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VIDEO: Triple therapy study and new recommendations provide guidance on CAPS
MADRID – Catastrophic antiphospholipid syndrome (CAPS) is associated with a high mortality rate, but new research presented at the European Congress of Rheumatology shows that patient survival can be significantly improved by a triple therapy treatment approach.
Researchers at the Congress also presented clinical practice guidelines for the diagnosis and management of the rare disease, which accounts for just 1% of patients with antiphospholipid syndrome (APS).
CAPS is characterized by a fast onset of widespread thrombosis, mainly in the small vessels, and, often, microangiopathic hemolytic anemia is seen in the laboratory. If undiagnosed or left untreated, patients may present with multiorgan failure needing intensive care treatment, which can be fatal in up to 50% of cases.
At the Congress, Ignasi Rodríguez-Pintó, MD, presented new data from the CAPS Registry that looks at the combined effect of anticoagulation, corticosteroids, and plasma exchange or intravenous immunoglobulins on the survival of patients with CAPS as well as the new clinical practice guidelines.
CAPS Registry study
The aim of the study Dr. Rodríguez-Pintó presented on behalf of the CAPS Registry Project Group was to determine what, if any, survival benefit would be incurred from a triple therapy approach when compared with other different combinations of anticoagulation, corticosteroids, and plasma exchange or intravenous immunoglobulins, or none of these treatments.
Although the triple therapy treatment approach is already being used in practice, its use is largely empirical, Dr. Rodríguez-Pintó of the department of autoimmune disease at the Hospital Clinic, Barcelona, explained in a video interview.
The investigators derived their data from episodes of CAPS occurring in patients in the CAPS Registry from the European Forum on Antiphospholipid Antibodies. This international registry was set up in 2000 and has been assembling the clinical, laboratory, and therapeutic findings of patients with CAPS for almost 20 years.
“We observed 525 episodes of CAPS in 502 patients. That means that some patients had two to three episodes of CAPS,” Dr. Rodríguez-Pintó said. Data on 38 episodes of CAPS had to be excluded from the analysis because of missing information, which left 487 episodes occurring in 471 patients.
The mean age of the 471 patients included in the analysis was 38 years. The majority (67.9%) were female and had primary (68.8%) APS. Triple therapy was given to about 40% of patients who experienced CAPS, with about 57% receiving other combinations of drugs and 2.5% receiving no treatment for CAPS.
Overall, 177 of the 487 (36.3%) episodes of CAPS were fatal.
“Triple therapy was associated with a higher chance of survival when compared to other combinations or to none of these treatments,” Dr. Rodríguez-Pintó said.
While 28% of patients with CAPS died in the triple therapy group, mortality was 41% with other combinations of treatments and 75% with none of these treatments.
All-cause mortality was reduced by 47% with triple therapy, compared with none of these treatments. The adjusted odds ratio (aOR) when comparing survival between triple therapy and no treatment was 7.7, with a 95% confidence interval of 2.0 to 29.7. The aOR comparing other drug combinations versus none of these treatments was 6.8 (95% CI, 1.7-29.6).
“For a long time, we have been saying that triple therapy would probably be the best approach, but we had no firm evidence,” Dr. Rodríguez-Pintó said.
“So, this is the first time that we have clear clinical evidence of the benefit of these approaches, and I think that these results are important because they will give us more confidence in how we treat patients and help develop guidance on [the treatment’s] use in the future.”
Guidelines
A steering committee composed of representatives from the European Commission–funded RARE-BestPractices project and McMaster University in Hamilton, Ont., used GRADE methodology to develop the guidelines for CAPS diagnosis and management. The committee answered three diagnostic and seven treatment questions that originated from a panel of 19 international stakeholders, including Dr. Rodríguez-Pintó, through systematic reviews of the literature that used Cochrane criteria.
Although the review of studies did not include the study of CAPS Registry data that Dr. Rodríguez-Pintó and his colleagues conducted, he said that the recommendations still confirm the value of using a triple therapy approach to treatment.
The panel created three diagnostic recommendations for patients suspected of having CAPS, all of which were conditional and based on very low certainty of evidence: use preliminary CAPS classification criteria to diagnose CAPS; use or nonuse of biopsy, depending on the circumstances, because of its high specificity but possibly low sensitivity for thrombotic microangiopathy; and test for antiphospholipid antibodies, which should not delay initiation of treatment.
All seven first-line treatment recommendations that the panel developed relied on a very low certainty of evidence, and most were conditional:
- Triple therapy combination treatment with corticosteroids, heparin, and plasma exchange or intravenous immunoglobulins instead of a single agent or other combination treatments.
- Therapeutic dose anticoagulation was one of only two treatment recommendations to be considered “strong,” but use of direct oral anticoagulants is not advised.
- Therapeutic plasma exchange is recommended for use with other therapies and should be strongly considered for patients with microangiopathic hemolytic anemia.
- Intravenous immunoglobulin is advised for use in conjunction with other therapies and should be given special consideration for patients with immune thrombocytopenia or renal insufficiency.
- Antiplatelet agents are conditionally recommended as an add-on therapy, but their potential mortality benefit is tempered by increased risk of bleeding when used with anticoagulants. Strong consideration should be given to their use as an alternative therapy to anticoagulation when anticoagulation is contraindicated for a reason other than bleeding.
- Rituximab (Rituxan) should not be used because of little available data on its use, uncertainty regarding long-term consequences, and its expense – except for refractory cases where other therapies have been insufficient.
- Corticosteroids should not be used because of their lack of efficacy in CAPS when used alone and potential for adverse effects, except for certain circumstances where they may be indicated.
The authors of the guidelines emphasized that these recommendations are not meant to apply to every CAPS patient. They also noted that the available evidence did not allow for temporal analysis of treatments and that conclusions could not be drawn regarding “first-line” versus “second-line” therapies.
None of the authors of the registry study or the guidelines had relevant conflicts of interest to declare.
MADRID – Catastrophic antiphospholipid syndrome (CAPS) is associated with a high mortality rate, but new research presented at the European Congress of Rheumatology shows that patient survival can be significantly improved by a triple therapy treatment approach.
Researchers at the Congress also presented clinical practice guidelines for the diagnosis and management of the rare disease, which accounts for just 1% of patients with antiphospholipid syndrome (APS).
CAPS is characterized by a fast onset of widespread thrombosis, mainly in the small vessels, and, often, microangiopathic hemolytic anemia is seen in the laboratory. If undiagnosed or left untreated, patients may present with multiorgan failure needing intensive care treatment, which can be fatal in up to 50% of cases.
At the Congress, Ignasi Rodríguez-Pintó, MD, presented new data from the CAPS Registry that looks at the combined effect of anticoagulation, corticosteroids, and plasma exchange or intravenous immunoglobulins on the survival of patients with CAPS as well as the new clinical practice guidelines.
CAPS Registry study
The aim of the study Dr. Rodríguez-Pintó presented on behalf of the CAPS Registry Project Group was to determine what, if any, survival benefit would be incurred from a triple therapy approach when compared with other different combinations of anticoagulation, corticosteroids, and plasma exchange or intravenous immunoglobulins, or none of these treatments.
Although the triple therapy treatment approach is already being used in practice, its use is largely empirical, Dr. Rodríguez-Pintó of the department of autoimmune disease at the Hospital Clinic, Barcelona, explained in a video interview.
The investigators derived their data from episodes of CAPS occurring in patients in the CAPS Registry from the European Forum on Antiphospholipid Antibodies. This international registry was set up in 2000 and has been assembling the clinical, laboratory, and therapeutic findings of patients with CAPS for almost 20 years.
“We observed 525 episodes of CAPS in 502 patients. That means that some patients had two to three episodes of CAPS,” Dr. Rodríguez-Pintó said. Data on 38 episodes of CAPS had to be excluded from the analysis because of missing information, which left 487 episodes occurring in 471 patients.
The mean age of the 471 patients included in the analysis was 38 years. The majority (67.9%) were female and had primary (68.8%) APS. Triple therapy was given to about 40% of patients who experienced CAPS, with about 57% receiving other combinations of drugs and 2.5% receiving no treatment for CAPS.
Overall, 177 of the 487 (36.3%) episodes of CAPS were fatal.
“Triple therapy was associated with a higher chance of survival when compared to other combinations or to none of these treatments,” Dr. Rodríguez-Pintó said.
While 28% of patients with CAPS died in the triple therapy group, mortality was 41% with other combinations of treatments and 75% with none of these treatments.
All-cause mortality was reduced by 47% with triple therapy, compared with none of these treatments. The adjusted odds ratio (aOR) when comparing survival between triple therapy and no treatment was 7.7, with a 95% confidence interval of 2.0 to 29.7. The aOR comparing other drug combinations versus none of these treatments was 6.8 (95% CI, 1.7-29.6).
“For a long time, we have been saying that triple therapy would probably be the best approach, but we had no firm evidence,” Dr. Rodríguez-Pintó said.
“So, this is the first time that we have clear clinical evidence of the benefit of these approaches, and I think that these results are important because they will give us more confidence in how we treat patients and help develop guidance on [the treatment’s] use in the future.”
Guidelines
A steering committee composed of representatives from the European Commission–funded RARE-BestPractices project and McMaster University in Hamilton, Ont., used GRADE methodology to develop the guidelines for CAPS diagnosis and management. The committee answered three diagnostic and seven treatment questions that originated from a panel of 19 international stakeholders, including Dr. Rodríguez-Pintó, through systematic reviews of the literature that used Cochrane criteria.
Although the review of studies did not include the study of CAPS Registry data that Dr. Rodríguez-Pintó and his colleagues conducted, he said that the recommendations still confirm the value of using a triple therapy approach to treatment.
