MD

To the Editor:

Biologic medications are increasingly utilized in adults with moderate to severe atopic dermatitis (AD) that is inadequately controlled with topical medication. By targeting the IL-4 receptor alpha subunit, dupilumab inhibits the biologic effects of IL-4 and IL-13, resulting in remarkable improvement in disease and quality of life for many patients with refractory AD.¹

In 2017, the US Food and Drug Administration approved dupilumab for use in AD, asthma, and chronic rhinosinusitis. However, there is evidence of the drug’s off-label efficacy in conditions such as eosinophilic annular erythema.² We present a patient with dyshidrotic eczema treated with dupilumab who experienced contemporaneous secondary improvement in chronic eosinophilic pneumonia (CEP) and interstitial lung disease (ILD).

A 45-year-old man was referred to our dermatology clinic for chronic hand dermatitis refractory to increasing strengths of topical corticosteroids. He had a history of progressive shortness of breath of unknown cause, which began 2 years prior, and he was being followed at our institution’s ILD clinic. Earlier pulmonary function testing revealed a restrictive pattern with interstitial infiltrates seen on chest computed tomography. A lung biopsy demonstrated features of fibrotic nonspecific interstitial pneumonitis with superimposed eosinophilic pneumonia. His pulmonary symptoms had progressively worsened; over a period of several months, the supplemental oxygen requirement had increased to 6 L at rest and 12 L upon exertion. Prednisone therapy was initiated, which alleviated respiratory symptoms; however, the patient was unable to tolerate a gradual wean of the medication, which rendered him steroid dependent at 30 mg/d.

Along with respiratory symptoms, the patient reported symptoms consistent with an autoimmune process, including dry eyes. Muscle weakness and tenderness also were noted. Ultimately, a diagnosis of anti–PL-7 (anti-threonyl-transfer RNA synthetase) antisynthetase syndrome was rendered by identification of anti–PL-7 antibodies and an elevated level of creatinine kinase.

Physical examination at our clinic revealed subtle palmar scaling on the hands and multiple small clear vesicles on the lateral aspects of the digits (Figure, A), consistent with dyshidrotic eczema. He initially was treated with clobetasol propionate ointment 0.05%. Despite adherence to this high-potency topical corticosteroid, he experienced only minimal improvement over a period of 3 months. Dupilumab was started at standard dosing—600 mg at initiation, followed by 300 mg every 2 weeks. The patient reported rapid improvement in dyshidrotic eczema over several months with near-complete resolution (Figure, B).

CT112005016_e_FigAB.jpg

Concurrent with initiation and continued use of dupilumab, without other changes in his medication regimen, the patient noted gradual improvement in respiratory symptoms. At 6-month follow-up he reported notable improvement in respiratory function and quality of life. He then tolerated a gradual wean of prednisone to 10 mg/d, with a similar reduction in supplemental oxygen.

Off-label use of dupilumab for various eosinophilic conditions has shown promising efficacy. Our patient experienced improvement in CEP shortly after initiation of dupilumab, enabling weaning of prednisone, which has a well established adverse effect profile associated with long term use.^3,4 In comparison, dupilumab generally is well tolerated, with rare ophthalmologic complications and injection-site reactions.⁵

One case report suggested that CEP may represent a potential rare adverse effect of dupilumab initiation.⁶ However, prior to initiation of dupilumab, that patient had poorly controlled asthma requiring frequent oral corticosteroid therapy. It is possible that CEP was subclinical prior to initiation of dupilumab and became more noticeable once the patient was weaned from corticosteroids, which had served as an indirect treatment.⁶ Nonetheless, more research is needed to definitively establish the efficacy of dupilumab in CEP prior to more widespread use.

Irrespective of the potential efficacy of dupilumab for the treatment of CEP, our case highlights the growing body of evidence that dupilumab should be considered in the treatment of dyshidrotic eczema, particularly in cases refractory to topical treatment.⁷ When a systemic medication is preferred, dupilumab likely represents an option with a relatively well-tolerated adverse effect profile compared to traditional systemic treatments for dyshidrotic eczema.

To the Editor:

Biologic medications are increasingly utilized in adults with moderate to severe atopic dermatitis (AD) that is inadequately controlled with topical medication. By targeting the IL-4 receptor alpha subunit, dupilumab inhibits the biologic effects of IL-4 and IL-13, resulting in remarkable improvement in disease and quality of life for many patients with refractory AD.¹

In 2017, the US Food and Drug Administration approved dupilumab for use in AD, asthma, and chronic rhinosinusitis. However, there is evidence of the drug’s off-label efficacy in conditions such as eosinophilic annular erythema.² We present a patient with dyshidrotic eczema treated with dupilumab who experienced contemporaneous secondary improvement in chronic eosinophilic pneumonia (CEP) and interstitial lung disease (ILD).

A 45-year-old man was referred to our dermatology clinic for chronic hand dermatitis refractory to increasing strengths of topical corticosteroids. He had a history of progressive shortness of breath of unknown cause, which began 2 years prior, and he was being followed at our institution’s ILD clinic. Earlier pulmonary function testing revealed a restrictive pattern with interstitial infiltrates seen on chest computed tomography. A lung biopsy demonstrated features of fibrotic nonspecific interstitial pneumonitis with superimposed eosinophilic pneumonia. His pulmonary symptoms had progressively worsened; over a period of several months, the supplemental oxygen requirement had increased to 6 L at rest and 12 L upon exertion. Prednisone therapy was initiated, which alleviated respiratory symptoms; however, the patient was unable to tolerate a gradual wean of the medication, which rendered him steroid dependent at 30 mg/d.

Along with respiratory symptoms, the patient reported symptoms consistent with an autoimmune process, including dry eyes. Muscle weakness and tenderness also were noted. Ultimately, a diagnosis of anti–PL-7 (anti-threonyl-transfer RNA synthetase) antisynthetase syndrome was rendered by identification of anti–PL-7 antibodies and an elevated level of creatinine kinase.

Physical examination at our clinic revealed subtle palmar scaling on the hands and multiple small clear vesicles on the lateral aspects of the digits (Figure, A), consistent with dyshidrotic eczema. He initially was treated with clobetasol propionate ointment 0.05%. Despite adherence to this high-potency topical corticosteroid, he experienced only minimal improvement over a period of 3 months. Dupilumab was started at standard dosing—600 mg at initiation, followed by 300 mg every 2 weeks. The patient reported rapid improvement in dyshidrotic eczema over several months with near-complete resolution (Figure, B).

CT112005016_e_FigAB.jpg

Concurrent with initiation and continued use of dupilumab, without other changes in his medication regimen, the patient noted gradual improvement in respiratory symptoms. At 6-month follow-up he reported notable improvement in respiratory function and quality of life. He then tolerated a gradual wean of prednisone to 10 mg/d, with a similar reduction in supplemental oxygen.

Off-label use of dupilumab for various eosinophilic conditions has shown promising efficacy. Our patient experienced improvement in CEP shortly after initiation of dupilumab, enabling weaning of prednisone, which has a well established adverse effect profile associated with long term use.^3,4 In comparison, dupilumab generally is well tolerated, with rare ophthalmologic complications and injection-site reactions.⁵

One case report suggested that CEP may represent a potential rare adverse effect of dupilumab initiation.⁶ However, prior to initiation of dupilumab, that patient had poorly controlled asthma requiring frequent oral corticosteroid therapy. It is possible that CEP was subclinical prior to initiation of dupilumab and became more noticeable once the patient was weaned from corticosteroids, which had served as an indirect treatment.⁶ Nonetheless, more research is needed to definitively establish the efficacy of dupilumab in CEP prior to more widespread use.

Irrespective of the potential efficacy of dupilumab for the treatment of CEP, our case highlights the growing body of evidence that dupilumab should be considered in the treatment of dyshidrotic eczema, particularly in cases refractory to topical treatment.⁷ When a systemic medication is preferred, dupilumab likely represents an option with a relatively well-tolerated adverse effect profile compared to traditional systemic treatments for dyshidrotic eczema.

To the Editor:

Biologic medications are increasingly utilized in adults with moderate to severe atopic dermatitis (AD) that is inadequately controlled with topical medication. By targeting the IL-4 receptor alpha subunit, dupilumab inhibits the biologic effects of IL-4 and IL-13, resulting in remarkable improvement in disease and quality of life for many patients with refractory AD.¹

In 2017, the US Food and Drug Administration approved dupilumab for use in AD, asthma, and chronic rhinosinusitis. However, there is evidence of the drug’s off-label efficacy in conditions such as eosinophilic annular erythema.² We present a patient with dyshidrotic eczema treated with dupilumab who experienced contemporaneous secondary improvement in chronic eosinophilic pneumonia (CEP) and interstitial lung disease (ILD).

A 45-year-old man was referred to our dermatology clinic for chronic hand dermatitis refractory to increasing strengths of topical corticosteroids. He had a history of progressive shortness of breath of unknown cause, which began 2 years prior, and he was being followed at our institution’s ILD clinic. Earlier pulmonary function testing revealed a restrictive pattern with interstitial infiltrates seen on chest computed tomography. A lung biopsy demonstrated features of fibrotic nonspecific interstitial pneumonitis with superimposed eosinophilic pneumonia. His pulmonary symptoms had progressively worsened; over a period of several months, the supplemental oxygen requirement had increased to 6 L at rest and 12 L upon exertion. Prednisone therapy was initiated, which alleviated respiratory symptoms; however, the patient was unable to tolerate a gradual wean of the medication, which rendered him steroid dependent at 30 mg/d.

Along with respiratory symptoms, the patient reported symptoms consistent with an autoimmune process, including dry eyes. Muscle weakness and tenderness also were noted. Ultimately, a diagnosis of anti–PL-7 (anti-threonyl-transfer RNA synthetase) antisynthetase syndrome was rendered by identification of anti–PL-7 antibodies and an elevated level of creatinine kinase.

Physical examination at our clinic revealed subtle palmar scaling on the hands and multiple small clear vesicles on the lateral aspects of the digits (Figure, A), consistent with dyshidrotic eczema. He initially was treated with clobetasol propionate ointment 0.05%. Despite adherence to this high-potency topical corticosteroid, he experienced only minimal improvement over a period of 3 months. Dupilumab was started at standard dosing—600 mg at initiation, followed by 300 mg every 2 weeks. The patient reported rapid improvement in dyshidrotic eczema over several months with near-complete resolution (Figure, B).

CT112005016_e_FigAB.jpg

Concurrent with initiation and continued use of dupilumab, without other changes in his medication regimen, the patient noted gradual improvement in respiratory symptoms. At 6-month follow-up he reported notable improvement in respiratory function and quality of life. He then tolerated a gradual wean of prednisone to 10 mg/d, with a similar reduction in supplemental oxygen.

Off-label use of dupilumab for various eosinophilic conditions has shown promising efficacy. Our patient experienced improvement in CEP shortly after initiation of dupilumab, enabling weaning of prednisone, which has a well established adverse effect profile associated with long term use.^3,4 In comparison, dupilumab generally is well tolerated, with rare ophthalmologic complications and injection-site reactions.⁵

One case report suggested that CEP may represent a potential rare adverse effect of dupilumab initiation.⁶ However, prior to initiation of dupilumab, that patient had poorly controlled asthma requiring frequent oral corticosteroid therapy. It is possible that CEP was subclinical prior to initiation of dupilumab and became more noticeable once the patient was weaned from corticosteroids, which had served as an indirect treatment.⁶ Nonetheless, more research is needed to definitively establish the efficacy of dupilumab in CEP prior to more widespread use.

Irrespective of the potential efficacy of dupilumab for the treatment of CEP, our case highlights the growing body of evidence that dupilumab should be considered in the treatment of dyshidrotic eczema, particularly in cases refractory to topical treatment.⁷ When a systemic medication is preferred, dupilumab likely represents an option with a relatively well-tolerated adverse effect profile compared to traditional systemic treatments for dyshidrotic eczema.

BACKGROUND

In 2017, the Thoracic Tumor Board realized that there were patients whose lung resections had critical review of the slides and reports prior to presentation. Errors were found which resulted in a change of the pathology Tumor Nodal Metastases (pTNM) staging for the patient. The impacts were important for determining appropriate therapy. It was decided to systematically review all lung cancer resections for accuracy before determining definitive therapy recommendations.

METHODS

All lung resections for malignancy were examined prior and up to 2 days of completion for accuracy of tumor type, tumor size, tumor grade, lymph node metastases and pathologic stage (pTNM). Any errors found were given to the original pathologist for a change in the report before release or for a modified report to be issued.

RESULTS

From June 2017 to December 2020, there were 91 lung resections with 28 (30.77%) errors. Errors included: 16 incorrect pathologic staging, 5 missed tumors in lung and lymph nodes, 2 unexamined stapled surgical margins, 1 wrong site, 1 incorrect lymph node number and 2 missed tumor vascular invasion.

IMPLICATIONS

Quality improvement (QI) review of lung resections by a second pathologist is important and may clearly improve pathologic staging for lung cancer patients. It can be added to QI programs currently used in Surgical Pathology. It is important in directing appropriate postsurgical therapies.

BACKGROUND

In 2017, the Thoracic Tumor Board realized that there were patients whose lung resections had critical review of the slides and reports prior to presentation. Errors were found which resulted in a change of the pathology Tumor Nodal Metastases (pTNM) staging for the patient. The impacts were important for determining appropriate therapy. It was decided to systematically review all lung cancer resections for accuracy before determining definitive therapy recommendations.

METHODS

All lung resections for malignancy were examined prior and up to 2 days of completion for accuracy of tumor type, tumor size, tumor grade, lymph node metastases and pathologic stage (pTNM). Any errors found were given to the original pathologist for a change in the report before release or for a modified report to be issued.

RESULTS

From June 2017 to December 2020, there were 91 lung resections with 28 (30.77%) errors. Errors included: 16 incorrect pathologic staging, 5 missed tumors in lung and lymph nodes, 2 unexamined stapled surgical margins, 1 wrong site, 1 incorrect lymph node number and 2 missed tumor vascular invasion.

IMPLICATIONS

Quality improvement (QI) review of lung resections by a second pathologist is important and may clearly improve pathologic staging for lung cancer patients. It can be added to QI programs currently used in Surgical Pathology. It is important in directing appropriate postsurgical therapies.

BACKGROUND

In 2017, the Thoracic Tumor Board realized that there were patients whose lung resections had critical review of the slides and reports prior to presentation. Errors were found which resulted in a change of the pathology Tumor Nodal Metastases (pTNM) staging for the patient. The impacts were important for determining appropriate therapy. It was decided to systematically review all lung cancer resections for accuracy before determining definitive therapy recommendations.

METHODS

All lung resections for malignancy were examined prior and up to 2 days of completion for accuracy of tumor type, tumor size, tumor grade, lymph node metastases and pathologic stage (pTNM). Any errors found were given to the original pathologist for a change in the report before release or for a modified report to be issued.

RESULTS

From June 2017 to December 2020, there were 91 lung resections with 28 (30.77%) errors. Errors included: 16 incorrect pathologic staging, 5 missed tumors in lung and lymph nodes, 2 unexamined stapled surgical margins, 1 wrong site, 1 incorrect lymph node number and 2 missed tumor vascular invasion.

IMPLICATIONS

Quality improvement (QI) review of lung resections by a second pathologist is important and may clearly improve pathologic staging for lung cancer patients. It can be added to QI programs currently used in Surgical Pathology. It is important in directing appropriate postsurgical therapies.

INTRODUCTION

Leptomeningeal metastasis (LM) is an extremely rare complication of gastroesophageal (GE) cancer. Diagnosis is challenging due to frequently nonspecific clinical presentations, limited sensitivity of diagnostic testing, and potential overlap with neurologic immune-related adverse events (irAE). We describe a case of metastatic gastroesophageal cancer on immunotherapy presenting with LM masquerading as polyneuropathy.

CASE REPORT

A 74-year-old male with HER2+ GE junction cancer with peritoneal metastases diagnosed 6 months ago, on maintenance trastuzumab/pembrolizumab and with no previous history of cranial or spinal disease, presented with worsening ataxia, headache, and diplopia for one month with multiple negative outpatient MRIs. Examination showed left abducens nerve palsy, dysmetria and absent deep tendon reflexes in upper and lower extremities. CT head was unremarkable, and MRI showed non-specific mild enhancement of the right optic nerve, symmetrical lumbosacral nerve roots and cauda equina concerning for paraneoplastic versus immunotherapy-related polyneuropathy. He was started on empiric high-dose corticosteroids. PET-CT was negative for FDG-avid lesions. Cerebrospinal fluid (CSF) analysis revealed moderate pleocytosis with many large atypical cells, elevated protein (118 mg/dL) and LDH (28 IU/L). Immunohistochemistry was positive for CDX2, CA 19-9, CK7, and pankeratin, consistent with metastatic adenocarcinoma, negative for HER2 in contrast to the original tumor. He subsequently developed hydrocephalus requiring a ventriculoperitoneal shunt. He received ten fractions of whole brain irradiation before electing to pursue hospice care.

DISCUSSION

LM is an extremely rare complication of GE cancer with an incidence of <0.2% and carries a poor prognosis. Differentiation between LM and irAE in patients on immunotherapy can be challenging. Diagnosis relies mostly on CSF cytology, and lumbar puncture should not be delayed in patients with new neurologic symptoms. Treatment options are intrathecal chemotherapy, radiation and steroids. A recent phase II trial has shown promise for intrathecal trastuzumab in patients with HER2+ cancers, but options for HER2 negative disease remain mostly palliative.

CONCLUSIONS

Our case highlights the need for suspecting this rare metastatic site, as early diagnosis and genetic characterization allow for exploring more treatment options including targeted therapies which may improve overall survival and quality of life.

INTRODUCTION

Leptomeningeal metastasis (LM) is an extremely rare complication of gastroesophageal (GE) cancer. Diagnosis is challenging due to frequently nonspecific clinical presentations, limited sensitivity of diagnostic testing, and potential overlap with neurologic immune-related adverse events (irAE). We describe a case of metastatic gastroesophageal cancer on immunotherapy presenting with LM masquerading as polyneuropathy.

CASE REPORT

A 74-year-old male with HER2+ GE junction cancer with peritoneal metastases diagnosed 6 months ago, on maintenance trastuzumab/pembrolizumab and with no previous history of cranial or spinal disease, presented with worsening ataxia, headache, and diplopia for one month with multiple negative outpatient MRIs. Examination showed left abducens nerve palsy, dysmetria and absent deep tendon reflexes in upper and lower extremities. CT head was unremarkable, and MRI showed non-specific mild enhancement of the right optic nerve, symmetrical lumbosacral nerve roots and cauda equina concerning for paraneoplastic versus immunotherapy-related polyneuropathy. He was started on empiric high-dose corticosteroids. PET-CT was negative for FDG-avid lesions. Cerebrospinal fluid (CSF) analysis revealed moderate pleocytosis with many large atypical cells, elevated protein (118 mg/dL) and LDH (28 IU/L). Immunohistochemistry was positive for CDX2, CA 19-9, CK7, and pankeratin, consistent with metastatic adenocarcinoma, negative for HER2 in contrast to the original tumor. He subsequently developed hydrocephalus requiring a ventriculoperitoneal shunt. He received ten fractions of whole brain irradiation before electing to pursue hospice care.

DISCUSSION

LM is an extremely rare complication of GE cancer with an incidence of <0.2% and carries a poor prognosis. Differentiation between LM and irAE in patients on immunotherapy can be challenging. Diagnosis relies mostly on CSF cytology, and lumbar puncture should not be delayed in patients with new neurologic symptoms. Treatment options are intrathecal chemotherapy, radiation and steroids. A recent phase II trial has shown promise for intrathecal trastuzumab in patients with HER2+ cancers, but options for HER2 negative disease remain mostly palliative.

CONCLUSIONS

Our case highlights the need for suspecting this rare metastatic site, as early diagnosis and genetic characterization allow for exploring more treatment options including targeted therapies which may improve overall survival and quality of life.

INTRODUCTION

Leptomeningeal metastasis (LM) is an extremely rare complication of gastroesophageal (GE) cancer. Diagnosis is challenging due to frequently nonspecific clinical presentations, limited sensitivity of diagnostic testing, and potential overlap with neurologic immune-related adverse events (irAE). We describe a case of metastatic gastroesophageal cancer on immunotherapy presenting with LM masquerading as polyneuropathy.

CASE REPORT

A 74-year-old male with HER2+ GE junction cancer with peritoneal metastases diagnosed 6 months ago, on maintenance trastuzumab/pembrolizumab and with no previous history of cranial or spinal disease, presented with worsening ataxia, headache, and diplopia for one month with multiple negative outpatient MRIs. Examination showed left abducens nerve palsy, dysmetria and absent deep tendon reflexes in upper and lower extremities. CT head was unremarkable, and MRI showed non-specific mild enhancement of the right optic nerve, symmetrical lumbosacral nerve roots and cauda equina concerning for paraneoplastic versus immunotherapy-related polyneuropathy. He was started on empiric high-dose corticosteroids. PET-CT was negative for FDG-avid lesions. Cerebrospinal fluid (CSF) analysis revealed moderate pleocytosis with many large atypical cells, elevated protein (118 mg/dL) and LDH (28 IU/L). Immunohistochemistry was positive for CDX2, CA 19-9, CK7, and pankeratin, consistent with metastatic adenocarcinoma, negative for HER2 in contrast to the original tumor. He subsequently developed hydrocephalus requiring a ventriculoperitoneal shunt. He received ten fractions of whole brain irradiation before electing to pursue hospice care.

DISCUSSION

LM is an extremely rare complication of GE cancer with an incidence of <0.2% and carries a poor prognosis. Differentiation between LM and irAE in patients on immunotherapy can be challenging. Diagnosis relies mostly on CSF cytology, and lumbar puncture should not be delayed in patients with new neurologic symptoms. Treatment options are intrathecal chemotherapy, radiation and steroids. A recent phase II trial has shown promise for intrathecal trastuzumab in patients with HER2+ cancers, but options for HER2 negative disease remain mostly palliative.

CONCLUSIONS

Our case highlights the need for suspecting this rare metastatic site, as early diagnosis and genetic characterization allow for exploring more treatment options including targeted therapies which may improve overall survival and quality of life.

jaros_brian_headshot_2023_1.jpg

image001_1.jpg

Janus kinase inhibitors (JAKi) are a novel class of oral, targeted small-molecule inhibitors that are increasingly used to treat several different autoimmune conditions. In terms of rheumatologic indications, the FDA first approved tofacitinib (TOF) for use in moderate to severe rheumatoid arthritis (RA) unresponsive to methotrexate therapy. Eleven years later, the indications for JAKi use have expanded to include ulcerative colitis, ankylosing spondylitis, and psoriatic arthritis (PsA), among other diseases. As with any new therapeutic mechanism, there are questions as to how JAKi should be incorporated into the treatment paradigm of PsA. In this article, we briefly review the efficacy and safety data of these agents and discuss our approach to their use in PsA.

Two JAKi are currently FDA approved for the treatment of PsA: tofacitinib (TOF) and upadacitinib (UPA). Other JAKi, such as filgotinib and peficitinib, are only approved outside the United States and will not be discussed here. 

TOF was originally studied in skin psoriasis (PsO) before 2 pivotal studies demonstrated efficacy in PsA. TOF or adalimumab (ADA) were compared with placebo in patients who had failed conventional synthetic disease-modifying antirheumatic drugs (DMARD).¹ ACR20 response was superior with TOF 5 mg twice daily (BID) (50%) and 10 mg BID (61%) vs placebo (33%), and it was comparable to ADA (52%), which was used in this study as an active comparator. The overall rate of adverse events was similar with both doses of TOF when compared with ADA; however, patients taking TOF had numerically more cases of cancer, serious infection, and herpes zoster. 

