieces of information can be conveyed by the primary care physician. First, patients such as Ms. W should be told that the APOE gene is not deterministic; many people, even those with 2 ε4 alleles, never develop dementia. Second, no specific preventive measures or treatments exist based on an individual’s APOE genotype (see Vignette 5 for additional discussion).

In this scenario, patients may ask for numeric quantification of their risk for dementia (see TABLE 1⁴ for estimates). When conveying probabilistic risk, consider using simple percentages or pictographs (eg, out of 100 individuals with an ε4/ε4 genotype, 30 to 55 develop MCI or AD). Additionally, because people tend to exhibit confirmatory bias in thinking about probabilistic risk, providing opposing interpretations of an estimate may help them to consider alternative possibilities.¹⁷ For example, ε4/ε4 individuals have a 30% to 55% risk for MCI or AD. Alternatively, they have a 45% to 70% risk of not developing MCI or AD.

There are important caveats to the interpretation of APOE risk estimates. Because APOE risk estimates are probabilistic and averaged across a broader spectrum of people in large population cohorts,⁴ estimates may not accurately reflect a given individual’s risk. The ranges reflect the uncertainty in the estimates. The uncertainty arises from relatively small samples, the rareness of some genotypes (notably ε4/ε4) even in large samples, and variations in methods and sampling that can lead to differences in estimates beyond statistical variation.

Vignette 2

Eric J, age 85, presents for a new patient visit accompanied by his daughter. He lives independently, volunteers at a senior center several times a week, and exercises regularly, and neither he nor his daughter has any concerns about his memory. As a gift, he recently underwent DTC genetic testing and unexpectedly learned his APOE result, which is ε4/ε4. He wants to know about his chances of developing AD.

Risk conveyed by APOE genotype can be modified by a patient’s age. At age 85, Mr. J is healthy, highly functional, and cognitively unimpaired. Given his age, Mr. J has likely “outlived” much of the risk for dementia attributable to the ε4/ε4 genotype. His risk for dementia remains high, but this risk is likely driven more by age than by his APOE genotype. Data for individuals older than age 80 are limited, and thus risk estimates lack precision. Given Mr. J’s good health and functional status, his physician may want to perform a brief cognitive screening test to serve as a baseline for future evaluations.

Continue to: Vignette 3

Vignette 3

Audrey S is a 60-year-old African American woman who comes to the clinic for her annual visit. Because her father had AD, she recently purchased DTC genetic testing to learn about her APOE genotype and risk for AD. Her results are ε3/ε4. She is wondering what this may mean for her future.

Lack of diversity in research cohorts often limits the generalizability of estimates. For example, both the frequency and impact of APOE ε4 differ across racial groups.¹⁸ But most of the data on APOE lifetime risk estimates are from largely White patient samples. While APOE ε4 seems to confer increased risk for AD across sociocultural groups, these effects may be attenuated in African American and Hispanic populations.^19,20 If Ms. S is interested in numeric risk estimates, the physician can provide the estimate for ε3/ε4 (20%-25% lifetime risk), with the important caveat that this estimate may not be reflective of her individual risk.

Both the frequency and impact of APOE ε4 differ across racial groups, but most of the data on APOE lifetime risk estimates are from largely White patient samples.

It may be prudent to determine whether Ms. S, at age 60, has subjective memory concerns and if she does, to perform a brief cognitive exam to serve as a baseline for future evaluations. Additionally, while the Genetic Information Nondiscrimination Act (GINA, 2008) prohibits health insurers and employers from discriminating based on genetic testing results, no legal provisions exist regarding long-term care, disability, or life insurance. Documented conversations about APOE test results in the medical record may become part of patients’ applications for these insurance products, and physicians should be cautious before documenting such discussions in the medical record.

Vignette 4

Tina L, age 60, comes to the clinic for a routine wellness visit. She recently developed an interest in genealogy and purchased a DNA testing kit to learn more about her family tree. As part of this testing, she unexpectedly learned that she has an APOE ε4/ε4 genotype. She describes feeling distraught and anxious about what the result means for her future.

Ms. L’s reaction to receiving unexpected genetic results highlights a concern of DTC APOE testing. Her experience is quite different from individuals undergoing medically recommended genetic testing or those who are participating in research studies. They receive comprehensive pre-test counseling by licensed genetic counselors. The counseling includes psychological assessment, education, and discussion of expectations.²

In Ms. L’s case, it may be helpful to explain the limits of APOE lifetime risk estimates (see Vignettes 1-3). But it’s also important to address her concerns. There are behavior scales that can aid the assessment and monitoring of an individual’s well-being. The Impact of Genetic Testing for Alzheimer’s Disease (IGT-AD) scale is a tool that assesses psychological impact. It can help physicians to identify, monitor, and address concerns.²¹ Other useful tools include the Patient Health Questionnaire-9 (PHQ-9) and the Geriatric Depression Scale (GDS) for depression, and a suicide or self-harm assessment.^2,22,23 Finally, a follow-up visit at 2 to 4 weeks may be useful to reassess psychological well-being.

Vignette 4 (cont’d)

Ms. L returns to the clinic 2 weeks later, reporting continued anxiety about her APOE test result and feelings of hopelessness and despair.

Continue to: Some patients struggle...

Some patients struggle with knowing their APOE test result. Test result–related distress is often a combination of depression (as with Ms. L), anger, confusion, and grief.²⁴ Cognitions often include worries about uncertainty, stereotyped threat, and internalized stigma.^25,26 These issues can spill over to patient concerns about sharing an APOE test result with others.²⁷

Intolerance of uncertainty is a transdiagnostic risk factor that can influence psychological suffering.²⁸ Brief cognitive behavioral interventions that reinforce routines and encourage healthy and mindful practices may help alleviate patient distress from unexpected genetic test results.²⁹ Interventions that personalize and validate an individual’s experience can help address internalized stigma.³⁰ Referral to a psychologist or psychiatrist could be warranted. Additionally, referral to a genetic counselor may help provide patients with access to added expertise and guidance; useful web-based resources for identifying an appropriate referral include https://medlineplus.gov/genetics/­understanding/consult/findingprofessional/ and https://findageneticcounselor.nsgc.org/.

Vignette 5

Bob K, age 65, comes to the clinic for his annual exam. He is a current smoker and says he’s hoping to be more physically active now that he is retired. He says that his mother and grandmother both had AD. He recently purchased DTC genetic testing to learn more about his risk for AD. His learned his APOE genotype is ε3/ε4 and is wondering what he can do to decrease his chances of developing AD.

Mr. K likely would have benefited from pre-test counseling regarding the lack of current therapies to modify one’s genetic risk for AD. A pre-test counseling session often includes education about APOE testing and a brief evaluation to assess psychological readiness to undergo testing. Posttest educational information may help Mr. K avoid predatory advertising of products claiming—without scientific evidence—to modify risk for cognitive decline or to improve cognitive function.

Emerging evidence from RCTs suggests that healthy lifestyle modifications may benefit cognition in individuals with APOE ε4 alleles.

There are several important pieces of information that should be communicated to Mr. K. Emerging evidence from randomized controlled trials suggests that healthy lifestyle modifications may benefit cognition in individuals with APOE ε4 alleles.³¹ It would be prudent to address proper blood pressure control³² and counsel Mr. K on how he may be able to avoid diabetes through exercise and weight maintenance. Lifestyle recommendations for Mr. K could include: smoking cessation, regular aerobic exercise (eg, 150 min/wk), and a brain-healthy diet (eg, the Mediterranean-DASH Intervention for Neurodegenerative Delay [MIND] diet).^13,14 Moreover, dementia prevention also includes appropriately managing depression and chronic illnesses and preventing social isolation and hearing loss.^15,16 This information should be thoughtfully conveyed, as these interventions can improve overall (especially cardiovascular) health, as well as mitigating one’s personal risk for AD.

Vignette 6

Juan L, age 45, comes in for his annual physical exam. He has a strong family history of heart disease. His cardiologist recently ordered lipid disorder genetic testing for familial hypercholesterolemia. This panel included APOE testing and showed Mr. L’s genotype is ε2/ε4. He read that the APOE gene can be associated with an increased AD risk and asks for information about his genotype.

Mr. L received genetic testing results that were ordered by a physician for another health purpose. Current recommendations for genetic testing in cardiology advise pre-test genetic counseling.³³ But this counseling may not include discussion of the relationship of APOE and risk for MCI or AD. This additional information may be unexpected for Mr. L. Moreover, its significance in the context of his present concerns about cardiovascular disease may influence his reaction.

Continue to: The ε2/ε4 genotype...

The ε2/ε4 genotype is rare. One study showed that in healthy adults, the frequency was 7 in 210 (0.02 [0.01-0.04]).³⁴ Given the rarity of the ε2/ε4 genotype, data about it are sparse. However, since the ε4 allele increases risk but the ε2 allele decreases risk, it is likely that any increase in risk is more modest than with ε3/ε4. In addition, it would help Mr. L to know that AD occurs infrequently before age 60.³⁵ Given his relatively young age, he is unlikely to develop AD any time in the near future. In addition, particularly if he starts early, he might be able to mitigate any increased risk through some of the advice provided to Mr. K in Vignette 5.

Vignette 7

Joe J, age 65, comes to the clinic for a new patient visit. He has no concerns about his memory but has a family history of dementia and recently purchased DTC genetic testing to learn about his genetic health risks. His results showed an APOE ε4/ε4 genotype. He is concerned about developing AD. He heard on the news that there is a drug that can treat AD and wants to know if he is a candidate for this treatment.

Mr. J would benefit from the education provided to Ms. W in Vignette 1. Patients such as Mr. J should be advised that while an APOE ε4/ε4 genotype conveys an increased risk for AD, it is not deterministic of the disease. While there are no specific preventive measures or treatments based on APOE genotype, careful medical care and lifestyle factors can offset some of the risk (see Vignette 5 for discussion).

One reason for the aducanumab controversy is that the drug has potenially severe adverse effects.

Recently (and controversially), the FDA approved aducanumab, a drug that targets amyloid.^6,36 Of note, brain amyloid is more common in individuals with the APOE ε4/ε4 genotype, such as Mr. J. However, there would be no point in testing Mr. J for brain amyloid because at present the drug is only indicated in symptomatic individuals—and, even in this setting, it is controversial. One reason for the controversy is that aducanumab has potentially severe adverse effects. Patients with the ε4/ε4 genotype should know that this genotype carries increased risk for the most serious adverse event, ARIA—which can include brain edema and microhemorrhages.

What lies ahead?

More research is needed to explore the impact that greater AD gene and biomarker testing will have on the health system and workforce development. In addition, graduate schools and training programs will need to prepare clinicians to address probabilistic risk estimates for common diseases, such as AD. Finally, health systems and medical groups that employ clinicians may want to offer simulated training—similar to the vignettes in this article—as a practice requirement or as continuing medical education. This may also allow health systems or medical groups to put in place frameworks that support clinicians in proactively answering questions for patients and families about APOE and other emerging markers of disease risk.

CORRESPONDENCE
Shana Stites, University of Pennsylvania, 3615 Chestnut Street, Philadelphia, PA 19104; Stites@UPenn.edu

Advances in Alzheimer disease (AD) genes and biomarkers now allow older adults to undergo testing and learn about their risk for AD.¹ Current routes for doing so include testing in cardiology, screening for enrollment in secondary prevention trials (which use these tests to determine trial eligibility),² and direct-to-consumer (DTC) services that provide these results as part of large panels.³ Patients may also obtain apolipoprotein (APOE) genotype information as part of an assessment of the risks and benefits of treatment with aducanumab (Aduhelm) or other anti-amyloid therapies that have been developed to stop or slow the progression of AD pathologies.

Expanded access to testing, in combination with limited guidance from DTC companies, suggests more older adults may consult their primary care physicians about this testing. In this narrative review, we use a vignette-driven approach to summarize the current scientific knowledge of the topic and to offer guidance on provider-patient discussions and follow-up.

First, a look at APOE genotyping

In cognitively unimpaired older adults, the APOE gene is a known risk factor for mild cognitive impairment (MCI) or AD.³ A person has 2 alleles of the APOE gene, which has 3 variants: ε2, ε3, and ε4. The combination of alleles conveys varying levels of risk for developing clinical symptoms (TABLE 1⁴), with ε4 increasing risk and ε2 decreasing risk compared to the more common ε3; thus the ε4/ε4 genotype conveys the most risk and the ε2/ε2 the least.

The APOE gene differs from other genes that have been identified in early-onset familial AD. These other genes, which include APP, PSEN1, and PSEN2, are deterministic genes that are fully penetrant. The APOE gene is not deterministic, meaning there is no combination of APOE alleles that are necessary or sufficient to cause late-onset AD dementia.

In clinical trials of amyloid-modifying therapies, the APOE gene has been shown to convey a risk of amyloid-related imaging abnormalities (ARIA).⁵ That is, in addition to conveying a risk for AD, the gene also conveys a risk for adverse effects of emerging treatments that can result in serious injury or death. This includes the drug aducanumab that was recently approved by the US Food and Drug Administration (FDA).⁶ In this review, we focus primarily on common clinical scenarios related to APOE. However, in light of the recent controversy over aducanumab and whether the drug should be offered to patients,^7-9 we also describe how a patient’s APOE genotype may factor into drug candidacy decisions.

Testing, in clinic and “at home.” To date, practice guidelines have consistently recommended against APOE genetic testing in routine clinical practice. This is primarily due to low clinical prognostic utility and the lack of actionable results. Furthermore, no lifestyle or pharmaceutical interventions based on APOE genotype currently exist (although trials are underway¹⁰).

In 2017, the FDA approved marketing of DTC testing for the APOE gene.¹¹ While DTC companies tend to issue standardized test result reports, the content and quality can vary widely. In fact, some provide risk estimates that are too high and too definitive and may not reflect the most recent science.¹²

Continue to: 7 clinical scenarios and how to approach them

7 clinical scenarios and how to approach them

Six of the following vignettes describe common clinical scenarios in which patients seek medical advice regarding APOE test results. The seventh vignette describes a patient whose APOE genotype may play a role in possible disease-modifying treatments down the road. Each vignette is designed to guide your approach to patient discussions and follow-up. Recommendations and considerations are also summarized in TABLE 2^13-16.

Vignette 1

Janet W, age 65, comes to the clinic for a new patient visit. She has no concerns about her memory but recently purchased DTC genetic testing to learn about her genetic health risks. Her results showed an APOE ε4/ε4 genotype. She is now concerned about developing AD. Her mother was diagnosed with AD in her 70s.

Several important pieces of information can be conveyed by the primary care physician. First, patients such as Ms. W should be told that the APOE gene is not deterministic; many people, even those with 2 ε4 alleles, never develop dementia. Second, no specific preventive measures or treatments exist based on an individual’s APOE genotype (see Vignette 5 for additional discussion).

In this scenario, patients may ask for numeric quantification of their risk for dementia (see TABLE 1⁴ for estimates). When conveying probabilistic risk, consider using simple percentages or pictographs (eg, out of 100 individuals with an ε4/ε4 genotype, 30 to 55 develop MCI or AD). Additionally, because people tend to exhibit confirmatory bias in thinking about probabilistic risk, providing opposing interpretations of an estimate may help them to consider alternative possibilities.¹⁷ For example, ε4/ε4 individuals have a 30% to 55% risk for MCI or AD. Alternatively, they have a 45% to 70% risk of not developing MCI or AD.

There are important caveats to the interpretation of APOE risk estimates. Because APOE risk estimates are probabilistic and averaged across a broader spectrum of people in large population cohorts,⁴ estimates may not accurately reflect a given individual’s risk. The ranges reflect the uncertainty in the estimates. The uncertainty arises from relatively small samples, the rareness of some genotypes (notably ε4/ε4) even in large samples, and variations in methods and sampling that can lead to differences in estimates beyond statistical variation.

Vignette 2

Eric J, age 85, presents for a new patient visit accompanied by his daughter. He lives independently, volunteers at a senior center several times a week, and exercises regularly, and neither he nor his daughter has any concerns about his memory. As a gift, he recently underwent DTC genetic testing and unexpectedly learned his APOE result, which is ε4/ε4. He wants to know about his chances of developing AD.

Risk conveyed by APOE genotype can be modified by a patient’s age. At age 85, Mr. J is healthy, highly functional, and cognitively unimpaired. Given his age, Mr. J has likely “outlived” much of the risk for dementia attributable to the ε4/ε4 genotype. His risk for dementia remains high, but this risk is likely driven more by age than by his APOE genotype. Data for individuals older than age 80 are limited, and thus risk estimates lack precision. Given Mr. J’s good health and functional status, his physician may want to perform a brief cognitive screening test to serve as a baseline for future evaluations.

Continue to: Vignette 3

Vignette 3

Audrey S is a 60-year-old African American woman who comes to the clinic for her annual visit. Because her father had AD, she recently purchased DTC genetic testing to learn about her APOE genotype and risk for AD. Her results are ε3/ε4. She is wondering what this may mean for her future.

Lack of diversity in research cohorts often limits the generalizability of estimates. For example, both the frequency and impact of APOE ε4 differ across racial groups.¹⁸ But most of the data on APOE lifetime risk estimates are from largely White patient samples. While APOE ε4 seems to confer increased risk for AD across sociocultural groups, these effects may be attenuated in African American and Hispanic populations.^19,20 If Ms. S is interested in numeric risk estimates, the physician can provide the estimate for ε3/ε4 (20%-25% lifetime risk), with the important caveat that this estimate may not be reflective of her individual risk.

Both the frequency and impact of APOE ε4 differ across racial groups, but most of the data on APOE lifetime risk estimates are from largely White patient samples.

It may be prudent to determine whether Ms. S, at age 60, has subjective memory concerns and if she does, to perform a brief cognitive exam to serve as a baseline for future evaluations. Additionally, while the Genetic Information Nondiscrimination Act (GINA, 2008) prohibits health insurers and employers from discriminating based on genetic testing results, no legal provisions exist regarding long-term care, disability, or life insurance. Documented conversations about APOE test results in the medical record may become part of patients’ applications for these insurance products, and physicians should be cautious before documenting such discussions in the medical record.

Vignette 4

Tina L, age 60, comes to the clinic for a routine wellness visit. She recently developed an interest in genealogy and purchased a DNA testing kit to learn more about her family tree. As part of this testing, she unexpectedly learned that she has an APOE ε4/ε4 genotype. She describes feeling distraught and anxious about what the result means for her future.

Ms. L’s reaction to receiving unexpected genetic results highlights a concern of DTC APOE testing. Her experience is quite different from individuals undergoing medically recommended genetic testing or those who are participating in research studies. They receive comprehensive pre-test counseling by licensed genetic counselors. The counseling includes psychological assessment, education, and discussion of expectations.²

In Ms. L’s case, it may be helpful to explain the limits of APOE lifetime risk estimates (see Vignettes 1-3). But it’s also important to address her concerns. There are behavior scales that can aid the assessment and monitoring of an individual’s well-being. The Impact of Genetic Testing for Alzheimer’s Disease (IGT-AD) scale is a tool that assesses psychological impact. It can help physicians to identify, monitor, and address concerns.²¹ Other useful tools include the Patient Health Questionnaire-9 (PHQ-9) and the Geriatric Depression Scale (GDS) for depression, and a suicide or self-harm assessment.^2,22,23 Finally, a follow-up visit at 2 to 4 weeks may be useful to reassess psychological well-being.

Vignette 4 (cont’d)

Ms. L returns to the clinic 2 weeks later, reporting continued anxiety about her APOE test result and feelings of hopelessness and despair.

Continue to: Some patients struggle...

Some patients struggle with knowing their APOE test result. Test result–related distress is often a combination of depression (as with Ms. L), anger, confusion, and grief.²⁴ Cognitions often include worries about uncertainty, stereotyped threat, and internalized stigma.^25,26 These issues can spill over to patient concerns about sharing an APOE test result with others.²⁷

Intolerance of uncertainty is a transdiagnostic risk factor that can influence psychological suffering.²⁸ Brief cognitive behavioral interventions that reinforce routines and encourage healthy and mindful practices may help alleviate patient distress from unexpected genetic test results.²⁹ Interventions that personalize and validate an individual’s experience can help address internalized stigma.³⁰ Referral to a psychologist or psychiatrist could be warranted. Additionally, referral to a genetic counselor may help provide patients with access to added expertise and guidance; useful web-based resources for identifying an appropriate referral include https://medlineplus.gov/genetics/­understanding/consult/findingprofessional/ and https://findageneticcounselor.nsgc.org/.

Vignette 5

Bob K, age 65, comes to the clinic for his annual exam. He is a current smoker and says he’s hoping to be more physically active now that he is retired. He says that his mother and grandmother both had AD. He recently purchased DTC genetic testing to learn more about his risk for AD. His learned his APOE genotype is ε3/ε4 and is wondering what he can do to decrease his chances of developing AD.

Mr. K likely would have benefited from pre-test counseling regarding the lack of current therapies to modify one’s genetic risk for AD. A pre-test counseling session often includes education about APOE testing and a brief evaluation to assess psychological readiness to undergo testing. Posttest educational information may help Mr. K avoid predatory advertising of products claiming—without scientific evidence—to modify risk for cognitive decline or to improve cognitive function.

Emerging evidence from RCTs suggests that healthy lifestyle modifications may benefit cognition in individuals with APOE ε4 alleles.

There are several important pieces of information that should be communicated to Mr. K. Emerging evidence from randomized controlled trials suggests that healthy lifestyle modifications may benefit cognition in individuals with APOE ε4 alleles.³¹ It would be prudent to address proper blood pressure control³² and counsel Mr. K on how he may be able to avoid diabetes through exercise and weight maintenance. Lifestyle recommendations for Mr. K could include: smoking cessation, regular aerobic exercise (eg, 150 min/wk), and a brain-healthy diet (eg, the Mediterranean-DASH Intervention for Neurodegenerative Delay [MIND] diet).^13,14 Moreover, dementia prevention also includes appropriately managing depression and chronic illnesses and preventing social isolation and hearing loss.^15,16 This information should be thoughtfully conveyed, as these interventions can improve overall (especially cardiovascular) health, as well as mitigating one’s personal risk for AD.

Vignette 6

Juan L, age 45, comes in for his annual physical exam. He has a strong family history of heart disease. His cardiologist recently ordered lipid disorder genetic testing for familial hypercholesterolemia. This panel included APOE testing and showed Mr. L’s genotype is ε2/ε4. He read that the APOE gene can be associated with an increased AD risk and asks for information about his genotype.