The panel created three diagnostic recommendations for patients suspected of having CAPS, all of which were conditional and based on very low certainty of evidence: use preliminary CAPS classification criteria to diagnose CAPS; use or nonuse of biopsy, depending on the circumstances, because of its high specificity but possibly low sensitivity for thrombotic microangiopathy; and test for antiphospholipid antibodies, which should not delay initiation of treatment.
All seven first-line treatment recommendations that the panel developed relied on a very low certainty of evidence, and most were conditional:
- Triple therapy combination treatment with corticosteroids, heparin, and plasma exchange or intravenous immunoglobulins instead of a single agent or other combination treatments.
- Therapeutic dose anticoagulation was one of only two treatment recommendations to be considered “strong,” but use of direct oral anticoagulants is not advised.
- Therapeutic plasma exchange is recommended for use with other therapies and should be strongly considered for patients with microangiopathic hemolytic anemia.
- Intravenous immunoglobulin is advised for use in conjunction with other therapies and should be given special consideration for patients with immune thrombocytopenia or renal insufficiency.
- Antiplatelet agents are conditionally recommended as an add-on therapy, but their potential mortality benefit is tempered by increased risk of bleeding when used with anticoagulants. Strong consideration should be given to their use as an alternative therapy to anticoagulation when anticoagulation is contraindicated for a reason other than bleeding.
- Rituximab (Rituxan) should not be used because of little available data on its use, uncertainty regarding long-term consequences, and its expense – except for refractory cases where other therapies have been insufficient.
- Corticosteroids should not be used because of their lack of efficacy in CAPS when used alone and potential for adverse effects, except for certain circumstances where they may be indicated.
The authors of the guidelines emphasized that these recommendations are not meant to apply to every CAPS patient. They also noted that the available evidence did not allow for temporal analysis of treatments and that conclusions could not be drawn regarding “first-line” versus “second-line” therapies.
None of the authors of the registry study or the guidelines had relevant conflicts of interest to declare.
MADRID – Catastrophic antiphospholipid syndrome (CAPS) is associated with a high mortality rate, but new research presented at the European Congress of Rheumatology shows that patient survival can be significantly improved by a triple therapy treatment approach.
Researchers at the Congress also presented clinical practice guidelines for the diagnosis and management of the rare disease, which accounts for just 1% of patients with antiphospholipid syndrome (APS).
CAPS is characterized by a fast onset of widespread thrombosis, mainly in the small vessels, and, often, microangiopathic hemolytic anemia is seen in the laboratory. If undiagnosed or left untreated, patients may present with multiorgan failure needing intensive care treatment, which can be fatal in up to 50% of cases.
At the Congress, Ignasi Rodríguez-Pintó, MD, presented new data from the CAPS Registry that looks at the combined effect of anticoagulation, corticosteroids, and plasma exchange or intravenous immunoglobulins on the survival of patients with CAPS as well as the new clinical practice guidelines.
CAPS Registry study
The aim of the study Dr. Rodríguez-Pintó presented on behalf of the CAPS Registry Project Group was to determine what, if any, survival benefit would be incurred from a triple therapy approach when compared with other different combinations of anticoagulation, corticosteroids, and plasma exchange or intravenous immunoglobulins, or none of these treatments.
Although the triple therapy treatment approach is already being used in practice, its use is largely empirical, Dr. Rodríguez-Pintó of the department of autoimmune disease at the Hospital Clinic, Barcelona, explained in a video interview.
The investigators derived their data from episodes of CAPS occurring in patients in the CAPS Registry from the European Forum on Antiphospholipid Antibodies. This international registry was set up in 2000 and has been assembling the clinical, laboratory, and therapeutic findings of patients with CAPS for almost 20 years.
“We observed 525 episodes of CAPS in 502 patients. That means that some patients had two to three episodes of CAPS,” Dr. Rodríguez-Pintó said. Data on 38 episodes of CAPS had to be excluded from the analysis because of missing information, which left 487 episodes occurring in 471 patients.
The mean age of the 471 patients included in the analysis was 38 years. The majority (67.9%) were female and had primary (68.8%) APS. Triple therapy was given to about 40% of patients who experienced CAPS, with about 57% receiving other combinations of drugs and 2.5% receiving no treatment for CAPS.
Overall, 177 of the 487 (36.3%) episodes of CAPS were fatal.
“Triple therapy was associated with a higher chance of survival when compared to other combinations or to none of these treatments,” Dr. Rodríguez-Pintó said.
While 28% of patients with CAPS died in the triple therapy group, mortality was 41% with other combinations of treatments and 75% with none of these treatments.
All-cause mortality was reduced by 47% with triple therapy, compared with none of these treatments. The adjusted odds ratio (aOR) when comparing survival between triple therapy and no treatment was 7.7, with a 95% confidence interval of 2.0 to 29.7. The aOR comparing other drug combinations versus none of these treatments was 6.8 (95% CI, 1.7-29.6).
“For a long time, we have been saying that triple therapy would probably be the best approach, but we had no firm evidence,” Dr. Rodríguez-Pintó said.
“So, this is the first time that we have clear clinical evidence of the benefit of these approaches, and I think that these results are important because they will give us more confidence in how we treat patients and help develop guidance on [the treatment’s] use in the future.”
Guidelines
A steering committee composed of representatives from the European Commission–funded RARE-BestPractices project and McMaster University in Hamilton, Ont., used GRADE methodology to develop the guidelines for CAPS diagnosis and management. The committee answered three diagnostic and seven treatment questions that originated from a panel of 19 international stakeholders, including Dr. Rodríguez-Pintó, through systematic reviews of the literature that used Cochrane criteria.
Although the review of studies did not include the study of CAPS Registry data that Dr. Rodríguez-Pintó and his colleagues conducted, he said that the recommendations still confirm the value of using a triple therapy approach to treatment.
The panel created three diagnostic recommendations for patients suspected of having CAPS, all of which were conditional and based on very low certainty of evidence: use preliminary CAPS classification criteria to diagnose CAPS; use or nonuse of biopsy, depending on the circumstances, because of its high specificity but possibly low sensitivity for thrombotic microangiopathy; and test for antiphospholipid antibodies, which should not delay initiation of treatment.
All seven first-line treatment recommendations that the panel developed relied on a very low certainty of evidence, and most were conditional:
- Triple therapy combination treatment with corticosteroids, heparin, and plasma exchange or intravenous immunoglobulins instead of a single agent or other combination treatments.
- Therapeutic dose anticoagulation was one of only two treatment recommendations to be considered “strong,” but use of direct oral anticoagulants is not advised.
- Therapeutic plasma exchange is recommended for use with other therapies and should be strongly considered for patients with microangiopathic hemolytic anemia.
- Intravenous immunoglobulin is advised for use in conjunction with other therapies and should be given special consideration for patients with immune thrombocytopenia or renal insufficiency.
- Antiplatelet agents are conditionally recommended as an add-on therapy, but their potential mortality benefit is tempered by increased risk of bleeding when used with anticoagulants. Strong consideration should be given to their use as an alternative therapy to anticoagulation when anticoagulation is contraindicated for a reason other than bleeding.
- Rituximab (Rituxan) should not be used because of little available data on its use, uncertainty regarding long-term consequences, and its expense – except for refractory cases where other therapies have been insufficient.
- Corticosteroids should not be used because of their lack of efficacy in CAPS when used alone and potential for adverse effects, except for certain circumstances where they may be indicated.
The authors of the guidelines emphasized that these recommendations are not meant to apply to every CAPS patient. They also noted that the available evidence did not allow for temporal analysis of treatments and that conclusions could not be drawn regarding “first-line” versus “second-line” therapies.
None of the authors of the registry study or the guidelines had relevant conflicts of interest to declare.
AT THE EULAR 2017 CONGRESS
Key clinical point:
Major finding: Mortality was 28% with triple therapy, 41% with other combinations of treatments, and 75% with none of these treatments.
Data source: A registry study of 471 CAPS patients and clinical practice guidelines for CAPS.
Disclosures: None of the authors of the registry study or the guidelines had relevant conflicts of interest to declare.
Attitudes and beliefs affecting methotrexate adherence identified
MADRID – Negative beliefs and uncertainty regarding treatment with methotrexate, as well as dislike for the drug, contribute the most to rheumatoid arthritis patients’ nonadherence to the therapy, with one study finding that about one-third were nonadherent at the time they were eligible to start biologic therapy.
The French cross-sectional survey of 244 patients who were not responding to methotrexate found that 34% actually had poor adherence, including 54% who skipped doses and 38% who temporarily stopped treatment without their doctors’ recommendation. In comparison, patients who were deemed adherent had a lower rate of skipping doses (15%) or temporarily stopped treatment without their doctors’ recommendation (4%), both of which were statistically significant differences, Catherine Beauvais, MD, reported at the European Congress of Rheumatology. Nonadherence was defined as taking less than 80% of doses, according to the CQR19 (Compliance Questionnaire for Rheumatology).
“We have identified profiles of adherence,” Dr. Beauvais of Saint-Antoine Hospital in Paris commented in an interview.
“Among nonadherent patients, there are two profiles,” she added. “We have patients who are not responding to methotrexate but they also have negative beliefs, low levels of support, and they have professional impairment. [Then,] there are patients who do not like their treatment [although it is being well tolerated].”
The other profiles identified were of patients with good adherence to methotrexate with a higher or lower impact on patient outcomes.
In a poster presentation, Dr. Beauvais and her coauthors suggested that the “detection of patients’ profiles may allow targeted strategies to improve or maintain adherence.”
The FORGET survey was conducted over a 3-month period starting in July 2016. A total of 78 rheumatologists recruited patients who were inadequately responding to methotrexate and, thus, eligible to start biologic treatment for rheumatoid arthritis. Both the rheumatologists and the patients completed questionnaires, with 200 questionnaires being completed by patients and their rheumatologist.