Another study evaluated TOF compared with placebo in patients with PsA who had an inadequate response to tumor necrosis factor inhibitor (TNFi) therapy.² The study showed an ACR20 response of 50% in patients taking TOF 5 mg BID and 47% in patients taking 10 mg BID, compared with 24% in those taking placebo. Patients who received the 10 mg TOF dose continuously had higher rates of adverse events compared to TOF 5 mg, placebo, and patients who crossed over from placebo to TOF at either dose. In the TOF groups, there were cases of serious infection and herpes zoster, as well as 2 patients with major adverse cardiovascular events (MACE). Following review of these data, the FDA approved only the 5 mg BID dose, and later an 11-mg daily extended-release formulation that was pharmacokinetically similar.

The efficacy for UPA in PsA was shown in 2 pivotal phase 3 trials. SELECT-PsA1 compared UPA at 2 doses, 15 mg and 30 mg daily, vs placebo and vs ADA in patients with biologic DMARD (bDMARD)-naïve PsA.³ This trial demonstrated superiority of UPA in the ACR20 response at both doses (71% and 79%, respectively) compared with placebo (36%). The 15-mg dose of UPA was comparable to ADA (65%), while the 30-mg dose achieved superiority compared to ADA. Secondary outcomes including skin activity, patient-reported symptoms, and inhibition of radiographic progression were also superior in UPA compared with placebo and similar or greater with UPA compared with ADA, depending on the specific outcome.⁴ SELECT-PsA2 compared UPA 15 mg, 30 mg, and placebo in patients with prior incomplete response or intolerance to a bDMARD.⁵ At week 12 of the study, patients taking UPA 15 mg and 30 mg had an ACR20 response of 57% and 64%, respectively, compared with placebo (24%). At week 24, minimal disease activity was achieved by 25% of patients taking UPA 15 mg and 29% of patients taking UPA 30 mg, which was superior to placebo (3%). 

Both studies found a significant increase in infections, including serious infections, at the 30-mg UPA dose compared with the placebo and adalimumab groups. Cytopenia and elevated creatine kinase (CK) level also occurred more frequently in the UPA 30-mg group. Rates of cancer were low overall and comparable between the patients treated with UPA and ADA. Given the higher incidence of adverse events with the 30-mg dose and the relatively similar efficacy, the sponsor elected to submit only the lower dose to the FDA for approval.

In the last few years, concerns for safety with JAKi use grew after the publication of data from the ORAL SURVEILLANCE trial, an FDA-mandated, post-approval safety study of TOF in RA. In this trial, patients with active RA over 50 years of age and with at least 1 additional cardiovascular risk factor were randomized to TOF at 1 of 2 doses, 5 mg or 10 mg BID, or a TNFi.⁶ This trial was designed as a noninferiority study, and TOF did not meet the noninferiority threshold compared to TNFi, with hazard ratios of 1.33 and 1.48 for MACE and malignancy, respectively. The results of this trial prompted the FDA to add a black box warning to the label for all JAKi, pointing out the risk of malignancy and MACE, as well as infection, mortality, and thrombosis. 

In the ORAL SURVEILLANCE trial, the increased risk of MACE and malignancy was primarily seen in the study patients with high risk for a cardiovascular event. To address the question of whether a similar risk profile exists when using JAKi to treat PsA, or whether this is a disease-specific process related to RA, a post hoc analysis of 3 PsA trials and 7 PsO trials of patients treated with TOF was conducted.⁷ The analysis found that patients with a history of atherosclerotic cardiovascular disease (ASCVD) or metabolic syndrome, or patients at high risk for ASCVD (score > 20%) had increased incidence rates of MACE compared with those with low risk scores for ASCVD. Interestingly, as in RA, increased incidence rates of malignancy were seen in patients with preexisting or at high risk for ASCVD.

While the FDA recommends JAKi use in patients who have failed or are inappropriate for treatment with a TNFi, we would consider the use of JAKi for first-line therapy in PsA on an individual basis. One advantage of JAKi is their efficacy across multiple PsA domains, including peripheral arthritis, axial disease, enthesitis, dactylitis, and skin disease (although the approved dose of TOF was not statistically effective for PsO in the pivotal trials). Based on this efficacy, we believe that patients with overlapping, multifaceted disease may benefit the most from these medications. Patient risk factors and comorbidities are a prominent consideration in our use of JAKi to ensure safety, as the risk for MACE and malignancy is informed partly by baseline cardiovascular status. In younger patients without cardiovascular risk factors, JAKi may be a strong candidate for first-line therapy, particularly in patients averse to subcutaneous or intravenous therapy. We do counsel all patients on the increased risk of infection, and we do recommend inactivated herpes zoster vaccination in previously unvaccinated patients planning to start JAKi therapy. 

On the horizon are the development of novel, oral agents targeting tyrosine kinase 2 (TYK2), which is a member of the JAK family of signaling proteins. In fact, the TYK2 inhibitor deucravacitinib was approved by the FDA in 2022 for the treatment of PsO. TYK2 inhibitors appear to have the advantage of a more selective mechanism of action, with fewer off-target effects. There were fewer adverse events in the deucravacitinib trials, which led to its prompt PsO authorization, and the FDA approval for the drug did not include the same black box warning that appears in the label for other JAKi.⁸ A phase 2 study showed early promise for the efficacy and safety of deucravacitinib in PsA.⁹ Further investigation will be needed to better understand the role of deucravacitinib and other TYK2 inhibitors being developed for the treatment of PsA. In the meantime, JAKi continue to be a prominent consideration for first-line PsA therapy in a carefully selected patient population. 

jaros_brian_headshot_2023_1.jpg

image001_1.jpg

Janus kinase inhibitors (JAKi) are a novel class of oral, targeted small-molecule inhibitors that are increasingly used to treat several different autoimmune conditions. In terms of rheumatologic indications, the FDA first approved tofacitinib (TOF) for use in moderate to severe rheumatoid arthritis (RA) unresponsive to methotrexate therapy. Eleven years later, the indications for JAKi use have expanded to include ulcerative colitis, ankylosing spondylitis, and psoriatic arthritis (PsA), among other diseases. As with any new therapeutic mechanism, there are questions as to how JAKi should be incorporated into the treatment paradigm of PsA. In this article, we briefly review the efficacy and safety data of these agents and discuss our approach to their use in PsA.

Two JAKi are currently FDA approved for the treatment of PsA: tofacitinib (TOF) and upadacitinib (UPA). Other JAKi, such as filgotinib and peficitinib, are only approved outside the United States and will not be discussed here. 

TOF was originally studied in skin psoriasis (PsO) before 2 pivotal studies demonstrated efficacy in PsA. TOF or adalimumab (ADA) were compared with placebo in patients who had failed conventional synthetic disease-modifying antirheumatic drugs (DMARD).¹ ACR20 response was superior with TOF 5 mg twice daily (BID) (50%) and 10 mg BID (61%) vs placebo (33%), and it was comparable to ADA (52%), which was used in this study as an active comparator. The overall rate of adverse events was similar with both doses of TOF when compared with ADA; however, patients taking TOF had numerically more cases of cancer, serious infection, and herpes zoster. 

Another study evaluated TOF compared with placebo in patients with PsA who had an inadequate response to tumor necrosis factor inhibitor (TNFi) therapy.² The study showed an ACR20 response of 50% in patients taking TOF 5 mg BID and 47% in patients taking 10 mg BID, compared with 24% in those taking placebo. Patients who received the 10 mg TOF dose continuously had higher rates of adverse events compared to TOF 5 mg, placebo, and patients who crossed over from placebo to TOF at either dose. In the TOF groups, there were cases of serious infection and herpes zoster, as well as 2 patients with major adverse cardiovascular events (MACE). Following review of these data, the FDA approved only the 5 mg BID dose, and later an 11-mg daily extended-release formulation that was pharmacokinetically similar.

The efficacy for UPA in PsA was shown in 2 pivotal phase 3 trials. SELECT-PsA1 compared UPA at 2 doses, 15 mg and 30 mg daily, vs placebo and vs ADA in patients with biologic DMARD (bDMARD)-naïve PsA.³ This trial demonstrated superiority of UPA in the ACR20 response at both doses (71% and 79%, respectively) compared with placebo (36%). The 15-mg dose of UPA was comparable to ADA (65%), while the 30-mg dose achieved superiority compared to ADA. Secondary outcomes including skin activity, patient-reported symptoms, and inhibition of radiographic progression were also superior in UPA compared with placebo and similar or greater with UPA compared with ADA, depending on the specific outcome.⁴ SELECT-PsA2 compared UPA 15 mg, 30 mg, and placebo in patients with prior incomplete response or intolerance to a bDMARD.⁵ At week 12 of the study, patients taking UPA 15 mg and 30 mg had an ACR20 response of 57% and 64%, respectively, compared with placebo (24%). At week 24, minimal disease activity was achieved by 25% of patients taking UPA 15 mg and 29% of patients taking UPA 30 mg, which was superior to placebo (3%). 

Both studies found a significant increase in infections, including serious infections, at the 30-mg UPA dose compared with the placebo and adalimumab groups. Cytopenia and elevated creatine kinase (CK) level also occurred more frequently in the UPA 30-mg group. Rates of cancer were low overall and comparable between the patients treated with UPA and ADA. Given the higher incidence of adverse events with the 30-mg dose and the relatively similar efficacy, the sponsor elected to submit only the lower dose to the FDA for approval.

In the last few years, concerns for safety with JAKi use grew after the publication of data from the ORAL SURVEILLANCE trial, an FDA-mandated, post-approval safety study of TOF in RA. In this trial, patients with active RA over 50 years of age and with at least 1 additional cardiovascular risk factor were randomized to TOF at 1 of 2 doses, 5 mg or 10 mg BID, or a TNFi.⁶ This trial was designed as a noninferiority study, and TOF did not meet the noninferiority threshold compared to TNFi, with hazard ratios of 1.33 and 1.48 for MACE and malignancy, respectively. The results of this trial prompted the FDA to add a black box warning to the label for all JAKi, pointing out the risk of malignancy and MACE, as well as infection, mortality, and thrombosis. 

In the ORAL SURVEILLANCE trial, the increased risk of MACE and malignancy was primarily seen in the study patients with high risk for a cardiovascular event. To address the question of whether a similar risk profile exists when using JAKi to treat PsA, or whether this is a disease-specific process related to RA, a post hoc analysis of 3 PsA trials and 7 PsO trials of patients treated with TOF was conducted.⁷ The analysis found that patients with a history of atherosclerotic cardiovascular disease (ASCVD) or metabolic syndrome, or patients at high risk for ASCVD (score > 20%) had increased incidence rates of MACE compared with those with low risk scores for ASCVD. Interestingly, as in RA, increased incidence rates of malignancy were seen in patients with preexisting or at high risk for ASCVD.

While the FDA recommends JAKi use in patients who have failed or are inappropriate for treatment with a TNFi, we would consider the use of JAKi for first-line therapy in PsA on an individual basis. One advantage of JAKi is their efficacy across multiple PsA domains, including peripheral arthritis, axial disease, enthesitis, dactylitis, and skin disease (although the approved dose of TOF was not statistically effective for PsO in the pivotal trials). Based on this efficacy, we believe that patients with overlapping, multifaceted disease may benefit the most from these medications. Patient risk factors and comorbidities are a prominent consideration in our use of JAKi to ensure safety, as the risk for MACE and malignancy is informed partly by baseline cardiovascular status. In younger patients without cardiovascular risk factors, JAKi may be a strong candidate for first-line therapy, particularly in patients averse to subcutaneous or intravenous therapy. We do counsel all patients on the increased risk of infection, and we do recommend inactivated herpes zoster vaccination in previously unvaccinated patients planning to start JAKi therapy. 

On the horizon are the development of novel, oral agents targeting tyrosine kinase 2 (TYK2), which is a member of the JAK family of signaling proteins. In fact, the TYK2 inhibitor deucravacitinib was approved by the FDA in 2022 for the treatment of PsO. TYK2 inhibitors appear to have the advantage of a more selective mechanism of action, with fewer off-target effects. There were fewer adverse events in the deucravacitinib trials, which led to its prompt PsO authorization, and the FDA approval for the drug did not include the same black box warning that appears in the label for other JAKi.⁸ A phase 2 study showed early promise for the efficacy and safety of deucravacitinib in PsA.⁹ Further investigation will be needed to better understand the role of deucravacitinib and other TYK2 inhibitors being developed for the treatment of PsA. In the meantime, JAKi continue to be a prominent consideration for first-line PsA therapy in a carefully selected patient population. 

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Janus kinase inhibitors (JAKi) are a novel class of oral, targeted small-molecule inhibitors that are increasingly used to treat several different autoimmune conditions. In terms of rheumatologic indications, the FDA first approved tofacitinib (TOF) for use in moderate to severe rheumatoid arthritis (RA) unresponsive to methotrexate therapy. Eleven years later, the indications for JAKi use have expanded to include ulcerative colitis, ankylosing spondylitis, and psoriatic arthritis (PsA), among other diseases. As with any new therapeutic mechanism, there are questions as to how JAKi should be incorporated into the treatment paradigm of PsA. In this article, we briefly review the efficacy and safety data of these agents and discuss our approach to their use in PsA.

Two JAKi are currently FDA approved for the treatment of PsA: tofacitinib (TOF) and upadacitinib (UPA). Other JAKi, such as filgotinib and peficitinib, are only approved outside the United States and will not be discussed here. 

TOF was originally studied in skin psoriasis (PsO) before 2 pivotal studies demonstrated efficacy in PsA. TOF or adalimumab (ADA) were compared with placebo in patients who had failed conventional synthetic disease-modifying antirheumatic drugs (DMARD).¹ ACR20 response was superior with TOF 5 mg twice daily (BID) (50%) and 10 mg BID (61%) vs placebo (33%), and it was comparable to ADA (52%), which was used in this study as an active comparator. The overall rate of adverse events was similar with both doses of TOF when compared with ADA; however, patients taking TOF had numerically more cases of cancer, serious infection, and herpes zoster. 

Another study evaluated TOF compared with placebo in patients with PsA who had an inadequate response to tumor necrosis factor inhibitor (TNFi) therapy.² The study showed an ACR20 response of 50% in patients taking TOF 5 mg BID and 47% in patients taking 10 mg BID, compared with 24% in those taking placebo. Patients who received the 10 mg TOF dose continuously had higher rates of adverse events compared to TOF 5 mg, placebo, and patients who crossed over from placebo to TOF at either dose. In the TOF groups, there were cases of serious infection and herpes zoster, as well as 2 patients with major adverse cardiovascular events (MACE). Following review of these data, the FDA approved only the 5 mg BID dose, and later an 11-mg daily extended-release formulation that was pharmacokinetically similar.

The efficacy for UPA in PsA was shown in 2 pivotal phase 3 trials. SELECT-PsA1 compared UPA at 2 doses, 15 mg and 30 mg daily, vs placebo and vs ADA in patients with biologic DMARD (bDMARD)-naïve PsA.³ This trial demonstrated superiority of UPA in the ACR20 response at both doses (71% and 79%, respectively) compared with placebo (36%). The 15-mg dose of UPA was comparable to ADA (65%), while the 30-mg dose achieved superiority compared to ADA. Secondary outcomes including skin activity, patient-reported symptoms, and inhibition of radiographic progression were also superior in UPA compared with placebo and similar or greater with UPA compared with ADA, depending on the specific outcome.⁴ SELECT-PsA2 compared UPA 15 mg, 30 mg, and placebo in patients with prior incomplete response or intolerance to a bDMARD.⁵ At week 12 of the study, patients taking UPA 15 mg and 30 mg had an ACR20 response of 57% and 64%, respectively, compared with placebo (24%). At week 24, minimal disease activity was achieved by 25% of patients taking UPA 15 mg and 29% of patients taking UPA 30 mg, which was superior to placebo (3%). 

Both studies found a significant increase in infections, including serious infections, at the 30-mg UPA dose compared with the placebo and adalimumab groups. Cytopenia and elevated creatine kinase (CK) level also occurred more frequently in the UPA 30-mg group. Rates of cancer were low overall and comparable between the patients treated with UPA and ADA. Given the higher incidence of adverse events with the 30-mg dose and the relatively similar efficacy, the sponsor elected to submit only the lower dose to the FDA for approval.

In the last few years, concerns for safety with JAKi use grew after the publication of data from the ORAL SURVEILLANCE trial, an FDA-mandated, post-approval safety study of TOF in RA. In this trial, patients with active RA over 50 years of age and with at least 1 additional cardiovascular risk factor were randomized to TOF at 1 of 2 doses, 5 mg or 10 mg BID, or a TNFi.⁶ This trial was designed as a noninferiority study, and TOF did not meet the noninferiority threshold compared to TNFi, with hazard ratios of 1.33 and 1.48 for MACE and malignancy, respectively. The results of this trial prompted the FDA to add a black box warning to the label for all JAKi, pointing out the risk of malignancy and MACE, as well as infection, mortality, and thrombosis. 

In the ORAL SURVEILLANCE trial, the increased risk of MACE and malignancy was primarily seen in the study patients with high risk for a cardiovascular event. To address the question of whether a similar risk profile exists when using JAKi to treat PsA, or whether this is a disease-specific process related to RA, a post hoc analysis of 3 PsA trials and 7 PsO trials of patients treated with TOF was conducted.⁷ The analysis found that patients with a history of atherosclerotic cardiovascular disease (ASCVD) or metabolic syndrome, or patients at high risk for ASCVD (score > 20%) had increased incidence rates of MACE compared with those with low risk scores for ASCVD. Interestingly, as in RA, increased incidence rates of malignancy were seen in patients with preexisting or at high risk for ASCVD.

While the FDA recommends JAKi use in patients who have failed or are inappropriate for treatment with a TNFi, we would consider the use of JAKi for first-line therapy in PsA on an individual basis. One advantage of JAKi is their efficacy across multiple PsA domains, including peripheral arthritis, axial disease, enthesitis, dactylitis, and skin disease (although the approved dose of TOF was not statistically effective for PsO in the pivotal trials). Based on this efficacy, we believe that patients with overlapping, multifaceted disease may benefit the most from these medications. Patient risk factors and comorbidities are a prominent consideration in our use of JAKi to ensure safety, as the risk for MACE and malignancy is informed partly by baseline cardiovascular status. In younger patients without cardiovascular risk factors, JAKi may be a strong candidate for first-line therapy, particularly in patients averse to subcutaneous or intravenous therapy. We do counsel all patients on the increased risk of infection, and we do recommend inactivated herpes zoster vaccination in previously unvaccinated patients planning to start JAKi therapy. 

On the horizon are the development of novel, oral agents targeting tyrosine kinase 2 (TYK2), which is a member of the JAK family of signaling proteins. In fact, the TYK2 inhibitor deucravacitinib was approved by the FDA in 2022 for the treatment of PsO. TYK2 inhibitors appear to have the advantage of a more selective mechanism of action, with fewer off-target effects. There were fewer adverse events in the deucravacitinib trials, which led to its prompt PsO authorization, and the FDA approval for the drug did not include the same black box warning that appears in the label for other JAKi.⁸ A phase 2 study showed early promise for the efficacy and safety of deucravacitinib in PsA.⁹ Further investigation will be needed to better understand the role of deucravacitinib and other TYK2 inhibitors being developed for the treatment of PsA. In the meantime, JAKi continue to be a prominent consideration for first-line PsA therapy in a carefully selected patient population. 

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1. The treatment of multiple myeloma has evolved significantly in recent years. What are some of the most important things you consider in the treatment of your newly diagnosed, transplant-ineligible patients?

We’ve seen great progress in the treatment of multiple myeloma over the last decade, and outcomes continue to improve for many patients.¹ Still, it is important to keep in mind that more than 34,000 patients will be diagnosed and more than 12,000 people will die from the disease this year.² We may have the greatest opportunity to impact the course of disease in the treatment of newly diagnosed patients due to the nature of this cancer:

• Multiple myeloma is characterized by relapse, and we know the length of remission generally decreases with each relapse and subsequent line of therapy.³
• Patients often become refractory to treatment over time.

When I meet with a patient who has been diagnosed with multiple myeloma, the first thing I consider is their eligibility for autologous stem cell transplant (ASCT). In my opinion, the introduction of ASCT is one of the biggest advancements in the last few decades, and we’ve found that ASCT followed by maintenance therapy with targeted tools improves progression-free survival (PFS).⁴

Unfortunately, many newly diagnosed patients are not eligible for ASCT–either because of comorbidities or other complexities related to the presentation of their disease.  

For patients who are transplant-ineligible (TIE), it is important to have treatment options that are proven effective in extending PFS and overall survival (OS), and capable of producing deep and durable responses.

2. What are the challenges associated with treating newly diagnosed patients who are not eligible for ASCT?

We still consider multiple myeloma to be an incurable disease but, in my opinion, the treatment of TIE patients is less challenging today than a decade ago due to the emergence of novel therapies. That said, TIE patients are typically older and present with more advanced disease and comorbidities, including diabetes or cardiovascular events.⁵ 

A retrospective analysis published in 2020 by Rafael Fonseca examined frontline treatment patterns and attrition rates by line of therapy among newly diagnosed multiple myeloma (NDMM) patients who are TIE. More than 22,000 patients were identified from three patient-level databases between 2000 and 2018 - the OPTUM Commercial Claims database, the OPTUM Electronic Medical Records database, and the Surveillance, Epidemiology, and End Results-Meidcare Linked database. Patients included had to have a multiple myeloma diagnosis on or after January 1, 2007. Results showed that attrition rates among newly diagnosed, TIE patients with multiple myeloma increase with each line of therapy, with the proportion of patients who receive a second line of therapy decreasing by 50 percent with each subsequent line.³ 

3. Can you provide more detail on the goals of therapy for newly diagnosed, transplant-ineligible patients?

When I discuss treatment goals with TIE patients, I feel it is important to emphasize managing side effects and achieving deep and durable responses. I have the benefit of being in an academic setting, where I regularly exchange information with my colleagues about what we’re learning from the clinical studies in which we participate. Choosing which treatment to administer is complex and involves other considerations. For example, if two regimens have comparable efficacy, I may recommend the regimen with a more established safety profile or more robust evidence so I can properly anticipate and manage toxicities in my patients. Overall survival is one of the most important endpoints I consider, in addition to depth of response and PFS. In recent years, we’ve seen increasing evidence pointing to the importance of  using a proven effective treatment in frontline patients that are ineligible for transplant. 

4. A key study in newly-diagnosed, transplant-ineligible multiple myeloma is the Phase 3 MAIA study. Can you share the key takeaways from this study and discuss how the results have shaped treatment for this patient population?

Of course. The MAIA study is a randomized Phase 3 study evaluating DARZALEX^® (daratumumab) intravenous injection in combination with lenalidomide and dexamethasone (D-Rd) compared with Rd in 737 adult patients with newly diagnosed, transplant-ineligible multiple myeloma. The median age of patients participating in the MAIA study was 73 (range 45-90), an important consideration since the median age for multiple myeloma diagnosis is approximately 66-70 years of age.⁶ The study evaluated PFS as the primary endpoint, and overall survival as a key secondary endpoint, and supported the FDA approval of DARZALEX^® in combination with lenalidomide and dexamethasone for adult patients with newly diagnosed, multiple myeloma who are ineligible for ASCT.

MAIA study design⁷

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The baseline demographic and disease characteristics were similar between the 2 treatment groups. Forty-four percent of the patients were  ≥75 years of age. Fifty-two percent (52%) of patients were male, 92% White, 4% Black or African American, and 1% Asian. Three percent (3%) of patients reported an ethnicity of Hispanic or Latino. Thirty-four (34%) had an Eastern Cooperative Oncology Group (ECOG) performance score of 0, 50% had an ECOG performance score of 1, and 17% had an ECOG performance score of ≥2. Twenty-seven percent had International Staging System (ISS) Stage I, 43% had ISS Stage II, and 29% had ISS Stage III disease. 