Mr. L received genetic testing results that were ordered by a physician for another health purpose. Current recommendations for genetic testing in cardiology advise pre-test genetic counseling.³³ But this counseling may not include discussion of the relationship of APOE and risk for MCI or AD. This additional information may be unexpected for Mr. L. Moreover, its significance in the context of his present concerns about cardiovascular disease may influence his reaction.

Continue to: The ε2/ε4 genotype...

The ε2/ε4 genotype is rare. One study showed that in healthy adults, the frequency was 7 in 210 (0.02 [0.01-0.04]).³⁴ Given the rarity of the ε2/ε4 genotype, data about it are sparse. However, since the ε4 allele increases risk but the ε2 allele decreases risk, it is likely that any increase in risk is more modest than with ε3/ε4. In addition, it would help Mr. L to know that AD occurs infrequently before age 60.³⁵ Given his relatively young age, he is unlikely to develop AD any time in the near future. In addition, particularly if he starts early, he might be able to mitigate any increased risk through some of the advice provided to Mr. K in Vignette 5.

Vignette 7

Joe J, age 65, comes to the clinic for a new patient visit. He has no concerns about his memory but has a family history of dementia and recently purchased DTC genetic testing to learn about his genetic health risks. His results showed an APOE ε4/ε4 genotype. He is concerned about developing AD. He heard on the news that there is a drug that can treat AD and wants to know if he is a candidate for this treatment.

Mr. J would benefit from the education provided to Ms. W in Vignette 1. Patients such as Mr. J should be advised that while an APOE ε4/ε4 genotype conveys an increased risk for AD, it is not deterministic of the disease. While there are no specific preventive measures or treatments based on APOE genotype, careful medical care and lifestyle factors can offset some of the risk (see Vignette 5 for discussion).

One reason for the aducanumab controversy is that the drug has potenially severe adverse effects.

Recently (and controversially), the FDA approved aducanumab, a drug that targets amyloid.^6,36 Of note, brain amyloid is more common in individuals with the APOE ε4/ε4 genotype, such as Mr. J. However, there would be no point in testing Mr. J for brain amyloid because at present the drug is only indicated in symptomatic individuals—and, even in this setting, it is controversial. One reason for the controversy is that aducanumab has potentially severe adverse effects. Patients with the ε4/ε4 genotype should know that this genotype carries increased risk for the most serious adverse event, ARIA—which can include brain edema and microhemorrhages.

What lies ahead?

More research is needed to explore the impact that greater AD gene and biomarker testing will have on the health system and workforce development. In addition, graduate schools and training programs will need to prepare clinicians to address probabilistic risk estimates for common diseases, such as AD. Finally, health systems and medical groups that employ clinicians may want to offer simulated training—similar to the vignettes in this article—as a practice requirement or as continuing medical education. This may also allow health systems or medical groups to put in place frameworks that support clinicians in proactively answering questions for patients and families about APOE and other emerging markers of disease risk.

CORRESPONDENCE
Shana Stites, University of Pennsylvania, 3615 Chestnut Street, Philadelphia, PA 19104; Stites@UPenn.edu

Advances in Alzheimer disease (AD) genes and biomarkers now allow older adults to undergo testing and learn about their risk for AD.¹ Current routes for doing so include testing in cardiology, screening for enrollment in secondary prevention trials (which use these tests to determine trial eligibility),² and direct-to-consumer (DTC) services that provide these results as part of large panels.³ Patients may also obtain apolipoprotein (APOE) genotype information as part of an assessment of the risks and benefits of treatment with aducanumab (Aduhelm) or other anti-amyloid therapies that have been developed to stop or slow the progression of AD pathologies.

Expanded access to testing, in combination with limited guidance from DTC companies, suggests more older adults may consult their primary care physicians about this testing. In this narrative review, we use a vignette-driven approach to summarize the current scientific knowledge of the topic and to offer guidance on provider-patient discussions and follow-up.

First, a look at APOE genotyping

In cognitively unimpaired older adults, the APOE gene is a known risk factor for mild cognitive impairment (MCI) or AD.³ A person has 2 alleles of the APOE gene, which has 3 variants: ε2, ε3, and ε4. The combination of alleles conveys varying levels of risk for developing clinical symptoms (TABLE 1⁴), with ε4 increasing risk and ε2 decreasing risk compared to the more common ε3; thus the ε4/ε4 genotype conveys the most risk and the ε2/ε2 the least.

The APOE gene differs from other genes that have been identified in early-onset familial AD. These other genes, which include APP, PSEN1, and PSEN2, are deterministic genes that are fully penetrant. The APOE gene is not deterministic, meaning there is no combination of APOE alleles that are necessary or sufficient to cause late-onset AD dementia.

In clinical trials of amyloid-modifying therapies, the APOE gene has been shown to convey a risk of amyloid-related imaging abnormalities (ARIA).⁵ That is, in addition to conveying a risk for AD, the gene also conveys a risk for adverse effects of emerging treatments that can result in serious injury or death. This includes the drug aducanumab that was recently approved by the US Food and Drug Administration (FDA).⁶ In this review, we focus primarily on common clinical scenarios related to APOE. However, in light of the recent controversy over aducanumab and whether the drug should be offered to patients,^7-9 we also describe how a patient’s APOE genotype may factor into drug candidacy decisions.

Testing, in clinic and “at home.” To date, practice guidelines have consistently recommended against APOE genetic testing in routine clinical practice. This is primarily due to low clinical prognostic utility and the lack of actionable results. Furthermore, no lifestyle or pharmaceutical interventions based on APOE genotype currently exist (although trials are underway¹⁰).

In 2017, the FDA approved marketing of DTC testing for the APOE gene.¹¹ While DTC companies tend to issue standardized test result reports, the content and quality can vary widely. In fact, some provide risk estimates that are too high and too definitive and may not reflect the most recent science.¹²

Continue to: 7 clinical scenarios and how to approach them

7 clinical scenarios and how to approach them

Six of the following vignettes describe common clinical scenarios in which patients seek medical advice regarding APOE test results. The seventh vignette describes a patient whose APOE genotype may play a role in possible disease-modifying treatments down the road. Each vignette is designed to guide your approach to patient discussions and follow-up. Recommendations and considerations are also summarized in TABLE 2^13-16.

Vignette 1

Janet W, age 65, comes to the clinic for a new patient visit. She has no concerns about her memory but recently purchased DTC genetic testing to learn about her genetic health risks. Her results showed an APOE ε4/ε4 genotype. She is now concerned about developing AD. Her mother was diagnosed with AD in her 70s.

Several important pieces of information can be conveyed by the primary care physician. First, patients such as Ms. W should be told that the APOE gene is not deterministic; many people, even those with 2 ε4 alleles, never develop dementia. Second, no specific preventive measures or treatments exist based on an individual’s APOE genotype (see Vignette 5 for additional discussion).

In this scenario, patients may ask for numeric quantification of their risk for dementia (see TABLE 1⁴ for estimates). When conveying probabilistic risk, consider using simple percentages or pictographs (eg, out of 100 individuals with an ε4/ε4 genotype, 30 to 55 develop MCI or AD). Additionally, because people tend to exhibit confirmatory bias in thinking about probabilistic risk, providing opposing interpretations of an estimate may help them to consider alternative possibilities.¹⁷ For example, ε4/ε4 individuals have a 30% to 55% risk for MCI or AD. Alternatively, they have a 45% to 70% risk of not developing MCI or AD.

There are important caveats to the interpretation of APOE risk estimates. Because APOE risk estimates are probabilistic and averaged across a broader spectrum of people in large population cohorts,⁴ estimates may not accurately reflect a given individual’s risk. The ranges reflect the uncertainty in the estimates. The uncertainty arises from relatively small samples, the rareness of some genotypes (notably ε4/ε4) even in large samples, and variations in methods and sampling that can lead to differences in estimates beyond statistical variation.

Vignette 2

Eric J, age 85, presents for a new patient visit accompanied by his daughter. He lives independently, volunteers at a senior center several times a week, and exercises regularly, and neither he nor his daughter has any concerns about his memory. As a gift, he recently underwent DTC genetic testing and unexpectedly learned his APOE result, which is ε4/ε4. He wants to know about his chances of developing AD.

Risk conveyed by APOE genotype can be modified by a patient’s age. At age 85, Mr. J is healthy, highly functional, and cognitively unimpaired. Given his age, Mr. J has likely “outlived” much of the risk for dementia attributable to the ε4/ε4 genotype. His risk for dementia remains high, but this risk is likely driven more by age than by his APOE genotype. Data for individuals older than age 80 are limited, and thus risk estimates lack precision. Given Mr. J’s good health and functional status, his physician may want to perform a brief cognitive screening test to serve as a baseline for future evaluations.

Continue to: Vignette 3

Vignette 3

Audrey S is a 60-year-old African American woman who comes to the clinic for her annual visit. Because her father had AD, she recently purchased DTC genetic testing to learn about her APOE genotype and risk for AD. Her results are ε3/ε4. She is wondering what this may mean for her future.

Lack of diversity in research cohorts often limits the generalizability of estimates. For example, both the frequency and impact of APOE ε4 differ across racial groups.¹⁸ But most of the data on APOE lifetime risk estimates are from largely White patient samples. While APOE ε4 seems to confer increased risk for AD across sociocultural groups, these effects may be attenuated in African American and Hispanic populations.^19,20 If Ms. S is interested in numeric risk estimates, the physician can provide the estimate for ε3/ε4 (20%-25% lifetime risk), with the important caveat that this estimate may not be reflective of her individual risk.

Both the frequency and impact of APOE ε4 differ across racial groups, but most of the data on APOE lifetime risk estimates are from largely White patient samples.

It may be prudent to determine whether Ms. S, at age 60, has subjective memory concerns and if she does, to perform a brief cognitive exam to serve as a baseline for future evaluations. Additionally, while the Genetic Information Nondiscrimination Act (GINA, 2008) prohibits health insurers and employers from discriminating based on genetic testing results, no legal provisions exist regarding long-term care, disability, or life insurance. Documented conversations about APOE test results in the medical record may become part of patients’ applications for these insurance products, and physicians should be cautious before documenting such discussions in the medical record.

Vignette 4

Tina L, age 60, comes to the clinic for a routine wellness visit. She recently developed an interest in genealogy and purchased a DNA testing kit to learn more about her family tree. As part of this testing, she unexpectedly learned that she has an APOE ε4/ε4 genotype. She describes feeling distraught and anxious about what the result means for her future.

Ms. L’s reaction to receiving unexpected genetic results highlights a concern of DTC APOE testing. Her experience is quite different from individuals undergoing medically recommended genetic testing or those who are participating in research studies. They receive comprehensive pre-test counseling by licensed genetic counselors. The counseling includes psychological assessment, education, and discussion of expectations.²

In Ms. L’s case, it may be helpful to explain the limits of APOE lifetime risk estimates (see Vignettes 1-3). But it’s also important to address her concerns. There are behavior scales that can aid the assessment and monitoring of an individual’s well-being. The Impact of Genetic Testing for Alzheimer’s Disease (IGT-AD) scale is a tool that assesses psychological impact. It can help physicians to identify, monitor, and address concerns.²¹ Other useful tools include the Patient Health Questionnaire-9 (PHQ-9) and the Geriatric Depression Scale (GDS) for depression, and a suicide or self-harm assessment.^2,22,23 Finally, a follow-up visit at 2 to 4 weeks may be useful to reassess psychological well-being.

Vignette 4 (cont’d)

Ms. L returns to the clinic 2 weeks later, reporting continued anxiety about her APOE test result and feelings of hopelessness and despair.

Continue to: Some patients struggle...

Some patients struggle with knowing their APOE test result. Test result–related distress is often a combination of depression (as with Ms. L), anger, confusion, and grief.²⁴ Cognitions often include worries about uncertainty, stereotyped threat, and internalized stigma.^25,26 These issues can spill over to patient concerns about sharing an APOE test result with others.²⁷

Intolerance of uncertainty is a transdiagnostic risk factor that can influence psychological suffering.²⁸ Brief cognitive behavioral interventions that reinforce routines and encourage healthy and mindful practices may help alleviate patient distress from unexpected genetic test results.²⁹ Interventions that personalize and validate an individual’s experience can help address internalized stigma.³⁰ Referral to a psychologist or psychiatrist could be warranted. Additionally, referral to a genetic counselor may help provide patients with access to added expertise and guidance; useful web-based resources for identifying an appropriate referral include https://medlineplus.gov/genetics/­understanding/consult/findingprofessional/ and https://findageneticcounselor.nsgc.org/.

Vignette 5

Bob K, age 65, comes to the clinic for his annual exam. He is a current smoker and says he’s hoping to be more physically active now that he is retired. He says that his mother and grandmother both had AD. He recently purchased DTC genetic testing to learn more about his risk for AD. His learned his APOE genotype is ε3/ε4 and is wondering what he can do to decrease his chances of developing AD.

Mr. K likely would have benefited from pre-test counseling regarding the lack of current therapies to modify one’s genetic risk for AD. A pre-test counseling session often includes education about APOE testing and a brief evaluation to assess psychological readiness to undergo testing. Posttest educational information may help Mr. K avoid predatory advertising of products claiming—without scientific evidence—to modify risk for cognitive decline or to improve cognitive function.

Emerging evidence from RCTs suggests that healthy lifestyle modifications may benefit cognition in individuals with APOE ε4 alleles.

There are several important pieces of information that should be communicated to Mr. K. Emerging evidence from randomized controlled trials suggests that healthy lifestyle modifications may benefit cognition in individuals with APOE ε4 alleles.³¹ It would be prudent to address proper blood pressure control³² and counsel Mr. K on how he may be able to avoid diabetes through exercise and weight maintenance. Lifestyle recommendations for Mr. K could include: smoking cessation, regular aerobic exercise (eg, 150 min/wk), and a brain-healthy diet (eg, the Mediterranean-DASH Intervention for Neurodegenerative Delay [MIND] diet).^13,14 Moreover, dementia prevention also includes appropriately managing depression and chronic illnesses and preventing social isolation and hearing loss.^15,16 This information should be thoughtfully conveyed, as these interventions can improve overall (especially cardiovascular) health, as well as mitigating one’s personal risk for AD.

Vignette 6

Juan L, age 45, comes in for his annual physical exam. He has a strong family history of heart disease. His cardiologist recently ordered lipid disorder genetic testing for familial hypercholesterolemia. This panel included APOE testing and showed Mr. L’s genotype is ε2/ε4. He read that the APOE gene can be associated with an increased AD risk and asks for information about his genotype.

Mr. L received genetic testing results that were ordered by a physician for another health purpose. Current recommendations for genetic testing in cardiology advise pre-test genetic counseling.³³ But this counseling may not include discussion of the relationship of APOE and risk for MCI or AD. This additional information may be unexpected for Mr. L. Moreover, its significance in the context of his present concerns about cardiovascular disease may influence his reaction.

Continue to: The ε2/ε4 genotype...

The ε2/ε4 genotype is rare. One study showed that in healthy adults, the frequency was 7 in 210 (0.02 [0.01-0.04]).³⁴ Given the rarity of the ε2/ε4 genotype, data about it are sparse. However, since the ε4 allele increases risk but the ε2 allele decreases risk, it is likely that any increase in risk is more modest than with ε3/ε4. In addition, it would help Mr. L to know that AD occurs infrequently before age 60.³⁵ Given his relatively young age, he is unlikely to develop AD any time in the near future. In addition, particularly if he starts early, he might be able to mitigate any increased risk through some of the advice provided to Mr. K in Vignette 5.

Vignette 7

Joe J, age 65, comes to the clinic for a new patient visit. He has no concerns about his memory but has a family history of dementia and recently purchased DTC genetic testing to learn about his genetic health risks. His results showed an APOE ε4/ε4 genotype. He is concerned about developing AD. He heard on the news that there is a drug that can treat AD and wants to know if he is a candidate for this treatment.

Mr. J would benefit from the education provided to Ms. W in Vignette 1. Patients such as Mr. J should be advised that while an APOE ε4/ε4 genotype conveys an increased risk for AD, it is not deterministic of the disease. While there are no specific preventive measures or treatments based on APOE genotype, careful medical care and lifestyle factors can offset some of the risk (see Vignette 5 for discussion).

One reason for the aducanumab controversy is that the drug has potenially severe adverse effects.

Recently (and controversially), the FDA approved aducanumab, a drug that targets amyloid.^6,36 Of note, brain amyloid is more common in individuals with the APOE ε4/ε4 genotype, such as Mr. J. However, there would be no point in testing Mr. J for brain amyloid because at present the drug is only indicated in symptomatic individuals—and, even in this setting, it is controversial. One reason for the controversy is that aducanumab has potentially severe adverse effects. Patients with the ε4/ε4 genotype should know that this genotype carries increased risk for the most serious adverse event, ARIA—which can include brain edema and microhemorrhages.

What lies ahead?

More research is needed to explore the impact that greater AD gene and biomarker testing will have on the health system and workforce development. In addition, graduate schools and training programs will need to prepare clinicians to address probabilistic risk estimates for common diseases, such as AD. Finally, health systems and medical groups that employ clinicians may want to offer simulated training—similar to the vignettes in this article—as a practice requirement or as continuing medical education. This may also allow health systems or medical groups to put in place frameworks that support clinicians in proactively answering questions for patients and families about APOE and other emerging markers of disease risk.

CORRESPONDENCE
Shana Stites, University of Pennsylvania, 3615 Chestnut Street, Philadelphia, PA 19104; Stites@UPenn.edu

Some adults who have an intellectual or other developmental disability (IDD) require extensive subspecialty care; many, however, depend primarily on their family physician for the bulk of their health care. With that reliance in mind, this article provides (1) an overview of important services that family physicians can provide for their adult patients with IDD and (2) pragmatic clinical suggestions for tailoring that care. Note: We highlight only some high-impact areas of clinical focus; refer to the 2018 Canadian consensus guidelines for a comprehensive approach to optimizing primary care for this population.¹

CASE

Laura S, a 24-year-old woman with Down syndrome, is visiting your clinic with her mother to establish care. Ms. S has several medical comorbidities, including type 2 diabetes, hyperlipidemia, repaired congenital heart disease, schizoaffective disorder, and hypothyroidism. She is under the care of multiple specialists, including a cardiologist and an endocrinologist. Her medications include the atypical antipsychotic risperidone, which was prescribed for her through the services of a community mental health center.

Ms. S is due for multiple preventive health screenings. She indicates that she feels nervous today talking about these screenings with a new physician.

First step in care: Proficiency in the lexicon of IDD

Three core concepts of IDD are impairment, disability, and handicap. According to the World Health Organization²:

• impairment “is any loss or abnormality of psychological, physiological, or anatomical structure or function.”
• disability “is any restriction or lack (resulting from an impairment) of ability to perform an activity in the manner or within the range considered normal for a human being.”
• handicap therefore “represents socialization of an impairment or disability, and as such it reflects the consequences for the individual—cultural, social, economic, and environmental—that stem from the presence of impairment and disability.”

Essential transition: Pediatric to adult health care

Health care transition (HCT) is the planned process of transferring care from a pediatric to an adult-based health care setting,³ comprising 3 phases:

• preparation
• transfer from pediatric to adult care
• integration into adult-based care.

Two critical components of a smooth HCT include initiating the transition early in adolescence and providing transition-support resources, which are often lacking, even in large, integrated health systems.⁴ Got Transition, created by the National Alliance to Advance Adolescent Health, outlines core elements of an organized HCT process (www.gottransition.org) specific to young adults with IDD, including young adults with autism spectrum disorder.^5,6 

Even young people who are served by a family physician and who intend to remain in that family practice as they age into adulthood require HCT services that include⁶:

• assessment of readiness to transition to adult care
• update of the medical history
• assessment and promotion of self-care skills
• consent discussions and optimized participation in decision-making
• transition of specialty care from pediatric to adult specialists.

Continue to: For an ideal HCT...

For an ideal health care transition, full engagement of the patient, the medical home, and the patient’s family (including the primary caregiver or guardian) is critical.

For an ideal HCT, full engagement of the patient, the medical home (physicians, nursing staff, and care coordinators), and the patient’s family (including the primary caregiver or guardian) is critical. In addition to preventive care visits and management of chronic disease, additional domains that require explicit attention in transitioning young people with IDD include health insurance, transportation, employment, and postsecondary education.

Young people who have special health care needs and receive high-quality HCT demonstrate improvements in adherence to care, disease-specific measures, quality of life, self-care skills, satisfaction with care, and health care utilization.⁷TABLE 1³ lists resources identified by Berens and colleagues that are helpful in facilitating the transition.

Teach and practice disability etiquette

Societal prejudice harms people with IDD—leading to self-deprecation, alienation from the larger community, and isolation from others with IDD.⁸ To promote acceptance and inclusivity in residential communities, the workplace, recreational venues, and clinical settings, disability etiquette should be utilized—a set of guidelines on how to interact with patients with IDD. These include speaking to the patient directly, using clear language in an adult voice, and avoiding stereotypes about people with disabilities.⁹ The entire health care team, including all front-facing staff (receptionists and care and financial coordinators) and clinical staff (physicians, nurses, medical assistants), need to be educated in, and practice, disability etiquette.

Preparing for in-person visits. Pre-­visit preparation, ideally by means of dialogue between health care staff and the patient or caregiver (or both), typically by telephone and in advance of the scheduled visit, is often critical for a successful first face-to-face encounter. (See “Pre-visit telephone questionnaire and script for a new adult patient with IDD,” page 287, which we developed for use in our office practice.) Outcomes of the pre-visit preparation should include identifying:

• words or actions that can trigger anxiety or panic
• de-escalation techniques, such as specific calming words and actions
• strategies for optimal communication, physical access, and physical examination.

Initial appointments should focus on building trust and rapport with the health care team and desensitizing the patient to the clinical environment.¹⁰ Examination techniques used with pediatric patients can be applied to this population: for example, demonstrating an examination maneuver first on the parent or caregiver; beginning the examination with the least invasive or anxiety-­provoking components; and stating what you plan to do next—before you do it.

Continue to: Systematic health checks provide great value

A health check is a systematic and comprehensive health assessment that is provided annually to adults with IDD, and includes:

• specific review of signs and symptoms of health conditions that often co-­occur in adults with IDD (TABLE 2Calibri¹¹)
• screening for changes in adaptive functioning and secondary disability
• lifestyle counseling
• medication review and counseling
• immunization update
• discussion of caregiver concerns.

Successful implementation of preventive health screening tests for a patient with IDD often requires ingenuity and creativity to allay fears and anxieties.