As might be suspected for an RA population, 72% of respondents were women, with a mean age of 54 years. Over half (58%) had at least one comorbidity, and the mean disease activity score in 28 joints at the time of the survey was 4.07.
Significant factors for nonadherence were feeling constrained about taking treatment, cited by 29% of respondents; feeling “less good” with a change in dosage (31%); and feeling that treatment was “doing me more harm than good” (19% of respondents).
Surprisingly, most rheumatologists seemed to be unaware of their patients’ lack of adherence to their medication, despite saying that they asked about adherence in more than 80% of their patients.
Rheumatologists proposed the addition of a biologic to methotrexate more often if patients were nonadherent than if patients showed good compliance (91% vs. 68%; P less than .01).
Effect of patient attitudes on compliance
A team of U.K. researchers evaluated how attitudes toward treatment with methotrexate affected patients’ compliance in a separate poster presentation at the meeting.
RAMS is a 1-year observational study of patients with RA who are starting treatment with methotrexate. Patients recruited into the study completed weekly diaries, noting whether they took methotrexate (adherence) and, if not, their reasons for not doing so. Patients were deemed nonadherent if they did not take methotrexate correctly for 90% of the time over a period of 6 months.
Lower adherence was significantly associated with negative or uncertain views about treatment, with an odds ratio of 2.7. Conversely, being positive or certain about treatment lowered patients’ odds of being nonadherent (OR, 0.32).
“People who are uncertain about how to attribute illness events are less likely to adhere within the first 6 months of starting methotrexate therapy,” Ms. Hope and her coauthors observed.
“Encouraging patients to actively monitor their progress with therapy and providing them with support to understand likely effects of methotrexate may help optimize disease-modifying antirheumatic drug use,” they concluded.
Ms. Hope and Dr. Beauvais had no conflicts of interest to disclose. The FORGET survey was funded by Chugai Pharma France.
MADRID – Negative beliefs and uncertainty regarding treatment with methotrexate, as well as dislike for the drug, contribute the most to rheumatoid arthritis patients’ nonadherence to the therapy, with one study finding that about one-third were nonadherent at the time they were eligible to start biologic therapy.
The French cross-sectional survey of 244 patients who were not responding to methotrexate found that 34% actually had poor adherence, including 54% who skipped doses and 38% who temporarily stopped treatment without their doctors’ recommendation. In comparison, patients who were deemed adherent had a lower rate of skipping doses (15%) or temporarily stopped treatment without their doctors’ recommendation (4%), both of which were statistically significant differences, Catherine Beauvais, MD, reported at the European Congress of Rheumatology. Nonadherence was defined as taking less than 80% of doses, according to the CQR19 (Compliance Questionnaire for Rheumatology).
“We have identified profiles of adherence,” Dr. Beauvais of Saint-Antoine Hospital in Paris commented in an interview.
“Among nonadherent patients, there are two profiles,” she added. “We have patients who are not responding to methotrexate but they also have negative beliefs, low levels of support, and they have professional impairment. [Then,] there are patients who do not like their treatment [although it is being well tolerated].”
The other profiles identified were of patients with good adherence to methotrexate with a higher or lower impact on patient outcomes.
In a poster presentation, Dr. Beauvais and her coauthors suggested that the “detection of patients’ profiles may allow targeted strategies to improve or maintain adherence.”
The FORGET survey was conducted over a 3-month period starting in July 2016. A total of 78 rheumatologists recruited patients who were inadequately responding to methotrexate and, thus, eligible to start biologic treatment for rheumatoid arthritis. Both the rheumatologists and the patients completed questionnaires, with 200 questionnaires being completed by patients and their rheumatologist.
As might be suspected for an RA population, 72% of respondents were women, with a mean age of 54 years. Over half (58%) had at least one comorbidity, and the mean disease activity score in 28 joints at the time of the survey was 4.07.
Significant factors for nonadherence were feeling constrained about taking treatment, cited by 29% of respondents; feeling “less good” with a change in dosage (31%); and feeling that treatment was “doing me more harm than good” (19% of respondents).
Surprisingly, most rheumatologists seemed to be unaware of their patients’ lack of adherence to their medication, despite saying that they asked about adherence in more than 80% of their patients.
Rheumatologists proposed the addition of a biologic to methotrexate more often if patients were nonadherent than if patients showed good compliance (91% vs. 68%; P less than .01).
Effect of patient attitudes on compliance
A team of U.K. researchers evaluated how attitudes toward treatment with methotrexate affected patients’ compliance in a separate poster presentation at the meeting.
RAMS is a 1-year observational study of patients with RA who are starting treatment with methotrexate. Patients recruited into the study completed weekly diaries, noting whether they took methotrexate (adherence) and, if not, their reasons for not doing so. Patients were deemed nonadherent if they did not take methotrexate correctly for 90% of the time over a period of 6 months.
Lower adherence was significantly associated with negative or uncertain views about treatment, with an odds ratio of 2.7. Conversely, being positive or certain about treatment lowered patients’ odds of being nonadherent (OR, 0.32).
“People who are uncertain about how to attribute illness events are less likely to adhere within the first 6 months of starting methotrexate therapy,” Ms. Hope and her coauthors observed.
“Encouraging patients to actively monitor their progress with therapy and providing them with support to understand likely effects of methotrexate may help optimize disease-modifying antirheumatic drug use,” they concluded.
Ms. Hope and Dr. Beauvais had no conflicts of interest to disclose. The FORGET survey was funded by Chugai Pharma France.
MADRID – Negative beliefs and uncertainty regarding treatment with methotrexate, as well as dislike for the drug, contribute the most to rheumatoid arthritis patients’ nonadherence to the therapy, with one study finding that about one-third were nonadherent at the time they were eligible to start biologic therapy.
The French cross-sectional survey of 244 patients who were not responding to methotrexate found that 34% actually had poor adherence, including 54% who skipped doses and 38% who temporarily stopped treatment without their doctors’ recommendation. In comparison, patients who were deemed adherent had a lower rate of skipping doses (15%) or temporarily stopped treatment without their doctors’ recommendation (4%), both of which were statistically significant differences, Catherine Beauvais, MD, reported at the European Congress of Rheumatology. Nonadherence was defined as taking less than 80% of doses, according to the CQR19 (Compliance Questionnaire for Rheumatology).
“We have identified profiles of adherence,” Dr. Beauvais of Saint-Antoine Hospital in Paris commented in an interview.
“Among nonadherent patients, there are two profiles,” she added. “We have patients who are not responding to methotrexate but they also have negative beliefs, low levels of support, and they have professional impairment. [Then,] there are patients who do not like their treatment [although it is being well tolerated].”
The other profiles identified were of patients with good adherence to methotrexate with a higher or lower impact on patient outcomes.
In a poster presentation, Dr. Beauvais and her coauthors suggested that the “detection of patients’ profiles may allow targeted strategies to improve or maintain adherence.”
The FORGET survey was conducted over a 3-month period starting in July 2016. A total of 78 rheumatologists recruited patients who were inadequately responding to methotrexate and, thus, eligible to start biologic treatment for rheumatoid arthritis. Both the rheumatologists and the patients completed questionnaires, with 200 questionnaires being completed by patients and their rheumatologist.
As might be suspected for an RA population, 72% of respondents were women, with a mean age of 54 years. Over half (58%) had at least one comorbidity, and the mean disease activity score in 28 joints at the time of the survey was 4.07.
Significant factors for nonadherence were feeling constrained about taking treatment, cited by 29% of respondents; feeling “less good” with a change in dosage (31%); and feeling that treatment was “doing me more harm than good” (19% of respondents).
Surprisingly, most rheumatologists seemed to be unaware of their patients’ lack of adherence to their medication, despite saying that they asked about adherence in more than 80% of their patients.
Rheumatologists proposed the addition of a biologic to methotrexate more often if patients were nonadherent than if patients showed good compliance (91% vs. 68%; P less than .01).
Effect of patient attitudes on compliance
A team of U.K. researchers evaluated how attitudes toward treatment with methotrexate affected patients’ compliance in a separate poster presentation at the meeting.
RAMS is a 1-year observational study of patients with RA who are starting treatment with methotrexate. Patients recruited into the study completed weekly diaries, noting whether they took methotrexate (adherence) and, if not, their reasons for not doing so. Patients were deemed nonadherent if they did not take methotrexate correctly for 90% of the time over a period of 6 months.
Lower adherence was significantly associated with negative or uncertain views about treatment, with an odds ratio of 2.7. Conversely, being positive or certain about treatment lowered patients’ odds of being nonadherent (OR, 0.32).
“People who are uncertain about how to attribute illness events are less likely to adhere within the first 6 months of starting methotrexate therapy,” Ms. Hope and her coauthors observed.
“Encouraging patients to actively monitor their progress with therapy and providing them with support to understand likely effects of methotrexate may help optimize disease-modifying antirheumatic drug use,” they concluded.
Ms. Hope and Dr. Beauvais had no conflicts of interest to disclose. The FORGET survey was funded by Chugai Pharma France.
AT THE EULAR 2017 CONGRESS
Key clinical point:
Major finding: One-third (34%) of RA patients were nonadherent to methotrexate at the initiation of biologic therapy; having negative and uncertain beliefs about the effects of treatment increased the odds of nonadherence.
Data source: The cross-sectional FORGET survey of 78 rheumatologists and 269 patients with rheumatoid arthritis conducted in France and the Rheumatoid Arthritis Medications Study (RAMS) of 200 adherent and nonadherent patients.
Disclosures: The authors had no conflicts of interest to disclose. The FORGET survey was funded by Chugai Pharma France.
Novel knee osteoarthritis drugs target pain, joint space narrowing
MADRID – Two independently conducted, randomized, phase 2 trials of novel agents for moderate to severe knee osteoarthritis have produced promising results, as reported at the European Congress of Rheumatology.