Select Important Safety Information: 

CONTRAINDICATIONS

DARZALEX^® is contraindicated in patients with a history of severe hypersensitivity (eg, anaphylactic reactions) to daratumumab or any of the components of the formulation.

WARNINGS AND PRECAUTIONS
Infusion-Related Reactions: DARZALEX^® can cause severe and/or serious infusion-related reactions including anaphylactic reactions.
These reactions can be life-threatening, and fatal outcomes have been reported. Please scroll down to read Important Safety Information for DARZALEX^®. 

Primary findings from the study, which were published in 2019, showed an improvement in PFS in patients receiving D-Rd compared with those receiving Rd alone.⁷ The median PFS was not reached in the D-Rd arm and was reached at 31.9 months in the Rd arm (HR 0.56; 95% CI 0.43-0.73; P<0.0001).⁷ At a median of 30 months of follow-up, the data showed the clinical benefit of D-Rd therapy, with a 44% reduction in the risk of disease progression or death in patients receiving D-Rd compared with Rd alone.⁷ 

Progression-free survival in TIE NDMM after ~30 months of treatment with D-Rd^7,8

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Additionally, 70.6% of patients (95% CI, 65.0-75.4) had no progressive disease with D-Rd treatment at median 30 months of follow-up, compared with 55.6% (95% CI, 49.5-61.3) of patients in the Rd group.⁷

In terms of depth of response, the percentage of patients with a complete response or better was 47.6% in patients receiving D-Rd compared with 24.9% in the Rd group.⁷

Overall response rate with D-Rd in TIE NDMM at ~30 months of follow-up⁸

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An overview of the most frequent adverse events at 30-months of follow-up are provided below. The most frequent adverse reactions were reported in ≥20% of patients, with at least a 5% greater frequency in the D-Rd arm compared with Rd alone.⁸ 

Most frequent adverse events at ~30 months of follow-up with D-Rd in TIE NDMM⁸

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Most frequent hematologic laboratory abnormalities with D-Rd in TIE NDMM at ~30 months⁸

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Serious adverse reactions with a 2% greater incidence in the D-Rd arm compared with the Rd arm were pneumonia (D-Rd 15% vs Rd 8%), bronchitis (D-Rd 4% vs Rd 2%), and dehydration (D-Rd 2% vs Rd <1).
• Discontinuation rates due to any adverse event: 7% with D-Rd vs 16% with Rd
• Infusion-related reactions (IRRs) with D-Rd occurred in 41% of patients; 2% were Grade 3 and <1% were Grade 4
• IRRs of any grade or severity may require management by interruption, modification, and/or discontinuation of the infusion
• Most IRRs occurred during first infusion

5. Thanks for that overview. In addition to these results, The Lancet Oncology has published updated overall survival data from a 5-year follow-up on the MAIA study. Can you provide an overview of these data and insights on their potential for patients?  

The MAIA trial was an important study, and for me, the results were practice changing. We see that after a median of nearly 5 years of follow-up, D-Rd significantly improved OS in TIE NDMM patients who were treated to progression compared with Rd alone (66.3% vs. 53.1% [HR=0.68; 95% CI, 0.53-0.86; P=0.0013]).⁹ This equates to approximately a 32% reduction in death when DARZALEX^® was added to a two-drug regimen, which is a meaningful consideration when selecting the most appropriate regimens for my newly diagnosed, transplant-ineligible patients.⁹

Overall survival data at ~5 years with D-Rd compared to Rd alone in TIE NDMM⁹

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Importantly, efficacy that resulted from longer treatment with D-Rd is also supported by approximately 5 years of safety evaluation. Below is information from a follow-up analysis of the MAIA study. This information is not included in the current Prescribing Information and has not been evaluated by the FDA. Treatment-emergent adverse events are reported as observed. These analyses have not been adjusted for multiple comparisons and no conclusions should be drawn. In what I’ve observed through published data and in my practice, longer treatment has not revealed new safety signals.

Most frequent treatment-emergent adverse events (any grade reported in ≥30% of patients and/or Grade 3/4 reported in ≥10% of patients) at ~5 years⁹

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Select Important Safety Information: 

DARZALEX^® can cause severe and/or serious infusion-related reactions including anaphylactic reactions. These reactions can be life threatening, and fatal outcomes have been reported. In clinical trials (monotherapy and combination: N=2066), infusion-related reactions occurred in 37% of patients with the Week 1 (16 mg/kg) infusion, 2% with the Week 2 infusion, and cumulatively 6% with subsequent infusions. Less than 1% of patients had a Grade 3/4 infusion-related reaction at Week 2 or subsequent infusions. The median time to onset was 1.5 hours (range: 0 to 73 hours). Nearly all reactions occurred during infusion or within 4 hours of completing DARZALEX^®. Severe reactions have occurred, including bronchospasm, hypoxia, dyspnea, hypertension, tachycardia, headache, laryngeal edema, pulmonary edema, and ocular adverse reactions, including choroidal effusion, acute myopia, and acute angle closure glaucoma. Signs and symptoms may include respiratory symptoms, such as nasal congestion, cough, throat irritation, as well as chills, vomiting, and nausea. Less common signs and symptoms were wheezing, allergic rhinitis, pyrexia, chest discomfort, pruritus, hypotension and blurred vision. Please scroll down to see Important Safety Information for DARZALEX^®.

6. Does the availability of OS data influence your decisions on treatment selection in TIE NDMM?

Overall survival absolutely remains the gold standard and informs my practice. Prior to OS data being available, I will often look at other efficacy endpoints that are available sooner. In MAIA, I was encouraged by efficacy endpoints in earlier data, which were later confirmed by the latest data on OS.

7. The MAIA study shows that treating to disease progression or unacceptable toxicity is important. How does that impact your approach to treatment?

It's important to keep in mind that the MAIA trial was designed to evaluate treatment until progression or unacceptable toxicity. The results revealed a significant difference between the DR-d and Rd treatment arms, but results observed in this study are contingent on this treatment approach. From a clinical perspective, unless there is considerable toxicity, I advocate for treating with D-Rd to progression.

In the clinic, we also see that TIE patients who have higher frailty scores are more likely to discontinue treatment prior to progression.¹⁰ There can be other reasons too – such as a patient simply wanting to have a break from treatment. These conversations are not always easy, but it is important to have an honest dialogue with patients.

8. What can we learn from studies like the MAIA trial that included a wide range of patient populations including patients who are elderly, frail, or had high cytogenetic risk? 

Several patient subgroups were analyzed as part of the MAIA study. It is important to note that these subgroup analyses are not included in the Prescribing Information for DARZALEX^®. These analyses were not adjusted for multiple comparisons, and there are insufficient numbers of patients per subgroup to make definitive conclusions of efficacy among the subgroups.

As mentioned above, the MAIA study evaluated a wide range of patients (n=737). The baseline demographic and disease characteristics were similar between the D-Rd and Rd treatment groups and the median age was 73 (range: 45-90) years, with 44% of the patients ≥75 years of age.

In the various patient subgroups that were analyzed as part of the MAIA study, it was found that at ~3-years of follow-up the PFS numerically favored DRd compared with Rd alone in most subgroups (see table below).

Median progression-free survival by sub-population at ~3 year follow-up⁸

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The MAIA trial also included patients who were frail and a post hoc analysis was conducted in this subgroup of patients. These analyses are not included in the Prescribing Information for DARZALEX^®. These analyses were conducted post hoc and there are insufficient numbers of patients per subgroup to make definitive conclusions of efficacy among the subgroups.

A frailty assessment was performed retrospectively using age, the Charlson Comorbidity Index (CCI) – which is calculated based on a retrospective review of the patient’s medical history to predict the 10-year mortality – and the baseline Eastern Cooperative Oncology Group (ECOG) performance status score, used to measure a patient’s level of functioning in terms of their ability to care for themselves, daily activity, and physical activity. The frailty scores were then added up to classify patients into fit (0), intermediate (1), or frail (≥2). Frailty status was further simplified into 2 categories: non-frail (0-1) and frail (≥2). The median age in the frail subgroup was 77 years (range: 57-80 years), with 88% of patients having ECOG performance score ≥1. CCI was calculated based on retrospective review of each patient’s medical history.¹²

The charts below illustrate the frailty scoring system with an overview of the patient population included in the 3-year post hoc analysis, PFS rate, and adverse events.

MAIA post hoc subgroup analysis by frailty status score¹²

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The retrospective assessment of frailty score was a limitation of this study. Retrospective CCI calculations were based on reported medical history, which may contain missing data and result in underestimating or overestimating the number of patients in each frailty subgroup. The ECOG PS score parameter used for frailty score calculations in the study is more subjective, with susceptibility to intra- and inter-observer bias, compared with the ADL (activities of daily living) and IADL (instrumental activities of daily living) scales used in the IMWG scoring system. While the frailty scale used in the study is based on parameters that are routinely assessed in clinical practice for clinical use, the use of comprehensive frailty assessments that more accurately reflect biological or functional frailty will remain important for the further optimization of treatment strategies for frail patients. Patients with an ECOG PS score ≥3 and patients with comorbidities that may interfere with the study procedures were excluded from MAIA; the inclusion and exclusion criteria for the study limits the generalizability of these results to more frail patients seen in clinical practice.

Progression-free survival in a ~3-year subgroup analysis of frail patients following treatment with D-Rd in TIE NDMM¹²

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Most frequent Grade 3/4 treatment-emergent adverse events (≥10%) in frail patients at ~3 year follow-up of MAIA trial¹²

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Please see additional Important Safety Information for DARZALEX^® below.

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS

DARZALEX^® is contraindicated in patients with a history of severe hypersensitivity (eg, anaphylactic reactions) to daratumumab or any of the components of the formulation.

WARNINGS AND PRECAUTIONS

Infusion-Related Reactions

DARZALEX^® can cause severe and/or serious infusion-related reactions including anaphylactic reactions. These reactions can be life‑threatening, and fatal outcomes have been reported. In clinical trials (monotherapy and combination: N=2066), infusion-related reactions occurred in 37% of patients with the Week 1 (16 mg/kg) infusion, 2% with the Week 2 infusion, and cumulatively 6% with subsequent infusions. Less than 1% of patients had a Grade 3/4 infusion-related reaction at Week 2 or subsequent infusions. The median time to onset was 1.5 hours (range: 0 to 73 hours). Nearly all reactions occurred during infusion or within 4 hours of completing DARZALEX^®. Severe reactions have occurred, including bronchospasm, hypoxia, dyspnea, hypertension, tachycardia, headache, laryngeal edema, pulmonary edema, and ocular adverse reactions, including choroidal effusion, acute myopia, and acute angle closure glaucoma. Signs and symptoms may include respiratory symptoms, such as nasal congestion, cough, throat irritation, as well as chills, vomiting, and nausea. Less common signs and symptoms were wheezing, allergic rhinitis, pyrexia, chest discomfort, pruritus, hypotension and blurred vision.

When DARZALEX^® dosing was interrupted in the setting of ASCT (CASSIOPEIA) for a median of 3.75 months (range: 2.4 to 6.9 months), upon re-initiation of DARZALEX^®, the incidence of infusion-related reactions was 11% for the first infusion following ASCT. Infusion-related reactions occurring at re-initiation of DARZALEX^® following ASCT were consistent in terms of symptoms and severity (Grade 3 or 4: <1%) with those reported in previous studies at Week 2 or subsequent infusions. In EQUULEUS, patients receiving combination treatment (n=97) were administered the first 16 mg/kg dose at Week 1 split over two days, ie, 8 mg/kg on Day 1 and Day 2, respectively. The incidence of any grade infusion-related reactions was 42%, with 36% of patients experiencing infusion-related reactions on Day 1 of Week 1, 4% on Day 2 of Week 1, and 8% with subsequent infusions.

Pre-medicate patients with antihistamines, antipyretics, and corticosteroids. Frequently monitor patients during the entire infusion. Interrupt DARZALEX^® infusion for reactions of any severity and institute medical management as needed. Permanently discontinue DARZALEX^® therapy if an anaphylactic reaction or life-threatening (Grade 4) reaction occurs and institute appropriate emergency care. For patients with Grade 1, 2, or 3 reactions, reduce the infusion rate when re-starting the infusion.

To reduce the risk of delayed infusion-related reactions, administer oral corticosteroids to all patients following DARZALEX^® infusions. Patients with a history of chronic obstructive pulmonary disease may require additional post-infusion medications to manage respiratory complications. Consider prescribing short- and long-acting bronchodilators and inhaled corticosteroids for patients with chronic obstructive pulmonary disease.

Ocular adverse reactions, including acute myopia and narrowing of the anterior chamber angle due to ciliochoroidal effusions with potential for increased intraocular pressure or glaucoma, have occurred with DARZALEX infusion. If ocular symptoms occur, interrupt DARZALEX infusion and seek immediate ophthalmologic evaluation prior to restarting DARZALEX.

Interference With Serological Testing

Daratumumab binds to CD38 on red blood cells (RBCs) and results in a positive indirect antiglobulin test (indirect Coombs test). Daratumumab-mediated positive indirect antiglobulin test may persist for up to 6 months after the last daratumumab infusion. Daratumumab bound to RBCs masks detection of antibodies to minor antigens in the patient’s serum. The determination of a patient’s ABO and Rh blood type is not impacted. Notify blood transfusion centers of this interference with serological testing and inform blood banks that a patient has received DARZALEX^®. Type and screen patients prior to starting DARZALEX^®.

Neutropenia and Thrombocytopenia

DARZALEX^® may increase neutropenia and thrombocytopenia induced by background therapy. Monitor complete blood cell counts periodically during treatment according to manufacturer’s prescribing information for background therapies. Monitor patients with neutropenia for signs of infection. Consider withholding DARZALEX^® until recovery of neutrophils or for recovery of platelets.

Interference With Determination of Complete Response

Daratumumab is a human immunoglobulin G (IgG) kappa monoclonal antibody that can be detected on both the serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for the clinical monitoring of endogenous M-protein. This interference can impact the determination of complete response and of disease progression in some patients with IgG kappa myeloma protein.

Embryo-Fetal Toxicity

Based on the mechanism of action, DARZALEX^® can cause fetal harm when administered to a pregnant woman. DARZALEX^® may cause depletion of fetal immune cells and decreased bone density. Advise pregnant women of the potential risk to a fetus. Advise females with reproductive potential to use effective contraception during treatment with DARZALEX^® and for 3 months after the last dose.

The combination of DARZALEX^® with lenalidomide, pomalidomide, or thalidomide is contraindicated in pregnant women because lenalidomide, pomalidomide, and thalidomide may cause birth defects and death of the unborn child. Refer to the lenalidomide, pomalidomide, or thalidomide prescribing information on use during pregnancy.

ADVERSE REACTIONS

The most frequently reported adverse reactions (incidence ≥20%) were: upper respiratory infection, neutropenia, infusion‑related reactions, thrombocytopenia, diarrhea, constipation, anemia, peripheral sensory neuropathy, fatigue, peripheral edema, nausea, cough, pyrexia, dyspnea, and asthenia. The most common hematologic laboratory abnormalities (≥40%) with DARZALEX^® are: neutropenia, lymphopenia, thrombocytopenia, leukopenia, and anemia.

INDICATIONS

DARZALEX^® (daratumumab) is indicated for the treatment of adult patients with multiple myeloma:

• In combination with lenalidomide and dexamethasone in newly diagnosed patients who are ineligible for autologous stem cell transplant and in patients with relapsed or refractory multiple myeloma who have received at least one prior therapy
• In combination with bortezomib, melphalan, and prednisone in newly diagnosed patients who are ineligible for autologous stem cell transplant
• In combination with bortezomib, thalidomide, and dexamethasone in newly diagnosed patients who are eligible for autologous stem cell transplant
• In combination with bortezomib and dexamethasone in patients who have received at least one prior therapy
• In combination with carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma who have received one to three prior lines of therapy
• In combination with pomalidomide and dexamethasone in patients who have received at least two prior therapies including lenalidomide and a proteasome inhibitor
• As monotherapy in patients who have received at least three prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent or who are double-refractory to a PI and an immunomodulatory agent

Please click here to see the full Prescribing Information.

dr._atrash_headshot.jpg

1. The treatment of multiple myeloma has evolved significantly in recent years. What are some of the most important things you consider in the treatment of your newly diagnosed, transplant-ineligible patients?

We’ve seen great progress in the treatment of multiple myeloma over the last decade, and outcomes continue to improve for many patients.¹ Still, it is important to keep in mind that more than 34,000 patients will be diagnosed and more than 12,000 people will die from the disease this year.² We may have the greatest opportunity to impact the course of disease in the treatment of newly diagnosed patients due to the nature of this cancer:

• Multiple myeloma is characterized by relapse, and we know the length of remission generally decreases with each relapse and subsequent line of therapy.³
• Patients often become refractory to treatment over time.

When I meet with a patient who has been diagnosed with multiple myeloma, the first thing I consider is their eligibility for autologous stem cell transplant (ASCT). In my opinion, the introduction of ASCT is one of the biggest advancements in the last few decades, and we’ve found that ASCT followed by maintenance therapy with targeted tools improves progression-free survival (PFS).⁴

Unfortunately, many newly diagnosed patients are not eligible for ASCT–either because of comorbidities or other complexities related to the presentation of their disease.  

For patients who are transplant-ineligible (TIE), it is important to have treatment options that are proven effective in extending PFS and overall survival (OS), and capable of producing deep and durable responses.

2. What are the challenges associated with treating newly diagnosed patients who are not eligible for ASCT?

We still consider multiple myeloma to be an incurable disease but, in my opinion, the treatment of TIE patients is less challenging today than a decade ago due to the emergence of novel therapies. That said, TIE patients are typically older and present with more advanced disease and comorbidities, including diabetes or cardiovascular events.⁵ 

A retrospective analysis published in 2020 by Rafael Fonseca examined frontline treatment patterns and attrition rates by line of therapy among newly diagnosed multiple myeloma (NDMM) patients who are TIE. More than 22,000 patients were identified from three patient-level databases between 2000 and 2018 - the OPTUM Commercial Claims database, the OPTUM Electronic Medical Records database, and the Surveillance, Epidemiology, and End Results-Meidcare Linked database. Patients included had to have a multiple myeloma diagnosis on or after January 1, 2007. Results showed that attrition rates among newly diagnosed, TIE patients with multiple myeloma increase with each line of therapy, with the proportion of patients who receive a second line of therapy decreasing by 50 percent with each subsequent line.³ 

3. Can you provide more detail on the goals of therapy for newly diagnosed, transplant-ineligible patients?

When I discuss treatment goals with TIE patients, I feel it is important to emphasize managing side effects and achieving deep and durable responses. I have the benefit of being in an academic setting, where I regularly exchange information with my colleagues about what we’re learning from the clinical studies in which we participate. Choosing which treatment to administer is complex and involves other considerations. For example, if two regimens have comparable efficacy, I may recommend the regimen with a more established safety profile or more robust evidence so I can properly anticipate and manage toxicities in my patients. Overall survival is one of the most important endpoints I consider, in addition to depth of response and PFS. In recent years, we’ve seen increasing evidence pointing to the importance of  using a proven effective treatment in frontline patients that are ineligible for transplant. 

4. A key study in newly-diagnosed, transplant-ineligible multiple myeloma is the Phase 3 MAIA study. Can you share the key takeaways from this study and discuss how the results have shaped treatment for this patient population?

Of course. The MAIA study is a randomized Phase 3 study evaluating DARZALEX^® (daratumumab) intravenous injection in combination with lenalidomide and dexamethasone (D-Rd) compared with Rd in 737 adult patients with newly diagnosed, transplant-ineligible multiple myeloma. The median age of patients participating in the MAIA study was 73 (range 45-90), an important consideration since the median age for multiple myeloma diagnosis is approximately 66-70 years of age.⁶ The study evaluated PFS as the primary endpoint, and overall survival as a key secondary endpoint, and supported the FDA approval of DARZALEX^® in combination with lenalidomide and dexamethasone for adult patients with newly diagnosed, multiple myeloma who are ineligible for ASCT.

MAIA study design⁷

janssenglobal_hemedarzalexindividualchartspullingfromlargeasset_20221013_jm-01.png

The baseline demographic and disease characteristics were similar between the 2 treatment groups. Forty-four percent of the patients were  ≥75 years of age. Fifty-two percent (52%) of patients were male, 92% White, 4% Black or African American, and 1% Asian. Three percent (3%) of patients reported an ethnicity of Hispanic or Latino. Thirty-four (34%) had an Eastern Cooperative Oncology Group (ECOG) performance score of 0, 50% had an ECOG performance score of 1, and 17% had an ECOG performance score of ≥2. Twenty-seven percent had International Staging System (ISS) Stage I, 43% had ISS Stage II, and 29% had ISS Stage III disease. 

Select Important Safety Information: 

CONTRAINDICATIONS

DARZALEX^® is contraindicated in patients with a history of severe hypersensitivity (eg, anaphylactic reactions) to daratumumab or any of the components of the formulation.

WARNINGS AND PRECAUTIONS
Infusion-Related Reactions: DARZALEX^® can cause severe and/or serious infusion-related reactions including anaphylactic reactions.
These reactions can be life-threatening, and fatal outcomes have been reported. Please scroll down to read Important Safety Information for DARZALEX^®. 

Primary findings from the study, which were published in 2019, showed an improvement in PFS in patients receiving D-Rd compared with those receiving Rd alone.⁷ The median PFS was not reached in the D-Rd arm and was reached at 31.9 months in the Rd arm (HR 0.56; 95% CI 0.43-0.73; P<0.0001).⁷ At a median of 30 months of follow-up, the data showed the clinical benefit of D-Rd therapy, with a 44% reduction in the risk of disease progression or death in patients receiving D-Rd compared with Rd alone.⁷ 

Progression-free survival in TIE NDMM after ~30 months of treatment with D-Rd^7,8

janssenglobal_hemedarzalexindividualchartspullingfromlargeasset_20221013_jm-02.png

Additionally, 70.6% of patients (95% CI, 65.0-75.4) had no progressive disease with D-Rd treatment at median 30 months of follow-up, compared with 55.6% (95% CI, 49.5-61.3) of patients in the Rd group.⁷

In terms of depth of response, the percentage of patients with a complete response or better was 47.6% in patients receiving D-Rd compared with 24.9% in the Rd group.⁷

Overall response rate with D-Rd in TIE NDMM at ~30 months of follow-up⁸

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An overview of the most frequent adverse events at 30-months of follow-up are provided below. The most frequent adverse reactions were reported in ≥20% of patients, with at least a 5% greater frequency in the D-Rd arm compared with Rd alone.⁸ 

Most frequent adverse events at ~30 months of follow-up with D-Rd in TIE NDMM⁸

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Most frequent hematologic laboratory abnormalities with D-Rd in TIE NDMM at ~30 months⁸

janssenglobal_hemedarzalexindividualchartspullingfromlargeasset_20221013_jm-05.png

Serious adverse reactions with a 2% greater incidence in the D-Rd arm compared with the Rd arm were pneumonia (D-Rd 15% vs Rd 8%), bronchitis (D-Rd 4% vs Rd 2%), and dehydration (D-Rd 2% vs Rd <1).
• Discontinuation rates due to any adverse event: 7% with D-Rd vs 16% with Rd
• Infusion-related reactions (IRRs) with D-Rd occurred in 41% of patients; 2% were Grade 3 and <1% were Grade 4
• IRRs of any grade or severity may require management by interruption, modification, and/or discontinuation of the infusion
• Most IRRs occurred during first infusion

5. Thanks for that overview. In addition to these results, The Lancet Oncology has published updated overall survival data from a 5-year follow-up on the MAIA study. Can you provide an overview of these data and insights on their potential for patients?  