Regarding the last point: Many caregivers are the aging parents of the adult patient with IDD—people who have their own emerging health and support needs. You should initiate conversations about advanced planning for the needs of patients, which often involves engaging siblings and other family members to assume a greater role in caregiving.¹²

Benefits of the health check. A systematic review of 38 studies, comprising more than 5000 patients with IDD, found that health checks increased the detection of serious conditions, improved screening for sensory impairments, and increased the immunization rate.¹³ Although many patients with IDD generally understand the need for a periodic health examination, you can enhance their experience by better explaining the rationale for the health check; scheduling sufficient time for the appointment, based on the individual clinical situation; and discussing the value of laboratory testing and referrals to specialists.¹⁴

Tailoring preventive care

Many of the preventive services recommendations typically utilized by family physicians, such as guidelines from the US Preventive Services Task Force, have been developed for the general population at average risk of conditions of interest.¹⁵ Adults with IDD, depending on the cause of their developmental disability and their behavioral risk profile, might be at significantly higher (or lower) risk of cancer, heart disease, or other conditions than the general population. To address these differences, preventive care guidelines tailored to patients with certain developmental disabilities have been created, including guidelines specific to adults with Down syndrome, fragile X syndrome, Prader-Willi syndrome, Smith-Magenis syndrome, and 22q11.2 deletion (DiGeorge) syndrome.¹⁶

Clarifying the molecular genetic etiology of many developmental disabilities has led to more precise understandings about physical and behavioral health issues associated with specific developmental disabilities. For that reason, patients without a known cause for their IDD might benefit from referral to a geneticist—even in early or middle adulthood. Variables generally associated with a higher likelihood of an abnormal genetic test result include¹⁷:

• a family history of developmental disability
• a congenital malformation or dysmorphic features
• a dual diagnosis of developmental disability and co-occurring mental illness
• hypotonia
• severe or profound IDD.

Continue to: Successful implementation of preventive health screening tests...

Successful implementation of preventive health screening tests often requires ingenuity and the collective creativity of the patient, family members, staff, and family physician to allay fears and anxieties. Examples: Women who have been advised to undergo screening mammography might feel less anxious by undergoing tandem screening with their sister or mother, and colorectal cancer screening might be more easily accomplished using a fecal DNA test rather than by colonoscopy. Procedural desensitization strategies and preventive care instructional materials targeting people with IDD are posted on YouTube (for example, the “DD CARES Best Practices” series [see www.youtube.com/watch?v=EPJy4zvg4io]) and other websites.

Management of chronic disease

Evidence of health disparities in patients with IDD includes suboptimal management of chronic diseases, such as diabetes¹⁸ and hypertension,¹⁹ despite contact with a primary care physician. Nonadherence to a medication regimen might be more common in patients who live with their family or in a residential setting where there is a lower degree of supervision—that is, compared to a residence that maintains 24-hour staffing with daily nursing care and supervision. For a patient who is not so closely supervised, reviewing the medication refill history with the pharmacy, or using the so-called brown-bag technique of counting pill bottles brought to appointments, can ensure medication adherence.

CASE

As you interview Ms. S, you note that she is shy, avoids eye contact, and appears generally anxious. You calm her by noticing and complimenting her jewelry and fingernail polish. Ms. S smiles and talks about her favorite polish colors.

Evaluation of suspected mental and behavioral health issues begins with assessment for medical conditions that might be causing pain and distress or stereotypies.

Her mother reports that, when Ms. S is stressed, she talks to herself alone in her bedroom. However, you do not observe evidence of schizoaffective disorder, and begin to wonder whether she needs to be taking risperidone.

Essentials of mental health care

It is estimated that one-third of adults with IDD have significant mental and behavioral health care needs.²⁰ Patients with IDD suffer the same psychiatric disorders as the general population; some also engage in problematic behaviors, such as self-injurious actions, physical or verbal aggression (or both), property destruction, and resistance to caregiving assistance.

Continue to: Mental and behavioral health problems...

Mental and behavioral health problems can have a profound impact on the quality of life of patients with IDD, their peers, and their family and other caregivers. If untreated, these problems can lead to premature institutionalization, loss of employment or desired program participation, fractured social relationships, and caregiver withdrawal and burnout.

Initial evaluation of suspected mental and behavioral health problems begins with careful assessment for medical conditions that might be causing pain and distress, stereotypies, and other problematic behaviors. Common sources of pain and discomfort include dental and other oral disease, dysphagia, gastroesophageal reflux disease, gastritis, constipation, allergic disease, headache, musculoskeletal pathology, lower urinary tract disease, and gynecologic disorders.¹¹ Identification and optimal treatment of medical conditions might not eliminate problematic behaviors but often decrease their frequency and intensity.

Psychoactive medications are prescribed for many patients with IDD. Many have behavioral adverse effects, such as akathisia, aggression, and disinhibition—leading to a prescribing cascade of psychoactive medication polypharmacy and escalating dosages.²¹ Antipsychotic medications are often initiated without a careful diagnosis, explicit outcome targets, or adequate clinical monitoring for effectiveness; in addition, they often lead to insulin resistance, metabolic syndrome, and massive weight gain.²¹ Even a family physician who is not the prescriber can perform an important advocacy role by critically reviewing psychoactive medications, documenting adverse effects, insisting on a clear therapeutic target, and calling for discontinuation of medications that appear to be ineffective.

Evaluation of mental and behavioral health problems requires a developmental perspective to interpret specific, observable behaviors with a proper clinical lens. For example, many patients with IDD engage in self-talk (soliloquizing) as a means of processing the world around them. This practice might escalate during a time of physical or psychological stress, and the unwary clinician might misinterpret this behavior as psychotic, leading to inappropriate prescribing of antipsychotic medication. Other psychotoform behaviors that, superficially, mimic but are typically not truly psychotic, include talk with or about imaginary friends and repetitive retelling of sometimes elaborate or grandiose tales or assertions. The failure of clinicians to recognize developmentally determined expressions of distress often leads to a misdiagnosis of schizophrenia or other psychotic illness and, consequently, inappropriate psychopharmacotherapy. 

Family physicians, familiar with the use of psychiatric scales for diagnosis and treatment monitoring, should use similar scales that have been developed specifically for patients with IDD (TABLE 3¹¹). In addition, a psychiatric diagnosis manual, the Diagnostic Manual—Intellectual Disability 2, specific to people with IDD (and analogous to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition) provides modification of diagnostic criteria to account for patients who have difficulty articulating their internal emotional state and inner thoughts.²²

Continue to: Problematic behaviors

Problematic behaviors that are not features of a bona fide psychiatric disorder are often best understood through functional behavioral analysis, which examines antecedents and consequences of problematic behaviors and identifies their predictable outcomes, such as gaining attention, avoiding a task, or securing a desired item. Rather than being given a prescription for psychoactive medication, many adult patients with IDD and problematic behaviors might be best served by having you order consultation with a certified behavior analyst. The analyst will conduct an evaluation and, along with family or residential staff and the patient, craft a behavioral support plan to address core drivers of the undesired behavior. Behavioral support plans might be enriched by multidisciplinary input from a speech and language pathologist, habilitation professionals, occupational and physical therapists, a neuropsychologist, and others.²³

Antipsychotic medications are often initiated without a careful diagnosis. In addition, they often lead to insulin resistance, metabolic syndrome, and massive weight gain.

Resources to help you address the physical, mental, and behavioral health problems of these patients are available online through Vanderbilt Kennedy Center’s “Toolkit for primary care providers” (https://iddtoolkit.vkcsites.org).

CASE

During your examination, you review Ms. S’s vital signs, including body mass index (BMI). You calculate that she is morbidly obese—BMI, 37—in the setting of a known comorbidity, diabetes.

Ms. S tells you that she is interested in having a healthy lifestyle, but feels frustrated because she does not know how to make the necessary changes. You discuss with her how some medications, including risperidone, can promote weight gain, and that it is important for her mental health provider to carefully reassess whether she needs to continue the drug.

Weight management in a patient population that tends to be sedentary

Patients with IDD are more likely to live a sedentary lifestyle. Compared to adults who do not have IDD, adults with IDD—especially women and patients with Down syndrome—are reported to have a higher prevalence of obesity.²⁴

Continue to: As in the general population...

Similarly, undesired weight loss demands careful evaluation and management because such loss can reflect a medically significant condition, such as gastroesophageal reflux, constipation, dysphagia, neglect, and cancer.²⁷

Boosting the amount and effectiveness of physical activity

Young people with IDD participate in physical activity less often than their neurotypical peers; as a result, they tend to be less fit and have a higher prevalence of obesity.²⁸ Based on a meta-analysis, interventions that focus on sport and movement skills training, such as soccer, basketball, and ball-throwing programs, might be more effective than general physical activity programs.²⁸ In addition to year-round sports training and athletic competitions, Special Olympics conducts vital health screenings of athletes and supports community-based initiatives that address bias against patients with IDD, promote inclusion, and foster social relationships (www.specialolympics.org/our-work/inclusive-health?locale=en).

Success in weight management involves multidisciplinary treatment, including nutritional support, physical activity, behavioral changes, and close follow-up.

Emphasize regular activity. In adulthood, fewer than 10% of patients with IDD exercise regularly.²¹ According to the second edition of Physical Activity Guidelines for Americans,²⁹ “all adults, with or without a disability, should get at least 150 minutes of aerobic physical activity a week. Activities can be broken down into smaller amounts, such as about 25 minutes a day every day.”³⁰ Supplementation with muscle-strengthening activities (eg, yoga, weight training, and resistance-band training) provides further health benefit, such as improvement in posture and prevention of future injury.³¹ An ideal exercise program proposed by Tyler and Baker is based on a daily, “3-2-1” schedule (ie, of every hour of activity, 30 minutes should be of aerobic exercise; 20 minutes, of strength building; and 10 minutes, of flexibility).¹¹ By participating in any type of physical activity, there is potential for considerable health benefit in reducing psychosocial stressors, improving mental health, counteracting metabolic syndromes, and, ultimately, reducing morbidity and mortality related to physical inactivity.

CASE

With permission from Ms. S, you send your progress notes by fax to her mental health provider at the community mental health center and request a call to discuss her case—in particular, to examine potential alternatives to risperidone. With Ms. S’s input, you also co-create an exercise prescription that includes a daily 20-minute walking program with her mother.

At the follow-up visit that is scheduled in 3 months, you anticipate adding a resistance component and balance activity to the exercise prescription to enrich Ms. S’s physical activity regimen.

CORRESPONDENCE
Carl V. Tyler Jr., MD, 14601 Detroit Avenue, Lakewood, OH, 44107; catyle@ccf.org

Some adults who have an intellectual or other developmental disability (IDD) require extensive subspecialty care; many, however, depend primarily on their family physician for the bulk of their health care. With that reliance in mind, this article provides (1) an overview of important services that family physicians can provide for their adult patients with IDD and (2) pragmatic clinical suggestions for tailoring that care. Note: We highlight only some high-impact areas of clinical focus; refer to the 2018 Canadian consensus guidelines for a comprehensive approach to optimizing primary care for this population.¹

CASE

Laura S, a 24-year-old woman with Down syndrome, is visiting your clinic with her mother to establish care. Ms. S has several medical comorbidities, including type 2 diabetes, hyperlipidemia, repaired congenital heart disease, schizoaffective disorder, and hypothyroidism. She is under the care of multiple specialists, including a cardiologist and an endocrinologist. Her medications include the atypical antipsychotic risperidone, which was prescribed for her through the services of a community mental health center.

Ms. S is due for multiple preventive health screenings. She indicates that she feels nervous today talking about these screenings with a new physician.

First step in care: Proficiency in the lexicon of IDD

Three core concepts of IDD are impairment, disability, and handicap. According to the World Health Organization²:

• impairment “is any loss or abnormality of psychological, physiological, or anatomical structure or function.”
• disability “is any restriction or lack (resulting from an impairment) of ability to perform an activity in the manner or within the range considered normal for a human being.”
• handicap therefore “represents socialization of an impairment or disability, and as such it reflects the consequences for the individual—cultural, social, economic, and environmental—that stem from the presence of impairment and disability.”

Essential transition: Pediatric to adult health care

Health care transition (HCT) is the planned process of transferring care from a pediatric to an adult-based health care setting,³ comprising 3 phases:

• preparation
• transfer from pediatric to adult care
• integration into adult-based care.

Two critical components of a smooth HCT include initiating the transition early in adolescence and providing transition-support resources, which are often lacking, even in large, integrated health systems.⁴ Got Transition, created by the National Alliance to Advance Adolescent Health, outlines core elements of an organized HCT process (www.gottransition.org) specific to young adults with IDD, including young adults with autism spectrum disorder.^5,6 

Even young people who are served by a family physician and who intend to remain in that family practice as they age into adulthood require HCT services that include⁶:

• assessment of readiness to transition to adult care
• update of the medical history
• assessment and promotion of self-care skills
• consent discussions and optimized participation in decision-making
• transition of specialty care from pediatric to adult specialists.

Continue to: For an ideal HCT...

For an ideal health care transition, full engagement of the patient, the medical home, and the patient’s family (including the primary caregiver or guardian) is critical.

For an ideal HCT, full engagement of the patient, the medical home (physicians, nursing staff, and care coordinators), and the patient’s family (including the primary caregiver or guardian) is critical. In addition to preventive care visits and management of chronic disease, additional domains that require explicit attention in transitioning young people with IDD include health insurance, transportation, employment, and postsecondary education.

Young people who have special health care needs and receive high-quality HCT demonstrate improvements in adherence to care, disease-specific measures, quality of life, self-care skills, satisfaction with care, and health care utilization.⁷TABLE 1³ lists resources identified by Berens and colleagues that are helpful in facilitating the transition.

Teach and practice disability etiquette

Societal prejudice harms people with IDD—leading to self-deprecation, alienation from the larger community, and isolation from others with IDD.⁸ To promote acceptance and inclusivity in residential communities, the workplace, recreational venues, and clinical settings, disability etiquette should be utilized—a set of guidelines on how to interact with patients with IDD. These include speaking to the patient directly, using clear language in an adult voice, and avoiding stereotypes about people with disabilities.⁹ The entire health care team, including all front-facing staff (receptionists and care and financial coordinators) and clinical staff (physicians, nurses, medical assistants), need to be educated in, and practice, disability etiquette.

Preparing for in-person visits. Pre-­visit preparation, ideally by means of dialogue between health care staff and the patient or caregiver (or both), typically by telephone and in advance of the scheduled visit, is often critical for a successful first face-to-face encounter. (See “Pre-visit telephone questionnaire and script for a new adult patient with IDD,” page 287, which we developed for use in our office practice.) Outcomes of the pre-visit preparation should include identifying:

• words or actions that can trigger anxiety or panic
• de-escalation techniques, such as specific calming words and actions
• strategies for optimal communication, physical access, and physical examination.

Initial appointments should focus on building trust and rapport with the health care team and desensitizing the patient to the clinical environment.¹⁰ Examination techniques used with pediatric patients can be applied to this population: for example, demonstrating an examination maneuver first on the parent or caregiver; beginning the examination with the least invasive or anxiety-­provoking components; and stating what you plan to do next—before you do it.

Continue to: Systematic health checks provide great value

A health check is a systematic and comprehensive health assessment that is provided annually to adults with IDD, and includes:

• specific review of signs and symptoms of health conditions that often co-­occur in adults with IDD (TABLE 2Calibri¹¹)
• screening for changes in adaptive functioning and secondary disability
• lifestyle counseling
• medication review and counseling
• immunization update
• discussion of caregiver concerns.

Successful implementation of preventive health screening tests for a patient with IDD often requires ingenuity and creativity to allay fears and anxieties.

Regarding the last point: Many caregivers are the aging parents of the adult patient with IDD—people who have their own emerging health and support needs. You should initiate conversations about advanced planning for the needs of patients, which often involves engaging siblings and other family members to assume a greater role in caregiving.¹²

Benefits of the health check. A systematic review of 38 studies, comprising more than 5000 patients with IDD, found that health checks increased the detection of serious conditions, improved screening for sensory impairments, and increased the immunization rate.¹³ Although many patients with IDD generally understand the need for a periodic health examination, you can enhance their experience by better explaining the rationale for the health check; scheduling sufficient time for the appointment, based on the individual clinical situation; and discussing the value of laboratory testing and referrals to specialists.¹⁴

Tailoring preventive care

Many of the preventive services recommendations typically utilized by family physicians, such as guidelines from the US Preventive Services Task Force, have been developed for the general population at average risk of conditions of interest.¹⁵ Adults with IDD, depending on the cause of their developmental disability and their behavioral risk profile, might be at significantly higher (or lower) risk of cancer, heart disease, or other conditions than the general population. To address these differences, preventive care guidelines tailored to patients with certain developmental disabilities have been created, including guidelines specific to adults with Down syndrome, fragile X syndrome, Prader-Willi syndrome, Smith-Magenis syndrome, and 22q11.2 deletion (DiGeorge) syndrome.¹⁶

Clarifying the molecular genetic etiology of many developmental disabilities has led to more precise understandings about physical and behavioral health issues associated with specific developmental disabilities. For that reason, patients without a known cause for their IDD might benefit from referral to a geneticist—even in early or middle adulthood. Variables generally associated with a higher likelihood of an abnormal genetic test result include¹⁷:

• a family history of developmental disability
• a congenital malformation or dysmorphic features
• a dual diagnosis of developmental disability and co-occurring mental illness
• hypotonia
• severe or profound IDD.

Continue to: Successful implementation of preventive health screening tests...

Successful implementation of preventive health screening tests often requires ingenuity and the collective creativity of the patient, family members, staff, and family physician to allay fears and anxieties. Examples: Women who have been advised to undergo screening mammography might feel less anxious by undergoing tandem screening with their sister or mother, and colorectal cancer screening might be more easily accomplished using a fecal DNA test rather than by colonoscopy. Procedural desensitization strategies and preventive care instructional materials targeting people with IDD are posted on YouTube (for example, the “DD CARES Best Practices” series [see www.youtube.com/watch?v=EPJy4zvg4io]) and other websites.

Management of chronic disease

Evidence of health disparities in patients with IDD includes suboptimal management of chronic diseases, such as diabetes¹⁸ and hypertension,¹⁹ despite contact with a primary care physician. Nonadherence to a medication regimen might be more common in patients who live with their family or in a residential setting where there is a lower degree of supervision—that is, compared to a residence that maintains 24-hour staffing with daily nursing care and supervision. For a patient who is not so closely supervised, reviewing the medication refill history with the pharmacy, or using the so-called brown-bag technique of counting pill bottles brought to appointments, can ensure medication adherence.

CASE

As you interview Ms. S, you note that she is shy, avoids eye contact, and appears generally anxious. You calm her by noticing and complimenting her jewelry and fingernail polish. Ms. S smiles and talks about her favorite polish colors.

Evaluation of suspected mental and behavioral health issues begins with assessment for medical conditions that might be causing pain and distress or stereotypies.

Her mother reports that, when Ms. S is stressed, she talks to herself alone in her bedroom. However, you do not observe evidence of schizoaffective disorder, and begin to wonder whether she needs to be taking risperidone.

Essentials of mental health care

It is estimated that one-third of adults with IDD have significant mental and behavioral health care needs.²⁰ Patients with IDD suffer the same psychiatric disorders as the general population; some also engage in problematic behaviors, such as self-injurious actions, physical or verbal aggression (or both), property destruction, and resistance to caregiving assistance.

Continue to: Mental and behavioral health problems...

Mental and behavioral health problems can have a profound impact on the quality of life of patients with IDD, their peers, and their family and other caregivers. If untreated, these problems can lead to premature institutionalization, loss of employment or desired program participation, fractured social relationships, and caregiver withdrawal and burnout.

Initial evaluation of suspected mental and behavioral health problems begins with careful assessment for medical conditions that might be causing pain and distress, stereotypies, and other problematic behaviors. Common sources of pain and discomfort include dental and other oral disease, dysphagia, gastroesophageal reflux disease, gastritis, constipation, allergic disease, headache, musculoskeletal pathology, lower urinary tract disease, and gynecologic disorders.¹¹ Identification and optimal treatment of medical conditions might not eliminate problematic behaviors but often decrease their frequency and intensity.

Psychoactive medications are prescribed for many patients with IDD. Many have behavioral adverse effects, such as akathisia, aggression, and disinhibition—leading to a prescribing cascade of psychoactive medication polypharmacy and escalating dosages.²¹ Antipsychotic medications are often initiated without a careful diagnosis, explicit outcome targets, or adequate clinical monitoring for effectiveness; in addition, they often lead to insulin resistance, metabolic syndrome, and massive weight gain.²¹ Even a family physician who is not the prescriber can perform an important advocacy role by critically reviewing psychoactive medications, documenting adverse effects, insisting on a clear therapeutic target, and calling for discontinuation of medications that appear to be ineffective.

Evaluation of mental and behavioral health problems requires a developmental perspective to interpret specific, observable behaviors with a proper clinical lens. For example, many patients with IDD engage in self-talk (soliloquizing) as a means of processing the world around them. This practice might escalate during a time of physical or psychological stress, and the unwary clinician might misinterpret this behavior as psychotic, leading to inappropriate prescribing of antipsychotic medication. Other psychotoform behaviors that, superficially, mimic but are typically not truly psychotic, include talk with or about imaginary friends and repetitive retelling of sometimes elaborate or grandiose tales or assertions. The failure of clinicians to recognize developmentally determined expressions of distress often leads to a misdiagnosis of schizophrenia or other psychotic illness and, consequently, inappropriate psychopharmacotherapy. 

Family physicians, familiar with the use of psychiatric scales for diagnosis and treatment monitoring, should use similar scales that have been developed specifically for patients with IDD (TABLE 3¹¹). In addition, a psychiatric diagnosis manual, the Diagnostic Manual—Intellectual Disability 2, specific to people with IDD (and analogous to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition) provides modification of diagnostic criteria to account for patients who have difficulty articulating their internal emotional state and inner thoughts.²²

Continue to: Problematic behaviors

Problematic behaviors that are not features of a bona fide psychiatric disorder are often best understood through functional behavioral analysis, which examines antecedents and consequences of problematic behaviors and identifies their predictable outcomes, such as gaining attention, avoiding a task, or securing a desired item. Rather than being given a prescription for psychoactive medication, many adult patients with IDD and problematic behaviors might be best served by having you order consultation with a certified behavior analyst. The analyst will conduct an evaluation and, along with family or residential staff and the patient, craft a behavioral support plan to address core drivers of the undesired behavior. Behavioral support plans might be enriched by multidisciplinary input from a speech and language pathologist, habilitation professionals, occupational and physical therapists, a neuropsychologist, and others.²³

Antipsychotic medications are often initiated without a careful diagnosis. In addition, they often lead to insulin resistance, metabolic syndrome, and massive weight gain.

Resources to help you address the physical, mental, and behavioral health problems of these patients are available online through Vanderbilt Kennedy Center’s “Toolkit for primary care providers” (https://iddtoolkit.vkcsites.org).