In the 24-week, dose-ranging TRIUMPH trial involving 175 patients, treatment with the synthetic trans-capsaicin CNTX-4975 was associated with improvements in several clinical parameters, such as pain when walking, knee stiffness, and physical function, as well as being generally well tolerated.
These findings suggest that both could be future alternatives to using nonsteroidal anti-inflammatory drugs (NSAIDs), injected corticosteroids, and opioid analgesics, which are currently used to help manage knee OA.
Synthetic trans-capsaicin CNTX-4975
“Few effective pharmacologic therapies are available to manage the chronic pain of OA,” said Randall Stevens, MD, chief medical officer for Centrexion Therapeutics (Boston), the company developing CNTX-4975. Both NSAIDs and corticosteroids are associated with substantial toxicities, he argued, and opioid analgesics are not ideal to use long term because of the risk of side effects and addiction.
CNTX-4975 is a nonopioid analgesic that acts directly on the pain fibers in the knee, Dr. Stevens explained. Specifically, after a single injection, it targets the capsaicin receptor (transient receptor potential vanilloid 1, TRPV1) to inactivate only the local fibers transmitting pain signals to the brain. It does not affect other sensory fibers involved in sensation to touch or pressure, he said.
The aim of the phase 2b TRIUMPH trial was to examine the efficacy and safety of two doses (0.5 mg and 1.0 mg) of the synthetic trans-capsaicin versus placebo in patients with chronic, stable, moderate to severe knee OA who had been experiencing knee pain for at least 2 months or more. For inclusion, patients could be aged between 45 and 80 years, have a body mass index of up to 45 kg/m2, and had to have failed treatment or not be able to tolerate oral or intra-articular analgesics. Patients who had undergone recent knee surgery were excluded.
The primary endpoint was the change in pain with walking from baseline to week 12 measured as the area under the curve (AUC) for daily Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) A1 score. Significant improvements were seen, with a least squares mean difference (LSMD) of –0.8 (P = .07) and –1.6 (P less than .0001) with the 0.5 mg and 1.0 mg doses of CNTX-4975, respectively, versus placebo.
The effects of CNTX-4975 were maintained to 24 weeks, Dr. Stevens reported, with significant improvements in pain with walking, comparing the 1.0-mg dose with placebo (LSMD, –1.35; P = .0002).
“These are the largest effect sizes I’ve seen with osteoarthritis knee pain,” Dr. Stevens said.
The investigators saw improvements in other efficacy endpoints, such as the weekly pain with walking (WOMAC A1) score and the change in weekly average joint stiffness (WOMAC B subscale, LSMD: −2.5; P = .0013) and physical function (WOMAC C subscale, LSMD: −18.3; P = .004) versus placebo at week 12. Numerically greater improvements occurred at week 24.
A similar percentage of patients experienced any treatment-emergent adverse events in the 1.0-mg (29.6%) CNTX-4975 treated and placebo groups (30%). Although a higher percentage of patients given the lower CNTX-4975 dose reported side effects (47.1%), most were mild to moderate and were considered unrelated to study treatment. Arthralgia was the most common side effect with CNTX-4975 1.0 mg versus placebo (7% vs. 5.7%).
“With these findings, we are moving in to phase 3 with the 1.0-mg dose,” Dr. Stevens said.
Wnt inhibitor SM04690
Promising data from the phase 2 trial of the Wnt inhibitor SM04690 also suggest that it, too, could soon be heading into phase 3 trials.
Several early clinical studies have been completed already, noted Yusuf Yazici, MD, chief medical officer of Samumed (San Diego), the California-based company that is developing SMO4690.
SM04690 is a small molecule inhibitor of the Wnt pathway, which is involved in increased bone formation and turnover, he explained. The hypothesis is that by blocking this pathway, the joint can be protected and cartilage could perhaps be regenerated.
Dr. Yazici presented radiographic outcomes at 26 weeks from a 52-week trial that “demonstrated SM04690 treatment maintained or increased medial joint space width compared to placebo.” This is important, as “joint space narrowing is indicative of OA progression and is predictive of knee surgery,” and radiographic progression remains a “gold standard” for assessing potential disease modification in OA, said Dr. Yazici, who is also clinical associate professor and director of the Seligman Center for Advanced Therapeutics at New York University.
In the phase 2 trial he presented, three doses of SM04690 (0.03 mg, 0.07 mg, and 0.23 mg), given as one 2-mL intra-articular injection into a single target knee, were tested and compared against placebo. The target knee was the knee designated as causing the patient the most pain, according to the study investigator.
Radiographs of both knees were taken at the start of treatment, at week 26, and again at week 52, with the change in medial joint space width analyzed. Clinical assessments included changes in WOMAC total, function, and pain subscale scores, and patients’ and physicians’ global assessments.
A total of 455 subjects, mean age 60 years, were randomized into the trial.
Considering all patients, the mean increase in medial joint space width from baseline to 26-week assessment versus placebo was –0.07 mm in the SM04690 0.03-mg group, –0.16 mm in the SM04690 0.07-mg group, and –0.03 mm in the SM04690 0.23-mg group.
An improvement in mean medial joint space narrowing was observed in 47.6% with SM04690 0.03 mg, 40.5% with 0.07 mg, 39.6% with 0.23 mg, and 30.5% with placebo. There was no change in a respective 7.6%, 9%, 17.8%, and 11.4%, and narrowing in the remainder (44.8%, 50.5%, 42,6%, and 58.1%) in this intent-to-treat population.
The investigators conducted prespecified subanalyses in a “unilateral symptomatic” population of 164 patients, and this showed slightly better results, with a higher probability of improved medial joint space width with SM04690 than with placebo (odds ratio, 5.2; 95% confidence interval, 2.1-12.8; P less than .001).
However, an important limitation of the study is that it was not formerly powered to look at radiographic progression, Dr. Yazici said. Nevertheless, radiographs were centrally read and high intra- and inter-observer reproducibility was observed.
Safety and clinical outcomes from the trial, which were reported separately in a poster at the meeting, showed no undue concerns and clinically meaningful improvements in both patients’ and physicians’ global assessments of pain with SM04690 versus placebo.
“Radiographic and clinical outcomes from this 26-week interim analysis of a 52-week trial suggest that SM04690 has potential as a disease-modifying osteoarthritis drug (DMOAD) for knee OA,” Dr. Yazici concluded.
The studies were supported by Samumed and by Centrexion Therapeutics. Dr. Yazici is an employee and shareholder of Samumed. Dr. Stevens is an employee and shareholder of Centrexion Therapeutics.
MADRID – Two independently conducted, randomized, phase 2 trials of novel agents for moderate to severe knee osteoarthritis have produced promising results, as reported at the European Congress of Rheumatology.
In the 24-week, dose-ranging TRIUMPH trial involving 175 patients, treatment with the synthetic trans-capsaicin CNTX-4975 was associated with improvements in several clinical parameters, such as pain when walking, knee stiffness, and physical function, as well as being generally well tolerated.
These findings suggest that both could be future alternatives to using nonsteroidal anti-inflammatory drugs (NSAIDs), injected corticosteroids, and opioid analgesics, which are currently used to help manage knee OA.
Synthetic trans-capsaicin CNTX-4975
“Few effective pharmacologic therapies are available to manage the chronic pain of OA,” said Randall Stevens, MD, chief medical officer for Centrexion Therapeutics (Boston), the company developing CNTX-4975. Both NSAIDs and corticosteroids are associated with substantial toxicities, he argued, and opioid analgesics are not ideal to use long term because of the risk of side effects and addiction.
CNTX-4975 is a nonopioid analgesic that acts directly on the pain fibers in the knee, Dr. Stevens explained. Specifically, after a single injection, it targets the capsaicin receptor (transient receptor potential vanilloid 1, TRPV1) to inactivate only the local fibers transmitting pain signals to the brain. It does not affect other sensory fibers involved in sensation to touch or pressure, he said.
The aim of the phase 2b TRIUMPH trial was to examine the efficacy and safety of two doses (0.5 mg and 1.0 mg) of the synthetic trans-capsaicin versus placebo in patients with chronic, stable, moderate to severe knee OA who had been experiencing knee pain for at least 2 months or more. For inclusion, patients could be aged between 45 and 80 years, have a body mass index of up to 45 kg/m2, and had to have failed treatment or not be able to tolerate oral or intra-articular analgesics. Patients who had undergone recent knee surgery were excluded.
The primary endpoint was the change in pain with walking from baseline to week 12 measured as the area under the curve (AUC) for daily Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) A1 score. Significant improvements were seen, with a least squares mean difference (LSMD) of –0.8 (P = .07) and –1.6 (P less than .0001) with the 0.5 mg and 1.0 mg doses of CNTX-4975, respectively, versus placebo.
The effects of CNTX-4975 were maintained to 24 weeks, Dr. Stevens reported, with significant improvements in pain with walking, comparing the 1.0-mg dose with placebo (LSMD, –1.35; P = .0002).
“These are the largest effect sizes I’ve seen with osteoarthritis knee pain,” Dr. Stevens said.
The investigators saw improvements in other efficacy endpoints, such as the weekly pain with walking (WOMAC A1) score and the change in weekly average joint stiffness (WOMAC B subscale, LSMD: −2.5; P = .0013) and physical function (WOMAC C subscale, LSMD: −18.3; P = .004) versus placebo at week 12. Numerically greater improvements occurred at week 24.
A similar percentage of patients experienced any treatment-emergent adverse events in the 1.0-mg (29.6%) CNTX-4975 treated and placebo groups (30%). Although a higher percentage of patients given the lower CNTX-4975 dose reported side effects (47.1%), most were mild to moderate and were considered unrelated to study treatment. Arthralgia was the most common side effect with CNTX-4975 1.0 mg versus placebo (7% vs. 5.7%).
“With these findings, we are moving in to phase 3 with the 1.0-mg dose,” Dr. Stevens said.