The MAIA trial was an important study, and for me, the results were practice changing. We see that after a median of nearly 5 years of follow-up, D-Rd significantly improved OS in TIE NDMM patients who were treated to progression compared with Rd alone (66.3% vs. 53.1% [HR=0.68; 95% CI, 0.53-0.86; P=0.0013]).⁹ This equates to approximately a 32% reduction in death when DARZALEX^® was added to a two-drug regimen, which is a meaningful consideration when selecting the most appropriate regimens for my newly diagnosed, transplant-ineligible patients.⁹

Overall survival data at ~5 years with D-Rd compared to Rd alone in TIE NDMM⁹

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Importantly, efficacy that resulted from longer treatment with D-Rd is also supported by approximately 5 years of safety evaluation. Below is information from a follow-up analysis of the MAIA study. This information is not included in the current Prescribing Information and has not been evaluated by the FDA. Treatment-emergent adverse events are reported as observed. These analyses have not been adjusted for multiple comparisons and no conclusions should be drawn. In what I’ve observed through published data and in my practice, longer treatment has not revealed new safety signals.

Most frequent treatment-emergent adverse events (any grade reported in ≥30% of patients and/or Grade 3/4 reported in ≥10% of patients) at ~5 years⁹

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Select Important Safety Information: 

DARZALEX^® can cause severe and/or serious infusion-related reactions including anaphylactic reactions. These reactions can be life threatening, and fatal outcomes have been reported. In clinical trials (monotherapy and combination: N=2066), infusion-related reactions occurred in 37% of patients with the Week 1 (16 mg/kg) infusion, 2% with the Week 2 infusion, and cumulatively 6% with subsequent infusions. Less than 1% of patients had a Grade 3/4 infusion-related reaction at Week 2 or subsequent infusions. The median time to onset was 1.5 hours (range: 0 to 73 hours). Nearly all reactions occurred during infusion or within 4 hours of completing DARZALEX^®. Severe reactions have occurred, including bronchospasm, hypoxia, dyspnea, hypertension, tachycardia, headache, laryngeal edema, pulmonary edema, and ocular adverse reactions, including choroidal effusion, acute myopia, and acute angle closure glaucoma. Signs and symptoms may include respiratory symptoms, such as nasal congestion, cough, throat irritation, as well as chills, vomiting, and nausea. Less common signs and symptoms were wheezing, allergic rhinitis, pyrexia, chest discomfort, pruritus, hypotension and blurred vision. Please scroll down to see Important Safety Information for DARZALEX^®.

6. Does the availability of OS data influence your decisions on treatment selection in TIE NDMM?

Overall survival absolutely remains the gold standard and informs my practice. Prior to OS data being available, I will often look at other efficacy endpoints that are available sooner. In MAIA, I was encouraged by efficacy endpoints in earlier data, which were later confirmed by the latest data on OS.

7. The MAIA study shows that treating to disease progression or unacceptable toxicity is important. How does that impact your approach to treatment?

It's important to keep in mind that the MAIA trial was designed to evaluate treatment until progression or unacceptable toxicity. The results revealed a significant difference between the DR-d and Rd treatment arms, but results observed in this study are contingent on this treatment approach. From a clinical perspective, unless there is considerable toxicity, I advocate for treating with D-Rd to progression.

In the clinic, we also see that TIE patients who have higher frailty scores are more likely to discontinue treatment prior to progression.¹⁰ There can be other reasons too – such as a patient simply wanting to have a break from treatment. These conversations are not always easy, but it is important to have an honest dialogue with patients.

8. What can we learn from studies like the MAIA trial that included a wide range of patient populations including patients who are elderly, frail, or had high cytogenetic risk? 

Several patient subgroups were analyzed as part of the MAIA study. It is important to note that these subgroup analyses are not included in the Prescribing Information for DARZALEX^®. These analyses were not adjusted for multiple comparisons, and there are insufficient numbers of patients per subgroup to make definitive conclusions of efficacy among the subgroups.

As mentioned above, the MAIA study evaluated a wide range of patients (n=737). The baseline demographic and disease characteristics were similar between the D-Rd and Rd treatment groups and the median age was 73 (range: 45-90) years, with 44% of the patients ≥75 years of age.

In the various patient subgroups that were analyzed as part of the MAIA study, it was found that at ~3-years of follow-up the PFS numerically favored DRd compared with Rd alone in most subgroups (see table below).

Median progression-free survival by sub-population at ~3 year follow-up⁸

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The MAIA trial also included patients who were frail and a post hoc analysis was conducted in this subgroup of patients. These analyses are not included in the Prescribing Information for DARZALEX^®. These analyses were conducted post hoc and there are insufficient numbers of patients per subgroup to make definitive conclusions of efficacy among the subgroups.

A frailty assessment was performed retrospectively using age, the Charlson Comorbidity Index (CCI) – which is calculated based on a retrospective review of the patient’s medical history to predict the 10-year mortality – and the baseline Eastern Cooperative Oncology Group (ECOG) performance status score, used to measure a patient’s level of functioning in terms of their ability to care for themselves, daily activity, and physical activity. The frailty scores were then added up to classify patients into fit (0), intermediate (1), or frail (≥2). Frailty status was further simplified into 2 categories: non-frail (0-1) and frail (≥2). The median age in the frail subgroup was 77 years (range: 57-80 years), with 88% of patients having ECOG performance score ≥1. CCI was calculated based on retrospective review of each patient’s medical history.¹²

The charts below illustrate the frailty scoring system with an overview of the patient population included in the 3-year post hoc analysis, PFS rate, and adverse events.

MAIA post hoc subgroup analysis by frailty status score¹²

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The retrospective assessment of frailty score was a limitation of this study. Retrospective CCI calculations were based on reported medical history, which may contain missing data and result in underestimating or overestimating the number of patients in each frailty subgroup. The ECOG PS score parameter used for frailty score calculations in the study is more subjective, with susceptibility to intra- and inter-observer bias, compared with the ADL (activities of daily living) and IADL (instrumental activities of daily living) scales used in the IMWG scoring system. While the frailty scale used in the study is based on parameters that are routinely assessed in clinical practice for clinical use, the use of comprehensive frailty assessments that more accurately reflect biological or functional frailty will remain important for the further optimization of treatment strategies for frail patients. Patients with an ECOG PS score ≥3 and patients with comorbidities that may interfere with the study procedures were excluded from MAIA; the inclusion and exclusion criteria for the study limits the generalizability of these results to more frail patients seen in clinical practice.

Progression-free survival in a ~3-year subgroup analysis of frail patients following treatment with D-Rd in TIE NDMM¹²

janssenglobal_hemedarzalexindividualchartspullingfromlargeasset_20221013_jm-09.png

Most frequent Grade 3/4 treatment-emergent adverse events (≥10%) in frail patients at ~3 year follow-up of MAIA trial¹²

janssenglobal_hemedarzalexindividualchartspullingfromlargeasset_20221013_jm-10.png

Please see additional Important Safety Information for DARZALEX^® below.

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS

DARZALEX^® is contraindicated in patients with a history of severe hypersensitivity (eg, anaphylactic reactions) to daratumumab or any of the components of the formulation.

WARNINGS AND PRECAUTIONS

Infusion-Related Reactions

DARZALEX^® can cause severe and/or serious infusion-related reactions including anaphylactic reactions. These reactions can be life‑threatening, and fatal outcomes have been reported. In clinical trials (monotherapy and combination: N=2066), infusion-related reactions occurred in 37% of patients with the Week 1 (16 mg/kg) infusion, 2% with the Week 2 infusion, and cumulatively 6% with subsequent infusions. Less than 1% of patients had a Grade 3/4 infusion-related reaction at Week 2 or subsequent infusions. The median time to onset was 1.5 hours (range: 0 to 73 hours). Nearly all reactions occurred during infusion or within 4 hours of completing DARZALEX^®. Severe reactions have occurred, including bronchospasm, hypoxia, dyspnea, hypertension, tachycardia, headache, laryngeal edema, pulmonary edema, and ocular adverse reactions, including choroidal effusion, acute myopia, and acute angle closure glaucoma. Signs and symptoms may include respiratory symptoms, such as nasal congestion, cough, throat irritation, as well as chills, vomiting, and nausea. Less common signs and symptoms were wheezing, allergic rhinitis, pyrexia, chest discomfort, pruritus, hypotension and blurred vision.

When DARZALEX^® dosing was interrupted in the setting of ASCT (CASSIOPEIA) for a median of 3.75 months (range: 2.4 to 6.9 months), upon re-initiation of DARZALEX^®, the incidence of infusion-related reactions was 11% for the first infusion following ASCT. Infusion-related reactions occurring at re-initiation of DARZALEX^® following ASCT were consistent in terms of symptoms and severity (Grade 3 or 4: <1%) with those reported in previous studies at Week 2 or subsequent infusions. In EQUULEUS, patients receiving combination treatment (n=97) were administered the first 16 mg/kg dose at Week 1 split over two days, ie, 8 mg/kg on Day 1 and Day 2, respectively. The incidence of any grade infusion-related reactions was 42%, with 36% of patients experiencing infusion-related reactions on Day 1 of Week 1, 4% on Day 2 of Week 1, and 8% with subsequent infusions.

Pre-medicate patients with antihistamines, antipyretics, and corticosteroids. Frequently monitor patients during the entire infusion. Interrupt DARZALEX^® infusion for reactions of any severity and institute medical management as needed. Permanently discontinue DARZALEX^® therapy if an anaphylactic reaction or life-threatening (Grade 4) reaction occurs and institute appropriate emergency care. For patients with Grade 1, 2, or 3 reactions, reduce the infusion rate when re-starting the infusion.

To reduce the risk of delayed infusion-related reactions, administer oral corticosteroids to all patients following DARZALEX^® infusions. Patients with a history of chronic obstructive pulmonary disease may require additional post-infusion medications to manage respiratory complications. Consider prescribing short- and long-acting bronchodilators and inhaled corticosteroids for patients with chronic obstructive pulmonary disease.

Ocular adverse reactions, including acute myopia and narrowing of the anterior chamber angle due to ciliochoroidal effusions with potential for increased intraocular pressure or glaucoma, have occurred with DARZALEX infusion. If ocular symptoms occur, interrupt DARZALEX infusion and seek immediate ophthalmologic evaluation prior to restarting DARZALEX.

Interference With Serological Testing

Daratumumab binds to CD38 on red blood cells (RBCs) and results in a positive indirect antiglobulin test (indirect Coombs test). Daratumumab-mediated positive indirect antiglobulin test may persist for up to 6 months after the last daratumumab infusion. Daratumumab bound to RBCs masks detection of antibodies to minor antigens in the patient’s serum. The determination of a patient’s ABO and Rh blood type is not impacted. Notify blood transfusion centers of this interference with serological testing and inform blood banks that a patient has received DARZALEX^®. Type and screen patients prior to starting DARZALEX^®.

Neutropenia and Thrombocytopenia

DARZALEX^® may increase neutropenia and thrombocytopenia induced by background therapy. Monitor complete blood cell counts periodically during treatment according to manufacturer’s prescribing information for background therapies. Monitor patients with neutropenia for signs of infection. Consider withholding DARZALEX^® until recovery of neutrophils or for recovery of platelets.

Interference With Determination of Complete Response

Daratumumab is a human immunoglobulin G (IgG) kappa monoclonal antibody that can be detected on both the serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for the clinical monitoring of endogenous M-protein. This interference can impact the determination of complete response and of disease progression in some patients with IgG kappa myeloma protein.

Embryo-Fetal Toxicity

Based on the mechanism of action, DARZALEX^® can cause fetal harm when administered to a pregnant woman. DARZALEX^® may cause depletion of fetal immune cells and decreased bone density. Advise pregnant women of the potential risk to a fetus. Advise females with reproductive potential to use effective contraception during treatment with DARZALEX^® and for 3 months after the last dose.

The combination of DARZALEX^® with lenalidomide, pomalidomide, or thalidomide is contraindicated in pregnant women because lenalidomide, pomalidomide, and thalidomide may cause birth defects and death of the unborn child. Refer to the lenalidomide, pomalidomide, or thalidomide prescribing information on use during pregnancy.

ADVERSE REACTIONS

The most frequently reported adverse reactions (incidence ≥20%) were: upper respiratory infection, neutropenia, infusion‑related reactions, thrombocytopenia, diarrhea, constipation, anemia, peripheral sensory neuropathy, fatigue, peripheral edema, nausea, cough, pyrexia, dyspnea, and asthenia. The most common hematologic laboratory abnormalities (≥40%) with DARZALEX^® are: neutropenia, lymphopenia, thrombocytopenia, leukopenia, and anemia.

INDICATIONS

DARZALEX^® (daratumumab) is indicated for the treatment of adult patients with multiple myeloma:

• In combination with lenalidomide and dexamethasone in newly diagnosed patients who are ineligible for autologous stem cell transplant and in patients with relapsed or refractory multiple myeloma who have received at least one prior therapy
• In combination with bortezomib, melphalan, and prednisone in newly diagnosed patients who are ineligible for autologous stem cell transplant
• In combination with bortezomib, thalidomide, and dexamethasone in newly diagnosed patients who are eligible for autologous stem cell transplant
• In combination with bortezomib and dexamethasone in patients who have received at least one prior therapy
• In combination with carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma who have received one to three prior lines of therapy
• In combination with pomalidomide and dexamethasone in patients who have received at least two prior therapies including lenalidomide and a proteasome inhibitor
• As monotherapy in patients who have received at least three prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent or who are double-refractory to a PI and an immunomodulatory agent

Please click here to see the full Prescribing Information.

dr._atrash_headshot.jpg

1. The treatment of multiple myeloma has evolved significantly in recent years. What are some of the most important things you consider in the treatment of your newly diagnosed, transplant-ineligible patients?

We’ve seen great progress in the treatment of multiple myeloma over the last decade, and outcomes continue to improve for many patients.¹ Still, it is important to keep in mind that more than 34,000 patients will be diagnosed and more than 12,000 people will die from the disease this year.² We may have the greatest opportunity to impact the course of disease in the treatment of newly diagnosed patients due to the nature of this cancer:

• Multiple myeloma is characterized by relapse, and we know the length of remission generally decreases with each relapse and subsequent line of therapy.³
• Patients often become refractory to treatment over time.

When I meet with a patient who has been diagnosed with multiple myeloma, the first thing I consider is their eligibility for autologous stem cell transplant (ASCT). In my opinion, the introduction of ASCT is one of the biggest advancements in the last few decades, and we’ve found that ASCT followed by maintenance therapy with targeted tools improves progression-free survival (PFS).⁴

Unfortunately, many newly diagnosed patients are not eligible for ASCT–either because of comorbidities or other complexities related to the presentation of their disease.  

For patients who are transplant-ineligible (TIE), it is important to have treatment options that are proven effective in extending PFS and overall survival (OS), and capable of producing deep and durable responses.

2. What are the challenges associated with treating newly diagnosed patients who are not eligible for ASCT?

We still consider multiple myeloma to be an incurable disease but, in my opinion, the treatment of TIE patients is less challenging today than a decade ago due to the emergence of novel therapies. That said, TIE patients are typically older and present with more advanced disease and comorbidities, including diabetes or cardiovascular events.⁵ 

A retrospective analysis published in 2020 by Rafael Fonseca examined frontline treatment patterns and attrition rates by line of therapy among newly diagnosed multiple myeloma (NDMM) patients who are TIE. More than 22,000 patients were identified from three patient-level databases between 2000 and 2018 - the OPTUM Commercial Claims database, the OPTUM Electronic Medical Records database, and the Surveillance, Epidemiology, and End Results-Meidcare Linked database. Patients included had to have a multiple myeloma diagnosis on or after January 1, 2007. Results showed that attrition rates among newly diagnosed, TIE patients with multiple myeloma increase with each line of therapy, with the proportion of patients who receive a second line of therapy decreasing by 50 percent with each subsequent line.³ 

3. Can you provide more detail on the goals of therapy for newly diagnosed, transplant-ineligible patients?

When I discuss treatment goals with TIE patients, I feel it is important to emphasize managing side effects and achieving deep and durable responses. I have the benefit of being in an academic setting, where I regularly exchange information with my colleagues about what we’re learning from the clinical studies in which we participate. Choosing which treatment to administer is complex and involves other considerations. For example, if two regimens have comparable efficacy, I may recommend the regimen with a more established safety profile or more robust evidence so I can properly anticipate and manage toxicities in my patients. Overall survival is one of the most important endpoints I consider, in addition to depth of response and PFS. In recent years, we’ve seen increasing evidence pointing to the importance of  using a proven effective treatment in frontline patients that are ineligible for transplant. 

4. A key study in newly-diagnosed, transplant-ineligible multiple myeloma is the Phase 3 MAIA study. Can you share the key takeaways from this study and discuss how the results have shaped treatment for this patient population?

Of course. The MAIA study is a randomized Phase 3 study evaluating DARZALEX^® (daratumumab) intravenous injection in combination with lenalidomide and dexamethasone (D-Rd) compared with Rd in 737 adult patients with newly diagnosed, transplant-ineligible multiple myeloma. The median age of patients participating in the MAIA study was 73 (range 45-90), an important consideration since the median age for multiple myeloma diagnosis is approximately 66-70 years of age.⁶ The study evaluated PFS as the primary endpoint, and overall survival as a key secondary endpoint, and supported the FDA approval of DARZALEX^® in combination with lenalidomide and dexamethasone for adult patients with newly diagnosed, multiple myeloma who are ineligible for ASCT.

MAIA study design⁷

janssenglobal_hemedarzalexindividualchartspullingfromlargeasset_20221013_jm-01.png

The baseline demographic and disease characteristics were similar between the 2 treatment groups. Forty-four percent of the patients were  ≥75 years of age. Fifty-two percent (52%) of patients were male, 92% White, 4% Black or African American, and 1% Asian. Three percent (3%) of patients reported an ethnicity of Hispanic or Latino. Thirty-four (34%) had an Eastern Cooperative Oncology Group (ECOG) performance score of 0, 50% had an ECOG performance score of 1, and 17% had an ECOG performance score of ≥2. Twenty-seven percent had International Staging System (ISS) Stage I, 43% had ISS Stage II, and 29% had ISS Stage III disease. 

Select Important Safety Information: 

CONTRAINDICATIONS

DARZALEX^® is contraindicated in patients with a history of severe hypersensitivity (eg, anaphylactic reactions) to daratumumab or any of the components of the formulation.

WARNINGS AND PRECAUTIONS
Infusion-Related Reactions: DARZALEX^® can cause severe and/or serious infusion-related reactions including anaphylactic reactions.
These reactions can be life-threatening, and fatal outcomes have been reported. Please scroll down to read Important Safety Information for DARZALEX^®. 

Primary findings from the study, which were published in 2019, showed an improvement in PFS in patients receiving D-Rd compared with those receiving Rd alone.⁷ The median PFS was not reached in the D-Rd arm and was reached at 31.9 months in the Rd arm (HR 0.56; 95% CI 0.43-0.73; P<0.0001).⁷ At a median of 30 months of follow-up, the data showed the clinical benefit of D-Rd therapy, with a 44% reduction in the risk of disease progression or death in patients receiving D-Rd compared with Rd alone.⁷ 

Progression-free survival in TIE NDMM after ~30 months of treatment with D-Rd^7,8

janssenglobal_hemedarzalexindividualchartspullingfromlargeasset_20221013_jm-02.png

Additionally, 70.6% of patients (95% CI, 65.0-75.4) had no progressive disease with D-Rd treatment at median 30 months of follow-up, compared with 55.6% (95% CI, 49.5-61.3) of patients in the Rd group.⁷

In terms of depth of response, the percentage of patients with a complete response or better was 47.6% in patients receiving D-Rd compared with 24.9% in the Rd group.⁷

Overall response rate with D-Rd in TIE NDMM at ~30 months of follow-up⁸

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An overview of the most frequent adverse events at 30-months of follow-up are provided below. The most frequent adverse reactions were reported in ≥20% of patients, with at least a 5% greater frequency in the D-Rd arm compared with Rd alone.⁸ 

Most frequent adverse events at ~30 months of follow-up with D-Rd in TIE NDMM⁸

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Most frequent hematologic laboratory abnormalities with D-Rd in TIE NDMM at ~30 months⁸

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Serious adverse reactions with a 2% greater incidence in the D-Rd arm compared with the Rd arm were pneumonia (D-Rd 15% vs Rd 8%), bronchitis (D-Rd 4% vs Rd 2%), and dehydration (D-Rd 2% vs Rd <1).
• Discontinuation rates due to any adverse event: 7% with D-Rd vs 16% with Rd
• Infusion-related reactions (IRRs) with D-Rd occurred in 41% of patients; 2% were Grade 3 and <1% were Grade 4
• IRRs of any grade or severity may require management by interruption, modification, and/or discontinuation of the infusion
• Most IRRs occurred during first infusion

5. Thanks for that overview. In addition to these results, The Lancet Oncology has published updated overall survival data from a 5-year follow-up on the MAIA study. Can you provide an overview of these data and insights on their potential for patients?  

The MAIA trial was an important study, and for me, the results were practice changing. We see that after a median of nearly 5 years of follow-up, D-Rd significantly improved OS in TIE NDMM patients who were treated to progression compared with Rd alone (66.3% vs. 53.1% [HR=0.68; 95% CI, 0.53-0.86; P=0.0013]).⁹ This equates to approximately a 32% reduction in death when DARZALEX^® was added to a two-drug regimen, which is a meaningful consideration when selecting the most appropriate regimens for my newly diagnosed, transplant-ineligible patients.⁹

Overall survival data at ~5 years with D-Rd compared to Rd alone in TIE NDMM⁹

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Importantly, efficacy that resulted from longer treatment with D-Rd is also supported by approximately 5 years of safety evaluation. Below is information from a follow-up analysis of the MAIA study. This information is not included in the current Prescribing Information and has not been evaluated by the FDA. Treatment-emergent adverse events are reported as observed. These analyses have not been adjusted for multiple comparisons and no conclusions should be drawn. In what I’ve observed through published data and in my practice, longer treatment has not revealed new safety signals.

Most frequent treatment-emergent adverse events (any grade reported in ≥30% of patients and/or Grade 3/4 reported in ≥10% of patients) at ~5 years⁹

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Select Important Safety Information: 

DARZALEX^® can cause severe and/or serious infusion-related reactions including anaphylactic reactions. These reactions can be life threatening, and fatal outcomes have been reported. In clinical trials (monotherapy and combination: N=2066), infusion-related reactions occurred in 37% of patients with the Week 1 (16 mg/kg) infusion, 2% with the Week 2 infusion, and cumulatively 6% with subsequent infusions. Less than 1% of patients had a Grade 3/4 infusion-related reaction at Week 2 or subsequent infusions. The median time to onset was 1.5 hours (range: 0 to 73 hours). Nearly all reactions occurred during infusion or within 4 hours of completing DARZALEX^®. Severe reactions have occurred, including bronchospasm, hypoxia, dyspnea, hypertension, tachycardia, headache, laryngeal edema, pulmonary edema, and ocular adverse reactions, including choroidal effusion, acute myopia, and acute angle closure glaucoma. Signs and symptoms may include respiratory symptoms, such as nasal congestion, cough, throat irritation, as well as chills, vomiting, and nausea. Less common signs and symptoms were wheezing, allergic rhinitis, pyrexia, chest discomfort, pruritus, hypotension and blurred vision. Please scroll down to see Important Safety Information for DARZALEX^®.

6. Does the availability of OS data influence your decisions on treatment selection in TIE NDMM?

Overall survival absolutely remains the gold standard and informs my practice. Prior to OS data being available, I will often look at other efficacy endpoints that are available sooner. In MAIA, I was encouraged by efficacy endpoints in earlier data, which were later confirmed by the latest data on OS.

7. The MAIA study shows that treating to disease progression or unacceptable toxicity is important. How does that impact your approach to treatment?