CASE

During your examination, you review Ms. S’s vital signs, including body mass index (BMI). You calculate that she is morbidly obese—BMI, 37—in the setting of a known comorbidity, diabetes.

Ms. S tells you that she is interested in having a healthy lifestyle, but feels frustrated because she does not know how to make the necessary changes. You discuss with her how some medications, including risperidone, can promote weight gain, and that it is important for her mental health provider to carefully reassess whether she needs to continue the drug.

Weight management in a patient population that tends to be sedentary

Patients with IDD are more likely to live a sedentary lifestyle. Compared to adults who do not have IDD, adults with IDD—especially women and patients with Down syndrome—are reported to have a higher prevalence of obesity.²⁴

Continue to: As in the general population...

Similarly, undesired weight loss demands careful evaluation and management because such loss can reflect a medically significant condition, such as gastroesophageal reflux, constipation, dysphagia, neglect, and cancer.²⁷

Boosting the amount and effectiveness of physical activity

Young people with IDD participate in physical activity less often than their neurotypical peers; as a result, they tend to be less fit and have a higher prevalence of obesity.²⁸ Based on a meta-analysis, interventions that focus on sport and movement skills training, such as soccer, basketball, and ball-throwing programs, might be more effective than general physical activity programs.²⁸ In addition to year-round sports training and athletic competitions, Special Olympics conducts vital health screenings of athletes and supports community-based initiatives that address bias against patients with IDD, promote inclusion, and foster social relationships (www.specialolympics.org/our-work/inclusive-health?locale=en).

Success in weight management involves multidisciplinary treatment, including nutritional support, physical activity, behavioral changes, and close follow-up.

Emphasize regular activity. In adulthood, fewer than 10% of patients with IDD exercise regularly.²¹ According to the second edition of Physical Activity Guidelines for Americans,²⁹ “all adults, with or without a disability, should get at least 150 minutes of aerobic physical activity a week. Activities can be broken down into smaller amounts, such as about 25 minutes a day every day.”³⁰ Supplementation with muscle-strengthening activities (eg, yoga, weight training, and resistance-band training) provides further health benefit, such as improvement in posture and prevention of future injury.³¹ An ideal exercise program proposed by Tyler and Baker is based on a daily, “3-2-1” schedule (ie, of every hour of activity, 30 minutes should be of aerobic exercise; 20 minutes, of strength building; and 10 minutes, of flexibility).¹¹ By participating in any type of physical activity, there is potential for considerable health benefit in reducing psychosocial stressors, improving mental health, counteracting metabolic syndromes, and, ultimately, reducing morbidity and mortality related to physical inactivity.

CASE

With permission from Ms. S, you send your progress notes by fax to her mental health provider at the community mental health center and request a call to discuss her case—in particular, to examine potential alternatives to risperidone. With Ms. S’s input, you also co-create an exercise prescription that includes a daily 20-minute walking program with her mother.

At the follow-up visit that is scheduled in 3 months, you anticipate adding a resistance component and balance activity to the exercise prescription to enrich Ms. S’s physical activity regimen.

CORRESPONDENCE
Carl V. Tyler Jr., MD, 14601 Detroit Avenue, Lakewood, OH, 44107; catyle@ccf.org

Some adults who have an intellectual or other developmental disability (IDD) require extensive subspecialty care; many, however, depend primarily on their family physician for the bulk of their health care. With that reliance in mind, this article provides (1) an overview of important services that family physicians can provide for their adult patients with IDD and (2) pragmatic clinical suggestions for tailoring that care. Note: We highlight only some high-impact areas of clinical focus; refer to the 2018 Canadian consensus guidelines for a comprehensive approach to optimizing primary care for this population.¹

CASE

Laura S, a 24-year-old woman with Down syndrome, is visiting your clinic with her mother to establish care. Ms. S has several medical comorbidities, including type 2 diabetes, hyperlipidemia, repaired congenital heart disease, schizoaffective disorder, and hypothyroidism. She is under the care of multiple specialists, including a cardiologist and an endocrinologist. Her medications include the atypical antipsychotic risperidone, which was prescribed for her through the services of a community mental health center.

Ms. S is due for multiple preventive health screenings. She indicates that she feels nervous today talking about these screenings with a new physician.

First step in care: Proficiency in the lexicon of IDD

Three core concepts of IDD are impairment, disability, and handicap. According to the World Health Organization²:

• impairment “is any loss or abnormality of psychological, physiological, or anatomical structure or function.”
• disability “is any restriction or lack (resulting from an impairment) of ability to perform an activity in the manner or within the range considered normal for a human being.”
• handicap therefore “represents socialization of an impairment or disability, and as such it reflects the consequences for the individual—cultural, social, economic, and environmental—that stem from the presence of impairment and disability.”

Essential transition: Pediatric to adult health care

Health care transition (HCT) is the planned process of transferring care from a pediatric to an adult-based health care setting,³ comprising 3 phases:

• preparation
• transfer from pediatric to adult care
• integration into adult-based care.

Two critical components of a smooth HCT include initiating the transition early in adolescence and providing transition-support resources, which are often lacking, even in large, integrated health systems.⁴ Got Transition, created by the National Alliance to Advance Adolescent Health, outlines core elements of an organized HCT process (www.gottransition.org) specific to young adults with IDD, including young adults with autism spectrum disorder.^5,6 

Even young people who are served by a family physician and who intend to remain in that family practice as they age into adulthood require HCT services that include⁶:

• assessment of readiness to transition to adult care
• update of the medical history
• assessment and promotion of self-care skills
• consent discussions and optimized participation in decision-making
• transition of specialty care from pediatric to adult specialists.

Continue to: For an ideal HCT...

For an ideal health care transition, full engagement of the patient, the medical home, and the patient’s family (including the primary caregiver or guardian) is critical.

For an ideal HCT, full engagement of the patient, the medical home (physicians, nursing staff, and care coordinators), and the patient’s family (including the primary caregiver or guardian) is critical. In addition to preventive care visits and management of chronic disease, additional domains that require explicit attention in transitioning young people with IDD include health insurance, transportation, employment, and postsecondary education.

Young people who have special health care needs and receive high-quality HCT demonstrate improvements in adherence to care, disease-specific measures, quality of life, self-care skills, satisfaction with care, and health care utilization.⁷TABLE 1³ lists resources identified by Berens and colleagues that are helpful in facilitating the transition.

Teach and practice disability etiquette

Societal prejudice harms people with IDD—leading to self-deprecation, alienation from the larger community, and isolation from others with IDD.⁸ To promote acceptance and inclusivity in residential communities, the workplace, recreational venues, and clinical settings, disability etiquette should be utilized—a set of guidelines on how to interact with patients with IDD. These include speaking to the patient directly, using clear language in an adult voice, and avoiding stereotypes about people with disabilities.⁹ The entire health care team, including all front-facing staff (receptionists and care and financial coordinators) and clinical staff (physicians, nurses, medical assistants), need to be educated in, and practice, disability etiquette.

Preparing for in-person visits. Pre-­visit preparation, ideally by means of dialogue between health care staff and the patient or caregiver (or both), typically by telephone and in advance of the scheduled visit, is often critical for a successful first face-to-face encounter. (See “Pre-visit telephone questionnaire and script for a new adult patient with IDD,” page 287, which we developed for use in our office practice.) Outcomes of the pre-visit preparation should include identifying:

• words or actions that can trigger anxiety or panic
• de-escalation techniques, such as specific calming words and actions
• strategies for optimal communication, physical access, and physical examination.

Initial appointments should focus on building trust and rapport with the health care team and desensitizing the patient to the clinical environment.¹⁰ Examination techniques used with pediatric patients can be applied to this population: for example, demonstrating an examination maneuver first on the parent or caregiver; beginning the examination with the least invasive or anxiety-­provoking components; and stating what you plan to do next—before you do it.

Continue to: Systematic health checks provide great value

A health check is a systematic and comprehensive health assessment that is provided annually to adults with IDD, and includes:

• specific review of signs and symptoms of health conditions that often co-­occur in adults with IDD (TABLE 2Calibri¹¹)
• screening for changes in adaptive functioning and secondary disability
• lifestyle counseling
• medication review and counseling
• immunization update
• discussion of caregiver concerns.

Successful implementation of preventive health screening tests for a patient with IDD often requires ingenuity and creativity to allay fears and anxieties.

Regarding the last point: Many caregivers are the aging parents of the adult patient with IDD—people who have their own emerging health and support needs. You should initiate conversations about advanced planning for the needs of patients, which often involves engaging siblings and other family members to assume a greater role in caregiving.¹²

Benefits of the health check. A systematic review of 38 studies, comprising more than 5000 patients with IDD, found that health checks increased the detection of serious conditions, improved screening for sensory impairments, and increased the immunization rate.¹³ Although many patients with IDD generally understand the need for a periodic health examination, you can enhance their experience by better explaining the rationale for the health check; scheduling sufficient time for the appointment, based on the individual clinical situation; and discussing the value of laboratory testing and referrals to specialists.¹⁴

Tailoring preventive care

Many of the preventive services recommendations typically utilized by family physicians, such as guidelines from the US Preventive Services Task Force, have been developed for the general population at average risk of conditions of interest.¹⁵ Adults with IDD, depending on the cause of their developmental disability and their behavioral risk profile, might be at significantly higher (or lower) risk of cancer, heart disease, or other conditions than the general population. To address these differences, preventive care guidelines tailored to patients with certain developmental disabilities have been created, including guidelines specific to adults with Down syndrome, fragile X syndrome, Prader-Willi syndrome, Smith-Magenis syndrome, and 22q11.2 deletion (DiGeorge) syndrome.¹⁶

Clarifying the molecular genetic etiology of many developmental disabilities has led to more precise understandings about physical and behavioral health issues associated with specific developmental disabilities. For that reason, patients without a known cause for their IDD might benefit from referral to a geneticist—even in early or middle adulthood. Variables generally associated with a higher likelihood of an abnormal genetic test result include¹⁷:

• a family history of developmental disability
• a congenital malformation or dysmorphic features
• a dual diagnosis of developmental disability and co-occurring mental illness
• hypotonia
• severe or profound IDD.

Continue to: Successful implementation of preventive health screening tests...

Successful implementation of preventive health screening tests often requires ingenuity and the collective creativity of the patient, family members, staff, and family physician to allay fears and anxieties. Examples: Women who have been advised to undergo screening mammography might feel less anxious by undergoing tandem screening with their sister or mother, and colorectal cancer screening might be more easily accomplished using a fecal DNA test rather than by colonoscopy. Procedural desensitization strategies and preventive care instructional materials targeting people with IDD are posted on YouTube (for example, the “DD CARES Best Practices” series [see www.youtube.com/watch?v=EPJy4zvg4io]) and other websites.

Management of chronic disease

Evidence of health disparities in patients with IDD includes suboptimal management of chronic diseases, such as diabetes¹⁸ and hypertension,¹⁹ despite contact with a primary care physician. Nonadherence to a medication regimen might be more common in patients who live with their family or in a residential setting where there is a lower degree of supervision—that is, compared to a residence that maintains 24-hour staffing with daily nursing care and supervision. For a patient who is not so closely supervised, reviewing the medication refill history with the pharmacy, or using the so-called brown-bag technique of counting pill bottles brought to appointments, can ensure medication adherence.

CASE

As you interview Ms. S, you note that she is shy, avoids eye contact, and appears generally anxious. You calm her by noticing and complimenting her jewelry and fingernail polish. Ms. S smiles and talks about her favorite polish colors.

Evaluation of suspected mental and behavioral health issues begins with assessment for medical conditions that might be causing pain and distress or stereotypies.

Her mother reports that, when Ms. S is stressed, she talks to herself alone in her bedroom. However, you do not observe evidence of schizoaffective disorder, and begin to wonder whether she needs to be taking risperidone.

Essentials of mental health care

It is estimated that one-third of adults with IDD have significant mental and behavioral health care needs.²⁰ Patients with IDD suffer the same psychiatric disorders as the general population; some also engage in problematic behaviors, such as self-injurious actions, physical or verbal aggression (or both), property destruction, and resistance to caregiving assistance.

Continue to: Mental and behavioral health problems...

Mental and behavioral health problems can have a profound impact on the quality of life of patients with IDD, their peers, and their family and other caregivers. If untreated, these problems can lead to premature institutionalization, loss of employment or desired program participation, fractured social relationships, and caregiver withdrawal and burnout.

Initial evaluation of suspected mental and behavioral health problems begins with careful assessment for medical conditions that might be causing pain and distress, stereotypies, and other problematic behaviors. Common sources of pain and discomfort include dental and other oral disease, dysphagia, gastroesophageal reflux disease, gastritis, constipation, allergic disease, headache, musculoskeletal pathology, lower urinary tract disease, and gynecologic disorders.¹¹ Identification and optimal treatment of medical conditions might not eliminate problematic behaviors but often decrease their frequency and intensity.

Psychoactive medications are prescribed for many patients with IDD. Many have behavioral adverse effects, such as akathisia, aggression, and disinhibition—leading to a prescribing cascade of psychoactive medication polypharmacy and escalating dosages.²¹ Antipsychotic medications are often initiated without a careful diagnosis, explicit outcome targets, or adequate clinical monitoring for effectiveness; in addition, they often lead to insulin resistance, metabolic syndrome, and massive weight gain.²¹ Even a family physician who is not the prescriber can perform an important advocacy role by critically reviewing psychoactive medications, documenting adverse effects, insisting on a clear therapeutic target, and calling for discontinuation of medications that appear to be ineffective.

Evaluation of mental and behavioral health problems requires a developmental perspective to interpret specific, observable behaviors with a proper clinical lens. For example, many patients with IDD engage in self-talk (soliloquizing) as a means of processing the world around them. This practice might escalate during a time of physical or psychological stress, and the unwary clinician might misinterpret this behavior as psychotic, leading to inappropriate prescribing of antipsychotic medication. Other psychotoform behaviors that, superficially, mimic but are typically not truly psychotic, include talk with or about imaginary friends and repetitive retelling of sometimes elaborate or grandiose tales or assertions. The failure of clinicians to recognize developmentally determined expressions of distress often leads to a misdiagnosis of schizophrenia or other psychotic illness and, consequently, inappropriate psychopharmacotherapy. 

Family physicians, familiar with the use of psychiatric scales for diagnosis and treatment monitoring, should use similar scales that have been developed specifically for patients with IDD (TABLE 3¹¹). In addition, a psychiatric diagnosis manual, the Diagnostic Manual—Intellectual Disability 2, specific to people with IDD (and analogous to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition) provides modification of diagnostic criteria to account for patients who have difficulty articulating their internal emotional state and inner thoughts.²²

Continue to: Problematic behaviors

Problematic behaviors that are not features of a bona fide psychiatric disorder are often best understood through functional behavioral analysis, which examines antecedents and consequences of problematic behaviors and identifies their predictable outcomes, such as gaining attention, avoiding a task, or securing a desired item. Rather than being given a prescription for psychoactive medication, many adult patients with IDD and problematic behaviors might be best served by having you order consultation with a certified behavior analyst. The analyst will conduct an evaluation and, along with family or residential staff and the patient, craft a behavioral support plan to address core drivers of the undesired behavior. Behavioral support plans might be enriched by multidisciplinary input from a speech and language pathologist, habilitation professionals, occupational and physical therapists, a neuropsychologist, and others.²³

Antipsychotic medications are often initiated without a careful diagnosis. In addition, they often lead to insulin resistance, metabolic syndrome, and massive weight gain.

Resources to help you address the physical, mental, and behavioral health problems of these patients are available online through Vanderbilt Kennedy Center’s “Toolkit for primary care providers” (https://iddtoolkit.vkcsites.org).

CASE

During your examination, you review Ms. S’s vital signs, including body mass index (BMI). You calculate that she is morbidly obese—BMI, 37—in the setting of a known comorbidity, diabetes.

Ms. S tells you that she is interested in having a healthy lifestyle, but feels frustrated because she does not know how to make the necessary changes. You discuss with her how some medications, including risperidone, can promote weight gain, and that it is important for her mental health provider to carefully reassess whether she needs to continue the drug.

Weight management in a patient population that tends to be sedentary

Patients with IDD are more likely to live a sedentary lifestyle. Compared to adults who do not have IDD, adults with IDD—especially women and patients with Down syndrome—are reported to have a higher prevalence of obesity.²⁴

Continue to: As in the general population...

Similarly, undesired weight loss demands careful evaluation and management because such loss can reflect a medically significant condition, such as gastroesophageal reflux, constipation, dysphagia, neglect, and cancer.²⁷

Boosting the amount and effectiveness of physical activity

Young people with IDD participate in physical activity less often than their neurotypical peers; as a result, they tend to be less fit and have a higher prevalence of obesity.²⁸ Based on a meta-analysis, interventions that focus on sport and movement skills training, such as soccer, basketball, and ball-throwing programs, might be more effective than general physical activity programs.²⁸ In addition to year-round sports training and athletic competitions, Special Olympics conducts vital health screenings of athletes and supports community-based initiatives that address bias against patients with IDD, promote inclusion, and foster social relationships (www.specialolympics.org/our-work/inclusive-health?locale=en).

Success in weight management involves multidisciplinary treatment, including nutritional support, physical activity, behavioral changes, and close follow-up.

Emphasize regular activity. In adulthood, fewer than 10% of patients with IDD exercise regularly.²¹ According to the second edition of Physical Activity Guidelines for Americans,²⁹ “all adults, with or without a disability, should get at least 150 minutes of aerobic physical activity a week. Activities can be broken down into smaller amounts, such as about 25 minutes a day every day.”³⁰ Supplementation with muscle-strengthening activities (eg, yoga, weight training, and resistance-band training) provides further health benefit, such as improvement in posture and prevention of future injury.³¹ An ideal exercise program proposed by Tyler and Baker is based on a daily, “3-2-1” schedule (ie, of every hour of activity, 30 minutes should be of aerobic exercise; 20 minutes, of strength building; and 10 minutes, of flexibility).¹¹ By participating in any type of physical activity, there is potential for considerable health benefit in reducing psychosocial stressors, improving mental health, counteracting metabolic syndromes, and, ultimately, reducing morbidity and mortality related to physical inactivity.

CASE

With permission from Ms. S, you send your progress notes by fax to her mental health provider at the community mental health center and request a call to discuss her case—in particular, to examine potential alternatives to risperidone. With Ms. S’s input, you also co-create an exercise prescription that includes a daily 20-minute walking program with her mother.

At the follow-up visit that is scheduled in 3 months, you anticipate adding a resistance component and balance activity to the exercise prescription to enrich Ms. S’s physical activity regimen.

CORRESPONDENCE
Carl V. Tyler Jr., MD, 14601 Detroit Avenue, Lakewood, OH, 44107; catyle@ccf.org

As the population of older adults rises, primary osteoporosis has become a problem of public health significance, resulting in more than 2 million fractures and $19 billion in related costs annually in the United States.¹ Despite the availability of effective primary and secondary preventive measures, many older adults do not receive adequate information on bone health from their primary care provider.² Initiation of osteoporosis treatment is low even among patients who have had an osteoporotic fracture: Fewer than one-­quarter of older adults with hip fracture have begun taking osteoporosis medication within 12 months of hospital discharge.³

In this overview of osteoporosis care, we provide information on how to evaluate and manage older adults in primary care settings who are at risk of, or have been given a diagnosis of, primary osteoporosis. The guidance that we offer reflects the most recent updates and recommendations by relevant professional societies.^1,4-7

The nature and scope of an urgent problem

Osteoporosis is a skeletal disorder characterized by low bone mass and deterioration of bone structure that causes bone fragility and increases the risk of fracture.⁸ Operationally, it is defined by the World Health Organization as a bone mineral density (BMD) score below 2.5 SD from the mean value for a young White woman (ie, T-score ≤ –2.5).⁹ Primary osteoporosis is age related and occurs mostly in postmenopausal women and older men, affecting 25% of women and 5% of men ≥ 65 years.¹⁰

An osteoporotic fracture is particularly devastating in an older adult because it can cause pain, reduced mobility, depression, and social isolation and can increase the risk of related mortality.¹ The National Osteoporosis Foundation estimates that 20% of older adults who sustain a hip fracture die within 1 year due to complications of the fracture itself or surgical repair.¹ Therefore, it is of paramount importance to identify patients who are at increased risk of fracture and intervene early.

The National Osteoporosis Foundation estimates that 20% of older adults who sustain a hip fracture die within 1 year due to complications of the fracture itself or surgical repair.

Clinical manifestations

Osteoporosis does not have a primary presentation; rather, disease manifests clinically when a patient develops complications. Often, a fragility fracture is the first sign in an older person.¹¹

A fracture is the most important complication of osteoporosis and can result from low-trauma injury or a fall from standing height—thus, the term “fragility fracture.” Osteoporotic fractures commonly involve the vertebra, hip, and wrist. Hip and extremity fractures can result in limited or lost mobility and depression. Vertebral fractures can be asymptomatic or result in kyphosis and loss of height. Fractures can give rise to pain.

Age and female sexare risk factors

TABLE 1^1,6,10 lists risk factors associated with osteoporosis. Age is the most important; prevalence of osteoporosis increases with age. Other nonmodifiable risk factors include female sex (the disease appears earlier in women who enter menopause prematurely), family history of osteoporosis, and race and ethnicity. Twenty percent of Asian and non-Hispanic White women > 50 years have osteoporosis.¹ A study showed that Mexican Americans are at higher risk of osteoporosis than non-Hispanic Whites; non-Hispanic Blacks are least affected.¹⁰

Other risk factors include low body weight (< 127 lb) and a history of fractures after age 50. Behavioral risk factors include smoking, excessive alcohol intake (> 3 drinks/d), poor nutrition, and a sedentary lifestyle.^1,6

Continue to: Who should be screened?...

Who should be screened?

Screening is generally performed with a clinical evaluation and a dual-energy x-ray absorptiometry (DXA) scan of BMD. Measurement of BMD is generally recommended for screening all women ≥ 65 years and those < 65 years whose 10-year risk of fracture is equivalent to that of a 65-year-old White woman (see “Assessment of fracture risk” later in the article). For men, the US Preventive Services Task Force recommends screening those with a prior fracture or a secondary risk factor for disease.⁵ However, the National Osteoporosis Foundation recommends screening all men ≥ 70 years and those 50 to 69 years whose risk profile shows heightened risk.^1,4

DXA of the spine and hip is preferred; the distal one-third of the radius (termed “33% radius”) of the nondominant arm can be used when spine and hip BMD cannot be interpreted because of bone changes from the disease process or artifacts, or in certain diseases in which the wrist region shows the earliest change (eg, primary hyperparathyroidism).^6,7

Clinical evaluation includes a detailed history, physical examination, laboratory screening, and assessment for risk of fracture.