Wnt inhibitor SM04690
Promising data from the phase 2 trial of the Wnt inhibitor SM04690 also suggest that it, too, could soon be heading into phase 3 trials.
Several early clinical studies have been completed already, noted Yusuf Yazici, MD, chief medical officer of Samumed (San Diego), the California-based company that is developing SMO4690.
SM04690 is a small molecule inhibitor of the Wnt pathway, which is involved in increased bone formation and turnover, he explained. The hypothesis is that by blocking this pathway, the joint can be protected and cartilage could perhaps be regenerated.
Dr. Yazici presented radiographic outcomes at 26 weeks from a 52-week trial that “demonstrated SM04690 treatment maintained or increased medial joint space width compared to placebo.” This is important, as “joint space narrowing is indicative of OA progression and is predictive of knee surgery,” and radiographic progression remains a “gold standard” for assessing potential disease modification in OA, said Dr. Yazici, who is also clinical associate professor and director of the Seligman Center for Advanced Therapeutics at New York University.
In the phase 2 trial he presented, three doses of SM04690 (0.03 mg, 0.07 mg, and 0.23 mg), given as one 2-mL intra-articular injection into a single target knee, were tested and compared against placebo. The target knee was the knee designated as causing the patient the most pain, according to the study investigator.
Radiographs of both knees were taken at the start of treatment, at week 26, and again at week 52, with the change in medial joint space width analyzed. Clinical assessments included changes in WOMAC total, function, and pain subscale scores, and patients’ and physicians’ global assessments.
A total of 455 subjects, mean age 60 years, were randomized into the trial.
Considering all patients, the mean increase in medial joint space width from baseline to 26-week assessment versus placebo was –0.07 mm in the SM04690 0.03-mg group, –0.16 mm in the SM04690 0.07-mg group, and –0.03 mm in the SM04690 0.23-mg group.
An improvement in mean medial joint space narrowing was observed in 47.6% with SM04690 0.03 mg, 40.5% with 0.07 mg, 39.6% with 0.23 mg, and 30.5% with placebo. There was no change in a respective 7.6%, 9%, 17.8%, and 11.4%, and narrowing in the remainder (44.8%, 50.5%, 42,6%, and 58.1%) in this intent-to-treat population.
The investigators conducted prespecified subanalyses in a “unilateral symptomatic” population of 164 patients, and this showed slightly better results, with a higher probability of improved medial joint space width with SM04690 than with placebo (odds ratio, 5.2; 95% confidence interval, 2.1-12.8; P less than .001).
However, an important limitation of the study is that it was not formerly powered to look at radiographic progression, Dr. Yazici said. Nevertheless, radiographs were centrally read and high intra- and inter-observer reproducibility was observed.
Safety and clinical outcomes from the trial, which were reported separately in a poster at the meeting, showed no undue concerns and clinically meaningful improvements in both patients’ and physicians’ global assessments of pain with SM04690 versus placebo.
“Radiographic and clinical outcomes from this 26-week interim analysis of a 52-week trial suggest that SM04690 has potential as a disease-modifying osteoarthritis drug (DMOAD) for knee OA,” Dr. Yazici concluded.
The studies were supported by Samumed and by Centrexion Therapeutics. Dr. Yazici is an employee and shareholder of Samumed. Dr. Stevens is an employee and shareholder of Centrexion Therapeutics.
MADRID – Two independently conducted, randomized, phase 2 trials of novel agents for moderate to severe knee osteoarthritis have produced promising results, as reported at the European Congress of Rheumatology.
In the 24-week, dose-ranging TRIUMPH trial involving 175 patients, treatment with the synthetic trans-capsaicin CNTX-4975 was associated with improvements in several clinical parameters, such as pain when walking, knee stiffness, and physical function, as well as being generally well tolerated.
These findings suggest that both could be future alternatives to using nonsteroidal anti-inflammatory drugs (NSAIDs), injected corticosteroids, and opioid analgesics, which are currently used to help manage knee OA.
Synthetic trans-capsaicin CNTX-4975
“Few effective pharmacologic therapies are available to manage the chronic pain of OA,” said Randall Stevens, MD, chief medical officer for Centrexion Therapeutics (Boston), the company developing CNTX-4975. Both NSAIDs and corticosteroids are associated with substantial toxicities, he argued, and opioid analgesics are not ideal to use long term because of the risk of side effects and addiction.
CNTX-4975 is a nonopioid analgesic that acts directly on the pain fibers in the knee, Dr. Stevens explained. Specifically, after a single injection, it targets the capsaicin receptor (transient receptor potential vanilloid 1, TRPV1) to inactivate only the local fibers transmitting pain signals to the brain. It does not affect other sensory fibers involved in sensation to touch or pressure, he said.
The aim of the phase 2b TRIUMPH trial was to examine the efficacy and safety of two doses (0.5 mg and 1.0 mg) of the synthetic trans-capsaicin versus placebo in patients with chronic, stable, moderate to severe knee OA who had been experiencing knee pain for at least 2 months or more. For inclusion, patients could be aged between 45 and 80 years, have a body mass index of up to 45 kg/m2, and had to have failed treatment or not be able to tolerate oral or intra-articular analgesics. Patients who had undergone recent knee surgery were excluded.
The primary endpoint was the change in pain with walking from baseline to week 12 measured as the area under the curve (AUC) for daily Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) A1 score. Significant improvements were seen, with a least squares mean difference (LSMD) of –0.8 (P = .07) and –1.6 (P less than .0001) with the 0.5 mg and 1.0 mg doses of CNTX-4975, respectively, versus placebo.
The effects of CNTX-4975 were maintained to 24 weeks, Dr. Stevens reported, with significant improvements in pain with walking, comparing the 1.0-mg dose with placebo (LSMD, –1.35; P = .0002).
“These are the largest effect sizes I’ve seen with osteoarthritis knee pain,” Dr. Stevens said.
The investigators saw improvements in other efficacy endpoints, such as the weekly pain with walking (WOMAC A1) score and the change in weekly average joint stiffness (WOMAC B subscale, LSMD: −2.5; P = .0013) and physical function (WOMAC C subscale, LSMD: −18.3; P = .004) versus placebo at week 12. Numerically greater improvements occurred at week 24.
A similar percentage of patients experienced any treatment-emergent adverse events in the 1.0-mg (29.6%) CNTX-4975 treated and placebo groups (30%). Although a higher percentage of patients given the lower CNTX-4975 dose reported side effects (47.1%), most were mild to moderate and were considered unrelated to study treatment. Arthralgia was the most common side effect with CNTX-4975 1.0 mg versus placebo (7% vs. 5.7%).
“With these findings, we are moving in to phase 3 with the 1.0-mg dose,” Dr. Stevens said.
Wnt inhibitor SM04690
Promising data from the phase 2 trial of the Wnt inhibitor SM04690 also suggest that it, too, could soon be heading into phase 3 trials.
Several early clinical studies have been completed already, noted Yusuf Yazici, MD, chief medical officer of Samumed (San Diego), the California-based company that is developing SMO4690.
SM04690 is a small molecule inhibitor of the Wnt pathway, which is involved in increased bone formation and turnover, he explained. The hypothesis is that by blocking this pathway, the joint can be protected and cartilage could perhaps be regenerated.
Dr. Yazici presented radiographic outcomes at 26 weeks from a 52-week trial that “demonstrated SM04690 treatment maintained or increased medial joint space width compared to placebo.” This is important, as “joint space narrowing is indicative of OA progression and is predictive of knee surgery,” and radiographic progression remains a “gold standard” for assessing potential disease modification in OA, said Dr. Yazici, who is also clinical associate professor and director of the Seligman Center for Advanced Therapeutics at New York University.
In the phase 2 trial he presented, three doses of SM04690 (0.03 mg, 0.07 mg, and 0.23 mg), given as one 2-mL intra-articular injection into a single target knee, were tested and compared against placebo. The target knee was the knee designated as causing the patient the most pain, according to the study investigator.
Radiographs of both knees were taken at the start of treatment, at week 26, and again at week 52, with the change in medial joint space width analyzed. Clinical assessments included changes in WOMAC total, function, and pain subscale scores, and patients’ and physicians’ global assessments.
A total of 455 subjects, mean age 60 years, were randomized into the trial.
Considering all patients, the mean increase in medial joint space width from baseline to 26-week assessment versus placebo was –0.07 mm in the SM04690 0.03-mg group, –0.16 mm in the SM04690 0.07-mg group, and –0.03 mm in the SM04690 0.23-mg group.
An improvement in mean medial joint space narrowing was observed in 47.6% with SM04690 0.03 mg, 40.5% with 0.07 mg, 39.6% with 0.23 mg, and 30.5% with placebo. There was no change in a respective 7.6%, 9%, 17.8%, and 11.4%, and narrowing in the remainder (44.8%, 50.5%, 42,6%, and 58.1%) in this intent-to-treat population.
The investigators conducted prespecified subanalyses in a “unilateral symptomatic” population of 164 patients, and this showed slightly better results, with a higher probability of improved medial joint space width with SM04690 than with placebo (odds ratio, 5.2; 95% confidence interval, 2.1-12.8; P less than .001).
However, an important limitation of the study is that it was not formerly powered to look at radiographic progression, Dr. Yazici said. Nevertheless, radiographs were centrally read and high intra- and inter-observer reproducibility was observed.
Safety and clinical outcomes from the trial, which were reported separately in a poster at the meeting, showed no undue concerns and clinically meaningful improvements in both patients’ and physicians’ global assessments of pain with SM04690 versus placebo.
“Radiographic and clinical outcomes from this 26-week interim analysis of a 52-week trial suggest that SM04690 has potential as a disease-modifying osteoarthritis drug (DMOAD) for knee OA,” Dr. Yazici concluded.