It's important to keep in mind that the MAIA trial was designed to evaluate treatment until progression or unacceptable toxicity. The results revealed a significant difference between the DR-d and Rd treatment arms, but results observed in this study are contingent on this treatment approach. From a clinical perspective, unless there is considerable toxicity, I advocate for treating with D-Rd to progression.

In the clinic, we also see that TIE patients who have higher frailty scores are more likely to discontinue treatment prior to progression.¹⁰ There can be other reasons too – such as a patient simply wanting to have a break from treatment. These conversations are not always easy, but it is important to have an honest dialogue with patients.

8. What can we learn from studies like the MAIA trial that included a wide range of patient populations including patients who are elderly, frail, or had high cytogenetic risk? 

Several patient subgroups were analyzed as part of the MAIA study. It is important to note that these subgroup analyses are not included in the Prescribing Information for DARZALEX^®. These analyses were not adjusted for multiple comparisons, and there are insufficient numbers of patients per subgroup to make definitive conclusions of efficacy among the subgroups.

As mentioned above, the MAIA study evaluated a wide range of patients (n=737). The baseline demographic and disease characteristics were similar between the D-Rd and Rd treatment groups and the median age was 73 (range: 45-90) years, with 44% of the patients ≥75 years of age.

In the various patient subgroups that were analyzed as part of the MAIA study, it was found that at ~3-years of follow-up the PFS numerically favored DRd compared with Rd alone in most subgroups (see table below).

Median progression-free survival by sub-population at ~3 year follow-up⁸

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The MAIA trial also included patients who were frail and a post hoc analysis was conducted in this subgroup of patients. These analyses are not included in the Prescribing Information for DARZALEX^®. These analyses were conducted post hoc and there are insufficient numbers of patients per subgroup to make definitive conclusions of efficacy among the subgroups.

A frailty assessment was performed retrospectively using age, the Charlson Comorbidity Index (CCI) – which is calculated based on a retrospective review of the patient’s medical history to predict the 10-year mortality – and the baseline Eastern Cooperative Oncology Group (ECOG) performance status score, used to measure a patient’s level of functioning in terms of their ability to care for themselves, daily activity, and physical activity. The frailty scores were then added up to classify patients into fit (0), intermediate (1), or frail (≥2). Frailty status was further simplified into 2 categories: non-frail (0-1) and frail (≥2). The median age in the frail subgroup was 77 years (range: 57-80 years), with 88% of patients having ECOG performance score ≥1. CCI was calculated based on retrospective review of each patient’s medical history.¹²

The charts below illustrate the frailty scoring system with an overview of the patient population included in the 3-year post hoc analysis, PFS rate, and adverse events.

MAIA post hoc subgroup analysis by frailty status score¹²

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The retrospective assessment of frailty score was a limitation of this study. Retrospective CCI calculations were based on reported medical history, which may contain missing data and result in underestimating or overestimating the number of patients in each frailty subgroup. The ECOG PS score parameter used for frailty score calculations in the study is more subjective, with susceptibility to intra- and inter-observer bias, compared with the ADL (activities of daily living) and IADL (instrumental activities of daily living) scales used in the IMWG scoring system. While the frailty scale used in the study is based on parameters that are routinely assessed in clinical practice for clinical use, the use of comprehensive frailty assessments that more accurately reflect biological or functional frailty will remain important for the further optimization of treatment strategies for frail patients. Patients with an ECOG PS score ≥3 and patients with comorbidities that may interfere with the study procedures were excluded from MAIA; the inclusion and exclusion criteria for the study limits the generalizability of these results to more frail patients seen in clinical practice.

Progression-free survival in a ~3-year subgroup analysis of frail patients following treatment with D-Rd in TIE NDMM¹²

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Most frequent Grade 3/4 treatment-emergent adverse events (≥10%) in frail patients at ~3 year follow-up of MAIA trial¹²

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Please see additional Important Safety Information for DARZALEX^® below.

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS

DARZALEX^® is contraindicated in patients with a history of severe hypersensitivity (eg, anaphylactic reactions) to daratumumab or any of the components of the formulation.

WARNINGS AND PRECAUTIONS

Infusion-Related Reactions

DARZALEX^® can cause severe and/or serious infusion-related reactions including anaphylactic reactions. These reactions can be life‑threatening, and fatal outcomes have been reported. In clinical trials (monotherapy and combination: N=2066), infusion-related reactions occurred in 37% of patients with the Week 1 (16 mg/kg) infusion, 2% with the Week 2 infusion, and cumulatively 6% with subsequent infusions. Less than 1% of patients had a Grade 3/4 infusion-related reaction at Week 2 or subsequent infusions. The median time to onset was 1.5 hours (range: 0 to 73 hours). Nearly all reactions occurred during infusion or within 4 hours of completing DARZALEX^®. Severe reactions have occurred, including bronchospasm, hypoxia, dyspnea, hypertension, tachycardia, headache, laryngeal edema, pulmonary edema, and ocular adverse reactions, including choroidal effusion, acute myopia, and acute angle closure glaucoma. Signs and symptoms may include respiratory symptoms, such as nasal congestion, cough, throat irritation, as well as chills, vomiting, and nausea. Less common signs and symptoms were wheezing, allergic rhinitis, pyrexia, chest discomfort, pruritus, hypotension and blurred vision.

When DARZALEX^® dosing was interrupted in the setting of ASCT (CASSIOPEIA) for a median of 3.75 months (range: 2.4 to 6.9 months), upon re-initiation of DARZALEX^®, the incidence of infusion-related reactions was 11% for the first infusion following ASCT. Infusion-related reactions occurring at re-initiation of DARZALEX^® following ASCT were consistent in terms of symptoms and severity (Grade 3 or 4: <1%) with those reported in previous studies at Week 2 or subsequent infusions. In EQUULEUS, patients receiving combination treatment (n=97) were administered the first 16 mg/kg dose at Week 1 split over two days, ie, 8 mg/kg on Day 1 and Day 2, respectively. The incidence of any grade infusion-related reactions was 42%, with 36% of patients experiencing infusion-related reactions on Day 1 of Week 1, 4% on Day 2 of Week 1, and 8% with subsequent infusions.

Pre-medicate patients with antihistamines, antipyretics, and corticosteroids. Frequently monitor patients during the entire infusion. Interrupt DARZALEX^® infusion for reactions of any severity and institute medical management as needed. Permanently discontinue DARZALEX^® therapy if an anaphylactic reaction or life-threatening (Grade 4) reaction occurs and institute appropriate emergency care. For patients with Grade 1, 2, or 3 reactions, reduce the infusion rate when re-starting the infusion.

To reduce the risk of delayed infusion-related reactions, administer oral corticosteroids to all patients following DARZALEX^® infusions. Patients with a history of chronic obstructive pulmonary disease may require additional post-infusion medications to manage respiratory complications. Consider prescribing short- and long-acting bronchodilators and inhaled corticosteroids for patients with chronic obstructive pulmonary disease.

Ocular adverse reactions, including acute myopia and narrowing of the anterior chamber angle due to ciliochoroidal effusions with potential for increased intraocular pressure or glaucoma, have occurred with DARZALEX infusion. If ocular symptoms occur, interrupt DARZALEX infusion and seek immediate ophthalmologic evaluation prior to restarting DARZALEX.

Interference With Serological Testing

Daratumumab binds to CD38 on red blood cells (RBCs) and results in a positive indirect antiglobulin test (indirect Coombs test). Daratumumab-mediated positive indirect antiglobulin test may persist for up to 6 months after the last daratumumab infusion. Daratumumab bound to RBCs masks detection of antibodies to minor antigens in the patient’s serum. The determination of a patient’s ABO and Rh blood type is not impacted. Notify blood transfusion centers of this interference with serological testing and inform blood banks that a patient has received DARZALEX^®. Type and screen patients prior to starting DARZALEX^®.

Neutropenia and Thrombocytopenia

DARZALEX^® may increase neutropenia and thrombocytopenia induced by background therapy. Monitor complete blood cell counts periodically during treatment according to manufacturer’s prescribing information for background therapies. Monitor patients with neutropenia for signs of infection. Consider withholding DARZALEX^® until recovery of neutrophils or for recovery of platelets.

Interference With Determination of Complete Response

Daratumumab is a human immunoglobulin G (IgG) kappa monoclonal antibody that can be detected on both the serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for the clinical monitoring of endogenous M-protein. This interference can impact the determination of complete response and of disease progression in some patients with IgG kappa myeloma protein.

Embryo-Fetal Toxicity

Based on the mechanism of action, DARZALEX^® can cause fetal harm when administered to a pregnant woman. DARZALEX^® may cause depletion of fetal immune cells and decreased bone density. Advise pregnant women of the potential risk to a fetus. Advise females with reproductive potential to use effective contraception during treatment with DARZALEX^® and for 3 months after the last dose.

The combination of DARZALEX^® with lenalidomide, pomalidomide, or thalidomide is contraindicated in pregnant women because lenalidomide, pomalidomide, and thalidomide may cause birth defects and death of the unborn child. Refer to the lenalidomide, pomalidomide, or thalidomide prescribing information on use during pregnancy.

ADVERSE REACTIONS

The most frequently reported adverse reactions (incidence ≥20%) were: upper respiratory infection, neutropenia, infusion‑related reactions, thrombocytopenia, diarrhea, constipation, anemia, peripheral sensory neuropathy, fatigue, peripheral edema, nausea, cough, pyrexia, dyspnea, and asthenia. The most common hematologic laboratory abnormalities (≥40%) with DARZALEX^® are: neutropenia, lymphopenia, thrombocytopenia, leukopenia, and anemia.

INDICATIONS

DARZALEX^® (daratumumab) is indicated for the treatment of adult patients with multiple myeloma:

• In combination with lenalidomide and dexamethasone in newly diagnosed patients who are ineligible for autologous stem cell transplant and in patients with relapsed or refractory multiple myeloma who have received at least one prior therapy
• In combination with bortezomib, melphalan, and prednisone in newly diagnosed patients who are ineligible for autologous stem cell transplant
• In combination with bortezomib, thalidomide, and dexamethasone in newly diagnosed patients who are eligible for autologous stem cell transplant
• In combination with bortezomib and dexamethasone in patients who have received at least one prior therapy
• In combination with carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma who have received one to three prior lines of therapy
• In combination with pomalidomide and dexamethasone in patients who have received at least two prior therapies including lenalidomide and a proteasome inhibitor
• As monotherapy in patients who have received at least three prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent or who are double-refractory to a PI and an immunomodulatory agent

Please click here to see the full Prescribing Information.

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Cervical cancer screening is often hailed as the most successful screening program ever implemented. Despite these past successes, cervical cancer incidence is no longer decreasing and is actually rising significantly in younger women within the United States. In a country with a well-established screening program, effective screening tools, and HPV vaccination, it seems unfathomable that we are witnessing an increase in cervical cancers. This alarming trend should be cause for concern among all healthcare professionals.

Click here to read more

sf352990_01-obgm-cover-page.jpg

Cervical cancer screening is often hailed as the most successful screening program ever implemented. Despite these past successes, cervical cancer incidence is no longer decreasing and is actually rising significantly in younger women within the United States. In a country with a well-established screening program, effective screening tools, and HPV vaccination, it seems unfathomable that we are witnessing an increase in cervical cancers. This alarming trend should be cause for concern among all healthcare professionals.

Click here to read more

sf352990_01-obgm-cover-page.jpg

Cervical cancer screening is often hailed as the most successful screening program ever implemented. Despite these past successes, cervical cancer incidence is no longer decreasing and is actually rising significantly in younger women within the United States. In a country with a well-established screening program, effective screening tools, and HPV vaccination, it seems unfathomable that we are witnessing an increase in cervical cancers. This alarming trend should be cause for concern among all healthcare professionals.

Click here to read more

Glucocorticoids (GCs) are among the most widely prescribed medications in dermatologic practice. Although GCs are highly effective anti-inflammatory agents, long-term systemic therapy can result in dangerous adverse effects, including GC-induced osteoporosis (GIO), a bone disease associated with a heightened risk for fragility fractures.^1,2 In the United States, an estimated 10.2 million adults have osteoporosis—defined as a T-score lower than −2.5 measured via a bone densitometry scan—and 43.4 million adults have low bone mineral density (BMD).^3,4 The prevalence of osteoporosis is increasing, and the diagnosis is more common in females and adults 55 years and older.² More than 2 million individuals have osteoporosis-related fractures annually, and the mortality risk is increased at 5 and 10 years following low-energy osteoporosis-related fractures.^3-5

Glucocorticoid therapy is the leading iatrogenic cause of secondary osteoporosis. As many as 30% of all patients treated with systemic GCs for more than 6 months develop GIO.^1,6,7 Glucocorticoid-induced BMD loss occurs at a rate of 6% to 12% of total BMD during the first year, slowing to approximately 3% per year during subsequent therapy.¹ The risk for insufficiency fractures increases by as much as 75% from baseline in adults with rheumatic, pulmonary, and skin disorders within the first 3 months of therapy and peaks at approximately 12 months.^1,2

Despite the risks, many long-term GC users never receive therapy to prevent bone loss; others are only started on therapy once they have sustained an insufficiency fracture. A 5-year international observational study including more than 40,000 postmenopausal women found that only 51% of patients who were on continuous GC therapy were undergoing BMD testing and appropriate medical management.⁸ This review highlights the existing evidence on the risks of osteoporosis and osteoporotic (OP) fractures in the setting of topical, intralesional, intramuscular, and systemic GC treatment, as well as recommendations for nutritional supplementation to reduce these risks.

Pathophysiology

The pathophysiology of GIO is multifactorial and occurs in both early and late phases.^9,10 The early phase is characterized by rapid BMD reduction due to excessive bone resorption. The late phase is characterized by slower and more progressive BMD reduction due to impaired bone formation.⁹ At the osteocyte level, GCs decrease cell viability and induce apoptosis.¹¹ At the osteoblast level, GCs impair cell replication and differentiation and have proapoptotic effects, resulting in decreased cell numbers and subsequent bone formation.¹⁰ At the osteoclast level, GCs increase expression of pro-osteoclastic cytokines and decrease mature osteoclast apoptosis, resulting in an expanded osteoclastic life span and prolonged bone resorption.^12,13 Indirectly, GCs alter calcium metabolism by decreasing gastrointestinal calcium absorption and impairing renal absorption.^14,15

GCs and Osteoporosis

Oral GCs—Glucocorticoid-induced osteoporosis and fracture risk are dose and duration dependent.⁶ A study of 244,235 patients taking GCs and 244,235 controls found the relative risk of vertebral fracture was 1.55 (range, 1.20–2.01) for daily prednisone use at less than 2.5 mg, 2.59 (range, 2.16–3.10) for daily prednisone use from 2.5 to 7.4 mg, and 5.18 (range, 4.25–6.31) for daily doses of 7.5 mg or higher; the relative risk for hip fractures was 0.99 (range, 0.82–1.20), 1.77 (range, 1.55–2.02), and 2.27 (range, 1.94–2.66), respectively.¹⁶ Another large retrospective cohort study found that continuous treatment with prednisone 10 mg/d for more than 90 days compared to no GC exposure increased the risk for hip fractures 7-fold and 17-fold for vertebral fractures.¹⁷ Although the minimum cumulative dose of GCs known to cause osteoporosis is not clearly established, the American College of Rheumatology has proposed an algorithm as a basic approach to anticipate, prevent, and treat GIO (Figure).^18,19 Fracture risk should be assessed in all patients who are prescribed prednisone 2.5 mg/d for 3 months or longer or an anticipated cumulative dose of more than 1 g per year. Patients 40 years and older with anticipated GC use of 3 months or longer should have both a bone densitometry scan and a Fracture Risk Assessment (FRAX) score. The FRAX tool estimates the 10-year probability of fracture in patients aged 40 to 80 years, and those patients can be further risk stratified as low (FRAX <10%), moderate (FRAX 10%–19%), or high (FRAX ≥20%) risk. In patients with moderate to high risk of fracture (FRAX >10%), initiation of pharmacologic treatment or referral to a metabolic bone specialist should be considered.^18,19 First-line therapy is an oral bisphosphonate, and second-line therapies include intravenous bisphosphonates, teriparatide, denosumab, or raloxifene for patients at high risk for GIO.¹⁹ Adults younger than 40 years with a history of OP fracture or considerable risk factors for OP fractures should have a bone densitometry scan, and, if results are abnormal, the patient should be referred to a metabolic bone specialist. Those with low fracture risk based on bone densitometry and FRAX and those with no risk factors should be assessed annually for bone health (additional risk factors, GC dose and duration, bone densitometry/FRAX if indicated).¹⁸ In addition to GC dose and duration, additional risk factors for GIO, which are factored into the FRAX tool, include advanced age, low body mass index, history of bone fracture, smoking, excessive alcohol use (≥3 drinks/d), history of falls, low BMD, family history of bone fracture, and hypovitaminosis D.⁶

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Topical GCs—Although there is strong evidence and clear guidelines regarding oral GIO, there is a dearth of data surrounding OP risk due to treatment with topical GCs. A recent retrospective nationwide Danish study evaluating the risk of osteoporosis and major OP fracture in 723,251 adults treated with potent or very potent topical steroids sought to evaluate these risks.²⁰ Patients were included if they had filled prescriptions of at least 500 g of topical mometasone or an equivalent alternative. The investigators reported a 3% increase in relative risk of osteoporosis and major OP fracture with doubling of the cumulative topical GC dose (hazard ratio [HR], 1.03 [95% CI, 1.02-1.04] for both). The overall population-attributable risk was 4.3% (95% CI, 2.7%-5.8%) for osteoporosis and 2.7% (95% CI, 1.7%-3.8%) for major OP fracture. Notably, at least 10,000 g of mometasone was required for 1 additional patient to have a major OP fracture.²⁰ In a commentary based on this study, Jackson²¹ noted that the number of patient-years of topical GC use needed for 1 fracture was 4-fold higher than that for high-dose oral GCs (40 mg/d prednisolone for ≥30 days). Another study assessed the effects of topical GCs on BMD in adults with moderate to severe atopic dermatitis over a 2-year period.²² No significant difference in BMD assessed via bone densitometry of either the lumbar spine or total hip at baseline or at 2-year follow-up was reported for either group treated with corticosteroids (<75 g per month or ≥75 g per month). Of note, the authors did not account for steroid potency, which ranged from class 1 through class 4.²² Although limited data exist, these studies suggest topical GCs used at conventional doses with appropriate breaks in therapy will not substantially increase risk for GIO or OP fracture; however, in the small subset of patients requiring chronic use of superpotent topical corticosteroids with other OP risk factors, transitioning to non–GC-based therapy or initiating bone health therapy may be advised to improve patient outcomes. Risk assessment, as in cases of chronic topical GC use, may be beneficial.

Intralesional GCs—Intralesional GCs are indicated for numerous inflammatory conditions including alopecia areata, discoid lupus erythematosus, keloids, and granuloma annulare. It generally is accepted that doses of triamcinolone acetonide should not exceed 20 mg per session spaced at least 3 weeks apart or up to 40 mg per month.¹⁸ One study demonstrated that doses of triamcinolone diacetate of 25 mg or less were unlikely to produce systemic effects and were determined to be a safe dose for intralesional injections.²³ A retrospective cross-sectional case series including 18 patients with alopecia areata reported decreased BMD in 9 patients receiving intralesional triamcinolone acetonide 10 mg/mL at 4- to 8-week intervals for at least 20 months, with cumulative doses greater than 500 mg. This was particularly notable in postmenopausal women and men older than 50 years; participants with a body mass index less than 18.5 kg/m², history of a stress fracture, family history of osteopenia or osteoporosis, and history of smoking; and those who did not regularly engage in weight-bearing exercises.²⁴ Patients receiving long-term (ie, >1 year) intralesional steroids should be evaluated for osteoporosis risk and preventative strategies should be considered (ie, regular weight-bearing exercises, calcium and vitamin D supplementation, bisphosphate therapy). As with topical GCs, there are no clear guidelines for risk assessment or treatment recommendations for GIO.

Intramuscular GCs—The data regarding intramuscular (IM) GCs and dermatologic disease is severely limited, and to the best of our knowledge, no studies specifically assess the risk for GIO or fracture secondary to intramuscular GCs; however, a retrospective study of 27 patients (4 female, 23 male; mean age, 33 years [range, 12–61 years]) with refractory alopecia areata receiving IM triamcinolone acetonide (40 mg every 4 weeks for 3–6 months) reported 1 patient (a 56-year-old woman) with notably decreased bone densitometry from baseline requiring treatment discontinuation.²⁵ No other patients at risk for osteoporosis had decreased BMD from treatment with IM triamcinolone; however, it was noted that 1 month following treatment, 10 of 11 assessed patients demonstrated decreased levels of morning serum cortisol and plasma adrenocorticotropic hormone—despite baseline levels within reference range—that resolved 3 months after treatment completion,²⁵ which suggests a prolonged release of IM triamcinolone and sustained systemic effect. One systematic review of 342 patients with dermatologic diseases treated with IM corticosteroids found the primary side effects included dysmenorrhea, injection-site lipoatrophy, and adrenocortical suppression, with only a single reported case of low BMD.²⁶ Given the paucity of evidence, additional studies are required to assess the effect of IM triamcinolone on BMD and risk for major OP fractures with regard to dosing and frequency. As there are no clear guidelines for osteoporosis evaluation in the setting of intramuscular GCs, it may be prudent to follow the algorithmic model recommended for oral steroids when anticipating at least 3 months of intramuscular GCs.

Diet and Prevention of Bone Loss

Given the profound impact that systemic GCs have on osteoporosis and fracture risk and the sparse data regarding risk from topical, intralesional, or intramuscular GCs, diet and nutrition represent a simple, safe, and potentially preventative method of slowing BMD loss and minimizing fracture risk. In higher-risk patients, nutritional assessment in combination with medical therapy also is likely warranted.

Calcium and Vitamin D₃—Patients treated with any GC dose longer than 3 months should undergo calcium and vitamin D optimization.¹⁹ Exceptions for supplementation include certain patients with sarcoidosis, which can be associated with high vitamin D levels; patients with a history of hypercalcemia or hypercalciuria; and patients with chronic kidney disease.⁶ In a meta-analysis including 30,970 patients in 8 randomized controlled trials, calcium (500–1200 mg/d) and vitamin D (400–800 IU/d) supplementation reduced the risk of total fractures by 15% (summary relative risk estimate, 0.85 [95% CI, 0.73-0.98]) and hip fractures by 30% (summary relative risk estimate, 0.70 [95% CI, 0.56-0.87]).⁴ One double-blind, placebo-controlled clinical trial conducted by the Women’s Health Initiative that included 36,282 postmenopausal women who were taking 1000 mg of calcium and 400 IU of vitamin D₃ daily for more than 5 years reported an HR of 0.62 (95% CI, 0.38-1.00) for hip fracture for supplementation vs placebo.²⁷ Lastly, a 2016 Cochrane Review including 12 randomized trials and 1343 participants reported a 43% lower risk of new vertebral fractures following supplementation with calcium, vitamin D, or both compared with controls.²⁸

Specific recommendations for calcium and vitamin D₃ supplementation vary based on age and sex. The US Preventive Services Task Force concluded that insufficient evidence exists to support calcium and vitamin D₃ supplementation in asymptomatic men and premenopausal women.²⁹ The National Osteoporosis Foundation (NOF) supports the use of calcium supplementation for fracture risk reduction in middle-aged and older adults.⁴ Furthermore, the NOF supports the Institute of Medicine recommendations³¹ that men aged 50 to 70 years consume 1000 mg/d of calcium and that women 51 years and older as well as men 71 years and older consume 1200 mg/d of calcium.³⁰ The NOF recommends 800 to 1000 IU/d of vitamin D in adults 50 years and older, while the Institute of Medicine recommends 600 IU/d in adults 70 years and younger and 800 IU/d in adults 71 years and older.³¹ These recommendations are similar to both the Endocrine Society and the American Geriatric Society.^32,33 Total calcium should not exceed 2000 mg/d due to risk of adverse effects.