❚ History. Explore the presence of risk factors, including fractures in adulthood, falls, medication use, alcohol and tobacco use, family history of osteoporosis, and chronic disease.^6,7

❚ Physical exam. Assess height, including any loss (> 1.5 in) since the patient’s second or third decade of life; kyphosis; frailty; and balance and mobility problems.^4,6,7

❚  Laboratory and imaging studies. Perform basic laboratory testing when DXA is abnormal, including thyroid function, serum calcium, and renal function.^6,12 Radiography of the lateral spine might be necessary, especially when there is kyphosis or loss of height. Assess for vertebral fracture, using lateral spine radiography, when vertebral involvement is suspected.^6,7

❚ Assessment of fracture risk. Fracture risk can be assessed with any of a number of tools, including:

• Simplified Calculated Osteoporosis Risk Estimation (SCORE): www.medicalalgorithms.com/simplified-calculated-osteoporosis-risk-estimation-tool
• Osteoporosis Risk Assessment Instrument (ORAI): www.physio-pedia.com/The_Osteoporosis_Risk_Assessment_Instrument_(ORAI)

• Osteoporosis Index of Risk (OSIRIS): https://www.tandfonline.com/doi/abs/10.1080/gye.16.3.245.250?journalCode=igye20
• Osteoporosis Self-Assessment Tool (OST): www.ncbi.nlm.nih.gov/books/NBK45516/figure/ch10.f2/
• FRAX tool⁵: www.sheffield.ac.uk/FRAX.

The FRAX tool is widely used. It assesses a patient’s 10-year risk of fracture.

Diagnosis is based on these criteria

Diagnosis of osteoporosis is based on any 1 or more of the following criteria⁶:

• a history of fragility fracture not explained by metabolic bone disease
• T-score ≤ –2.5 (lumbar, hip, femoral neck, or 33% radius)
• a nation-specific FRAX score (in the absence of access to DXA).

❚ Secondary disease. Patients in whom secondary osteoporosis is suspected should undergo laboratory investigation to ascertain the cause; treatment of the underlying pathology might then be required. Evaluation for a secondary cause might include a complete blood count, comprehensive metabolic panel, protein electrophoresis and urinary protein electrophoresis (to rule out myeloproliferative and hematologic diseases), and tests of serum 25-hydroxyvitamin D, parathyroid hormone, serum calcium, alkaline phosphatase, 24-hour urinary calcium, sodium, and creatinine.^6,7 Specialized testing for biochemical markers of bone turnover—so-called bone-turnover markers—can be considered as part of the initial evaluation and follow-up, although the tests are not recommended by the US Preventive Services Task Force (see “Monitoring the efficacy of treatment,” later in the article, for more information about these markers).⁶

Although BMD by DXA remains the gold standard in screening for and diagnosing osteoporosis, a high rate of fracture is seen in patients with certain diseases, such as type 2 diabetes and ankylosing spondylitis, who have a nonosteoporotic low T-score. This raises concerns about the usefulness of BMD for diagnosing osteoporosis in patients who have one of these diseases.^13-16

❚ Pharmacotherapy is recommended in all cases of osteoporosis and osteopenia when risk of fracture is high. Oral bisphosphonates can be used as initial treatment.

❚ Trabecular bone score (TBS), a surrogate bone-quality measure that is calculated based on the spine DXA image, has recently been introduced in clinical practice, and can be used to predict fracture risk in conjunction with BMD assessment by DXA and the FRAX score.¹⁷ TBS provides an indirect index of the trabecular microarchitecture using pixel gray-level variation in lumbar spine DXA images.¹⁸ Three categories of TBS (≤ 1.200, degraded microarchitecture; 1.200-1.350, partially degraded microarchitecture; and > 1.350, normal microarchitecture) have been reported to correspond with a T-score of, respectively, ≤ −2.5; −2.5 to −1.0; and > −1.0.¹⁸ TBS can be used only in patients with a body mass index of 15 to 37.5.^19,20

There is no recommendation for monitoring bone quality using TBS after osteoporosis treatment. Such monitoring is at the clinician’s discretion for appropriate patients who might not show a risk of fracture, based on BMD measurement.

Continue to: Putting preventive measures into practice...

Putting preventive measures into practice

Measures to prevent osteoporosis and preserve bone health (TABLE 2^1,6) are best started in childhood but can be initiated at any age and maintained through the lifespan. Encourage older adults to adopt dietary and behavioral strategies to improve their bone health and prevent fracture. We recommend the following strategies; take each patient’s individual situation into consideration when electing to adopt any of these measures.

❚ Vitamin D. Consider checking the serum 25-hydroxyvitamin D level and providing supplementation (800-1000 IU daily, the National Osteoporosis Foundation recommends¹) as necessary to maintain the level at 30-50 ng/mL.⁶

❚ Calcium. Encourage a daily dietary calcium intake of 1000-1200 mg. Supplement calcium if you determine that diet does not provide an adequate amount.

❚ Alcohol. Advise patients to limit consumption to < 3 drinks a day.

❚ Tobacco. Advise smoking cessation.

❚ Activity. Encourage an active lifestyle, including regular weight-bearing and balance exercises and resistance exercises such as Pilates, weightlifting, and tai chi. The regimen should be tailored to the patient’s individual situation.

❚ Medical therapy for concomitant illness. When possible, prescribe medications for chronic comorbidities that can also benefit bone health. For example, long-term use of angiotensin-converting enzyme (ACE) inhibitors and thiazide diuretics for hypertension are associated with a slower decline in BMD in some populations.^21-23

Tailor treatment to patient’s circumstances

TABLE 3^4,6,24 describes indications for pharmacotherapy in osteoporosis. Pharmacotherapy is recommended in all cases of osteoporosis and osteopenia when fracture risk is high.²⁴

Generally, you should undertake a discussion with the patient of the relative risks and benefits of treatment, taking into account their values and preferences, to come to a shared decision. Tailoring treatment, based on the patient’s distinctive circumstances, through shared decision-making is key to compliance.²⁵

Pharmacotherapy is not indicated in patients whose risk of fracture is low; however, you should reassess such patients every 2 to 4 years.²⁶ Women with a very high BMD might not need to be retested with DXA any sooner than every 10 to 15 years.

There are 3 main classes of first-line pharmacotherapeutic agents for osteoporosis in older adults (TABLE 4^4,6,7,26-41): antiresorptives (bisphosphonates and denosumab), anabolics (teriparatide and abaloparatide), and a monoclonal sclerostin antibody (romosozumab). (TABLE 4^4,6,7,26-41 and the discussion in this section also remark on the selective estrogen-receptor modulator raloxifene, which is used in special clinical circumstances but has been removed from the first line of osteoporosis pharmacotherapy.)

Continue to: Influence of chronic...

Influence of chronic diseaseon bone health

Chronic diseases—hypertension, type 2 diabetes, hyperthyroidism, rheumatoid arthritis, ankylosing spondylitis, and gastroenterologic disorders such as celiac disease and ulcerative colitis—are known to affect bone loss that can hasten osteoporosis.^16,18,21 Furthermore, medications used to treat chronic diseases are known to affect bone health: Some, such as statins, ACE inhibitors, and hydrochlorothiazide, are bone protective; others, such as steroids, pioglitazone, and selective serotonin reuptake inhibitors, accelerate bone loss.^1,14,42,43 It is important to be aware of the effect of a patient’s chronic diseases, and treatments for those diseases, on bone health, to help develop an individualized osteoporosis prevention plan.

Monitoring the efficacy of treatment

Treatment of osteoporosis should not be initiated without baseline measurement of BMD of the spine and hip. Subsequent to establishing that baseline, serial measurement of BMD can be used to (1) determine when treatment needs to be initiated for an untreated patient and (2) assess response in a treated patient. There is no consensus on the interval at which DXA should be repeated for the purpose of monitoring treatment response; frequency depends on the individual’s circumstances and the medication used. Notably, many physicians repeat DXA after 2 years of treatment⁸; however, the American College of Physicians recommends against repeating DXA within the first 5 years of pharmacotherapy in women.²⁴

Patients with suspected vertebral fracture or those with loss of height > 1.5 inches require lateral radiographs of the thoracic and lumbar spine to assess the status of fractures.^4,6

❚ Bone-turnover markers measured in serum can be used to assess treatment efficacy and patient adherence. The formation marker procollagen type I N-terminal propeptide (P1NP) and the resorption marker beta C-terminal cross-linking telopeptide of type 1 collagen (bCTX) are preferred for evaluating bone turnover in the clinical setting. Assessing P1NP and bCTX at baseline and after 3 months of treatment might be effective in monitoring adherence, particularly in patients taking a bisphosphonate.⁴⁴

Pharmacotherapy is not indicated in patients whose risk of fracture is low; however, you should reassess such patients every 2 to 4 years.

Be sure to address fall prevention

It is important to address falls, and how to prevent them, in patients with osteoporosis. Falls can precipitate fracture in older adults with reduced BMD, and fractures are the most common and debilitating manifestation of osteoporosis. Your discussion of falls with patients should include⁴⁵:

• consequences of falls
• cautions about medications that can cloud mental alertness
• use of appropriate footwear
• home safety, such as adequate lighting, removal of floor clutter, and installation of handrails in the bathroom and stairwells and on outside steps.
• having an annual comprehensive eye exam.

Osteoporosis is avoidable and treatable

Earlier research reported various expressions of number needed to treat for medical management of osteoporosis—making it difficult to follow a single number as a reference for gauging the effectiveness of pharmacotherapy.^46,47 However, for older adults of different ethnic and racial backgrounds with multiple comorbidities and polypharmacy, it might be more pragmatic in primary care to establish a model of goal-oriented, individualized care. By focusing on prevention of bone loss, and being mindful that the risk of fracture almost doubles with a decrease of 1 SD in BMD, you can translate numbers to goals of care.⁴⁸

In the United States, approximately one-half of osteoporosis cases in adults ≥ 50 years are managed by primary care providers. As a chronic disease, osteoporosis requires that you, first, provide regular monitoring and assessment, because risk can vary with comorbidities,⁴⁹ and, second, discuss and initiate screening and treatment as appropriate, which can be done annually during a well-care visit.

CORRESPONDENCE

Nahid Rianon, MD, DrPH, Department of Family and Community Medicine, UTHealth McGovern Medical School, 6431 Fannin Street #JJL 324C, Houston, TX, 77030; Nahid.J.Rianon@uth.tmc.edu

As the population of older adults rises, primary osteoporosis has become a problem of public health significance, resulting in more than 2 million fractures and $19 billion in related costs annually in the United States.¹ Despite the availability of effective primary and secondary preventive measures, many older adults do not receive adequate information on bone health from their primary care provider.² Initiation of osteoporosis treatment is low even among patients who have had an osteoporotic fracture: Fewer than one-­quarter of older adults with hip fracture have begun taking osteoporosis medication within 12 months of hospital discharge.³

In this overview of osteoporosis care, we provide information on how to evaluate and manage older adults in primary care settings who are at risk of, or have been given a diagnosis of, primary osteoporosis. The guidance that we offer reflects the most recent updates and recommendations by relevant professional societies.^1,4-7

The nature and scope of an urgent problem

Osteoporosis is a skeletal disorder characterized by low bone mass and deterioration of bone structure that causes bone fragility and increases the risk of fracture.⁸ Operationally, it is defined by the World Health Organization as a bone mineral density (BMD) score below 2.5 SD from the mean value for a young White woman (ie, T-score ≤ –2.5).⁹ Primary osteoporosis is age related and occurs mostly in postmenopausal women and older men, affecting 25% of women and 5% of men ≥ 65 years.¹⁰

An osteoporotic fracture is particularly devastating in an older adult because it can cause pain, reduced mobility, depression, and social isolation and can increase the risk of related mortality.¹ The National Osteoporosis Foundation estimates that 20% of older adults who sustain a hip fracture die within 1 year due to complications of the fracture itself or surgical repair.¹ Therefore, it is of paramount importance to identify patients who are at increased risk of fracture and intervene early.

The National Osteoporosis Foundation estimates that 20% of older adults who sustain a hip fracture die within 1 year due to complications of the fracture itself or surgical repair.

Clinical manifestations

Osteoporosis does not have a primary presentation; rather, disease manifests clinically when a patient develops complications. Often, a fragility fracture is the first sign in an older person.¹¹

A fracture is the most important complication of osteoporosis and can result from low-trauma injury or a fall from standing height—thus, the term “fragility fracture.” Osteoporotic fractures commonly involve the vertebra, hip, and wrist. Hip and extremity fractures can result in limited or lost mobility and depression. Vertebral fractures can be asymptomatic or result in kyphosis and loss of height. Fractures can give rise to pain.

Age and female sexare risk factors

TABLE 1^1,6,10 lists risk factors associated with osteoporosis. Age is the most important; prevalence of osteoporosis increases with age. Other nonmodifiable risk factors include female sex (the disease appears earlier in women who enter menopause prematurely), family history of osteoporosis, and race and ethnicity. Twenty percent of Asian and non-Hispanic White women > 50 years have osteoporosis.¹ A study showed that Mexican Americans are at higher risk of osteoporosis than non-Hispanic Whites; non-Hispanic Blacks are least affected.¹⁰

Other risk factors include low body weight (< 127 lb) and a history of fractures after age 50. Behavioral risk factors include smoking, excessive alcohol intake (> 3 drinks/d), poor nutrition, and a sedentary lifestyle.^1,6

Continue to: Who should be screened?...

Who should be screened?

Screening is generally performed with a clinical evaluation and a dual-energy x-ray absorptiometry (DXA) scan of BMD. Measurement of BMD is generally recommended for screening all women ≥ 65 years and those < 65 years whose 10-year risk of fracture is equivalent to that of a 65-year-old White woman (see “Assessment of fracture risk” later in the article). For men, the US Preventive Services Task Force recommends screening those with a prior fracture or a secondary risk factor for disease.⁵ However, the National Osteoporosis Foundation recommends screening all men ≥ 70 years and those 50 to 69 years whose risk profile shows heightened risk.^1,4

DXA of the spine and hip is preferred; the distal one-third of the radius (termed “33% radius”) of the nondominant arm can be used when spine and hip BMD cannot be interpreted because of bone changes from the disease process or artifacts, or in certain diseases in which the wrist region shows the earliest change (eg, primary hyperparathyroidism).^6,7

Clinical evaluation includes a detailed history, physical examination, laboratory screening, and assessment for risk of fracture.

❚ History. Explore the presence of risk factors, including fractures in adulthood, falls, medication use, alcohol and tobacco use, family history of osteoporosis, and chronic disease.^6,7

❚ Physical exam. Assess height, including any loss (> 1.5 in) since the patient’s second or third decade of life; kyphosis; frailty; and balance and mobility problems.^4,6,7

❚  Laboratory and imaging studies. Perform basic laboratory testing when DXA is abnormal, including thyroid function, serum calcium, and renal function.^6,12 Radiography of the lateral spine might be necessary, especially when there is kyphosis or loss of height. Assess for vertebral fracture, using lateral spine radiography, when vertebral involvement is suspected.^6,7

❚ Assessment of fracture risk. Fracture risk can be assessed with any of a number of tools, including:

• Simplified Calculated Osteoporosis Risk Estimation (SCORE): www.medicalalgorithms.com/simplified-calculated-osteoporosis-risk-estimation-tool
• Osteoporosis Risk Assessment Instrument (ORAI): www.physio-pedia.com/The_Osteoporosis_Risk_Assessment_Instrument_(ORAI)

• Osteoporosis Index of Risk (OSIRIS): https://www.tandfonline.com/doi/abs/10.1080/gye.16.3.245.250?journalCode=igye20
• Osteoporosis Self-Assessment Tool (OST): www.ncbi.nlm.nih.gov/books/NBK45516/figure/ch10.f2/
• FRAX tool⁵: www.sheffield.ac.uk/FRAX.

The FRAX tool is widely used. It assesses a patient’s 10-year risk of fracture.

Diagnosis is based on these criteria

Diagnosis of osteoporosis is based on any 1 or more of the following criteria⁶:

• a history of fragility fracture not explained by metabolic bone disease
• T-score ≤ –2.5 (lumbar, hip, femoral neck, or 33% radius)
• a nation-specific FRAX score (in the absence of access to DXA).

❚ Secondary disease. Patients in whom secondary osteoporosis is suspected should undergo laboratory investigation to ascertain the cause; treatment of the underlying pathology might then be required. Evaluation for a secondary cause might include a complete blood count, comprehensive metabolic panel, protein electrophoresis and urinary protein electrophoresis (to rule out myeloproliferative and hematologic diseases), and tests of serum 25-hydroxyvitamin D, parathyroid hormone, serum calcium, alkaline phosphatase, 24-hour urinary calcium, sodium, and creatinine.^6,7 Specialized testing for biochemical markers of bone turnover—so-called bone-turnover markers—can be considered as part of the initial evaluation and follow-up, although the tests are not recommended by the US Preventive Services Task Force (see “Monitoring the efficacy of treatment,” later in the article, for more information about these markers).⁶

Although BMD by DXA remains the gold standard in screening for and diagnosing osteoporosis, a high rate of fracture is seen in patients with certain diseases, such as type 2 diabetes and ankylosing spondylitis, who have a nonosteoporotic low T-score. This raises concerns about the usefulness of BMD for diagnosing osteoporosis in patients who have one of these diseases.^13-16

❚ Pharmacotherapy is recommended in all cases of osteoporosis and osteopenia when risk of fracture is high. Oral bisphosphonates can be used as initial treatment.

❚ Trabecular bone score (TBS), a surrogate bone-quality measure that is calculated based on the spine DXA image, has recently been introduced in clinical practice, and can be used to predict fracture risk in conjunction with BMD assessment by DXA and the FRAX score.¹⁷ TBS provides an indirect index of the trabecular microarchitecture using pixel gray-level variation in lumbar spine DXA images.¹⁸ Three categories of TBS (≤ 1.200, degraded microarchitecture; 1.200-1.350, partially degraded microarchitecture; and > 1.350, normal microarchitecture) have been reported to correspond with a T-score of, respectively, ≤ −2.5; −2.5 to −1.0; and > −1.0.¹⁸ TBS can be used only in patients with a body mass index of 15 to 37.5.^19,20

There is no recommendation for monitoring bone quality using TBS after osteoporosis treatment. Such monitoring is at the clinician’s discretion for appropriate patients who might not show a risk of fracture, based on BMD measurement.

Continue to: Putting preventive measures into practice...

Putting preventive measures into practice

Measures to prevent osteoporosis and preserve bone health (TABLE 2^1,6) are best started in childhood but can be initiated at any age and maintained through the lifespan. Encourage older adults to adopt dietary and behavioral strategies to improve their bone health and prevent fracture. We recommend the following strategies; take each patient’s individual situation into consideration when electing to adopt any of these measures.

❚ Vitamin D. Consider checking the serum 25-hydroxyvitamin D level and providing supplementation (800-1000 IU daily, the National Osteoporosis Foundation recommends¹) as necessary to maintain the level at 30-50 ng/mL.⁶

❚ Calcium. Encourage a daily dietary calcium intake of 1000-1200 mg. Supplement calcium if you determine that diet does not provide an adequate amount.

❚ Alcohol. Advise patients to limit consumption to < 3 drinks a day.

❚ Tobacco. Advise smoking cessation.

❚ Activity. Encourage an active lifestyle, including regular weight-bearing and balance exercises and resistance exercises such as Pilates, weightlifting, and tai chi. The regimen should be tailored to the patient’s individual situation.

❚ Medical therapy for concomitant illness. When possible, prescribe medications for chronic comorbidities that can also benefit bone health. For example, long-term use of angiotensin-converting enzyme (ACE) inhibitors and thiazide diuretics for hypertension are associated with a slower decline in BMD in some populations.^21-23

Tailor treatment to patient’s circumstances

TABLE 3^4,6,24 describes indications for pharmacotherapy in osteoporosis. Pharmacotherapy is recommended in all cases of osteoporosis and osteopenia when fracture risk is high.²⁴

Generally, you should undertake a discussion with the patient of the relative risks and benefits of treatment, taking into account their values and preferences, to come to a shared decision. Tailoring treatment, based on the patient’s distinctive circumstances, through shared decision-making is key to compliance.²⁵

Pharmacotherapy is not indicated in patients whose risk of fracture is low; however, you should reassess such patients every 2 to 4 years.²⁶ Women with a very high BMD might not need to be retested with DXA any sooner than every 10 to 15 years.

There are 3 main classes of first-line pharmacotherapeutic agents for osteoporosis in older adults (TABLE 4^4,6,7,26-41): antiresorptives (bisphosphonates and denosumab), anabolics (teriparatide and abaloparatide), and a monoclonal sclerostin antibody (romosozumab). (TABLE 4^4,6,7,26-41 and the discussion in this section also remark on the selective estrogen-receptor modulator raloxifene, which is used in special clinical circumstances but has been removed from the first line of osteoporosis pharmacotherapy.)

Continue to: Influence of chronic...

Influence of chronic diseaseon bone health

Chronic diseases—hypertension, type 2 diabetes, hyperthyroidism, rheumatoid arthritis, ankylosing spondylitis, and gastroenterologic disorders such as celiac disease and ulcerative colitis—are known to affect bone loss that can hasten osteoporosis.^16,18,21 Furthermore, medications used to treat chronic diseases are known to affect bone health: Some, such as statins, ACE inhibitors, and hydrochlorothiazide, are bone protective; others, such as steroids, pioglitazone, and selective serotonin reuptake inhibitors, accelerate bone loss.^1,14,42,43 It is important to be aware of the effect of a patient’s chronic diseases, and treatments for those diseases, on bone health, to help develop an individualized osteoporosis prevention plan.

Monitoring the efficacy of treatment

Treatment of osteoporosis should not be initiated without baseline measurement of BMD of the spine and hip. Subsequent to establishing that baseline, serial measurement of BMD can be used to (1) determine when treatment needs to be initiated for an untreated patient and (2) assess response in a treated patient. There is no consensus on the interval at which DXA should be repeated for the purpose of monitoring treatment response; frequency depends on the individual’s circumstances and the medication used. Notably, many physicians repeat DXA after 2 years of treatment⁸; however, the American College of Physicians recommends against repeating DXA within the first 5 years of pharmacotherapy in women.²⁴

Patients with suspected vertebral fracture or those with loss of height > 1.5 inches require lateral radiographs of the thoracic and lumbar spine to assess the status of fractures.^4,6

❚ Bone-turnover markers measured in serum can be used to assess treatment efficacy and patient adherence. The formation marker procollagen type I N-terminal propeptide (P1NP) and the resorption marker beta C-terminal cross-linking telopeptide of type 1 collagen (bCTX) are preferred for evaluating bone turnover in the clinical setting. Assessing P1NP and bCTX at baseline and after 3 months of treatment might be effective in monitoring adherence, particularly in patients taking a bisphosphonate.⁴⁴

Pharmacotherapy is not indicated in patients whose risk of fracture is low; however, you should reassess such patients every 2 to 4 years.