The studies were supported by Samumed and by Centrexion Therapeutics. Dr. Yazici is an employee and shareholder of Samumed. Dr. Stevens is an employee and shareholder of Centrexion Therapeutics.
AT THE EULAR 2017 CONGRESS
Key clinical point:
Major finding: Radiographic joint space narrowing was no worse or improved after treatment with the Wnt pathway inhibitor SM04690. Treatment with the synthetic trans-capsaicin CNTX-4975 improved pain when walking, knee stiffness, and physical function.
Data source: Two independently conducted randomized, phase 2 trials of patients with moderate to severe knee OA: a 52-week trial with SM04690 in 455 patients and a 24-week trial of CNTX-4975 in 175 patients.
Disclosures: Samumed and Centrexion Therapeutics sponsored the two separate studies. The presenting authors were employees and shareholders of their respective companies.
New classification system for systemic lupus erythematosus moves forward
MADRID – A proposed classification scheme for systemic lupus erythematosus (SLE) relies on a combination of antinuclear antibody titer and the weighted scoring of signs and symptoms in seven clinical and three immunologic domains.
Anyone with an ANA titer of at least 1:80 on immunofluorescence and 84 points accumulated from the domains can be classified as having the disease, according to the proposed system. An international collaboration between the American College of Rheumatology and the European League Against Rheumatism, the system is the first classification scheme update since 2012, said Sindhu Johnson, MD, PhD, who discussed it during the European Congress of Rheumatology.
[polldaddy:9802068]
The proposed system is not intended to be a diagnostic tool, Dr. Johnson said in an interview. Rather, it’s meant to better stratify patients into research studies. “The prior criteria were missing patients. And, since classification criteria are used to decide whether patients can get into a clinical trial, we all felt that we were doing patients an injustice if the criteria were excluding some and denying them an opportunity to receive a novel therapy.”
There are currently two classification criteria in use: the 1982 American College of Rheumatology criteria and the Systemic Lupus International Collaborating Clinics Criteria (SLICC 2012). New understandings of SLE pathogenesis have rendered the 1982 ACR criteria outdated, according to a recently published paper (Arthritis Care Res. 2017 July 10. doi: 10.1002/acr.23317). While the SLICC 2012 criteria incorporated some of the new concepts and have increased sensitivity, compared with the 1982 ACR criteria, their specificity actually declined, partially because the document assigned equal weight to each of the clinical and immunologic criteria. The ACR/EULAR project takes a different tack. Criteria are weighted to reflect the clinical impact of different signs and symptoms, Dr. Johnson said.
“In clinical practice, if someone has class III/IV lupus nephritis, that’s a very different patient than someone who has leukopenia. As clinicians, we weight things differently, and so do these criteria, putting more weight on serious or internal organ manifestations of SLE.”
The ACR/EULAR criteria begin with a confirmed ANA titer of at least 1:80. “This has never been a requirement before, but the consensus now is that you need to have a positive ANA to be classified.”
Once that baseline is established, patients can be assessed in seven clinical domains and three immunologic domains. Each contains a subgroup of weighted signs and symptoms. These are ordered from those with least impact to those with most impact. Within each domain, only the highest-scoring criterion is counted toward the total score. When assessing, clinicians should not score any symptom if a cause other than SLE is more likely. The symptoms are not time-bound either, Dr. Johnson said. A symptom may have occurred only one time in the past, and that’s sufficient to earn a score. At least one clinical criterion must be present to be classified as SLE-positive.
The clinical domains
Constitutional: Fever (13 points). The only symptom in this domain, it’s never before been assessed in SLE criteria, Dr. Johnson said. “Our inclusion of fever is new, but our work in phase 1 of this project found that fever is a feature that can distinguish early lupus from mimickers. We want to identify patients as early in the disease course as possible so we can intervene, and fever appears to improve the ability to detect those patients.”
Cutaneous: Nonscarring alopecia (13), oral ulcers (14), subacute cutaneous or discoid lupus (29), and acute cutaneous lupus (38).
“Skin has long been recognized as an important part of lupus, but it got a lot of weight that some people felt was inappropriate. These criteria still include skin, but a patient can’t be classified on skin findings alone. There is concern that skin findings by themselves may not be lupus but something else, and some people even consider that cutaneous and systemic lupus are two different things.”
Arthritis: Synovitis in at least two joints (34).
Neurologic: Delirium (12), psychosis (20), and seizure (34).
Serositis: Pleural or pericardial effusion (34) and acute pericarditis (38).
Hematologic: Leukopenia (12), thrombocytopenia (26), and autoimmune hemolysis (28).
Renal: Proteinuria more than 0.5 g/24 hours (27), renal biopsy with class II or V lupus nephritis (55), and renal biopsy with class III or IV lupus nephritis (74).
The immunologic domains
Antiphospholipid antibodies: Anticardiolipin immunoglobulin G more than 40 GPL units, anti-beta2GP1 IgG more than 40 units, or lupus anticoagulant positive (13).
Complement proteins: Low C3 or low C4 (19) and low C3 and low C4 (27).
Highly specific antibodies: Anti-dsDNA antibody (38) and anti-Smith antibody (40).
Moving forward
Screening 10 domains with their attendant components may seem a bit clunky now, Dr. Johnson noted, but the final iteration should be more streamlined. Plus, she said, the system will be presented on a computer application that makes calculation much easier. “We’re aiming for feasibility and simplicity, but, at the same time, when you have a complex disease, you don’t want oversimplification. You may lose sensitivity and specificity.”
After further streamlining, Dr. Johnson said, the next step will be validating in a large retrospective patient cohort. “Right now, we are still collecting data for the validation cohort, which will be drawn from 36 centers. We’ll analyze sensitivity and specificity, comparing this system with the other two. We hope to present all these data at the ACR meeting in the fall.”
While research classification is the system’s raison d’être, it will undoubtedly influence diagnosis and clinical assessment as well, Dr. Johnson said. “ACR and EULAR are very clear that they only support the validation of classification criteria. The diagnosis of SLE is still within the hands of the physician. But, we know that classification criteria do inform our concept of the disease, so it’s likely these will shift the way we think about diagnosing lupus as well. We do hope to identify patients with earlier disease, so they have the opportunity to be involved in research” that may modify their disease course and, ultimately, prevent permanent damage and improve quality of life.
Dr. Johnson had no disclosures related to the development of the classification criteria.
msullivan@frontlinemedcom.com
On Twitter @alz_gal
This joint ACR/EULAR effort is very large, involving over 40 international SLE experts and centers, including many Systemic Lupus International Collaborating Clinics Criteria members. The goals are to develop new criteria that will be both sensitive and specific for SLE, which is a very heterogeneous and often elusive disease, using newer rigorous expert opinion–based and data-driven methodologies (as has been accomplished recently for rheumatoid arthritis, scleroderma, and gout).
This is a tall order! While genetic and cytokine-based biomarkers are being developed for the identification of SLE, unfortunately, we were not able incorporate them as they are not available for routine use at this time. The SLE classification criteria are used worldwide for inclusion in clinical trials and studies.
The work has been preceding in phases: phase 1, item generation; phase 2, item reduction and definition of criteria; phase 3, multicriteria decision analysis and threshold identification; and phase 4, validation. Phases 1-3 involved many iterative, group discussions, data collection and review, and novel “forced choice” methodologies for arriving at group consensus. In phase 4 (validation), the goal is to compare classification using these criteria with the existing ACR and SLICC criteria, as well as SLE expert physician diagnosis. We will see how they do after all this effort!
Karen H. Costenbader, MD, is the lupus program director at Brigham and Women’s Hospital, Boston. She is a member of the classification criteria steering committee and is the senior author on a paper describing the process to develop the draft classification criteria (Arthritis Care Res. 2017 July 10. doi: 10.1002/acr.23317).
This joint ACR/EULAR effort is very large, involving over 40 international SLE experts and centers, including many Systemic Lupus International Collaborating Clinics Criteria members. The goals are to develop new criteria that will be both sensitive and specific for SLE, which is a very heterogeneous and often elusive disease, using newer rigorous expert opinion–based and data-driven methodologies (as has been accomplished recently for rheumatoid arthritis, scleroderma, and gout).
This is a tall order! While genetic and cytokine-based biomarkers are being developed for the identification of SLE, unfortunately, we were not able incorporate them as they are not available for routine use at this time. The SLE classification criteria are used worldwide for inclusion in clinical trials and studies.
The work has been preceding in phases: phase 1, item generation; phase 2, item reduction and definition of criteria; phase 3, multicriteria decision analysis and threshold identification; and phase 4, validation. Phases 1-3 involved many iterative, group discussions, data collection and review, and novel “forced choice” methodologies for arriving at group consensus. In phase 4 (validation), the goal is to compare classification using these criteria with the existing ACR and SLICC criteria, as well as SLE expert physician diagnosis. We will see how they do after all this effort!
Karen H. Costenbader, MD, is the lupus program director at Brigham and Women’s Hospital, Boston. She is a member of the classification criteria steering committee and is the senior author on a paper describing the process to develop the draft classification criteria (Arthritis Care Res. 2017 July 10. doi: 10.1002/acr.23317).
This joint ACR/EULAR effort is very large, involving over 40 international SLE experts and centers, including many Systemic Lupus International Collaborating Clinics Criteria members. The goals are to develop new criteria that will be both sensitive and specific for SLE, which is a very heterogeneous and often elusive disease, using newer rigorous expert opinion–based and data-driven methodologies (as has been accomplished recently for rheumatoid arthritis, scleroderma, and gout).
This is a tall order! While genetic and cytokine-based biomarkers are being developed for the identification of SLE, unfortunately, we were not able incorporate them as they are not available for routine use at this time. The SLE classification criteria are used worldwide for inclusion in clinical trials and studies.