Dietary sources of vitamin D include fatty fish, mushrooms, and fortified dairy products, though recommended doses rarely can be achieved through diet alone.³⁴ Dairy products are the primary source of dietary calcium. Other high-calcium foods include green leafy vegetables, nuts and seeds, soft-boned fish, and fortified beverages and cereals.³⁵

Probiotics—A growing body of evidence suggests that probiotics may be beneficial in promoting bone health by improving calcium homeostasis, reducing risk for hyperparathyroidism secondary to GC therapy, and decreasing age-related bone resorption.³⁶ An animal study demonstrated that probiotics can regulate bone resorption and formation as well as reduce bone loss secondary to GC therapy.³⁷ A randomized, double-blind, placebo-controlled, multicenter trial randomly assigned 249 healthy, early postmenopausal women to receive probiotic treatment containing 3 lactobacillus strains (Lactobacillus paracasei DSM 13434, Lactobacillus plantarum DSM 15312, and L plantarum DSM 15313) or placebo once daily for 12 months.³⁸ Bone mineral density was measured at baseline and at 12 months. Of the 234 participants who completed the study, lactobacillus treatment reduced lumbosacral BMD loss compared to the placebo group (mean difference, 0.71% [95% CI, 0.06-1.35]). They also reported significant lumbosacral BMD loss in the placebo group (−0.72% [95% CI, −1.22 to −0.22]) compared to no BMD loss in the group treated with lactobacillus (−0.01% [95% CI, −0.50 to 0.48]).³⁸ Although the data may be encouraging, more studies are needed to determine if probiotics should be regarded as an adjuvant treatment to calcium, vitamin D, and pharmacologic therapy for long-term prevention of bone loss in the setting of GIO.³⁹ Because existing studies on probiotics include varying compositions and doses, larger studies with consistent supplementation are required. Encouraging probiotic intake through fermented dairy products may represent a simple low-risk intervention to support bone health.

Anti-inflammatory Diet—The traditional Mediterranean diet is rich in fruits, vegetables, fish, nuts, whole grains, legumes, and monounsaturated fats and low in meat and dairy products. The Mediterranean diet has been shown to be modestly protective against osteoporosis and fracture risk. A large US observational study including 93,676 women showed that those with the highest quintile of the alternate Mediterranean diet score had a lower risk for hip fracture (HR, 0.80 [95% CI, 0.66-0.97]), with an absolute risk reduction of 0.29% and number needed to treat at 342.⁴⁰ A multicenter study involving adults from 8 European countries found that increased adherence to the Mediterranean diet was associated with a 7% reduction in hip fracture incidence (HR per 1 unit increase in Mediterranean diet, 0.93 [95% CI, 0.89-0.98]). High vegetable and fruit intake was associated with decreased hip fracture incidence (HR, 0.86 and 0.89 [95% CI, 0.79-0.94 and 0.82-0.97, respectively]), and high meat and excessive ethanol consumption were associated with increased fracture incidence (HR, 1.18 and 1.74 [95% CI, 1.06-1.31 and 1.32-2.31, respectively]).⁴¹ Similarly, a large observational study in Sweden that included 37,903 men and 33,403 women reported similar findings, noting a 6% lower hip fracture rate per one unit increase in alternate Mediterranean diet score (adjusted HR, 0.94 [95% CI, 0.92-0.96]).⁴² This is thought to be due in part to higher levels of dietary vitamin D present in many foods traditionally included in the Mediterranean diet.⁴³ Additionally, olive oil, a staple in the Mediterranean diet, appears to reduce bone loss by promoting osteoblast proliferation and maturation, inhibiting bone resorption, suppressing oxidative stress and inflammation, and increasing calcium deposition in the extracellular matrix.^44,45 Fruits, vegetables, legumes, and nuts also are rich in minerals including potassium and magnesium, which are important in bone health to promote osteoblast proliferation and vitamin D activation.^36,46-48

Final Thoughts

Osteoporosis-related fractures are common and are associated with high morbidity and health care costs. Dermatologists using and prescribing corticosteroids must be aware of the risk for GIO, particularly in patients with a pre-existing diagnosis of osteopenia or osteoporosis. There likely is no oral corticosteroid dose that does not increase a patient’s risk for osteoporosis; therefore, oral GCs should be used at the lowest effective daily dose for the shortest duration possible. Patients with an anticipated duration of at least 3 months—regardless of dose—should be assessed for their risk for GIO. Patients using topical and intralesional corticosteroids are unlikely to develop GIO; however, those with risk factors and a considerable cumulative dose may warrant further evaluation. In all cases, we advocate for supplementing with calcium and vitamin D as well as promoting probiotic intake and the Mediterranean diet. Those at moderate to high risk for fracture may require additional medical therapy. Dermatologists are uniquely positioned to identify this at-risk population, and because osteoporosis is a chronic illness, primary care providers should be notified of prolonged GC therapy to help with risk assessment, initiation of vitamin and mineral supplementation, and follow-up with metabolic bone health specialists. Through a multidisciplinary approach and patient education, GIO and the potential risk for fracture can be successfully mitigated in most patients.

Glucocorticoids (GCs) are among the most widely prescribed medications in dermatologic practice. Although GCs are highly effective anti-inflammatory agents, long-term systemic therapy can result in dangerous adverse effects, including GC-induced osteoporosis (GIO), a bone disease associated with a heightened risk for fragility fractures.^1,2 In the United States, an estimated 10.2 million adults have osteoporosis—defined as a T-score lower than −2.5 measured via a bone densitometry scan—and 43.4 million adults have low bone mineral density (BMD).^3,4 The prevalence of osteoporosis is increasing, and the diagnosis is more common in females and adults 55 years and older.² More than 2 million individuals have osteoporosis-related fractures annually, and the mortality risk is increased at 5 and 10 years following low-energy osteoporosis-related fractures.^3-5

Glucocorticoid therapy is the leading iatrogenic cause of secondary osteoporosis. As many as 30% of all patients treated with systemic GCs for more than 6 months develop GIO.^1,6,7 Glucocorticoid-induced BMD loss occurs at a rate of 6% to 12% of total BMD during the first year, slowing to approximately 3% per year during subsequent therapy.¹ The risk for insufficiency fractures increases by as much as 75% from baseline in adults with rheumatic, pulmonary, and skin disorders within the first 3 months of therapy and peaks at approximately 12 months.^1,2

Despite the risks, many long-term GC users never receive therapy to prevent bone loss; others are only started on therapy once they have sustained an insufficiency fracture. A 5-year international observational study including more than 40,000 postmenopausal women found that only 51% of patients who were on continuous GC therapy were undergoing BMD testing and appropriate medical management.⁸ This review highlights the existing evidence on the risks of osteoporosis and osteoporotic (OP) fractures in the setting of topical, intralesional, intramuscular, and systemic GC treatment, as well as recommendations for nutritional supplementation to reduce these risks.

Pathophysiology

The pathophysiology of GIO is multifactorial and occurs in both early and late phases.^9,10 The early phase is characterized by rapid BMD reduction due to excessive bone resorption. The late phase is characterized by slower and more progressive BMD reduction due to impaired bone formation.⁹ At the osteocyte level, GCs decrease cell viability and induce apoptosis.¹¹ At the osteoblast level, GCs impair cell replication and differentiation and have proapoptotic effects, resulting in decreased cell numbers and subsequent bone formation.¹⁰ At the osteoclast level, GCs increase expression of pro-osteoclastic cytokines and decrease mature osteoclast apoptosis, resulting in an expanded osteoclastic life span and prolonged bone resorption.^12,13 Indirectly, GCs alter calcium metabolism by decreasing gastrointestinal calcium absorption and impairing renal absorption.^14,15

GCs and Osteoporosis

Oral GCs—Glucocorticoid-induced osteoporosis and fracture risk are dose and duration dependent.⁶ A study of 244,235 patients taking GCs and 244,235 controls found the relative risk of vertebral fracture was 1.55 (range, 1.20–2.01) for daily prednisone use at less than 2.5 mg, 2.59 (range, 2.16–3.10) for daily prednisone use from 2.5 to 7.4 mg, and 5.18 (range, 4.25–6.31) for daily doses of 7.5 mg or higher; the relative risk for hip fractures was 0.99 (range, 0.82–1.20), 1.77 (range, 1.55–2.02), and 2.27 (range, 1.94–2.66), respectively.¹⁶ Another large retrospective cohort study found that continuous treatment with prednisone 10 mg/d for more than 90 days compared to no GC exposure increased the risk for hip fractures 7-fold and 17-fold for vertebral fractures.¹⁷ Although the minimum cumulative dose of GCs known to cause osteoporosis is not clearly established, the American College of Rheumatology has proposed an algorithm as a basic approach to anticipate, prevent, and treat GIO (Figure).^18,19 Fracture risk should be assessed in all patients who are prescribed prednisone 2.5 mg/d for 3 months or longer or an anticipated cumulative dose of more than 1 g per year. Patients 40 years and older with anticipated GC use of 3 months or longer should have both a bone densitometry scan and a Fracture Risk Assessment (FRAX) score. The FRAX tool estimates the 10-year probability of fracture in patients aged 40 to 80 years, and those patients can be further risk stratified as low (FRAX <10%), moderate (FRAX 10%–19%), or high (FRAX ≥20%) risk. In patients with moderate to high risk of fracture (FRAX >10%), initiation of pharmacologic treatment or referral to a metabolic bone specialist should be considered.^18,19 First-line therapy is an oral bisphosphonate, and second-line therapies include intravenous bisphosphonates, teriparatide, denosumab, or raloxifene for patients at high risk for GIO.¹⁹ Adults younger than 40 years with a history of OP fracture or considerable risk factors for OP fractures should have a bone densitometry scan, and, if results are abnormal, the patient should be referred to a metabolic bone specialist. Those with low fracture risk based on bone densitometry and FRAX and those with no risk factors should be assessed annually for bone health (additional risk factors, GC dose and duration, bone densitometry/FRAX if indicated).¹⁸ In addition to GC dose and duration, additional risk factors for GIO, which are factored into the FRAX tool, include advanced age, low body mass index, history of bone fracture, smoking, excessive alcohol use (≥3 drinks/d), history of falls, low BMD, family history of bone fracture, and hypovitaminosis D.⁶

CT110004201_Figure.jpg

Topical GCs—Although there is strong evidence and clear guidelines regarding oral GIO, there is a dearth of data surrounding OP risk due to treatment with topical GCs. A recent retrospective nationwide Danish study evaluating the risk of osteoporosis and major OP fracture in 723,251 adults treated with potent or very potent topical steroids sought to evaluate these risks.²⁰ Patients were included if they had filled prescriptions of at least 500 g of topical mometasone or an equivalent alternative. The investigators reported a 3% increase in relative risk of osteoporosis and major OP fracture with doubling of the cumulative topical GC dose (hazard ratio [HR], 1.03 [95% CI, 1.02-1.04] for both). The overall population-attributable risk was 4.3% (95% CI, 2.7%-5.8%) for osteoporosis and 2.7% (95% CI, 1.7%-3.8%) for major OP fracture. Notably, at least 10,000 g of mometasone was required for 1 additional patient to have a major OP fracture.²⁰ In a commentary based on this study, Jackson²¹ noted that the number of patient-years of topical GC use needed for 1 fracture was 4-fold higher than that for high-dose oral GCs (40 mg/d prednisolone for ≥30 days). Another study assessed the effects of topical GCs on BMD in adults with moderate to severe atopic dermatitis over a 2-year period.²² No significant difference in BMD assessed via bone densitometry of either the lumbar spine or total hip at baseline or at 2-year follow-up was reported for either group treated with corticosteroids (<75 g per month or ≥75 g per month). Of note, the authors did not account for steroid potency, which ranged from class 1 through class 4.²² Although limited data exist, these studies suggest topical GCs used at conventional doses with appropriate breaks in therapy will not substantially increase risk for GIO or OP fracture; however, in the small subset of patients requiring chronic use of superpotent topical corticosteroids with other OP risk factors, transitioning to non–GC-based therapy or initiating bone health therapy may be advised to improve patient outcomes. Risk assessment, as in cases of chronic topical GC use, may be beneficial.

Intralesional GCs—Intralesional GCs are indicated for numerous inflammatory conditions including alopecia areata, discoid lupus erythematosus, keloids, and granuloma annulare. It generally is accepted that doses of triamcinolone acetonide should not exceed 20 mg per session spaced at least 3 weeks apart or up to 40 mg per month.¹⁸ One study demonstrated that doses of triamcinolone diacetate of 25 mg or less were unlikely to produce systemic effects and were determined to be a safe dose for intralesional injections.²³ A retrospective cross-sectional case series including 18 patients with alopecia areata reported decreased BMD in 9 patients receiving intralesional triamcinolone acetonide 10 mg/mL at 4- to 8-week intervals for at least 20 months, with cumulative doses greater than 500 mg. This was particularly notable in postmenopausal women and men older than 50 years; participants with a body mass index less than 18.5 kg/m², history of a stress fracture, family history of osteopenia or osteoporosis, and history of smoking; and those who did not regularly engage in weight-bearing exercises.²⁴ Patients receiving long-term (ie, >1 year) intralesional steroids should be evaluated for osteoporosis risk and preventative strategies should be considered (ie, regular weight-bearing exercises, calcium and vitamin D supplementation, bisphosphate therapy). As with topical GCs, there are no clear guidelines for risk assessment or treatment recommendations for GIO.

Intramuscular GCs—The data regarding intramuscular (IM) GCs and dermatologic disease is severely limited, and to the best of our knowledge, no studies specifically assess the risk for GIO or fracture secondary to intramuscular GCs; however, a retrospective study of 27 patients (4 female, 23 male; mean age, 33 years [range, 12–61 years]) with refractory alopecia areata receiving IM triamcinolone acetonide (40 mg every 4 weeks for 3–6 months) reported 1 patient (a 56-year-old woman) with notably decreased bone densitometry from baseline requiring treatment discontinuation.²⁵ No other patients at risk for osteoporosis had decreased BMD from treatment with IM triamcinolone; however, it was noted that 1 month following treatment, 10 of 11 assessed patients demonstrated decreased levels of morning serum cortisol and plasma adrenocorticotropic hormone—despite baseline levels within reference range—that resolved 3 months after treatment completion,²⁵ which suggests a prolonged release of IM triamcinolone and sustained systemic effect. One systematic review of 342 patients with dermatologic diseases treated with IM corticosteroids found the primary side effects included dysmenorrhea, injection-site lipoatrophy, and adrenocortical suppression, with only a single reported case of low BMD.²⁶ Given the paucity of evidence, additional studies are required to assess the effect of IM triamcinolone on BMD and risk for major OP fractures with regard to dosing and frequency. As there are no clear guidelines for osteoporosis evaluation in the setting of intramuscular GCs, it may be prudent to follow the algorithmic model recommended for oral steroids when anticipating at least 3 months of intramuscular GCs.

Diet and Prevention of Bone Loss

Given the profound impact that systemic GCs have on osteoporosis and fracture risk and the sparse data regarding risk from topical, intralesional, or intramuscular GCs, diet and nutrition represent a simple, safe, and potentially preventative method of slowing BMD loss and minimizing fracture risk. In higher-risk patients, nutritional assessment in combination with medical therapy also is likely warranted.

Calcium and Vitamin D₃—Patients treated with any GC dose longer than 3 months should undergo calcium and vitamin D optimization.¹⁹ Exceptions for supplementation include certain patients with sarcoidosis, which can be associated with high vitamin D levels; patients with a history of hypercalcemia or hypercalciuria; and patients with chronic kidney disease.⁶ In a meta-analysis including 30,970 patients in 8 randomized controlled trials, calcium (500–1200 mg/d) and vitamin D (400–800 IU/d) supplementation reduced the risk of total fractures by 15% (summary relative risk estimate, 0.85 [95% CI, 0.73-0.98]) and hip fractures by 30% (summary relative risk estimate, 0.70 [95% CI, 0.56-0.87]).⁴ One double-blind, placebo-controlled clinical trial conducted by the Women’s Health Initiative that included 36,282 postmenopausal women who were taking 1000 mg of calcium and 400 IU of vitamin D₃ daily for more than 5 years reported an HR of 0.62 (95% CI, 0.38-1.00) for hip fracture for supplementation vs placebo.²⁷ Lastly, a 2016 Cochrane Review including 12 randomized trials and 1343 participants reported a 43% lower risk of new vertebral fractures following supplementation with calcium, vitamin D, or both compared with controls.²⁸

Specific recommendations for calcium and vitamin D₃ supplementation vary based on age and sex. The US Preventive Services Task Force concluded that insufficient evidence exists to support calcium and vitamin D₃ supplementation in asymptomatic men and premenopausal women.²⁹ The National Osteoporosis Foundation (NOF) supports the use of calcium supplementation for fracture risk reduction in middle-aged and older adults.⁴ Furthermore, the NOF supports the Institute of Medicine recommendations³¹ that men aged 50 to 70 years consume 1000 mg/d of calcium and that women 51 years and older as well as men 71 years and older consume 1200 mg/d of calcium.³⁰ The NOF recommends 800 to 1000 IU/d of vitamin D in adults 50 years and older, while the Institute of Medicine recommends 600 IU/d in adults 70 years and younger and 800 IU/d in adults 71 years and older.³¹ These recommendations are similar to both the Endocrine Society and the American Geriatric Society.^32,33 Total calcium should not exceed 2000 mg/d due to risk of adverse effects.

Dietary sources of vitamin D include fatty fish, mushrooms, and fortified dairy products, though recommended doses rarely can be achieved through diet alone.³⁴ Dairy products are the primary source of dietary calcium. Other high-calcium foods include green leafy vegetables, nuts and seeds, soft-boned fish, and fortified beverages and cereals.³⁵

Probiotics—A growing body of evidence suggests that probiotics may be beneficial in promoting bone health by improving calcium homeostasis, reducing risk for hyperparathyroidism secondary to GC therapy, and decreasing age-related bone resorption.³⁶ An animal study demonstrated that probiotics can regulate bone resorption and formation as well as reduce bone loss secondary to GC therapy.³⁷ A randomized, double-blind, placebo-controlled, multicenter trial randomly assigned 249 healthy, early postmenopausal women to receive probiotic treatment containing 3 lactobacillus strains (Lactobacillus paracasei DSM 13434, Lactobacillus plantarum DSM 15312, and L plantarum DSM 15313) or placebo once daily for 12 months.³⁸ Bone mineral density was measured at baseline and at 12 months. Of the 234 participants who completed the study, lactobacillus treatment reduced lumbosacral BMD loss compared to the placebo group (mean difference, 0.71% [95% CI, 0.06-1.35]). They also reported significant lumbosacral BMD loss in the placebo group (−0.72% [95% CI, −1.22 to −0.22]) compared to no BMD loss in the group treated with lactobacillus (−0.01% [95% CI, −0.50 to 0.48]).³⁸ Although the data may be encouraging, more studies are needed to determine if probiotics should be regarded as an adjuvant treatment to calcium, vitamin D, and pharmacologic therapy for long-term prevention of bone loss in the setting of GIO.³⁹ Because existing studies on probiotics include varying compositions and doses, larger studies with consistent supplementation are required. Encouraging probiotic intake through fermented dairy products may represent a simple low-risk intervention to support bone health.

Anti-inflammatory Diet—The traditional Mediterranean diet is rich in fruits, vegetables, fish, nuts, whole grains, legumes, and monounsaturated fats and low in meat and dairy products. The Mediterranean diet has been shown to be modestly protective against osteoporosis and fracture risk. A large US observational study including 93,676 women showed that those with the highest quintile of the alternate Mediterranean diet score had a lower risk for hip fracture (HR, 0.80 [95% CI, 0.66-0.97]), with an absolute risk reduction of 0.29% and number needed to treat at 342.⁴⁰ A multicenter study involving adults from 8 European countries found that increased adherence to the Mediterranean diet was associated with a 7% reduction in hip fracture incidence (HR per 1 unit increase in Mediterranean diet, 0.93 [95% CI, 0.89-0.98]). High vegetable and fruit intake was associated with decreased hip fracture incidence (HR, 0.86 and 0.89 [95% CI, 0.79-0.94 and 0.82-0.97, respectively]), and high meat and excessive ethanol consumption were associated with increased fracture incidence (HR, 1.18 and 1.74 [95% CI, 1.06-1.31 and 1.32-2.31, respectively]).⁴¹ Similarly, a large observational study in Sweden that included 37,903 men and 33,403 women reported similar findings, noting a 6% lower hip fracture rate per one unit increase in alternate Mediterranean diet score (adjusted HR, 0.94 [95% CI, 0.92-0.96]).⁴² This is thought to be due in part to higher levels of dietary vitamin D present in many foods traditionally included in the Mediterranean diet.⁴³ Additionally, olive oil, a staple in the Mediterranean diet, appears to reduce bone loss by promoting osteoblast proliferation and maturation, inhibiting bone resorption, suppressing oxidative stress and inflammation, and increasing calcium deposition in the extracellular matrix.^44,45 Fruits, vegetables, legumes, and nuts also are rich in minerals including potassium and magnesium, which are important in bone health to promote osteoblast proliferation and vitamin D activation.^36,46-48

Final Thoughts

Osteoporosis-related fractures are common and are associated with high morbidity and health care costs. Dermatologists using and prescribing corticosteroids must be aware of the risk for GIO, particularly in patients with a pre-existing diagnosis of osteopenia or osteoporosis. There likely is no oral corticosteroid dose that does not increase a patient’s risk for osteoporosis; therefore, oral GCs should be used at the lowest effective daily dose for the shortest duration possible. Patients with an anticipated duration of at least 3 months—regardless of dose—should be assessed for their risk for GIO. Patients using topical and intralesional corticosteroids are unlikely to develop GIO; however, those with risk factors and a considerable cumulative dose may warrant further evaluation. In all cases, we advocate for supplementing with calcium and vitamin D as well as promoting probiotic intake and the Mediterranean diet. Those at moderate to high risk for fracture may require additional medical therapy. Dermatologists are uniquely positioned to identify this at-risk population, and because osteoporosis is a chronic illness, primary care providers should be notified of prolonged GC therapy to help with risk assessment, initiation of vitamin and mineral supplementation, and follow-up with metabolic bone health specialists. Through a multidisciplinary approach and patient education, GIO and the potential risk for fracture can be successfully mitigated in most patients.

Glucocorticoids (GCs) are among the most widely prescribed medications in dermatologic practice. Although GCs are highly effective anti-inflammatory agents, long-term systemic therapy can result in dangerous adverse effects, including GC-induced osteoporosis (GIO), a bone disease associated with a heightened risk for fragility fractures.^1,2 In the United States, an estimated 10.2 million adults have osteoporosis—defined as a T-score lower than −2.5 measured via a bone densitometry scan—and 43.4 million adults have low bone mineral density (BMD).^3,4 The prevalence of osteoporosis is increasing, and the diagnosis is more common in females and adults 55 years and older.² More than 2 million individuals have osteoporosis-related fractures annually, and the mortality risk is increased at 5 and 10 years following low-energy osteoporosis-related fractures.^3-5

Glucocorticoid therapy is the leading iatrogenic cause of secondary osteoporosis. As many as 30% of all patients treated with systemic GCs for more than 6 months develop GIO.^1,6,7 Glucocorticoid-induced BMD loss occurs at a rate of 6% to 12% of total BMD during the first year, slowing to approximately 3% per year during subsequent therapy.¹ The risk for insufficiency fractures increases by as much as 75% from baseline in adults with rheumatic, pulmonary, and skin disorders within the first 3 months of therapy and peaks at approximately 12 months.^1,2

Despite the risks, many long-term GC users never receive therapy to prevent bone loss; others are only started on therapy once they have sustained an insufficiency fracture. A 5-year international observational study including more than 40,000 postmenopausal women found that only 51% of patients who were on continuous GC therapy were undergoing BMD testing and appropriate medical management.⁸ This review highlights the existing evidence on the risks of osteoporosis and osteoporotic (OP) fractures in the setting of topical, intralesional, intramuscular, and systemic GC treatment, as well as recommendations for nutritional supplementation to reduce these risks.