Be sure to address fall prevention

It is important to address falls, and how to prevent them, in patients with osteoporosis. Falls can precipitate fracture in older adults with reduced BMD, and fractures are the most common and debilitating manifestation of osteoporosis. Your discussion of falls with patients should include⁴⁵:

• consequences of falls
• cautions about medications that can cloud mental alertness
• use of appropriate footwear
• home safety, such as adequate lighting, removal of floor clutter, and installation of handrails in the bathroom and stairwells and on outside steps.
• having an annual comprehensive eye exam.

Osteoporosis is avoidable and treatable

Earlier research reported various expressions of number needed to treat for medical management of osteoporosis—making it difficult to follow a single number as a reference for gauging the effectiveness of pharmacotherapy.^46,47 However, for older adults of different ethnic and racial backgrounds with multiple comorbidities and polypharmacy, it might be more pragmatic in primary care to establish a model of goal-oriented, individualized care. By focusing on prevention of bone loss, and being mindful that the risk of fracture almost doubles with a decrease of 1 SD in BMD, you can translate numbers to goals of care.⁴⁸

In the United States, approximately one-half of osteoporosis cases in adults ≥ 50 years are managed by primary care providers. As a chronic disease, osteoporosis requires that you, first, provide regular monitoring and assessment, because risk can vary with comorbidities,⁴⁹ and, second, discuss and initiate screening and treatment as appropriate, which can be done annually during a well-care visit.

CORRESPONDENCE

Nahid Rianon, MD, DrPH, Department of Family and Community Medicine, UTHealth McGovern Medical School, 6431 Fannin Street #JJL 324C, Houston, TX, 77030; Nahid.J.Rianon@uth.tmc.edu

As the population of older adults rises, primary osteoporosis has become a problem of public health significance, resulting in more than 2 million fractures and $19 billion in related costs annually in the United States.¹ Despite the availability of effective primary and secondary preventive measures, many older adults do not receive adequate information on bone health from their primary care provider.² Initiation of osteoporosis treatment is low even among patients who have had an osteoporotic fracture: Fewer than one-­quarter of older adults with hip fracture have begun taking osteoporosis medication within 12 months of hospital discharge.³

In this overview of osteoporosis care, we provide information on how to evaluate and manage older adults in primary care settings who are at risk of, or have been given a diagnosis of, primary osteoporosis. The guidance that we offer reflects the most recent updates and recommendations by relevant professional societies.^1,4-7

The nature and scope of an urgent problem

Osteoporosis is a skeletal disorder characterized by low bone mass and deterioration of bone structure that causes bone fragility and increases the risk of fracture.⁸ Operationally, it is defined by the World Health Organization as a bone mineral density (BMD) score below 2.5 SD from the mean value for a young White woman (ie, T-score ≤ –2.5).⁹ Primary osteoporosis is age related and occurs mostly in postmenopausal women and older men, affecting 25% of women and 5% of men ≥ 65 years.¹⁰

An osteoporotic fracture is particularly devastating in an older adult because it can cause pain, reduced mobility, depression, and social isolation and can increase the risk of related mortality.¹ The National Osteoporosis Foundation estimates that 20% of older adults who sustain a hip fracture die within 1 year due to complications of the fracture itself or surgical repair.¹ Therefore, it is of paramount importance to identify patients who are at increased risk of fracture and intervene early.

The National Osteoporosis Foundation estimates that 20% of older adults who sustain a hip fracture die within 1 year due to complications of the fracture itself or surgical repair.

Clinical manifestations

Osteoporosis does not have a primary presentation; rather, disease manifests clinically when a patient develops complications. Often, a fragility fracture is the first sign in an older person.¹¹

A fracture is the most important complication of osteoporosis and can result from low-trauma injury or a fall from standing height—thus, the term “fragility fracture.” Osteoporotic fractures commonly involve the vertebra, hip, and wrist. Hip and extremity fractures can result in limited or lost mobility and depression. Vertebral fractures can be asymptomatic or result in kyphosis and loss of height. Fractures can give rise to pain.

Age and female sexare risk factors

TABLE 1^1,6,10 lists risk factors associated with osteoporosis. Age is the most important; prevalence of osteoporosis increases with age. Other nonmodifiable risk factors include female sex (the disease appears earlier in women who enter menopause prematurely), family history of osteoporosis, and race and ethnicity. Twenty percent of Asian and non-Hispanic White women > 50 years have osteoporosis.¹ A study showed that Mexican Americans are at higher risk of osteoporosis than non-Hispanic Whites; non-Hispanic Blacks are least affected.¹⁰

Other risk factors include low body weight (< 127 lb) and a history of fractures after age 50. Behavioral risk factors include smoking, excessive alcohol intake (> 3 drinks/d), poor nutrition, and a sedentary lifestyle.^1,6

Continue to: Who should be screened?...

Who should be screened?

Screening is generally performed with a clinical evaluation and a dual-energy x-ray absorptiometry (DXA) scan of BMD. Measurement of BMD is generally recommended for screening all women ≥ 65 years and those < 65 years whose 10-year risk of fracture is equivalent to that of a 65-year-old White woman (see “Assessment of fracture risk” later in the article). For men, the US Preventive Services Task Force recommends screening those with a prior fracture or a secondary risk factor for disease.⁵ However, the National Osteoporosis Foundation recommends screening all men ≥ 70 years and those 50 to 69 years whose risk profile shows heightened risk.^1,4

DXA of the spine and hip is preferred; the distal one-third of the radius (termed “33% radius”) of the nondominant arm can be used when spine and hip BMD cannot be interpreted because of bone changes from the disease process or artifacts, or in certain diseases in which the wrist region shows the earliest change (eg, primary hyperparathyroidism).^6,7

Clinical evaluation includes a detailed history, physical examination, laboratory screening, and assessment for risk of fracture.

❚ History. Explore the presence of risk factors, including fractures in adulthood, falls, medication use, alcohol and tobacco use, family history of osteoporosis, and chronic disease.^6,7

❚ Physical exam. Assess height, including any loss (> 1.5 in) since the patient’s second or third decade of life; kyphosis; frailty; and balance and mobility problems.^4,6,7

❚  Laboratory and imaging studies. Perform basic laboratory testing when DXA is abnormal, including thyroid function, serum calcium, and renal function.^6,12 Radiography of the lateral spine might be necessary, especially when there is kyphosis or loss of height. Assess for vertebral fracture, using lateral spine radiography, when vertebral involvement is suspected.^6,7

❚ Assessment of fracture risk. Fracture risk can be assessed with any of a number of tools, including:

• Simplified Calculated Osteoporosis Risk Estimation (SCORE): www.medicalalgorithms.com/simplified-calculated-osteoporosis-risk-estimation-tool
• Osteoporosis Risk Assessment Instrument (ORAI): www.physio-pedia.com/The_Osteoporosis_Risk_Assessment_Instrument_(ORAI)

• Osteoporosis Index of Risk (OSIRIS): https://www.tandfonline.com/doi/abs/10.1080/gye.16.3.245.250?journalCode=igye20
• Osteoporosis Self-Assessment Tool (OST): www.ncbi.nlm.nih.gov/books/NBK45516/figure/ch10.f2/
• FRAX tool⁵: www.sheffield.ac.uk/FRAX.

The FRAX tool is widely used. It assesses a patient’s 10-year risk of fracture.

Diagnosis is based on these criteria

Diagnosis of osteoporosis is based on any 1 or more of the following criteria⁶:

• a history of fragility fracture not explained by metabolic bone disease
• T-score ≤ –2.5 (lumbar, hip, femoral neck, or 33% radius)
• a nation-specific FRAX score (in the absence of access to DXA).

❚ Secondary disease. Patients in whom secondary osteoporosis is suspected should undergo laboratory investigation to ascertain the cause; treatment of the underlying pathology might then be required. Evaluation for a secondary cause might include a complete blood count, comprehensive metabolic panel, protein electrophoresis and urinary protein electrophoresis (to rule out myeloproliferative and hematologic diseases), and tests of serum 25-hydroxyvitamin D, parathyroid hormone, serum calcium, alkaline phosphatase, 24-hour urinary calcium, sodium, and creatinine.^6,7 Specialized testing for biochemical markers of bone turnover—so-called bone-turnover markers—can be considered as part of the initial evaluation and follow-up, although the tests are not recommended by the US Preventive Services Task Force (see “Monitoring the efficacy of treatment,” later in the article, for more information about these markers).⁶

Although BMD by DXA remains the gold standard in screening for and diagnosing osteoporosis, a high rate of fracture is seen in patients with certain diseases, such as type 2 diabetes and ankylosing spondylitis, who have a nonosteoporotic low T-score. This raises concerns about the usefulness of BMD for diagnosing osteoporosis in patients who have one of these diseases.^13-16

❚ Pharmacotherapy is recommended in all cases of osteoporosis and osteopenia when risk of fracture is high. Oral bisphosphonates can be used as initial treatment.

❚ Trabecular bone score (TBS), a surrogate bone-quality measure that is calculated based on the spine DXA image, has recently been introduced in clinical practice, and can be used to predict fracture risk in conjunction with BMD assessment by DXA and the FRAX score.¹⁷ TBS provides an indirect index of the trabecular microarchitecture using pixel gray-level variation in lumbar spine DXA images.¹⁸ Three categories of TBS (≤ 1.200, degraded microarchitecture; 1.200-1.350, partially degraded microarchitecture; and > 1.350, normal microarchitecture) have been reported to correspond with a T-score of, respectively, ≤ −2.5; −2.5 to −1.0; and > −1.0.¹⁸ TBS can be used only in patients with a body mass index of 15 to 37.5.^19,20

There is no recommendation for monitoring bone quality using TBS after osteoporosis treatment. Such monitoring is at the clinician’s discretion for appropriate patients who might not show a risk of fracture, based on BMD measurement.

Continue to: Putting preventive measures into practice...

Putting preventive measures into practice

Measures to prevent osteoporosis and preserve bone health (TABLE 2^1,6) are best started in childhood but can be initiated at any age and maintained through the lifespan. Encourage older adults to adopt dietary and behavioral strategies to improve their bone health and prevent fracture. We recommend the following strategies; take each patient’s individual situation into consideration when electing to adopt any of these measures.

❚ Vitamin D. Consider checking the serum 25-hydroxyvitamin D level and providing supplementation (800-1000 IU daily, the National Osteoporosis Foundation recommends¹) as necessary to maintain the level at 30-50 ng/mL.⁶

❚ Calcium. Encourage a daily dietary calcium intake of 1000-1200 mg. Supplement calcium if you determine that diet does not provide an adequate amount.

❚ Alcohol. Advise patients to limit consumption to < 3 drinks a day.

❚ Tobacco. Advise smoking cessation.

❚ Activity. Encourage an active lifestyle, including regular weight-bearing and balance exercises and resistance exercises such as Pilates, weightlifting, and tai chi. The regimen should be tailored to the patient’s individual situation.

❚ Medical therapy for concomitant illness. When possible, prescribe medications for chronic comorbidities that can also benefit bone health. For example, long-term use of angiotensin-converting enzyme (ACE) inhibitors and thiazide diuretics for hypertension are associated with a slower decline in BMD in some populations.^21-23

Tailor treatment to patient’s circumstances

TABLE 3^4,6,24 describes indications for pharmacotherapy in osteoporosis. Pharmacotherapy is recommended in all cases of osteoporosis and osteopenia when fracture risk is high.²⁴

Generally, you should undertake a discussion with the patient of the relative risks and benefits of treatment, taking into account their values and preferences, to come to a shared decision. Tailoring treatment, based on the patient’s distinctive circumstances, through shared decision-making is key to compliance.²⁵

Pharmacotherapy is not indicated in patients whose risk of fracture is low; however, you should reassess such patients every 2 to 4 years.²⁶ Women with a very high BMD might not need to be retested with DXA any sooner than every 10 to 15 years.

There are 3 main classes of first-line pharmacotherapeutic agents for osteoporosis in older adults (TABLE 4^4,6,7,26-41): antiresorptives (bisphosphonates and denosumab), anabolics (teriparatide and abaloparatide), and a monoclonal sclerostin antibody (romosozumab). (TABLE 4^4,6,7,26-41 and the discussion in this section also remark on the selective estrogen-receptor modulator raloxifene, which is used in special clinical circumstances but has been removed from the first line of osteoporosis pharmacotherapy.)

Continue to: Influence of chronic...

Influence of chronic diseaseon bone health

Chronic diseases—hypertension, type 2 diabetes, hyperthyroidism, rheumatoid arthritis, ankylosing spondylitis, and gastroenterologic disorders such as celiac disease and ulcerative colitis—are known to affect bone loss that can hasten osteoporosis.^16,18,21 Furthermore, medications used to treat chronic diseases are known to affect bone health: Some, such as statins, ACE inhibitors, and hydrochlorothiazide, are bone protective; others, such as steroids, pioglitazone, and selective serotonin reuptake inhibitors, accelerate bone loss.^1,14,42,43 It is important to be aware of the effect of a patient’s chronic diseases, and treatments for those diseases, on bone health, to help develop an individualized osteoporosis prevention plan.

Monitoring the efficacy of treatment

Treatment of osteoporosis should not be initiated without baseline measurement of BMD of the spine and hip. Subsequent to establishing that baseline, serial measurement of BMD can be used to (1) determine when treatment needs to be initiated for an untreated patient and (2) assess response in a treated patient. There is no consensus on the interval at which DXA should be repeated for the purpose of monitoring treatment response; frequency depends on the individual’s circumstances and the medication used. Notably, many physicians repeat DXA after 2 years of treatment⁸; however, the American College of Physicians recommends against repeating DXA within the first 5 years of pharmacotherapy in women.²⁴

Patients with suspected vertebral fracture or those with loss of height > 1.5 inches require lateral radiographs of the thoracic and lumbar spine to assess the status of fractures.^4,6

❚ Bone-turnover markers measured in serum can be used to assess treatment efficacy and patient adherence. The formation marker procollagen type I N-terminal propeptide (P1NP) and the resorption marker beta C-terminal cross-linking telopeptide of type 1 collagen (bCTX) are preferred for evaluating bone turnover in the clinical setting. Assessing P1NP and bCTX at baseline and after 3 months of treatment might be effective in monitoring adherence, particularly in patients taking a bisphosphonate.⁴⁴

Pharmacotherapy is not indicated in patients whose risk of fracture is low; however, you should reassess such patients every 2 to 4 years.

Be sure to address fall prevention

It is important to address falls, and how to prevent them, in patients with osteoporosis. Falls can precipitate fracture in older adults with reduced BMD, and fractures are the most common and debilitating manifestation of osteoporosis. Your discussion of falls with patients should include⁴⁵:

• consequences of falls
• cautions about medications that can cloud mental alertness
• use of appropriate footwear
• home safety, such as adequate lighting, removal of floor clutter, and installation of handrails in the bathroom and stairwells and on outside steps.
• having an annual comprehensive eye exam.

Osteoporosis is avoidable and treatable

Earlier research reported various expressions of number needed to treat for medical management of osteoporosis—making it difficult to follow a single number as a reference for gauging the effectiveness of pharmacotherapy.^46,47 However, for older adults of different ethnic and racial backgrounds with multiple comorbidities and polypharmacy, it might be more pragmatic in primary care to establish a model of goal-oriented, individualized care. By focusing on prevention of bone loss, and being mindful that the risk of fracture almost doubles with a decrease of 1 SD in BMD, you can translate numbers to goals of care.⁴⁸

In the United States, approximately one-half of osteoporosis cases in adults ≥ 50 years are managed by primary care providers. As a chronic disease, osteoporosis requires that you, first, provide regular monitoring and assessment, because risk can vary with comorbidities,⁴⁹ and, second, discuss and initiate screening and treatment as appropriate, which can be done annually during a well-care visit.

CORRESPONDENCE

Nahid Rianon, MD, DrPH, Department of Family and Community Medicine, UTHealth McGovern Medical School, 6431 Fannin Street #JJL 324C, Houston, TX, 77030; Nahid.J.Rianon@uth.tmc.edu

Hypertension and elevated blood pressure (BP) in children and adolescents correlate to hypertension in adults, insofar as complications and medical therapy increase with age.^1,2 Untreated, hypertension in children and adolescents can result in multiple harmful physiologic changes, including left ventricular hypertrophy, left atrial enlargement, diastolic dysfunction, arterial stiffening, endothelial dysfunction, and neurocognitive deficits.^3-5

In 2017, the American Academy of Pediatrics (AAP) published clinical practice guidelines for the diagnosis and management of elevated BP and hypertension in children and adolescents^a (TABLE 1⁶). Applying the definition of elevated BP set out in these guidelines yielded a 13% prevalence of hypertension in a cohort of subjects 10 to 18 years of age with comorbid obesity and diabetes mellitus (DM). AAP guideline definitions also improved the sensitivity for identifying hypertensive end-organ damage.⁷

The American Academy of Pediatrics recommends measuring BP annually in all children ≥ 3 years of age and at every encounter in patients with specific comorbid conditions and in those taking a medication known to increase BP

As the prevalence of hypertension increases, screening for and accurate diagnosis of this condition in children are becoming more important. Recognition and management remain a vital part of primary care. In this article, we review the updated guidance on diagnosis and treatment, including lifestyle modification and pharmacotherapy.

First step: Identifying hypertension

Risk factors

Risk factors for pediatric hypertension are similar to those in adults. These include obesity (body mass index ≥ 95th percentile for age), types 1 and 2 DM, elevated sodium intake, sleep-disordered breathing, and chronic kidney disease (CKD). Some risk factors, such as premature birth and coarctation of the aorta, are specific to the pediatric population.^8-14 Pediatric obesity strongly correlates with both pediatric and adult hypertension, and accelerated weight gain might increase the risk of elevated BP in adulthood.^15,16

Intervening early to mitigate or eliminate some of these modifiable risk factors can prevent or treat hypertension.¹⁷ Alternatively, having been breastfed as an infant has been reliably shown to reduce the risk of elevated BP in children.¹³

Recommendations for screening and measuring BP

The optimal age to start measuring BP is not clearly defined. AAP recommends measurement:

• annually in all children ≥ 3 years of age
• at every encounter in patients who have a specific comorbid condition, including obesity, DM, renal disease, and aortic-arch abnormalities (obstruction and coarctation) and in those who are taking medication known to increase BP.⁶

Protocol. Measure BP in the right arm for consistency and comparison with reference values. The width of the cuff bladder should be at least 40%, and the length, 80% to 100%, of arm circumference. Position the cuff bladder midway between the olecranon and acromion. Obtain the measurement in a quiet and comfortable environment after the patient has rested for 3 to 5 minutes. The patient should be seated, preferably with feet on the floor; elbows should be supported at the level of the heart.

Continue to: When an initial reading...

When an initial reading is elevated, whether by oscillometric or auscultatory measurement, 2 more auscultatory BP measurements should be taken during the same visit; these measurements are averaged to determine the BP category.¹⁸

TABLE 1⁶ defines BP categories based on age, sex, and height. We recommend using the free resource MD Calc (www.mdcalc.com/aap-pediatric-hypertension-guidelines) to assist in calculating the BP category.

TABLE 2⁶ describes the timing of follow-up based on the initial BP reading and diagnosis.

Ambulatory BP monitoring (ABPM) is a validated device that measures BP every 20 to 30 minutes throughout the day and night. ABPM should be performed initially in all patients with persistently elevated BP and routinely in children and adolescents with a high-risk comorbidity (TABLE 2⁶). Note: Insurance coverage of ABPM is limited.

Children older than 10 years who have been given a diagnosis of hypertension should be asked about smoking, alcohol, and other substance use.

ABPM is also used to diagnose so-called white-coat hypertension, defined as BP ≥ 95th percentile for age, sex, and height in the clinic setting but < 95th percentile during ABPM. This phenomenon can be challenging to diagnose.

Continue to: Home monitoring

Home monitoring. Do not use home BP monitoring to establish a diagnosis of hypertension, although one of these devices can be used as an adjunct to office and ambulatory BP monitoring after the diagnosis has been made.⁶

Evaluating hypertension in children and adolescents

Once a diagnosis of hypertension has been made, undertake a thorough history, physical examination, and diagnostic testing to evaluate for possible causes, comorbidities, and any evidence of end-organ damage.

Comprehensive history. Pertinent aspects include perinatal, nutritional, physical activity, psychosocial, family, medication—and of course, medical—histories.⁶

Maternal elevated BP or hypertension is related to an offspring’s elevated BP in childhood and adolescence.¹⁹ Other pertinent aspects of the perinatal history include complications of pregnancy, gestational age, birth weight, and neonatal complications.⁶

Nutritional and physical activity histories can highlight contributing factors in the development of hypertension and can be a guide to recommending lifestyle modifications.⁶ Sodium intake, which influences BP, should be part of the nutritional history.²⁰

Continue to: Important aspects...

The family history should include notation of first- and second-degree relatives with hypertension.⁶

Inquire about medications that can raise BP, including oral contraceptives, which are commonly prescribed in this population.^21,22

The physical exam should include measured height and weight, with calculation of the body mass index percentile for age; of note, obesity is strongly associated with hypertension, and poor growth might signal underlying chronic disease. Once elevated BP has been confirmed, the exam should include measurement of BP in both arms and in a leg (TABLE 2⁶). BP that is lower in the leg than in the arms (in any given patient, BP readings in the legs are usually higher than in the arms), or weak or absent femoral pulses, suggest coarctation of the aorta.⁶

Focus the balance of the physical exam on physical findings that suggest secondary causes of hypertension or evidence of end-organ damage.

Continue to: Testing

Testing. TABLE 3^6,23 summarizes the diagnostic testing recommended for all children and for specific populations; TABLE 2⁶ indicates when to obtain diagnostic testing. Patients 6 years and older who are overweight or obese and have a family history of hypertension likely have primary hypertension; they do not require an extensive work-up for secondary hypertension unless findings of the comprehensive history and physical examination lead in that direction.^6,23

TABLE 4^2,12,13,24 outlines the basis of primary and of secondary hypertension and common historical and physical findings that suggest a secondary cause.