The work has been preceding in phases: phase 1, item generation; phase 2, item reduction and definition of criteria; phase 3, multicriteria decision analysis and threshold identification; and phase 4, validation. Phases 1-3 involved many iterative, group discussions, data collection and review, and novel “forced choice” methodologies for arriving at group consensus. In phase 4 (validation), the goal is to compare classification using these criteria with the existing ACR and SLICC criteria, as well as SLE expert physician diagnosis. We will see how they do after all this effort!
Karen H. Costenbader, MD, is the lupus program director at Brigham and Women’s Hospital, Boston. She is a member of the classification criteria steering committee and is the senior author on a paper describing the process to develop the draft classification criteria (Arthritis Care Res. 2017 July 10. doi: 10.1002/acr.23317).
MADRID – A proposed classification scheme for systemic lupus erythematosus (SLE) relies on a combination of antinuclear antibody titer and the weighted scoring of signs and symptoms in seven clinical and three immunologic domains.
Anyone with an ANA titer of at least 1:80 on immunofluorescence and 84 points accumulated from the domains can be classified as having the disease, according to the proposed system. An international collaboration between the American College of Rheumatology and the European League Against Rheumatism, the system is the first classification scheme update since 2012, said Sindhu Johnson, MD, PhD, who discussed it during the European Congress of Rheumatology.
[polldaddy:9802068]
The proposed system is not intended to be a diagnostic tool, Dr. Johnson said in an interview. Rather, it’s meant to better stratify patients into research studies. “The prior criteria were missing patients. And, since classification criteria are used to decide whether patients can get into a clinical trial, we all felt that we were doing patients an injustice if the criteria were excluding some and denying them an opportunity to receive a novel therapy.”
There are currently two classification criteria in use: the 1982 American College of Rheumatology criteria and the Systemic Lupus International Collaborating Clinics Criteria (SLICC 2012). New understandings of SLE pathogenesis have rendered the 1982 ACR criteria outdated, according to a recently published paper (Arthritis Care Res. 2017 July 10. doi: 10.1002/acr.23317). While the SLICC 2012 criteria incorporated some of the new concepts and have increased sensitivity, compared with the 1982 ACR criteria, their specificity actually declined, partially because the document assigned equal weight to each of the clinical and immunologic criteria. The ACR/EULAR project takes a different tack. Criteria are weighted to reflect the clinical impact of different signs and symptoms, Dr. Johnson said.
“In clinical practice, if someone has class III/IV lupus nephritis, that’s a very different patient than someone who has leukopenia. As clinicians, we weight things differently, and so do these criteria, putting more weight on serious or internal organ manifestations of SLE.”
The ACR/EULAR criteria begin with a confirmed ANA titer of at least 1:80. “This has never been a requirement before, but the consensus now is that you need to have a positive ANA to be classified.”
Once that baseline is established, patients can be assessed in seven clinical domains and three immunologic domains. Each contains a subgroup of weighted signs and symptoms. These are ordered from those with least impact to those with most impact. Within each domain, only the highest-scoring criterion is counted toward the total score. When assessing, clinicians should not score any symptom if a cause other than SLE is more likely. The symptoms are not time-bound either, Dr. Johnson said. A symptom may have occurred only one time in the past, and that’s sufficient to earn a score. At least one clinical criterion must be present to be classified as SLE-positive.
The clinical domains
Constitutional: Fever (13 points). The only symptom in this domain, it’s never before been assessed in SLE criteria, Dr. Johnson said. “Our inclusion of fever is new, but our work in phase 1 of this project found that fever is a feature that can distinguish early lupus from mimickers. We want to identify patients as early in the disease course as possible so we can intervene, and fever appears to improve the ability to detect those patients.”
Cutaneous: Nonscarring alopecia (13), oral ulcers (14), subacute cutaneous or discoid lupus (29), and acute cutaneous lupus (38).
“Skin has long been recognized as an important part of lupus, but it got a lot of weight that some people felt was inappropriate. These criteria still include skin, but a patient can’t be classified on skin findings alone. There is concern that skin findings by themselves may not be lupus but something else, and some people even consider that cutaneous and systemic lupus are two different things.”
Arthritis: Synovitis in at least two joints (34).
Neurologic: Delirium (12), psychosis (20), and seizure (34).
Serositis: Pleural or pericardial effusion (34) and acute pericarditis (38).
Hematologic: Leukopenia (12), thrombocytopenia (26), and autoimmune hemolysis (28).
Renal: Proteinuria more than 0.5 g/24 hours (27), renal biopsy with class II or V lupus nephritis (55), and renal biopsy with class III or IV lupus nephritis (74).
The immunologic domains
Antiphospholipid antibodies: Anticardiolipin immunoglobulin G more than 40 GPL units, anti-beta2GP1 IgG more than 40 units, or lupus anticoagulant positive (13).
Complement proteins: Low C3 or low C4 (19) and low C3 and low C4 (27).
Highly specific antibodies: Anti-dsDNA antibody (38) and anti-Smith antibody (40).
Moving forward
Screening 10 domains with their attendant components may seem a bit clunky now, Dr. Johnson noted, but the final iteration should be more streamlined. Plus, she said, the system will be presented on a computer application that makes calculation much easier. “We’re aiming for feasibility and simplicity, but, at the same time, when you have a complex disease, you don’t want oversimplification. You may lose sensitivity and specificity.”
After further streamlining, Dr. Johnson said, the next step will be validating in a large retrospective patient cohort. “Right now, we are still collecting data for the validation cohort, which will be drawn from 36 centers. We’ll analyze sensitivity and specificity, comparing this system with the other two. We hope to present all these data at the ACR meeting in the fall.”
While research classification is the system’s raison d’être, it will undoubtedly influence diagnosis and clinical assessment as well, Dr. Johnson said. “ACR and EULAR are very clear that they only support the validation of classification criteria. The diagnosis of SLE is still within the hands of the physician. But, we know that classification criteria do inform our concept of the disease, so it’s likely these will shift the way we think about diagnosing lupus as well. We do hope to identify patients with earlier disease, so they have the opportunity to be involved in research” that may modify their disease course and, ultimately, prevent permanent damage and improve quality of life.
Dr. Johnson had no disclosures related to the development of the classification criteria.
msullivan@frontlinemedcom.com
On Twitter @alz_gal
MADRID – A proposed classification scheme for systemic lupus erythematosus (SLE) relies on a combination of antinuclear antibody titer and the weighted scoring of signs and symptoms in seven clinical and three immunologic domains.
Anyone with an ANA titer of at least 1:80 on immunofluorescence and 84 points accumulated from the domains can be classified as having the disease, according to the proposed system. An international collaboration between the American College of Rheumatology and the European League Against Rheumatism, the system is the first classification scheme update since 2012, said Sindhu Johnson, MD, PhD, who discussed it during the European Congress of Rheumatology.
[polldaddy:9802068]
The proposed system is not intended to be a diagnostic tool, Dr. Johnson said in an interview. Rather, it’s meant to better stratify patients into research studies. “The prior criteria were missing patients. And, since classification criteria are used to decide whether patients can get into a clinical trial, we all felt that we were doing patients an injustice if the criteria were excluding some and denying them an opportunity to receive a novel therapy.”
There are currently two classification criteria in use: the 1982 American College of Rheumatology criteria and the Systemic Lupus International Collaborating Clinics Criteria (SLICC 2012). New understandings of SLE pathogenesis have rendered the 1982 ACR criteria outdated, according to a recently published paper (Arthritis Care Res. 2017 July 10. doi: 10.1002/acr.23317). While the SLICC 2012 criteria incorporated some of the new concepts and have increased sensitivity, compared with the 1982 ACR criteria, their specificity actually declined, partially because the document assigned equal weight to each of the clinical and immunologic criteria. The ACR/EULAR project takes a different tack. Criteria are weighted to reflect the clinical impact of different signs and symptoms, Dr. Johnson said.
“In clinical practice, if someone has class III/IV lupus nephritis, that’s a very different patient than someone who has leukopenia. As clinicians, we weight things differently, and so do these criteria, putting more weight on serious or internal organ manifestations of SLE.”
The ACR/EULAR criteria begin with a confirmed ANA titer of at least 1:80. “This has never been a requirement before, but the consensus now is that you need to have a positive ANA to be classified.”
Once that baseline is established, patients can be assessed in seven clinical domains and three immunologic domains. Each contains a subgroup of weighted signs and symptoms. These are ordered from those with least impact to those with most impact. Within each domain, only the highest-scoring criterion is counted toward the total score. When assessing, clinicians should not score any symptom if a cause other than SLE is more likely. The symptoms are not time-bound either, Dr. Johnson said. A symptom may have occurred only one time in the past, and that’s sufficient to earn a score. At least one clinical criterion must be present to be classified as SLE-positive.
The clinical domains
Constitutional: Fever (13 points). The only symptom in this domain, it’s never before been assessed in SLE criteria, Dr. Johnson said. “Our inclusion of fever is new, but our work in phase 1 of this project found that fever is a feature that can distinguish early lupus from mimickers. We want to identify patients as early in the disease course as possible so we can intervene, and fever appears to improve the ability to detect those patients.”
Cutaneous: Nonscarring alopecia (13), oral ulcers (14), subacute cutaneous or discoid lupus (29), and acute cutaneous lupus (38).
“Skin has long been recognized as an important part of lupus, but it got a lot of weight that some people felt was inappropriate. These criteria still include skin, but a patient can’t be classified on skin findings alone. There is concern that skin findings by themselves may not be lupus but something else, and some people even consider that cutaneous and systemic lupus are two different things.”
Arthritis: Synovitis in at least two joints (34).
Neurologic: Delirium (12), psychosis (20), and seizure (34).
Serositis: Pleural or pericardial effusion (34) and acute pericarditis (38).
Hematologic: Leukopenia (12), thrombocytopenia (26), and autoimmune hemolysis (28).