Pathophysiology

The pathophysiology of GIO is multifactorial and occurs in both early and late phases.^9,10 The early phase is characterized by rapid BMD reduction due to excessive bone resorption. The late phase is characterized by slower and more progressive BMD reduction due to impaired bone formation.⁹ At the osteocyte level, GCs decrease cell viability and induce apoptosis.¹¹ At the osteoblast level, GCs impair cell replication and differentiation and have proapoptotic effects, resulting in decreased cell numbers and subsequent bone formation.¹⁰ At the osteoclast level, GCs increase expression of pro-osteoclastic cytokines and decrease mature osteoclast apoptosis, resulting in an expanded osteoclastic life span and prolonged bone resorption.^12,13 Indirectly, GCs alter calcium metabolism by decreasing gastrointestinal calcium absorption and impairing renal absorption.^14,15

GCs and Osteoporosis

Oral GCs—Glucocorticoid-induced osteoporosis and fracture risk are dose and duration dependent.⁶ A study of 244,235 patients taking GCs and 244,235 controls found the relative risk of vertebral fracture was 1.55 (range, 1.20–2.01) for daily prednisone use at less than 2.5 mg, 2.59 (range, 2.16–3.10) for daily prednisone use from 2.5 to 7.4 mg, and 5.18 (range, 4.25–6.31) for daily doses of 7.5 mg or higher; the relative risk for hip fractures was 0.99 (range, 0.82–1.20), 1.77 (range, 1.55–2.02), and 2.27 (range, 1.94–2.66), respectively.¹⁶ Another large retrospective cohort study found that continuous treatment with prednisone 10 mg/d for more than 90 days compared to no GC exposure increased the risk for hip fractures 7-fold and 17-fold for vertebral fractures.¹⁷ Although the minimum cumulative dose of GCs known to cause osteoporosis is not clearly established, the American College of Rheumatology has proposed an algorithm as a basic approach to anticipate, prevent, and treat GIO (Figure).^18,19 Fracture risk should be assessed in all patients who are prescribed prednisone 2.5 mg/d for 3 months or longer or an anticipated cumulative dose of more than 1 g per year. Patients 40 years and older with anticipated GC use of 3 months or longer should have both a bone densitometry scan and a Fracture Risk Assessment (FRAX) score. The FRAX tool estimates the 10-year probability of fracture in patients aged 40 to 80 years, and those patients can be further risk stratified as low (FRAX <10%), moderate (FRAX 10%–19%), or high (FRAX ≥20%) risk. In patients with moderate to high risk of fracture (FRAX >10%), initiation of pharmacologic treatment or referral to a metabolic bone specialist should be considered.^18,19 First-line therapy is an oral bisphosphonate, and second-line therapies include intravenous bisphosphonates, teriparatide, denosumab, or raloxifene for patients at high risk for GIO.¹⁹ Adults younger than 40 years with a history of OP fracture or considerable risk factors for OP fractures should have a bone densitometry scan, and, if results are abnormal, the patient should be referred to a metabolic bone specialist. Those with low fracture risk based on bone densitometry and FRAX and those with no risk factors should be assessed annually for bone health (additional risk factors, GC dose and duration, bone densitometry/FRAX if indicated).¹⁸ In addition to GC dose and duration, additional risk factors for GIO, which are factored into the FRAX tool, include advanced age, low body mass index, history of bone fracture, smoking, excessive alcohol use (≥3 drinks/d), history of falls, low BMD, family history of bone fracture, and hypovitaminosis D.⁶

CT110004201_Figure.jpg

Topical GCs—Although there is strong evidence and clear guidelines regarding oral GIO, there is a dearth of data surrounding OP risk due to treatment with topical GCs. A recent retrospective nationwide Danish study evaluating the risk of osteoporosis and major OP fracture in 723,251 adults treated with potent or very potent topical steroids sought to evaluate these risks.²⁰ Patients were included if they had filled prescriptions of at least 500 g of topical mometasone or an equivalent alternative. The investigators reported a 3% increase in relative risk of osteoporosis and major OP fracture with doubling of the cumulative topical GC dose (hazard ratio [HR], 1.03 [95% CI, 1.02-1.04] for both). The overall population-attributable risk was 4.3% (95% CI, 2.7%-5.8%) for osteoporosis and 2.7% (95% CI, 1.7%-3.8%) for major OP fracture. Notably, at least 10,000 g of mometasone was required for 1 additional patient to have a major OP fracture.²⁰ In a commentary based on this study, Jackson²¹ noted that the number of patient-years of topical GC use needed for 1 fracture was 4-fold higher than that for high-dose oral GCs (40 mg/d prednisolone for ≥30 days). Another study assessed the effects of topical GCs on BMD in adults with moderate to severe atopic dermatitis over a 2-year period.²² No significant difference in BMD assessed via bone densitometry of either the lumbar spine or total hip at baseline or at 2-year follow-up was reported for either group treated with corticosteroids (<75 g per month or ≥75 g per month). Of note, the authors did not account for steroid potency, which ranged from class 1 through class 4.²² Although limited data exist, these studies suggest topical GCs used at conventional doses with appropriate breaks in therapy will not substantially increase risk for GIO or OP fracture; however, in the small subset of patients requiring chronic use of superpotent topical corticosteroids with other OP risk factors, transitioning to non–GC-based therapy or initiating bone health therapy may be advised to improve patient outcomes. Risk assessment, as in cases of chronic topical GC use, may be beneficial.

Intralesional GCs—Intralesional GCs are indicated for numerous inflammatory conditions including alopecia areata, discoid lupus erythematosus, keloids, and granuloma annulare. It generally is accepted that doses of triamcinolone acetonide should not exceed 20 mg per session spaced at least 3 weeks apart or up to 40 mg per month.¹⁸ One study demonstrated that doses of triamcinolone diacetate of 25 mg or less were unlikely to produce systemic effects and were determined to be a safe dose for intralesional injections.²³ A retrospective cross-sectional case series including 18 patients with alopecia areata reported decreased BMD in 9 patients receiving intralesional triamcinolone acetonide 10 mg/mL at 4- to 8-week intervals for at least 20 months, with cumulative doses greater than 500 mg. This was particularly notable in postmenopausal women and men older than 50 years; participants with a body mass index less than 18.5 kg/m², history of a stress fracture, family history of osteopenia or osteoporosis, and history of smoking; and those who did not regularly engage in weight-bearing exercises.²⁴ Patients receiving long-term (ie, >1 year) intralesional steroids should be evaluated for osteoporosis risk and preventative strategies should be considered (ie, regular weight-bearing exercises, calcium and vitamin D supplementation, bisphosphate therapy). As with topical GCs, there are no clear guidelines for risk assessment or treatment recommendations for GIO.

Intramuscular GCs—The data regarding intramuscular (IM) GCs and dermatologic disease is severely limited, and to the best of our knowledge, no studies specifically assess the risk for GIO or fracture secondary to intramuscular GCs; however, a retrospective study of 27 patients (4 female, 23 male; mean age, 33 years [range, 12–61 years]) with refractory alopecia areata receiving IM triamcinolone acetonide (40 mg every 4 weeks for 3–6 months) reported 1 patient (a 56-year-old woman) with notably decreased bone densitometry from baseline requiring treatment discontinuation.²⁵ No other patients at risk for osteoporosis had decreased BMD from treatment with IM triamcinolone; however, it was noted that 1 month following treatment, 10 of 11 assessed patients demonstrated decreased levels of morning serum cortisol and plasma adrenocorticotropic hormone—despite baseline levels within reference range—that resolved 3 months after treatment completion,²⁵ which suggests a prolonged release of IM triamcinolone and sustained systemic effect. One systematic review of 342 patients with dermatologic diseases treated with IM corticosteroids found the primary side effects included dysmenorrhea, injection-site lipoatrophy, and adrenocortical suppression, with only a single reported case of low BMD.²⁶ Given the paucity of evidence, additional studies are required to assess the effect of IM triamcinolone on BMD and risk for major OP fractures with regard to dosing and frequency. As there are no clear guidelines for osteoporosis evaluation in the setting of intramuscular GCs, it may be prudent to follow the algorithmic model recommended for oral steroids when anticipating at least 3 months of intramuscular GCs.

Diet and Prevention of Bone Loss

Given the profound impact that systemic GCs have on osteoporosis and fracture risk and the sparse data regarding risk from topical, intralesional, or intramuscular GCs, diet and nutrition represent a simple, safe, and potentially preventative method of slowing BMD loss and minimizing fracture risk. In higher-risk patients, nutritional assessment in combination with medical therapy also is likely warranted.

Calcium and Vitamin D₃—Patients treated with any GC dose longer than 3 months should undergo calcium and vitamin D optimization.¹⁹ Exceptions for supplementation include certain patients with sarcoidosis, which can be associated with high vitamin D levels; patients with a history of hypercalcemia or hypercalciuria; and patients with chronic kidney disease.⁶ In a meta-analysis including 30,970 patients in 8 randomized controlled trials, calcium (500–1200 mg/d) and vitamin D (400–800 IU/d) supplementation reduced the risk of total fractures by 15% (summary relative risk estimate, 0.85 [95% CI, 0.73-0.98]) and hip fractures by 30% (summary relative risk estimate, 0.70 [95% CI, 0.56-0.87]).⁴ One double-blind, placebo-controlled clinical trial conducted by the Women’s Health Initiative that included 36,282 postmenopausal women who were taking 1000 mg of calcium and 400 IU of vitamin D₃ daily for more than 5 years reported an HR of 0.62 (95% CI, 0.38-1.00) for hip fracture for supplementation vs placebo.²⁷ Lastly, a 2016 Cochrane Review including 12 randomized trials and 1343 participants reported a 43% lower risk of new vertebral fractures following supplementation with calcium, vitamin D, or both compared with controls.²⁸

Specific recommendations for calcium and vitamin D₃ supplementation vary based on age and sex. The US Preventive Services Task Force concluded that insufficient evidence exists to support calcium and vitamin D₃ supplementation in asymptomatic men and premenopausal women.²⁹ The National Osteoporosis Foundation (NOF) supports the use of calcium supplementation for fracture risk reduction in middle-aged and older adults.⁴ Furthermore, the NOF supports the Institute of Medicine recommendations³¹ that men aged 50 to 70 years consume 1000 mg/d of calcium and that women 51 years and older as well as men 71 years and older consume 1200 mg/d of calcium.³⁰ The NOF recommends 800 to 1000 IU/d of vitamin D in adults 50 years and older, while the Institute of Medicine recommends 600 IU/d in adults 70 years and younger and 800 IU/d in adults 71 years and older.³¹ These recommendations are similar to both the Endocrine Society and the American Geriatric Society.^32,33 Total calcium should not exceed 2000 mg/d due to risk of adverse effects.

Dietary sources of vitamin D include fatty fish, mushrooms, and fortified dairy products, though recommended doses rarely can be achieved through diet alone.³⁴ Dairy products are the primary source of dietary calcium. Other high-calcium foods include green leafy vegetables, nuts and seeds, soft-boned fish, and fortified beverages and cereals.³⁵

Probiotics—A growing body of evidence suggests that probiotics may be beneficial in promoting bone health by improving calcium homeostasis, reducing risk for hyperparathyroidism secondary to GC therapy, and decreasing age-related bone resorption.³⁶ An animal study demonstrated that probiotics can regulate bone resorption and formation as well as reduce bone loss secondary to GC therapy.³⁷ A randomized, double-blind, placebo-controlled, multicenter trial randomly assigned 249 healthy, early postmenopausal women to receive probiotic treatment containing 3 lactobacillus strains (Lactobacillus paracasei DSM 13434, Lactobacillus plantarum DSM 15312, and L plantarum DSM 15313) or placebo once daily for 12 months.³⁸ Bone mineral density was measured at baseline and at 12 months. Of the 234 participants who completed the study, lactobacillus treatment reduced lumbosacral BMD loss compared to the placebo group (mean difference, 0.71% [95% CI, 0.06-1.35]). They also reported significant lumbosacral BMD loss in the placebo group (−0.72% [95% CI, −1.22 to −0.22]) compared to no BMD loss in the group treated with lactobacillus (−0.01% [95% CI, −0.50 to 0.48]).³⁸ Although the data may be encouraging, more studies are needed to determine if probiotics should be regarded as an adjuvant treatment to calcium, vitamin D, and pharmacologic therapy for long-term prevention of bone loss in the setting of GIO.³⁹ Because existing studies on probiotics include varying compositions and doses, larger studies with consistent supplementation are required. Encouraging probiotic intake through fermented dairy products may represent a simple low-risk intervention to support bone health.

Anti-inflammatory Diet—The traditional Mediterranean diet is rich in fruits, vegetables, fish, nuts, whole grains, legumes, and monounsaturated fats and low in meat and dairy products. The Mediterranean diet has been shown to be modestly protective against osteoporosis and fracture risk. A large US observational study including 93,676 women showed that those with the highest quintile of the alternate Mediterranean diet score had a lower risk for hip fracture (HR, 0.80 [95% CI, 0.66-0.97]), with an absolute risk reduction of 0.29% and number needed to treat at 342.⁴⁰ A multicenter study involving adults from 8 European countries found that increased adherence to the Mediterranean diet was associated with a 7% reduction in hip fracture incidence (HR per 1 unit increase in Mediterranean diet, 0.93 [95% CI, 0.89-0.98]). High vegetable and fruit intake was associated with decreased hip fracture incidence (HR, 0.86 and 0.89 [95% CI, 0.79-0.94 and 0.82-0.97, respectively]), and high meat and excessive ethanol consumption were associated with increased fracture incidence (HR, 1.18 and 1.74 [95% CI, 1.06-1.31 and 1.32-2.31, respectively]).⁴¹ Similarly, a large observational study in Sweden that included 37,903 men and 33,403 women reported similar findings, noting a 6% lower hip fracture rate per one unit increase in alternate Mediterranean diet score (adjusted HR, 0.94 [95% CI, 0.92-0.96]).⁴² This is thought to be due in part to higher levels of dietary vitamin D present in many foods traditionally included in the Mediterranean diet.⁴³ Additionally, olive oil, a staple in the Mediterranean diet, appears to reduce bone loss by promoting osteoblast proliferation and maturation, inhibiting bone resorption, suppressing oxidative stress and inflammation, and increasing calcium deposition in the extracellular matrix.^44,45 Fruits, vegetables, legumes, and nuts also are rich in minerals including potassium and magnesium, which are important in bone health to promote osteoblast proliferation and vitamin D activation.^36,46-48

Final Thoughts

Osteoporosis-related fractures are common and are associated with high morbidity and health care costs. Dermatologists using and prescribing corticosteroids must be aware of the risk for GIO, particularly in patients with a pre-existing diagnosis of osteopenia or osteoporosis. There likely is no oral corticosteroid dose that does not increase a patient’s risk for osteoporosis; therefore, oral GCs should be used at the lowest effective daily dose for the shortest duration possible. Patients with an anticipated duration of at least 3 months—regardless of dose—should be assessed for their risk for GIO. Patients using topical and intralesional corticosteroids are unlikely to develop GIO; however, those with risk factors and a considerable cumulative dose may warrant further evaluation. In all cases, we advocate for supplementing with calcium and vitamin D as well as promoting probiotic intake and the Mediterranean diet. Those at moderate to high risk for fracture may require additional medical therapy. Dermatologists are uniquely positioned to identify this at-risk population, and because osteoporosis is a chronic illness, primary care providers should be notified of prolonged GC therapy to help with risk assessment, initiation of vitamin and mineral supplementation, and follow-up with metabolic bone health specialists. Through a multidisciplinary approach and patient education, GIO and the potential risk for fracture can be successfully mitigated in most patients.

As reproductive specialists, part of our obligation is to improve a woman’s or couple’s ability to conceive in the most cost-effective manner, ideally through natural attempts at conception. While assisted reproductive technologies (ART) have provided impressive pregnancy rates across many diagnoses, including unexplained infertility, this advanced procedure comes with a significant financial cost to those without insurance and an emotional burden from the lack of a guaranteed outcome. Infertility procedures have minimal associated but potentially significant risks, most importantly multiple gestations. Contrary to popular belief, ovulation induction with intrauterine insemination (IUI) treatment has a greater risk of high-order multiple gestation when compared with IVF, given the inability of the former to control the number of embryos that may enter and implant in the endometrial cavity and the increased use of single embryo transfers with the latter. The specialist should evaluate the woman or couple for the basic issues of ovulation, tubal, and sperm function, as well as for lifestyle and environmental factors that can impede reproduction. As a result, “one size fits all” should not apply to patients, specifically those with infertility. This month’s column will present the detrimental effect of environmental and lifestyle factors on the goal of enhancing fertility through natural cycles of urine luteinizing-hormone timed intercourse.

Trolice_Mark _P_FLA_2022_web.jpg

Nutrition

Often overlooked in the infertility evaluation, an optimal diet improves fertility for both partners. Processed meat has been associated with reduced sperm quality. In ART, red meat has been associated with decreased embryo blastocyst formation. Lower trans fatty acids and higher omega-3s may improve fecundity. Considered one of the best overall diets, the Mediterranean diet consists of plant-based foods, such as whole grains, vegetables, legumes, fruits, nuts, seeds, herbs, and spices. Olive oil is the main source of added fat whereas fish, seafood, dairy, and poultry should be eaten in moderation. Fatty fish, such as mackerel, herring, sardines, albacore tuna, and salmon, are rich in omega-3 fatty acids, which have been shown to improve fecundity and IVF success, and have a positive association with blastocyst embryo development.^1-3

Stress

The emotional effect of an infertility diagnosis has been demonstrated to be equivalent to a diagnosis of cancer and other major medical morbidities.⁴ Whether stress causes or is a result of infertility has been a longstanding debate.⁵ Nevertheless, stress is the number-one reason patients discontinue fertility treatment.⁶ As fertility specialists, we must be cognizant of the devastation endured by infertility patients and maintain an open dialogue, as well as provide resources for coping strategies and counseling.

One popular method of improving mental health and fertility has been acupuncture. Initial enthusiasm originated from one of the first studies to explore the use of acupuncture during IVF. This was a prospective randomized study that showed treated patients had an approximately 100% improvement in clinical pregnancy rate. Unfortunately, there was no appropriate control group, just untreated controls.⁷ A subsequent study by the same investigator added a placebo acupuncture control group and did not show a statistically significant increase in pregnancy rates.⁸ Finally, a meta-analysis and reanalysis did not demonstrate any improvement in pregnancy outcome, whereas three of the studies analyzed suggested a possible reduction in pregnancies; placebo acupuncture was shown to have a higher success rate.^9-11 While acupuncture is relatively safe, there appears to be only a placebo effect that may be helpful.

The effect of stress on reproduction has been addressed in one of my previous columns.
 

Alcohol and caffeine

The damaging effects of alcohol on the fetus during pregnancy are legion – abnormal facial features, microcephaly, low birth weight, hyperactive behavior, vision or hearing deficits, speech and language delays, and intellectual disability. Less known is the amount of alcohol that may have an effect during preconception. One of the first reports on the effect of alcohol on IVF concluded: a 13% decrease in the number of eggs aspirated; a 2.86 times increase in risk of not achieving pregnancy; and a 2.21 times increase in risk of miscarriage. For men, one additional drink per day increased the risk of not achieving a live birth from 2.28 to 8.32 times.¹² Subsequent studies demonstrate a 16% reduction in IVF pregnancies in women who have at least four drinks per week; when the couple drank at least four drinks per week, the pregnancy rate decreased by 21%.¹³

However, a study from Denmark did not demonstrate a negative effect of low to moderate pretreatment amounts of alcohol and caffeine on IVF outcomes.¹⁴ Nevertheless, there is evidence that reducing or abstaining from alcohol intake may improve IVF outcomes.¹⁵ While there have been reports of higher miscarriage rates from caffeine,^16,17 not all reports support a negative association.¹⁸

Smoking

The use of tobacco has been estimated to contribute to 13% of female infertility in a dose-response manner, including secondhand smoke. During ART, smoking reduces ovarian response to gonadotropins and decreases IVF success by up to 50%. Discontinuing smoking for 6 months beforehand appears to restore normal outcomes.^19-20

The American Society for Reproductive Medicine Practice Committee on smoking provides the following invaluable information to share with patients on the harmful reproductive effects of smoking:²¹

• Early menopause by accelerating the loss of eggs.
• Higher rates of miscarriage and ectopic pregnancy.
• A decrease in sperm function.
• Possible genetic damage to eggs and sperm.
• Reduced sperm in son from maternal smoking.

Weight and exercise

Compared with normal-weight women, those with obesity are three times more likely to have ovulatory dysfunction;²² a lower chance for conception;²³ and infertility.²⁴ Obese women have higher rates of miscarriage and recurrent miscarriage, reduced success with ART, an increased number of canceled cycles, and poorer quality oocytes retrieved. During pregnancy, obese women have three to four times higher rates of gestational diabetes and preeclampsia,²⁵ as well as likelihood of having a fetus with macrosomia and birth defects, and a 1.3-2.1 times higher risk of stillbirth.²⁶

Regarding physical activity, the rate of pregnancies (39.0% vs. 16.0%, P = .002) and live births (24.4% vs. 7.4% (P = .004) were higher with regular exercise vs. being sedentary. Obese women who exercised regularly had a live birth rate over threefold higher compared with those who were not active.²⁷ Moderation should be employed given that women who exercise to exhaustion have 2.3 times the odds of fertility problems.²⁸ In men, obesity has been shown to increase estrogens and reduce spermatogenesis. Exercise has improved semen parameters and testosterone. Paternal physical and sedentary activities were not related to clinical pregnancy or live birth rates following infertility treatment.²⁹ As in women, men experience negative effects from high-intensity exercise, including bicycling, which can result in decreased semen parameters, follicle-stimulating hormone, LH, and testosterone levels.³⁰

In couples desiring a more natural approach to infertility, fertility specialists can address environmental and lifestyle factors that may improve reproduction. When natural attempts at conception are not applicable or successful, IUI and ART are appropriate treatment options after considering estimated success rates as well as the physical, emotional, and financial investment of patients.

Dr. Trolice is director of The IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando.
 

References

1. Wise LA et al. Am J Epidemiol. 2018;187:60-74.

2. Chui Y-H. Hum Reprod. 2018;33:156-65.

3. Ferreira Braga DPA et al. Reprod Biomed Online. 2015;31:30-8.

4. Domar AD et al. J Psychosom Obstet Gynaecol. 1993;14[suppl]:45-52.

5. Trolice MP. J Assist Reprod Genet. 2021 Apr;38[4]:873-5.

6. Gameiro S et al. Hum Reprod Update. 2012;18[6]:652-69.

7. Paulus WE et al. Fertil Steril. 2002;77:721-4.

8. Paulus WE et al. Hum Reprod. 2003;18:S18(abstr).

9. Wing SSE et al. Hum Reprod. 2009;24:341-8.

10. Hong Zheng C et al. Fertil Steril. 2012;97:599-611.

11. Meldrum DR et al. Fertil Steril. 2013;99:1821-4.

12. Klonoff-Cohen H et al. Fertil Steril. 2003;79:330-9.

13. Rossi BV et al. Obstet Gynecol. 2011;117:136-42.

14. Abadia L et al. Hum Reprod. 2017;32:1846-54.

15. Gormack AA et al. Hum Reprod. 2015;30:1617.

16. James JE. BMJ Evid Based Med. 2021;26:114-15.

17. Gaskins AJ et al. Eur J Nutr. 2018 Feb;57:107-17.

18. Machtinger R et al. Fertil Steril. 2017;108:1026-33.

19. Hughes EG et al. Fertil Steril. 1994;62:807.

20. de Ziegler D et al. Fertil Steril. 2013;100:927-8.