Mapping out the treatment plan

Pediatric hypertension should be treated in patients with stage 1 or higher hypertension.⁶ This threshold for therapy is based on evidence that reducing BP below a goal of (1) the 90th percentile (calculated based on age, sex, and height) in children up to 12 years of age or (2) of < 130/80 mm Hg for children ≥ 13 years reduces short- and long-term morbidity and mortality.^5,6,25

Ambulatory BP monitoring should be performed initially in all patients with persistently elevated BP and routinely in children and adolescents with a high-risk comorbidity.

Choice of initial treatment depends on the severity of BP elevation and the presence of comorbidities (FIGURE^6,20,25-28). The initial, fundamental treatment recommendation is lifestyle modification,^6,29 including regular physical exercise, a change in nutritional habits, weight loss (because obesity is a common comorbid condition), elimination of tobacco and substance use, and stress reduction.^25,26 Medications can be used as well, along with other treatments for specific causes of secondary hypertension.

Referral to a specialist can be considered if consultation for assistance with treatment is preferred (TABLE 2⁶) or if the patient has:

• treatment-resistant hypertension
• stage 2 hypertension that is not quickly responsive to initial treatment
• an identified secondary cause of ­hypertension.

Continue to: Lifestyle modification can make a big difference

Exercise. “Regular” physical exercise for children to reduce BP is defined as ≥ 30 to 60 minutes of active play daily.^6,29 Studies have shown significant improvement not only in BP but also in other cardiovascular disease risk parameters with regular physical exercise.²⁷ A study found that the reduction in systolic BP is, on average, approximately 6 mm Hg with physical activity alone.³⁰

Nutrition. DASH—Dietary Approaches to Stop Hypertension—is an evidence-based program to reduce BP. This nutritional guideline focuses on a diet rich in natural foods, including fruits, vegetables, minimally processed carbohydrates and whole grains, and low-fat dairy and meats. It also emphasizes the importance of avoiding foods high in processed sugars and reducing sodium intake.³¹ Higher-than-recommended sodium intake, based on age and sex (and established as part of dietary recommendations for children on the US Department of Health and Human Services’ website health.gov) directly correlates with the risk of prehypertension and hypertension—especially in overweight and obese children.^20,32 DASH has been shown to reliably reduce the incidence of hypertension in children; other studies have supported increased intake of fruits, vegetables, and legumes as strategies to reduce BP.^33,34

The family history should include notation of first- and second-degree relatives with hypertension. Inquire about medications that can raise BP, including oral contraceptives.

Other interventions. Techniques to improve adherence to exercise and nutritional modifications for children include motivational interviewing, community programs and education, and family counseling.^27,35 A recent study showed that a community-based lifestyle modification program that is focused on weight loss in obese children resulted in a significant reduction in BP values at higher stages of obesity.³⁶ There is evidence that techniques such as controlled breathing and meditation can reduce BP.³⁷ Last, screening and counseling to encourage tobacco and substance use discontinuation are recommended for children and adolescents to improve health outcomes.²⁵

Proceed with pharmacotherapy when these criteria are met

Medical therapy is recommended when certain criteria are met, although this decision should be individualized and made in agreement by the treating physician, patient, and family. These criteria (FIGURE^6,20,25-28) are^6,29:

• once a diagnosis of stage 1 hypertension has been established, failure to meet a BP goal after 3 to 6 months of attempting lifestyle modifications
• stage 2 hypertension without a modifiable risk factor, such as obesity

• any stage of hypertension with comorbid CKD, DM, or proteinuria
• target-organ damage, such as left ventricular hypertrophy

• symptomatic hypertension.^6,29

There are circumstances in which one or another specific antihypertensive agent is recommended for children; however, for most patients with primary hypertension, the following classes are recommended for first-line use^6,22:

• angiotensin-converting enzyme (ACE) inhibitors
• angiotensin receptor blockers (ARBs)
• calcium-channel blockers (CCBs)
• thiazide diuretics.

Continue to: For a child with known CKD...

For a child with known CKD, DM, or proteinuria, an ACE inhibitor or ARB is beneficial as first-line therapy.³⁸ Because ACE inhibitors and ARBs have teratogenic effects, however, a thorough review of fertility status is recommended for female patients before any of these agents are started. CCBs and thiazides are typically recommended as first-line agents for Black patients.^6,28 Beta-blockers are typically avoided in the first line because of their adverse effect profile.

Most antihypertensive medications can be titrated every 1 or 2 weeks; the patient’s BP can be monitored with a home BP cuff to track the effect of titration. In general, the patient should be seen for follow-up every 4 to 6 weeks for a BP recheck and review of medication tolerance and adverse effects. Once the treatment goal is achieved, it is reasonable to have the patient return every 3 to 6 months to reassess the treatment plan.

The initial, fundamental treatment recommendation is lifestyle modification, including regular physical exercise, a change in nutritional habits, and weight loss.

If the BP goal is difficult to achieve despite titration of medication and lifestyle changes, consider repeat ABPM assessment, a specialty referral, or both. It is reasonable for children who have been started on medication and have adhered to lifestyle modifications to practice a “step-down” approach to discontinuing medication; this approach can also be considered once any secondary cause has been corrected. Any target-organ abnormalities identified at diagnosis (eg, proteinuria, CKD, left ventricular hypertrophy) need to be reexamined at follow-up.⁶

Restrict activities—or not?

There is evidence that a child with stage 1 or well-controlled stage 2 hypertension without evidence of end-organ damage should not have restrictions on sports or activity. However, in uncontrolled stage 2 hypertension or when evidence of target end-organ damage is present, you should advise against participation in highly competitive sports and highly static sports (eg, weightlifting, wrestling), based on expert opinion^6,25 (FIGURE^6,20,25-28).

^aAAP guidelines on the management of pediatric hypertension vary from those of the US Preventive Services Task Force. See the Practice Alert, “A review of the latest USPSTF recommendations,” in the May 2021 issue.

CORRESPONDENCE
Dustin K. Smith, MD, Family Medicine Department, 2080 Child Street, Jacksonville, FL, 32214; dustinksmith@yahoo.com

Hypertension and elevated blood pressure (BP) in children and adolescents correlate to hypertension in adults, insofar as complications and medical therapy increase with age.^1,2 Untreated, hypertension in children and adolescents can result in multiple harmful physiologic changes, including left ventricular hypertrophy, left atrial enlargement, diastolic dysfunction, arterial stiffening, endothelial dysfunction, and neurocognitive deficits.^3-5

In 2017, the American Academy of Pediatrics (AAP) published clinical practice guidelines for the diagnosis and management of elevated BP and hypertension in children and adolescents^a (TABLE 1⁶). Applying the definition of elevated BP set out in these guidelines yielded a 13% prevalence of hypertension in a cohort of subjects 10 to 18 years of age with comorbid obesity and diabetes mellitus (DM). AAP guideline definitions also improved the sensitivity for identifying hypertensive end-organ damage.⁷

The American Academy of Pediatrics recommends measuring BP annually in all children ≥ 3 years of age and at every encounter in patients with specific comorbid conditions and in those taking a medication known to increase BP

As the prevalence of hypertension increases, screening for and accurate diagnosis of this condition in children are becoming more important. Recognition and management remain a vital part of primary care. In this article, we review the updated guidance on diagnosis and treatment, including lifestyle modification and pharmacotherapy.

First step: Identifying hypertension

Risk factors

Risk factors for pediatric hypertension are similar to those in adults. These include obesity (body mass index ≥ 95th percentile for age), types 1 and 2 DM, elevated sodium intake, sleep-disordered breathing, and chronic kidney disease (CKD). Some risk factors, such as premature birth and coarctation of the aorta, are specific to the pediatric population.^8-14 Pediatric obesity strongly correlates with both pediatric and adult hypertension, and accelerated weight gain might increase the risk of elevated BP in adulthood.^15,16

Intervening early to mitigate or eliminate some of these modifiable risk factors can prevent or treat hypertension.¹⁷ Alternatively, having been breastfed as an infant has been reliably shown to reduce the risk of elevated BP in children.¹³

Recommendations for screening and measuring BP

The optimal age to start measuring BP is not clearly defined. AAP recommends measurement:

• annually in all children ≥ 3 years of age
• at every encounter in patients who have a specific comorbid condition, including obesity, DM, renal disease, and aortic-arch abnormalities (obstruction and coarctation) and in those who are taking medication known to increase BP.⁶

Protocol. Measure BP in the right arm for consistency and comparison with reference values. The width of the cuff bladder should be at least 40%, and the length, 80% to 100%, of arm circumference. Position the cuff bladder midway between the olecranon and acromion. Obtain the measurement in a quiet and comfortable environment after the patient has rested for 3 to 5 minutes. The patient should be seated, preferably with feet on the floor; elbows should be supported at the level of the heart.

Continue to: When an initial reading...

When an initial reading is elevated, whether by oscillometric or auscultatory measurement, 2 more auscultatory BP measurements should be taken during the same visit; these measurements are averaged to determine the BP category.¹⁸

TABLE 1⁶ defines BP categories based on age, sex, and height. We recommend using the free resource MD Calc (www.mdcalc.com/aap-pediatric-hypertension-guidelines) to assist in calculating the BP category.

TABLE 2⁶ describes the timing of follow-up based on the initial BP reading and diagnosis.

Ambulatory BP monitoring (ABPM) is a validated device that measures BP every 20 to 30 minutes throughout the day and night. ABPM should be performed initially in all patients with persistently elevated BP and routinely in children and adolescents with a high-risk comorbidity (TABLE 2⁶). Note: Insurance coverage of ABPM is limited.

Children older than 10 years who have been given a diagnosis of hypertension should be asked about smoking, alcohol, and other substance use.

ABPM is also used to diagnose so-called white-coat hypertension, defined as BP ≥ 95th percentile for age, sex, and height in the clinic setting but < 95th percentile during ABPM. This phenomenon can be challenging to diagnose.

Continue to: Home monitoring

Home monitoring. Do not use home BP monitoring to establish a diagnosis of hypertension, although one of these devices can be used as an adjunct to office and ambulatory BP monitoring after the diagnosis has been made.⁶

Evaluating hypertension in children and adolescents

Once a diagnosis of hypertension has been made, undertake a thorough history, physical examination, and diagnostic testing to evaluate for possible causes, comorbidities, and any evidence of end-organ damage.

Comprehensive history. Pertinent aspects include perinatal, nutritional, physical activity, psychosocial, family, medication—and of course, medical—histories.⁶

Maternal elevated BP or hypertension is related to an offspring’s elevated BP in childhood and adolescence.¹⁹ Other pertinent aspects of the perinatal history include complications of pregnancy, gestational age, birth weight, and neonatal complications.⁶

Nutritional and physical activity histories can highlight contributing factors in the development of hypertension and can be a guide to recommending lifestyle modifications.⁶ Sodium intake, which influences BP, should be part of the nutritional history.²⁰

Continue to: Important aspects...

The family history should include notation of first- and second-degree relatives with hypertension.⁶

Inquire about medications that can raise BP, including oral contraceptives, which are commonly prescribed in this population.^21,22

The physical exam should include measured height and weight, with calculation of the body mass index percentile for age; of note, obesity is strongly associated with hypertension, and poor growth might signal underlying chronic disease. Once elevated BP has been confirmed, the exam should include measurement of BP in both arms and in a leg (TABLE 2⁶). BP that is lower in the leg than in the arms (in any given patient, BP readings in the legs are usually higher than in the arms), or weak or absent femoral pulses, suggest coarctation of the aorta.⁶

Focus the balance of the physical exam on physical findings that suggest secondary causes of hypertension or evidence of end-organ damage.

Continue to: Testing

Testing. TABLE 3^6,23 summarizes the diagnostic testing recommended for all children and for specific populations; TABLE 2⁶ indicates when to obtain diagnostic testing. Patients 6 years and older who are overweight or obese and have a family history of hypertension likely have primary hypertension; they do not require an extensive work-up for secondary hypertension unless findings of the comprehensive history and physical examination lead in that direction.^6,23

TABLE 4^2,12,13,24 outlines the basis of primary and of secondary hypertension and common historical and physical findings that suggest a secondary cause.

Mapping out the treatment plan

Pediatric hypertension should be treated in patients with stage 1 or higher hypertension.⁶ This threshold for therapy is based on evidence that reducing BP below a goal of (1) the 90th percentile (calculated based on age, sex, and height) in children up to 12 years of age or (2) of < 130/80 mm Hg for children ≥ 13 years reduces short- and long-term morbidity and mortality.^5,6,25

Ambulatory BP monitoring should be performed initially in all patients with persistently elevated BP and routinely in children and adolescents with a high-risk comorbidity.

Choice of initial treatment depends on the severity of BP elevation and the presence of comorbidities (FIGURE^6,20,25-28). The initial, fundamental treatment recommendation is lifestyle modification,^6,29 including regular physical exercise, a change in nutritional habits, weight loss (because obesity is a common comorbid condition), elimination of tobacco and substance use, and stress reduction.^25,26 Medications can be used as well, along with other treatments for specific causes of secondary hypertension.

Referral to a specialist can be considered if consultation for assistance with treatment is preferred (TABLE 2⁶) or if the patient has:

• treatment-resistant hypertension
• stage 2 hypertension that is not quickly responsive to initial treatment
• an identified secondary cause of ­hypertension.

Continue to: Lifestyle modification can make a big difference

Exercise. “Regular” physical exercise for children to reduce BP is defined as ≥ 30 to 60 minutes of active play daily.^6,29 Studies have shown significant improvement not only in BP but also in other cardiovascular disease risk parameters with regular physical exercise.²⁷ A study found that the reduction in systolic BP is, on average, approximately 6 mm Hg with physical activity alone.³⁰

Nutrition. DASH—Dietary Approaches to Stop Hypertension—is an evidence-based program to reduce BP. This nutritional guideline focuses on a diet rich in natural foods, including fruits, vegetables, minimally processed carbohydrates and whole grains, and low-fat dairy and meats. It also emphasizes the importance of avoiding foods high in processed sugars and reducing sodium intake.³¹ Higher-than-recommended sodium intake, based on age and sex (and established as part of dietary recommendations for children on the US Department of Health and Human Services’ website health.gov) directly correlates with the risk of prehypertension and hypertension—especially in overweight and obese children.^20,32 DASH has been shown to reliably reduce the incidence of hypertension in children; other studies have supported increased intake of fruits, vegetables, and legumes as strategies to reduce BP.^33,34

The family history should include notation of first- and second-degree relatives with hypertension. Inquire about medications that can raise BP, including oral contraceptives.

Other interventions. Techniques to improve adherence to exercise and nutritional modifications for children include motivational interviewing, community programs and education, and family counseling.^27,35 A recent study showed that a community-based lifestyle modification program that is focused on weight loss in obese children resulted in a significant reduction in BP values at higher stages of obesity.³⁶ There is evidence that techniques such as controlled breathing and meditation can reduce BP.³⁷ Last, screening and counseling to encourage tobacco and substance use discontinuation are recommended for children and adolescents to improve health outcomes.²⁵

Proceed with pharmacotherapy when these criteria are met

Medical therapy is recommended when certain criteria are met, although this decision should be individualized and made in agreement by the treating physician, patient, and family. These criteria (FIGURE^6,20,25-28) are^6,29:

• once a diagnosis of stage 1 hypertension has been established, failure to meet a BP goal after 3 to 6 months of attempting lifestyle modifications
• stage 2 hypertension without a modifiable risk factor, such as obesity

• any stage of hypertension with comorbid CKD, DM, or proteinuria
• target-organ damage, such as left ventricular hypertrophy

• symptomatic hypertension.^6,29

There are circumstances in which one or another specific antihypertensive agent is recommended for children; however, for most patients with primary hypertension, the following classes are recommended for first-line use^6,22:

• angiotensin-converting enzyme (ACE) inhibitors
• angiotensin receptor blockers (ARBs)
• calcium-channel blockers (CCBs)
• thiazide diuretics.

Continue to: For a child with known CKD...

For a child with known CKD, DM, or proteinuria, an ACE inhibitor or ARB is beneficial as first-line therapy.³⁸ Because ACE inhibitors and ARBs have teratogenic effects, however, a thorough review of fertility status is recommended for female patients before any of these agents are started. CCBs and thiazides are typically recommended as first-line agents for Black patients.^6,28 Beta-blockers are typically avoided in the first line because of their adverse effect profile.

Most antihypertensive medications can be titrated every 1 or 2 weeks; the patient’s BP can be monitored with a home BP cuff to track the effect of titration. In general, the patient should be seen for follow-up every 4 to 6 weeks for a BP recheck and review of medication tolerance and adverse effects. Once the treatment goal is achieved, it is reasonable to have the patient return every 3 to 6 months to reassess the treatment plan.

The initial, fundamental treatment recommendation is lifestyle modification, including regular physical exercise, a change in nutritional habits, and weight loss.

If the BP goal is difficult to achieve despite titration of medication and lifestyle changes, consider repeat ABPM assessment, a specialty referral, or both. It is reasonable for children who have been started on medication and have adhered to lifestyle modifications to practice a “step-down” approach to discontinuing medication; this approach can also be considered once any secondary cause has been corrected. Any target-organ abnormalities identified at diagnosis (eg, proteinuria, CKD, left ventricular hypertrophy) need to be reexamined at follow-up.⁶

Restrict activities—or not?

There is evidence that a child with stage 1 or well-controlled stage 2 hypertension without evidence of end-organ damage should not have restrictions on sports or activity. However, in uncontrolled stage 2 hypertension or when evidence of target end-organ damage is present, you should advise against participation in highly competitive sports and highly static sports (eg, weightlifting, wrestling), based on expert opinion^6,25 (FIGURE^6,20,25-28).

^aAAP guidelines on the management of pediatric hypertension vary from those of the US Preventive Services Task Force. See the Practice Alert, “A review of the latest USPSTF recommendations,” in the May 2021 issue.

CORRESPONDENCE
Dustin K. Smith, MD, Family Medicine Department, 2080 Child Street, Jacksonville, FL, 32214; dustinksmith@yahoo.com

Hypertension and elevated blood pressure (BP) in children and adolescents correlate to hypertension in adults, insofar as complications and medical therapy increase with age.^1,2 Untreated, hypertension in children and adolescents can result in multiple harmful physiologic changes, including left ventricular hypertrophy, left atrial enlargement, diastolic dysfunction, arterial stiffening, endothelial dysfunction, and neurocognitive deficits.^3-5

In 2017, the American Academy of Pediatrics (AAP) published clinical practice guidelines for the diagnosis and management of elevated BP and hypertension in children and adolescents^a (TABLE 1⁶). Applying the definition of elevated BP set out in these guidelines yielded a 13% prevalence of hypertension in a cohort of subjects 10 to 18 years of age with comorbid obesity and diabetes mellitus (DM). AAP guideline definitions also improved the sensitivity for identifying hypertensive end-organ damage.⁷

The American Academy of Pediatrics recommends measuring BP annually in all children ≥ 3 years of age and at every encounter in patients with specific comorbid conditions and in those taking a medication known to increase BP

As the prevalence of hypertension increases, screening for and accurate diagnosis of this condition in children are becoming more important. Recognition and management remain a vital part of primary care. In this article, we review the updated guidance on diagnosis and treatment, including lifestyle modification and pharmacotherapy.

First step: Identifying hypertension

Risk factors

Risk factors for pediatric hypertension are similar to those in adults. These include obesity (body mass index ≥ 95th percentile for age), types 1 and 2 DM, elevated sodium intake, sleep-disordered breathing, and chronic kidney disease (CKD). Some risk factors, such as premature birth and coarctation of the aorta, are specific to the pediatric population.^8-14 Pediatric obesity strongly correlates with both pediatric and adult hypertension, and accelerated weight gain might increase the risk of elevated BP in adulthood.^15,16

Intervening early to mitigate or eliminate some of these modifiable risk factors can prevent or treat hypertension.¹⁷ Alternatively, having been breastfed as an infant has been reliably shown to reduce the risk of elevated BP in children.¹³

Recommendations for screening and measuring BP

The optimal age to start measuring BP is not clearly defined. AAP recommends measurement:

• annually in all children ≥ 3 years of age
• at every encounter in patients who have a specific comorbid condition, including obesity, DM, renal disease, and aortic-arch abnormalities (obstruction and coarctation) and in those who are taking medication known to increase BP.⁶

Protocol. Measure BP in the right arm for consistency and comparison with reference values. The width of the cuff bladder should be at least 40%, and the length, 80% to 100%, of arm circumference. Position the cuff bladder midway between the olecranon and acromion. Obtain the measurement in a quiet and comfortable environment after the patient has rested for 3 to 5 minutes. The patient should be seated, preferably with feet on the floor; elbows should be supported at the level of the heart.

Continue to: When an initial reading...

When an initial reading is elevated, whether by oscillometric or auscultatory measurement, 2 more auscultatory BP measurements should be taken during the same visit; these measurements are averaged to determine the BP category.¹⁸

TABLE 1⁶ defines BP categories based on age, sex, and height. We recommend using the free resource MD Calc (www.mdcalc.com/aap-pediatric-hypertension-guidelines) to assist in calculating the BP category.

TABLE 2⁶ describes the timing of follow-up based on the initial BP reading and diagnosis.

Ambulatory BP monitoring (ABPM) is a validated device that measures BP every 20 to 30 minutes throughout the day and night. ABPM should be performed initially in all patients with persistently elevated BP and routinely in children and adolescents with a high-risk comorbidity (TABLE 2⁶). Note: Insurance coverage of ABPM is limited.

Children older than 10 years who have been given a diagnosis of hypertension should be asked about smoking, alcohol, and other substance use.

ABPM is also used to diagnose so-called white-coat hypertension, defined as BP ≥ 95th percentile for age, sex, and height in the clinic setting but < 95th percentile during ABPM. This phenomenon can be challenging to diagnose.

Continue to: Home monitoring

Home monitoring. Do not use home BP monitoring to establish a diagnosis of hypertension, although one of these devices can be used as an adjunct to office and ambulatory BP monitoring after the diagnosis has been made.⁶

Evaluating hypertension in children and adolescents

Once a diagnosis of hypertension has been made, undertake a thorough history, physical examination, and diagnostic testing to evaluate for possible causes, comorbidities, and any evidence of end-organ damage.

Comprehensive history. Pertinent aspects include perinatal, nutritional, physical activity, psychosocial, family, medication—and of course, medical—histories.⁶

Maternal elevated BP or hypertension is related to an offspring’s elevated BP in childhood and adolescence.¹⁹ Other pertinent aspects of the perinatal history include complications of pregnancy, gestational age, birth weight, and neonatal complications.⁶

Nutritional and physical activity histories can highlight contributing factors in the development of hypertension and can be a guide to recommending lifestyle modifications.⁶ Sodium intake, which influences BP, should be part of the nutritional history.²⁰

Continue to: Important aspects...