21. Practice Committee of the American Society for Reproductive Medicine. Fertil Steril. 2018;110:611-8.

22. Brewer CJ, Balen AH. Reproduction. 2010;140:347-64.

23. Wise LA et al. Hum Reprod. 2010;25:253-64.

24. Silvestris S et al. Reprod Biol Endocrinol. 2018;16[1]:22.

25. Alwash SM et al. Obes Res Clin Pract. 2021;15:425-30.

26. Aune D et al. JAMA. 2014;311:1536-46.

27. Palomba S et al. Reprod Biomed Online. 2014;29:72-9.

28. Gudmundsdottir SL et al. Hum Reprod. 2009;24[12]:3196-204.

29. Gaskins AJ et al. Hum Reprod. 2014;29:2575-82.

30. Wise LA et al. Fertil Steril. 2011;95:1025-30.

As reproductive specialists, part of our obligation is to improve a woman’s or couple’s ability to conceive in the most cost-effective manner, ideally through natural attempts at conception. While assisted reproductive technologies (ART) have provided impressive pregnancy rates across many diagnoses, including unexplained infertility, this advanced procedure comes with a significant financial cost to those without insurance and an emotional burden from the lack of a guaranteed outcome. Infertility procedures have minimal associated but potentially significant risks, most importantly multiple gestations. Contrary to popular belief, ovulation induction with intrauterine insemination (IUI) treatment has a greater risk of high-order multiple gestation when compared with IVF, given the inability of the former to control the number of embryos that may enter and implant in the endometrial cavity and the increased use of single embryo transfers with the latter. The specialist should evaluate the woman or couple for the basic issues of ovulation, tubal, and sperm function, as well as for lifestyle and environmental factors that can impede reproduction. As a result, “one size fits all” should not apply to patients, specifically those with infertility. This month’s column will present the detrimental effect of environmental and lifestyle factors on the goal of enhancing fertility through natural cycles of urine luteinizing-hormone timed intercourse.

Trolice_Mark _P_FLA_2022_web.jpg

Nutrition

Often overlooked in the infertility evaluation, an optimal diet improves fertility for both partners. Processed meat has been associated with reduced sperm quality. In ART, red meat has been associated with decreased embryo blastocyst formation. Lower trans fatty acids and higher omega-3s may improve fecundity. Considered one of the best overall diets, the Mediterranean diet consists of plant-based foods, such as whole grains, vegetables, legumes, fruits, nuts, seeds, herbs, and spices. Olive oil is the main source of added fat whereas fish, seafood, dairy, and poultry should be eaten in moderation. Fatty fish, such as mackerel, herring, sardines, albacore tuna, and salmon, are rich in omega-3 fatty acids, which have been shown to improve fecundity and IVF success, and have a positive association with blastocyst embryo development.^1-3

Stress

The emotional effect of an infertility diagnosis has been demonstrated to be equivalent to a diagnosis of cancer and other major medical morbidities.⁴ Whether stress causes or is a result of infertility has been a longstanding debate.⁵ Nevertheless, stress is the number-one reason patients discontinue fertility treatment.⁶ As fertility specialists, we must be cognizant of the devastation endured by infertility patients and maintain an open dialogue, as well as provide resources for coping strategies and counseling.

One popular method of improving mental health and fertility has been acupuncture. Initial enthusiasm originated from one of the first studies to explore the use of acupuncture during IVF. This was a prospective randomized study that showed treated patients had an approximately 100% improvement in clinical pregnancy rate. Unfortunately, there was no appropriate control group, just untreated controls.⁷ A subsequent study by the same investigator added a placebo acupuncture control group and did not show a statistically significant increase in pregnancy rates.⁸ Finally, a meta-analysis and reanalysis did not demonstrate any improvement in pregnancy outcome, whereas three of the studies analyzed suggested a possible reduction in pregnancies; placebo acupuncture was shown to have a higher success rate.^9-11 While acupuncture is relatively safe, there appears to be only a placebo effect that may be helpful.

The effect of stress on reproduction has been addressed in one of my previous columns.
 

Alcohol and caffeine

The damaging effects of alcohol on the fetus during pregnancy are legion – abnormal facial features, microcephaly, low birth weight, hyperactive behavior, vision or hearing deficits, speech and language delays, and intellectual disability. Less known is the amount of alcohol that may have an effect during preconception. One of the first reports on the effect of alcohol on IVF concluded: a 13% decrease in the number of eggs aspirated; a 2.86 times increase in risk of not achieving pregnancy; and a 2.21 times increase in risk of miscarriage. For men, one additional drink per day increased the risk of not achieving a live birth from 2.28 to 8.32 times.¹² Subsequent studies demonstrate a 16% reduction in IVF pregnancies in women who have at least four drinks per week; when the couple drank at least four drinks per week, the pregnancy rate decreased by 21%.¹³

However, a study from Denmark did not demonstrate a negative effect of low to moderate pretreatment amounts of alcohol and caffeine on IVF outcomes.¹⁴ Nevertheless, there is evidence that reducing or abstaining from alcohol intake may improve IVF outcomes.¹⁵ While there have been reports of higher miscarriage rates from caffeine,^16,17 not all reports support a negative association.¹⁸

Smoking

The use of tobacco has been estimated to contribute to 13% of female infertility in a dose-response manner, including secondhand smoke. During ART, smoking reduces ovarian response to gonadotropins and decreases IVF success by up to 50%. Discontinuing smoking for 6 months beforehand appears to restore normal outcomes.^19-20

The American Society for Reproductive Medicine Practice Committee on smoking provides the following invaluable information to share with patients on the harmful reproductive effects of smoking:²¹

• Early menopause by accelerating the loss of eggs.
• Higher rates of miscarriage and ectopic pregnancy.
• A decrease in sperm function.
• Possible genetic damage to eggs and sperm.
• Reduced sperm in son from maternal smoking.

Weight and exercise

Compared with normal-weight women, those with obesity are three times more likely to have ovulatory dysfunction;²² a lower chance for conception;²³ and infertility.²⁴ Obese women have higher rates of miscarriage and recurrent miscarriage, reduced success with ART, an increased number of canceled cycles, and poorer quality oocytes retrieved. During pregnancy, obese women have three to four times higher rates of gestational diabetes and preeclampsia,²⁵ as well as likelihood of having a fetus with macrosomia and birth defects, and a 1.3-2.1 times higher risk of stillbirth.²⁶

Regarding physical activity, the rate of pregnancies (39.0% vs. 16.0%, P = .002) and live births (24.4% vs. 7.4% (P = .004) were higher with regular exercise vs. being sedentary. Obese women who exercised regularly had a live birth rate over threefold higher compared with those who were not active.²⁷ Moderation should be employed given that women who exercise to exhaustion have 2.3 times the odds of fertility problems.²⁸ In men, obesity has been shown to increase estrogens and reduce spermatogenesis. Exercise has improved semen parameters and testosterone. Paternal physical and sedentary activities were not related to clinical pregnancy or live birth rates following infertility treatment.²⁹ As in women, men experience negative effects from high-intensity exercise, including bicycling, which can result in decreased semen parameters, follicle-stimulating hormone, LH, and testosterone levels.³⁰

In couples desiring a more natural approach to infertility, fertility specialists can address environmental and lifestyle factors that may improve reproduction. When natural attempts at conception are not applicable or successful, IUI and ART are appropriate treatment options after considering estimated success rates as well as the physical, emotional, and financial investment of patients.

Dr. Trolice is director of The IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando.
 

References

1. Wise LA et al. Am J Epidemiol. 2018;187:60-74.

2. Chui Y-H. Hum Reprod. 2018;33:156-65.

3. Ferreira Braga DPA et al. Reprod Biomed Online. 2015;31:30-8.

4. Domar AD et al. J Psychosom Obstet Gynaecol. 1993;14[suppl]:45-52.

5. Trolice MP. J Assist Reprod Genet. 2021 Apr;38[4]:873-5.

6. Gameiro S et al. Hum Reprod Update. 2012;18[6]:652-69.

7. Paulus WE et al. Fertil Steril. 2002;77:721-4.

8. Paulus WE et al. Hum Reprod. 2003;18:S18(abstr).

9. Wing SSE et al. Hum Reprod. 2009;24:341-8.

10. Hong Zheng C et al. Fertil Steril. 2012;97:599-611.

11. Meldrum DR et al. Fertil Steril. 2013;99:1821-4.

12. Klonoff-Cohen H et al. Fertil Steril. 2003;79:330-9.

13. Rossi BV et al. Obstet Gynecol. 2011;117:136-42.

14. Abadia L et al. Hum Reprod. 2017;32:1846-54.

15. Gormack AA et al. Hum Reprod. 2015;30:1617.

16. James JE. BMJ Evid Based Med. 2021;26:114-15.

17. Gaskins AJ et al. Eur J Nutr. 2018 Feb;57:107-17.

18. Machtinger R et al. Fertil Steril. 2017;108:1026-33.

19. Hughes EG et al. Fertil Steril. 1994;62:807.

20. de Ziegler D et al. Fertil Steril. 2013;100:927-8.

21. Practice Committee of the American Society for Reproductive Medicine. Fertil Steril. 2018;110:611-8.

22. Brewer CJ, Balen AH. Reproduction. 2010;140:347-64.

23. Wise LA et al. Hum Reprod. 2010;25:253-64.

24. Silvestris S et al. Reprod Biol Endocrinol. 2018;16[1]:22.

25. Alwash SM et al. Obes Res Clin Pract. 2021;15:425-30.

26. Aune D et al. JAMA. 2014;311:1536-46.

27. Palomba S et al. Reprod Biomed Online. 2014;29:72-9.

28. Gudmundsdottir SL et al. Hum Reprod. 2009;24[12]:3196-204.

29. Gaskins AJ et al. Hum Reprod. 2014;29:2575-82.

30. Wise LA et al. Fertil Steril. 2011;95:1025-30.

As reproductive specialists, part of our obligation is to improve a woman’s or couple’s ability to conceive in the most cost-effective manner, ideally through natural attempts at conception. While assisted reproductive technologies (ART) have provided impressive pregnancy rates across many diagnoses, including unexplained infertility, this advanced procedure comes with a significant financial cost to those without insurance and an emotional burden from the lack of a guaranteed outcome. Infertility procedures have minimal associated but potentially significant risks, most importantly multiple gestations. Contrary to popular belief, ovulation induction with intrauterine insemination (IUI) treatment has a greater risk of high-order multiple gestation when compared with IVF, given the inability of the former to control the number of embryos that may enter and implant in the endometrial cavity and the increased use of single embryo transfers with the latter. The specialist should evaluate the woman or couple for the basic issues of ovulation, tubal, and sperm function, as well as for lifestyle and environmental factors that can impede reproduction. As a result, “one size fits all” should not apply to patients, specifically those with infertility. This month’s column will present the detrimental effect of environmental and lifestyle factors on the goal of enhancing fertility through natural cycles of urine luteinizing-hormone timed intercourse.

Trolice_Mark _P_FLA_2022_web.jpg

Nutrition

Often overlooked in the infertility evaluation, an optimal diet improves fertility for both partners. Processed meat has been associated with reduced sperm quality. In ART, red meat has been associated with decreased embryo blastocyst formation. Lower trans fatty acids and higher omega-3s may improve fecundity. Considered one of the best overall diets, the Mediterranean diet consists of plant-based foods, such as whole grains, vegetables, legumes, fruits, nuts, seeds, herbs, and spices. Olive oil is the main source of added fat whereas fish, seafood, dairy, and poultry should be eaten in moderation. Fatty fish, such as mackerel, herring, sardines, albacore tuna, and salmon, are rich in omega-3 fatty acids, which have been shown to improve fecundity and IVF success, and have a positive association with blastocyst embryo development.^1-3

Stress

The emotional effect of an infertility diagnosis has been demonstrated to be equivalent to a diagnosis of cancer and other major medical morbidities.⁴ Whether stress causes or is a result of infertility has been a longstanding debate.⁵ Nevertheless, stress is the number-one reason patients discontinue fertility treatment.⁶ As fertility specialists, we must be cognizant of the devastation endured by infertility patients and maintain an open dialogue, as well as provide resources for coping strategies and counseling.

One popular method of improving mental health and fertility has been acupuncture. Initial enthusiasm originated from one of the first studies to explore the use of acupuncture during IVF. This was a prospective randomized study that showed treated patients had an approximately 100% improvement in clinical pregnancy rate. Unfortunately, there was no appropriate control group, just untreated controls.⁷ A subsequent study by the same investigator added a placebo acupuncture control group and did not show a statistically significant increase in pregnancy rates.⁸ Finally, a meta-analysis and reanalysis did not demonstrate any improvement in pregnancy outcome, whereas three of the studies analyzed suggested a possible reduction in pregnancies; placebo acupuncture was shown to have a higher success rate.^9-11 While acupuncture is relatively safe, there appears to be only a placebo effect that may be helpful.

The effect of stress on reproduction has been addressed in one of my previous columns.
 

Alcohol and caffeine

The damaging effects of alcohol on the fetus during pregnancy are legion – abnormal facial features, microcephaly, low birth weight, hyperactive behavior, vision or hearing deficits, speech and language delays, and intellectual disability. Less known is the amount of alcohol that may have an effect during preconception. One of the first reports on the effect of alcohol on IVF concluded: a 13% decrease in the number of eggs aspirated; a 2.86 times increase in risk of not achieving pregnancy; and a 2.21 times increase in risk of miscarriage. For men, one additional drink per day increased the risk of not achieving a live birth from 2.28 to 8.32 times.¹² Subsequent studies demonstrate a 16% reduction in IVF pregnancies in women who have at least four drinks per week; when the couple drank at least four drinks per week, the pregnancy rate decreased by 21%.¹³

However, a study from Denmark did not demonstrate a negative effect of low to moderate pretreatment amounts of alcohol and caffeine on IVF outcomes.¹⁴ Nevertheless, there is evidence that reducing or abstaining from alcohol intake may improve IVF outcomes.¹⁵ While there have been reports of higher miscarriage rates from caffeine,^16,17 not all reports support a negative association.¹⁸

Smoking

The use of tobacco has been estimated to contribute to 13% of female infertility in a dose-response manner, including secondhand smoke. During ART, smoking reduces ovarian response to gonadotropins and decreases IVF success by up to 50%. Discontinuing smoking for 6 months beforehand appears to restore normal outcomes.^19-20

The American Society for Reproductive Medicine Practice Committee on smoking provides the following invaluable information to share with patients on the harmful reproductive effects of smoking:²¹

• Early menopause by accelerating the loss of eggs.
• Higher rates of miscarriage and ectopic pregnancy.
• A decrease in sperm function.
• Possible genetic damage to eggs and sperm.
• Reduced sperm in son from maternal smoking.

Weight and exercise

Compared with normal-weight women, those with obesity are three times more likely to have ovulatory dysfunction;²² a lower chance for conception;²³ and infertility.²⁴ Obese women have higher rates of miscarriage and recurrent miscarriage, reduced success with ART, an increased number of canceled cycles, and poorer quality oocytes retrieved. During pregnancy, obese women have three to four times higher rates of gestational diabetes and preeclampsia,²⁵ as well as likelihood of having a fetus with macrosomia and birth defects, and a 1.3-2.1 times higher risk of stillbirth.²⁶

Regarding physical activity, the rate of pregnancies (39.0% vs. 16.0%, P = .002) and live births (24.4% vs. 7.4% (P = .004) were higher with regular exercise vs. being sedentary. Obese women who exercised regularly had a live birth rate over threefold higher compared with those who were not active.²⁷ Moderation should be employed given that women who exercise to exhaustion have 2.3 times the odds of fertility problems.²⁸ In men, obesity has been shown to increase estrogens and reduce spermatogenesis. Exercise has improved semen parameters and testosterone. Paternal physical and sedentary activities were not related to clinical pregnancy or live birth rates following infertility treatment.²⁹ As in women, men experience negative effects from high-intensity exercise, including bicycling, which can result in decreased semen parameters, follicle-stimulating hormone, LH, and testosterone levels.³⁰

In couples desiring a more natural approach to infertility, fertility specialists can address environmental and lifestyle factors that may improve reproduction. When natural attempts at conception are not applicable or successful, IUI and ART are appropriate treatment options after considering estimated success rates as well as the physical, emotional, and financial investment of patients.

Dr. Trolice is director of The IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando.
 

References

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Let’s pretend for a moment that you receive a call from one of your college roommates who thanks to his family connections has become a venture capitalist in California. His group is considering investing in a start-up that is developing a handheld instrument that it claims will use artificial intelligence to diagnose ear infections far more accurately than the human eye. He wonders if you would like to help him evaluate the company’s proposal and offers you a small percentage of the profits for your efforts should they choose to invest.

Your former roommate has done enough research on his own to understand that otitis media makes up a large chunk of a pediatrician’s workload and that making an accurate diagnosis can often be difficult in a struggling child. He describes his own experience watching a frustrated pediatrician attempting to remove wax from his child’s ear and eventually prescribing antibiotics “to be safe.”

Wilkoff_William_G_2_web.jpg

You agree and review the prospectus, which includes a paper from a peer-reviewed journal. What you discover is that the investigators used more than 600 high-resolution images of tympanic membranes taken “during operative myringotomy and tympanostomy tube placement” and the findings at tympanocentesis to train a neural network.

Once trained, the model they developed could differentiate with 95% accuracy between an image of a tympanic membrane that covered a normal middle ear from one that merely contained fluid and from one that contained infected fluid. When these same images were shown to 39 clinicians, more than half of which were pediatricians and included both faculty-level staff and trainees, the average diagnostic accuracy was 65%.

The prospectus includes prediction that this technology could easily be developed into a handheld instrument similar to a traditional otoscope, which could then be linked to the operator’s smartphone, giving the clinician an instant treat or no-treat answer.

Now, remember you have nothing to lose except maybe a friendship. How would you advise your old college roommate?

My advice to your college buddy would be one of caution! Yes, there is a potential big upside because there is a real need for a device that could provide a diagnostic accuracy that this AI model promises. While I suspect that AI will always be more accurate in diagnosis using static images, I bet that most people, clinicians and nonclinicians, could improve their accuracy by linking photos with diagnoses with an hour of practice.

However, evaluating a high-resolution photograph taken through an operative scope inserted into the cerumenless ear canal of a sedated, afrebrile child is several orders of magnitude less difficult than the real-world environment in which the diagnosis of otitis media is usually made.

If the venture capitalists were still interested in getting into the otitis media marketplace, you might suggest they look into companies that have already developed image capture otoscopes. At this point I could only find one on the Internet that was portable and it certainly isn’t small-child friendly. Once we have a tool that can capture images in real-world situations, the next step is to train AI systems to interpret them using the approach these researchers have developed. I bet it can be done. It will be only a matter of time ... and money.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at pdnews@mdedge.com.

Let’s pretend for a moment that you receive a call from one of your college roommates who thanks to his family connections has become a venture capitalist in California. His group is considering investing in a start-up that is developing a handheld instrument that it claims will use artificial intelligence to diagnose ear infections far more accurately than the human eye. He wonders if you would like to help him evaluate the company’s proposal and offers you a small percentage of the profits for your efforts should they choose to invest.

Your former roommate has done enough research on his own to understand that otitis media makes up a large chunk of a pediatrician’s workload and that making an accurate diagnosis can often be difficult in a struggling child. He describes his own experience watching a frustrated pediatrician attempting to remove wax from his child’s ear and eventually prescribing antibiotics “to be safe.”

Wilkoff_William_G_2_web.jpg

You agree and review the prospectus, which includes a paper from a peer-reviewed journal. What you discover is that the investigators used more than 600 high-resolution images of tympanic membranes taken “during operative myringotomy and tympanostomy tube placement” and the findings at tympanocentesis to train a neural network.

Once trained, the model they developed could differentiate with 95% accuracy between an image of a tympanic membrane that covered a normal middle ear from one that merely contained fluid and from one that contained infected fluid. When these same images were shown to 39 clinicians, more than half of which were pediatricians and included both faculty-level staff and trainees, the average diagnostic accuracy was 65%.

The prospectus includes prediction that this technology could easily be developed into a handheld instrument similar to a traditional otoscope, which could then be linked to the operator’s smartphone, giving the clinician an instant treat or no-treat answer.

Now, remember you have nothing to lose except maybe a friendship. How would you advise your old college roommate?

My advice to your college buddy would be one of caution! Yes, there is a potential big upside because there is a real need for a device that could provide a diagnostic accuracy that this AI model promises. While I suspect that AI will always be more accurate in diagnosis using static images, I bet that most people, clinicians and nonclinicians, could improve their accuracy by linking photos with diagnoses with an hour of practice.

However, evaluating a high-resolution photograph taken through an operative scope inserted into the cerumenless ear canal of a sedated, afrebrile child is several orders of magnitude less difficult than the real-world environment in which the diagnosis of otitis media is usually made.

If the venture capitalists were still interested in getting into the otitis media marketplace, you might suggest they look into companies that have already developed image capture otoscopes. At this point I could only find one on the Internet that was portable and it certainly isn’t small-child friendly. Once we have a tool that can capture images in real-world situations, the next step is to train AI systems to interpret them using the approach these researchers have developed. I bet it can be done. It will be only a matter of time ... and money.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at pdnews@mdedge.com.

Let’s pretend for a moment that you receive a call from one of your college roommates who thanks to his family connections has become a venture capitalist in California. His group is considering investing in a start-up that is developing a handheld instrument that it claims will use artificial intelligence to diagnose ear infections far more accurately than the human eye. He wonders if you would like to help him evaluate the company’s proposal and offers you a small percentage of the profits for your efforts should they choose to invest.

Your former roommate has done enough research on his own to understand that otitis media makes up a large chunk of a pediatrician’s workload and that making an accurate diagnosis can often be difficult in a struggling child. He describes his own experience watching a frustrated pediatrician attempting to remove wax from his child’s ear and eventually prescribing antibiotics “to be safe.”

Wilkoff_William_G_2_web.jpg

You agree and review the prospectus, which includes a paper from a peer-reviewed journal. What you discover is that the investigators used more than 600 high-resolution images of tympanic membranes taken “during operative myringotomy and tympanostomy tube placement” and the findings at tympanocentesis to train a neural network.

Once trained, the model they developed could differentiate with 95% accuracy between an image of a tympanic membrane that covered a normal middle ear from one that merely contained fluid and from one that contained infected fluid. When these same images were shown to 39 clinicians, more than half of which were pediatricians and included both faculty-level staff and trainees, the average diagnostic accuracy was 65%.

The prospectus includes prediction that this technology could easily be developed into a handheld instrument similar to a traditional otoscope, which could then be linked to the operator’s smartphone, giving the clinician an instant treat or no-treat answer.

Now, remember you have nothing to lose except maybe a friendship. How would you advise your old college roommate?

My advice to your college buddy would be one of caution! Yes, there is a potential big upside because there is a real need for a device that could provide a diagnostic accuracy that this AI model promises. While I suspect that AI will always be more accurate in diagnosis using static images, I bet that most people, clinicians and nonclinicians, could improve their accuracy by linking photos with diagnoses with an hour of practice.

However, evaluating a high-resolution photograph taken through an operative scope inserted into the cerumenless ear canal of a sedated, afrebrile child is several orders of magnitude less difficult than the real-world environment in which the diagnosis of otitis media is usually made.

If the venture capitalists were still interested in getting into the otitis media marketplace, you might suggest they look into companies that have already developed image capture otoscopes. At this point I could only find one on the Internet that was portable and it certainly isn’t small-child friendly. Once we have a tool that can capture images in real-world situations, the next step is to train AI systems to interpret them using the approach these researchers have developed. I bet it can be done. It will be only a matter of time ... and money.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at pdnews@mdedge.com.