The family history should include notation of first- and second-degree relatives with hypertension.⁶

Inquire about medications that can raise BP, including oral contraceptives, which are commonly prescribed in this population.^21,22

The physical exam should include measured height and weight, with calculation of the body mass index percentile for age; of note, obesity is strongly associated with hypertension, and poor growth might signal underlying chronic disease. Once elevated BP has been confirmed, the exam should include measurement of BP in both arms and in a leg (TABLE 2⁶). BP that is lower in the leg than in the arms (in any given patient, BP readings in the legs are usually higher than in the arms), or weak or absent femoral pulses, suggest coarctation of the aorta.⁶

Focus the balance of the physical exam on physical findings that suggest secondary causes of hypertension or evidence of end-organ damage.

Continue to: Testing

Testing. TABLE 3^6,23 summarizes the diagnostic testing recommended for all children and for specific populations; TABLE 2⁶ indicates when to obtain diagnostic testing. Patients 6 years and older who are overweight or obese and have a family history of hypertension likely have primary hypertension; they do not require an extensive work-up for secondary hypertension unless findings of the comprehensive history and physical examination lead in that direction.^6,23

TABLE 4^2,12,13,24 outlines the basis of primary and of secondary hypertension and common historical and physical findings that suggest a secondary cause.

Mapping out the treatment plan

Pediatric hypertension should be treated in patients with stage 1 or higher hypertension.⁶ This threshold for therapy is based on evidence that reducing BP below a goal of (1) the 90th percentile (calculated based on age, sex, and height) in children up to 12 years of age or (2) of < 130/80 mm Hg for children ≥ 13 years reduces short- and long-term morbidity and mortality.^5,6,25

Ambulatory BP monitoring should be performed initially in all patients with persistently elevated BP and routinely in children and adolescents with a high-risk comorbidity.

Choice of initial treatment depends on the severity of BP elevation and the presence of comorbidities (FIGURE^6,20,25-28). The initial, fundamental treatment recommendation is lifestyle modification,^6,29 including regular physical exercise, a change in nutritional habits, weight loss (because obesity is a common comorbid condition), elimination of tobacco and substance use, and stress reduction.^25,26 Medications can be used as well, along with other treatments for specific causes of secondary hypertension.

Referral to a specialist can be considered if consultation for assistance with treatment is preferred (TABLE 2⁶) or if the patient has:

• treatment-resistant hypertension
• stage 2 hypertension that is not quickly responsive to initial treatment
• an identified secondary cause of ­hypertension.

Continue to: Lifestyle modification can make a big difference

Exercise. “Regular” physical exercise for children to reduce BP is defined as ≥ 30 to 60 minutes of active play daily.^6,29 Studies have shown significant improvement not only in BP but also in other cardiovascular disease risk parameters with regular physical exercise.²⁷ A study found that the reduction in systolic BP is, on average, approximately 6 mm Hg with physical activity alone.³⁰

Nutrition. DASH—Dietary Approaches to Stop Hypertension—is an evidence-based program to reduce BP. This nutritional guideline focuses on a diet rich in natural foods, including fruits, vegetables, minimally processed carbohydrates and whole grains, and low-fat dairy and meats. It also emphasizes the importance of avoiding foods high in processed sugars and reducing sodium intake.³¹ Higher-than-recommended sodium intake, based on age and sex (and established as part of dietary recommendations for children on the US Department of Health and Human Services’ website health.gov) directly correlates with the risk of prehypertension and hypertension—especially in overweight and obese children.^20,32 DASH has been shown to reliably reduce the incidence of hypertension in children; other studies have supported increased intake of fruits, vegetables, and legumes as strategies to reduce BP.^33,34

The family history should include notation of first- and second-degree relatives with hypertension. Inquire about medications that can raise BP, including oral contraceptives.

Other interventions. Techniques to improve adherence to exercise and nutritional modifications for children include motivational interviewing, community programs and education, and family counseling.^27,35 A recent study showed that a community-based lifestyle modification program that is focused on weight loss in obese children resulted in a significant reduction in BP values at higher stages of obesity.³⁶ There is evidence that techniques such as controlled breathing and meditation can reduce BP.³⁷ Last, screening and counseling to encourage tobacco and substance use discontinuation are recommended for children and adolescents to improve health outcomes.²⁵

Proceed with pharmacotherapy when these criteria are met

Medical therapy is recommended when certain criteria are met, although this decision should be individualized and made in agreement by the treating physician, patient, and family. These criteria (FIGURE^6,20,25-28) are^6,29:

• once a diagnosis of stage 1 hypertension has been established, failure to meet a BP goal after 3 to 6 months of attempting lifestyle modifications
• stage 2 hypertension without a modifiable risk factor, such as obesity

• any stage of hypertension with comorbid CKD, DM, or proteinuria
• target-organ damage, such as left ventricular hypertrophy

• symptomatic hypertension.^6,29

There are circumstances in which one or another specific antihypertensive agent is recommended for children; however, for most patients with primary hypertension, the following classes are recommended for first-line use^6,22:

• angiotensin-converting enzyme (ACE) inhibitors
• angiotensin receptor blockers (ARBs)
• calcium-channel blockers (CCBs)
• thiazide diuretics.

Continue to: For a child with known CKD...

For a child with known CKD, DM, or proteinuria, an ACE inhibitor or ARB is beneficial as first-line therapy.³⁸ Because ACE inhibitors and ARBs have teratogenic effects, however, a thorough review of fertility status is recommended for female patients before any of these agents are started. CCBs and thiazides are typically recommended as first-line agents for Black patients.^6,28 Beta-blockers are typically avoided in the first line because of their adverse effect profile.

Most antihypertensive medications can be titrated every 1 or 2 weeks; the patient’s BP can be monitored with a home BP cuff to track the effect of titration. In general, the patient should be seen for follow-up every 4 to 6 weeks for a BP recheck and review of medication tolerance and adverse effects. Once the treatment goal is achieved, it is reasonable to have the patient return every 3 to 6 months to reassess the treatment plan.

The initial, fundamental treatment recommendation is lifestyle modification, including regular physical exercise, a change in nutritional habits, and weight loss.

If the BP goal is difficult to achieve despite titration of medication and lifestyle changes, consider repeat ABPM assessment, a specialty referral, or both. It is reasonable for children who have been started on medication and have adhered to lifestyle modifications to practice a “step-down” approach to discontinuing medication; this approach can also be considered once any secondary cause has been corrected. Any target-organ abnormalities identified at diagnosis (eg, proteinuria, CKD, left ventricular hypertrophy) need to be reexamined at follow-up.⁶

Restrict activities—or not?

There is evidence that a child with stage 1 or well-controlled stage 2 hypertension without evidence of end-organ damage should not have restrictions on sports or activity. However, in uncontrolled stage 2 hypertension or when evidence of target end-organ damage is present, you should advise against participation in highly competitive sports and highly static sports (eg, weightlifting, wrestling), based on expert opinion^6,25 (FIGURE^6,20,25-28).

^aAAP guidelines on the management of pediatric hypertension vary from those of the US Preventive Services Task Force. See the Practice Alert, “A review of the latest USPSTF recommendations,” in the May 2021 issue.

CORRESPONDENCE
Dustin K. Smith, MD, Family Medicine Department, 2080 Child Street, Jacksonville, FL, 32214; dustinksmith@yahoo.com

A 31-year-old Hispanic man presented for evaluation of numerous disfiguring growths on his scalp. They first appeared when he was 19 years old. A review of his family history revealed that his father had 2 “cysts” on his body.

The patient had 10 nodules on his scalp and upper back (Figures 1A and 1B). The ones on his scalp lacked puncta and appeared in a “turban tumor” configuration. The lesions were pink, smooth, and semisoft, and ranged in size from 1 to 6 cm.

Six years earlier, the patient had been seen for evaluation of 20 protuberant nodules. At the time, he had been referred to plastic surgery, where 15 lesions were excised. No other treatment was reported by the patient during the 6-year gap between exams.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Pilar cysts (PC), also known as trichilemma cysts, wen, or isthmus-catagen cysts, are benign cysts that manifest as smooth, firm, well-­circumscribed, pink nodules. PCs originate from the follicular isthmus of the hair’s external root sheath¹ and are found in 5% to 10% of the US population.² Possible sites of appearance include the face, neck, trunk, and extremities, although 90% of PCs develop on the scalp.¹ They tend to have an autosomal dominant pattern of inheritance with linkages to the short arm of chromosome 3.³ PCs can occasionally become inflamed following infection or trauma.

Characteristic histology of PCs demonstrates semisolid, keratin-filled, subepidermal cysts lined by stratified epithelium without a granular layer (trichilemmal keratinization). Lesions excised from this patient’s scalp showed 2 subtypes of PCs: nonproliferating (FIGURE 2A) and proliferating (FIGURE 2B). Subtypes appear similar on exam but can be differentiated on histology.

With gradual growth, proliferating PCs can reach up to 25 cm in diameter.¹ Rapid growth, size > 5 cm, infiltration, or a non-scalp location may indicate malignancy.⁴

Differential diagnosis includes lipomas

The differential diagnosis for a lesion such as this includes epidermal inclusion cysts, dermoid cysts, and lipomas. Epidermal inclusion cysts have a punctum, whereas PCs do not. Dermoid cysts are single congenital lesions that manifest much earlier than PCs. Lipomas are easily movable rubbery bulges that appear more frequently in lipid-dense areas of the body.

For this patient, the striking turban ­tumor–like presentation, with numerous large cysts on the scalp, initially inspired a differential diagnosis including several genetic tumor syndromes. However, unlike the association between Gardner syndrome and numerous epidermoid cysts or Brooke-Spiegler syndrome and spiradenomas, no syndromes have been linked to numerous trichilemmal cysts.

Continue to: Excision is effective

Excision is the treatment of choice for both proliferating and nonproliferating PCs.⁵ The local recurrence rate of proliferating PCs is 3.7% with a rare likelihood of transformation to trichilemmal carcinoma.⁶

Our patient continues to be followed in clinic for monitoring and periodic excision of bothersome cysts.

A 31-year-old Hispanic man presented for evaluation of numerous disfiguring growths on his scalp. They first appeared when he was 19 years old. A review of his family history revealed that his father had 2 “cysts” on his body.

The patient had 10 nodules on his scalp and upper back (Figures 1A and 1B). The ones on his scalp lacked puncta and appeared in a “turban tumor” configuration. The lesions were pink, smooth, and semisoft, and ranged in size from 1 to 6 cm.

Six years earlier, the patient had been seen for evaluation of 20 protuberant nodules. At the time, he had been referred to plastic surgery, where 15 lesions were excised. No other treatment was reported by the patient during the 6-year gap between exams.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Pilar cysts (PC), also known as trichilemma cysts, wen, or isthmus-catagen cysts, are benign cysts that manifest as smooth, firm, well-­circumscribed, pink nodules. PCs originate from the follicular isthmus of the hair’s external root sheath¹ and are found in 5% to 10% of the US population.² Possible sites of appearance include the face, neck, trunk, and extremities, although 90% of PCs develop on the scalp.¹ They tend to have an autosomal dominant pattern of inheritance with linkages to the short arm of chromosome 3.³ PCs can occasionally become inflamed following infection or trauma.

Characteristic histology of PCs demonstrates semisolid, keratin-filled, subepidermal cysts lined by stratified epithelium without a granular layer (trichilemmal keratinization). Lesions excised from this patient’s scalp showed 2 subtypes of PCs: nonproliferating (FIGURE 2A) and proliferating (FIGURE 2B). Subtypes appear similar on exam but can be differentiated on histology.

With gradual growth, proliferating PCs can reach up to 25 cm in diameter.¹ Rapid growth, size > 5 cm, infiltration, or a non-scalp location may indicate malignancy.⁴

Differential diagnosis includes lipomas

The differential diagnosis for a lesion such as this includes epidermal inclusion cysts, dermoid cysts, and lipomas. Epidermal inclusion cysts have a punctum, whereas PCs do not. Dermoid cysts are single congenital lesions that manifest much earlier than PCs. Lipomas are easily movable rubbery bulges that appear more frequently in lipid-dense areas of the body.

For this patient, the striking turban ­tumor–like presentation, with numerous large cysts on the scalp, initially inspired a differential diagnosis including several genetic tumor syndromes. However, unlike the association between Gardner syndrome and numerous epidermoid cysts or Brooke-Spiegler syndrome and spiradenomas, no syndromes have been linked to numerous trichilemmal cysts.

Continue to: Excision is effective

Excision is the treatment of choice for both proliferating and nonproliferating PCs.⁵ The local recurrence rate of proliferating PCs is 3.7% with a rare likelihood of transformation to trichilemmal carcinoma.⁶

Our patient continues to be followed in clinic for monitoring and periodic excision of bothersome cysts.

A 31-year-old Hispanic man presented for evaluation of numerous disfiguring growths on his scalp. They first appeared when he was 19 years old. A review of his family history revealed that his father had 2 “cysts” on his body.

The patient had 10 nodules on his scalp and upper back (Figures 1A and 1B). The ones on his scalp lacked puncta and appeared in a “turban tumor” configuration. The lesions were pink, smooth, and semisoft, and ranged in size from 1 to 6 cm.

Six years earlier, the patient had been seen for evaluation of 20 protuberant nodules. At the time, he had been referred to plastic surgery, where 15 lesions were excised. No other treatment was reported by the patient during the 6-year gap between exams.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Pilar cysts (PC), also known as trichilemma cysts, wen, or isthmus-catagen cysts, are benign cysts that manifest as smooth, firm, well-­circumscribed, pink nodules. PCs originate from the follicular isthmus of the hair’s external root sheath¹ and are found in 5% to 10% of the US population.² Possible sites of appearance include the face, neck, trunk, and extremities, although 90% of PCs develop on the scalp.¹ They tend to have an autosomal dominant pattern of inheritance with linkages to the short arm of chromosome 3.³ PCs can occasionally become inflamed following infection or trauma.

Characteristic histology of PCs demonstrates semisolid, keratin-filled, subepidermal cysts lined by stratified epithelium without a granular layer (trichilemmal keratinization). Lesions excised from this patient’s scalp showed 2 subtypes of PCs: nonproliferating (FIGURE 2A) and proliferating (FIGURE 2B). Subtypes appear similar on exam but can be differentiated on histology.

With gradual growth, proliferating PCs can reach up to 25 cm in diameter.¹ Rapid growth, size > 5 cm, infiltration, or a non-scalp location may indicate malignancy.⁴

Differential diagnosis includes lipomas

The differential diagnosis for a lesion such as this includes epidermal inclusion cysts, dermoid cysts, and lipomas. Epidermal inclusion cysts have a punctum, whereas PCs do not. Dermoid cysts are single congenital lesions that manifest much earlier than PCs. Lipomas are easily movable rubbery bulges that appear more frequently in lipid-dense areas of the body.

For this patient, the striking turban ­tumor–like presentation, with numerous large cysts on the scalp, initially inspired a differential diagnosis including several genetic tumor syndromes. However, unlike the association between Gardner syndrome and numerous epidermoid cysts or Brooke-Spiegler syndrome and spiradenomas, no syndromes have been linked to numerous trichilemmal cysts.

Continue to: Excision is effective

Excision is the treatment of choice for both proliferating and nonproliferating PCs.⁵ The local recurrence rate of proliferating PCs is 3.7% with a rare likelihood of transformation to trichilemmal carcinoma.⁶

Our patient continues to be followed in clinic for monitoring and periodic excision of bothersome cysts.

A 74-year-old woman presented to the dermatology clinic for follow-up 3 months after the surgical excision of a basal cell carcinoma on her left jawline. During this postop period, the patient developed new-onset hirsutism. She appeared to be in otherwise good health.

Family and personal medical history were unremarkable. Her medication regimen included aspirin 81 mg/d and a daily multivitamin. The patient was postmenopausal and had a body mass index of 28 and a history of acid reflux and osteoarthritis.

Physical examination of the patient’s scalp showed male-pattern alopecia (FIGURE 1A). She also had coarse terminal hairs on her forearms and back, as well as on her chin (FIGURE 1B).

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Dx: Androgen-secreting ovarian tumor

Based on the distribution of terminal hairs and marked change over 3 months, as well as the male-pattern alopecia, a diagnosis of androgen excess was suspected. Laboratory work-up, including thyroid-stimulating hormone, dehydroepiandrosterone sulfate (DHEAS), follicle-stimulating hormone, luteinizing hormone, prolactin, complete blood count, and complete metabolic panel, was within normal limits. Pelvic ultrasound of the ovaries and abdominal computed tomography (CT) of the adrenal glands were also normal.

Further testing showed an elevated testosterone level of 464 ng/dL (reference range: 2-45 ng/dL) and an elevated free testosterone level of 66.8 ng/dL (reference range: 0.2-3.7 ng/dL). These levels pointed to an androgen-secreting ovarian tumor; the androgen excess was likely the cause of her hirsutism.

Hirsutism or hypertrichosis?

Hirsutism, a common disorder affecting up to 8% of women, is defined by excess terminal hairs that appear in a male pattern in women due to production of excess androgens.¹ This should be distinguished from hypertrichosis, which is generalized excessive hair growth not caused by androgen excess.

Hirsutism is more often associated with adrenal or ovarian tumors in postmenopausal patients.

Testosterone and DHEAS—produced in the ovaries and adrenal glands, respectively—contribute to the development of hirsutism.¹ Hirsutism is more often associated with adrenal or ovarian tumors in postmenopausal patients.² Generalized hypertrichosis can be associated with porphyria cutanea tarda, severe anorexia nervosa, and rarely, malignancies; it also can be secondary to certain agents, such as cyclosporin, phenytoin, and minoxidil.

While hirsutism is associated with hyperandrogenemia, its degree correlates poorly with serum levels. Notably, about half of women with hirsutism have been found to have normal levels of circulating androgens.¹ Severe signs of hyperandrogenemia include rapid onset of symptoms, signs of virilization, and a palpable abdominal or pelvic mass.³

Continue to: Is the patient pre- or postmenopausal?

Is the patient pre- or postmenopausal? Polycystic ovary syndrome (PCOS) accounts for up to three-fourths of premenopausal hirsutism.³ The likelihood of hirsutism is actually decreased in postmenopausal women because estrogen levels can drop abruptly after menopause. That said, conditions linked to hirsutism in postmenopausal women include adrenal hyperplasia, thyroid dysfunction, Cushing syndrome, and least frequently, androgen-secreting tumors (seen in this patient). (Hirsutism can also be idiopathic or iatrogenic [medications].)

Methods for detection

Research suggests that when a female patient is given a diagnosis of hirsutism, it’s important to explore possible underlying ovarian and/or adrenal tumors and adult-onset adrenal hyperplasia.¹ The following tests and procedure can be helpful:

Serum testosterone and DHEAS. Levels of total testosterone > 200 ng/dL and/or DHEAS > 700 ng/dL are strongly indicative of androgen-secreting tumors.¹

Imaging—including ultrasound, CT, or magnetic resonance imaging—can be used for evaluation of the adrenal glands and ovaries. However, imaging is often unable to identify these small tumors.⁴

Selective venous catheterization can be useful in the localization and lateralization of an androgen-secreting tumor, although a nondiagnostic result with this technique is not uncommon.⁴

Continue to: Dynamic hormonal testing

Dynamic hormonal testing may assist in determining the pathology of disease but not laterality.² For example, testing for gonadotropin-releasing hormone agonists can be helpful because the constant administration of such agonists can lead to ovarian suppression without affecting adrenal androgen secretion.⁵

Testing with oral dexamethasone may induce adrenal hormonal depression of androgens and subsequent estradiol through aromatase conversion, which can help rule out an ovarian source.⁶ Exogenous administration of follicle-stimulating hormone or luteinizing hormone can further differentiate the source from ovarian theca or granulosa cell production.⁴

Treatment varies

The specific etiology of a patient’s hirsutism dictates the most appropriate treatment. For example, medication-induced hirsutism often requires discontinuation of the offending agent, whereas PCOS would necessitate appropriate nonpharmacologic and pharmacologic interventions.

For our patient, the elevated testosterone and free testosterone levels with normal DHEAS strongly suggested the presence of an androgen-secreting ovarian tumor. These findings led to a referral for bilateral salpingo-oophorectomy. The surgical gross appearance of the patient’s ovaries was unremarkable, but gross dissection and pathology of the ovaries (which were not postoperatively identified to determine laterality) showed one was larger (2.7 × 1.5 × 0.8 cm vs 3.2 × 1.4 × 1.2 cm).

The larger ovary contained an area of brown induration measuring 2.3 × 1.1 × 1.1 cm. This area corresponded to abundant eosinophilic cytoplasm with nuclear, rich, round-cell proliferation, consistent with the diagnosis of a benign ovarian Leydig cell tumor (FIGURE 2). Thus, the bilateral salpingo-oophorectomy was both diagnostic and therapeutic.

Six weeks after the surgery, blood work showed normalization of testosterone and free testosterone levels. The patient’s hirsutism completely resolved over the course of the next several months.

A 74-year-old woman presented to the dermatology clinic for follow-up 3 months after the surgical excision of a basal cell carcinoma on her left jawline. During this postop period, the patient developed new-onset hirsutism. She appeared to be in otherwise good health.

Family and personal medical history were unremarkable. Her medication regimen included aspirin 81 mg/d and a daily multivitamin. The patient was postmenopausal and had a body mass index of 28 and a history of acid reflux and osteoarthritis.

Physical examination of the patient’s scalp showed male-pattern alopecia (FIGURE 1A). She also had coarse terminal hairs on her forearms and back, as well as on her chin (FIGURE 1B).

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Dx: Androgen-secreting ovarian tumor

Based on the distribution of terminal hairs and marked change over 3 months, as well as the male-pattern alopecia, a diagnosis of androgen excess was suspected. Laboratory work-up, including thyroid-stimulating hormone, dehydroepiandrosterone sulfate (DHEAS), follicle-stimulating hormone, luteinizing hormone, prolactin, complete blood count, and complete metabolic panel, was within normal limits. Pelvic ultrasound of the ovaries and abdominal computed tomography (CT) of the adrenal glands were also normal.

Further testing showed an elevated testosterone level of 464 ng/dL (reference range: 2-45 ng/dL) and an elevated free testosterone level of 66.8 ng/dL (reference range: 0.2-3.7 ng/dL). These levels pointed to an androgen-secreting ovarian tumor; the androgen excess was likely the cause of her hirsutism.

Hirsutism or hypertrichosis?

Hirsutism, a common disorder affecting up to 8% of women, is defined by excess terminal hairs that appear in a male pattern in women due to production of excess androgens.¹ This should be distinguished from hypertrichosis, which is generalized excessive hair growth not caused by androgen excess.