Renal: Proteinuria more than 0.5 g/24 hours (27), renal biopsy with class II or V lupus nephritis (55), and renal biopsy with class III or IV lupus nephritis (74).
The immunologic domains
Antiphospholipid antibodies: Anticardiolipin immunoglobulin G more than 40 GPL units, anti-beta2GP1 IgG more than 40 units, or lupus anticoagulant positive (13).
Complement proteins: Low C3 or low C4 (19) and low C3 and low C4 (27).
Highly specific antibodies: Anti-dsDNA antibody (38) and anti-Smith antibody (40).
Moving forward
Screening 10 domains with their attendant components may seem a bit clunky now, Dr. Johnson noted, but the final iteration should be more streamlined. Plus, she said, the system will be presented on a computer application that makes calculation much easier. “We’re aiming for feasibility and simplicity, but, at the same time, when you have a complex disease, you don’t want oversimplification. You may lose sensitivity and specificity.”
After further streamlining, Dr. Johnson said, the next step will be validating in a large retrospective patient cohort. “Right now, we are still collecting data for the validation cohort, which will be drawn from 36 centers. We’ll analyze sensitivity and specificity, comparing this system with the other two. We hope to present all these data at the ACR meeting in the fall.”
While research classification is the system’s raison d’être, it will undoubtedly influence diagnosis and clinical assessment as well, Dr. Johnson said. “ACR and EULAR are very clear that they only support the validation of classification criteria. The diagnosis of SLE is still within the hands of the physician. But, we know that classification criteria do inform our concept of the disease, so it’s likely these will shift the way we think about diagnosing lupus as well. We do hope to identify patients with earlier disease, so they have the opportunity to be involved in research” that may modify their disease course and, ultimately, prevent permanent damage and improve quality of life.
Dr. Johnson had no disclosures related to the development of the classification criteria.
msullivan@frontlinemedcom.com
On Twitter @alz_gal
AT THE EULAR 2017 CONGRESS
Unresolved fatigue lingers for most PsA patients
MADRID – Fatigue is an important symptom in patients with psoriatic arthritis but often goes unaddressed when treatment only involves disease modifying drugs.
A survey of more than 1,000 patients with psoriatic arthritis (PsA) in Denmark found that more than half had moderate or severe levels of fatigue, and a principal component analysis of the sources of fatigue found three factors responsible for the majority of reported patient fatigue: chronic inflammation, chronic pain, and chronification of the PsA, Tanja S. Jørgensen, PhD, said at the European Congress of Rheumatology.
“Pain is the most important symptom in patients with psoriatic arthritis, but fatigue is second-most important. It has a huge impact on patient quality of life,” she said.
“Just treating inflammation doesn’t do it all. We need to do more, think differently, think outside the box” of relying primarily on disease-modifying antirheumatic drugs, especially biological drugs, to resolve symptoms in PsA patients. “We should not think that biologicals do it all.”
The upshot is that PsA patients may have their inflammatory markers under control with treatment but still report that they don’t feel well, have pain, are tired, and have no energy.
But Dr. Jørgensen admitted that she couldn’t say with any certainty what additional interventions might help resolve pain and fatigue in PsA patients.
“I tell them to walk and be active; I think that may help. But we don’t really know what to do,” she said in an interview.
Her study included 1,062 PsA patients enrolled during December 2013-December 2014 in the Danish DANBIO registry of patients with inflammatory arthritides who received treatment with a biological drug. These participants also agreed to both complete a painDETECT Questionnaire and to rate their fatigue on a visual analog scale.
Dr. Jørgensen and her associates designated a visual analog scale score of at least 57 out of 100 as representing moderate or severe fatigue and found that 542 (51%) of the patients had fatigue self-ratings that fell in this range. Patients with this higher fatigue level also had significantly worse PsA with significantly higher numbers of swollen and tender joints, higher painDETECT scores, and higher scores on their Health Assessment Questionnaire and their 28-joint Disease Activity Score using C-reactive protein.
When the researchers ran a principal component analysis on these data, they identified three primary factors contributing to fatigue. Chronic inflammation contributed 31% of the fatigue effect, chronification contributed 17%, and chronic pain contributed 15%, Dr. Jørgensen reported.
Dr. Jørgensen has received research support from AbbVie, Biogen, Novartis, Pfizer, Roche, and UCB.
mzoler@frontlinemedcom.com
On Twitter @mitchelzoler
MADRID – Fatigue is an important symptom in patients with psoriatic arthritis but often goes unaddressed when treatment only involves disease modifying drugs.
A survey of more than 1,000 patients with psoriatic arthritis (PsA) in Denmark found that more than half had moderate or severe levels of fatigue, and a principal component analysis of the sources of fatigue found three factors responsible for the majority of reported patient fatigue: chronic inflammation, chronic pain, and chronification of the PsA, Tanja S. Jørgensen, PhD, said at the European Congress of Rheumatology.
“Pain is the most important symptom in patients with psoriatic arthritis, but fatigue is second-most important. It has a huge impact on patient quality of life,” she said.
“Just treating inflammation doesn’t do it all. We need to do more, think differently, think outside the box” of relying primarily on disease-modifying antirheumatic drugs, especially biological drugs, to resolve symptoms in PsA patients. “We should not think that biologicals do it all.”
The upshot is that PsA patients may have their inflammatory markers under control with treatment but still report that they don’t feel well, have pain, are tired, and have no energy.
But Dr. Jørgensen admitted that she couldn’t say with any certainty what additional interventions might help resolve pain and fatigue in PsA patients.
“I tell them to walk and be active; I think that may help. But we don’t really know what to do,” she said in an interview.
Her study included 1,062 PsA patients enrolled during December 2013-December 2014 in the Danish DANBIO registry of patients with inflammatory arthritides who received treatment with a biological drug. These participants also agreed to both complete a painDETECT Questionnaire and to rate their fatigue on a visual analog scale.
Dr. Jørgensen and her associates designated a visual analog scale score of at least 57 out of 100 as representing moderate or severe fatigue and found that 542 (51%) of the patients had fatigue self-ratings that fell in this range. Patients with this higher fatigue level also had significantly worse PsA with significantly higher numbers of swollen and tender joints, higher painDETECT scores, and higher scores on their Health Assessment Questionnaire and their 28-joint Disease Activity Score using C-reactive protein.
When the researchers ran a principal component analysis on these data, they identified three primary factors contributing to fatigue. Chronic inflammation contributed 31% of the fatigue effect, chronification contributed 17%, and chronic pain contributed 15%, Dr. Jørgensen reported.
Dr. Jørgensen has received research support from AbbVie, Biogen, Novartis, Pfizer, Roche, and UCB.
mzoler@frontlinemedcom.com
On Twitter @mitchelzoler
MADRID – Fatigue is an important symptom in patients with psoriatic arthritis but often goes unaddressed when treatment only involves disease modifying drugs.
A survey of more than 1,000 patients with psoriatic arthritis (PsA) in Denmark found that more than half had moderate or severe levels of fatigue, and a principal component analysis of the sources of fatigue found three factors responsible for the majority of reported patient fatigue: chronic inflammation, chronic pain, and chronification of the PsA, Tanja S. Jørgensen, PhD, said at the European Congress of Rheumatology.
“Pain is the most important symptom in patients with psoriatic arthritis, but fatigue is second-most important. It has a huge impact on patient quality of life,” she said.
“Just treating inflammation doesn’t do it all. We need to do more, think differently, think outside the box” of relying primarily on disease-modifying antirheumatic drugs, especially biological drugs, to resolve symptoms in PsA patients. “We should not think that biologicals do it all.”
The upshot is that PsA patients may have their inflammatory markers under control with treatment but still report that they don’t feel well, have pain, are tired, and have no energy.
But Dr. Jørgensen admitted that she couldn’t say with any certainty what additional interventions might help resolve pain and fatigue in PsA patients.
“I tell them to walk and be active; I think that may help. But we don’t really know what to do,” she said in an interview.
Her study included 1,062 PsA patients enrolled during December 2013-December 2014 in the Danish DANBIO registry of patients with inflammatory arthritides who received treatment with a biological drug. These participants also agreed to both complete a painDETECT Questionnaire and to rate their fatigue on a visual analog scale.
Dr. Jørgensen and her associates designated a visual analog scale score of at least 57 out of 100 as representing moderate or severe fatigue and found that 542 (51%) of the patients had fatigue self-ratings that fell in this range. Patients with this higher fatigue level also had significantly worse PsA with significantly higher numbers of swollen and tender joints, higher painDETECT scores, and higher scores on their Health Assessment Questionnaire and their 28-joint Disease Activity Score using C-reactive protein.
When the researchers ran a principal component analysis on these data, they identified three primary factors contributing to fatigue. Chronic inflammation contributed 31% of the fatigue effect, chronification contributed 17%, and chronic pain contributed 15%, Dr. Jørgensen reported.
Dr. Jørgensen has received research support from AbbVie, Biogen, Novartis, Pfizer, Roche, and UCB.
mzoler@frontlinemedcom.com
On Twitter @mitchelzoler
AT THE EULAR 2017 CONGRESS
Key clinical point:
Major finding: Visual analog scoring showed 51% of patients rated their fatigue as 57 or higher on a 0-100 scale.
Data source: A review of 1,062 Danish psoriatic arthritis patients treated with a biological drug and enrolled in the DANBIO registry
Disclosures: Dr. Jørgensen has received research support from AbbVie, Biogen, Novartis, Pfizer, Roche, and UCB.
Erosive hand OA evades dual IL-1 blocker’s effects
MADRID – Treatment with the dual interleukin (IL) 1 blocker ABT-981 did not improve pain scores or erosive joint damage in patients with hand osteoarthritis (OA) in a phase 2a trial reported at the European Congress of Rheumatology.
The disappointing findings suggest that IL-1 may not be an effective target in erosive hand OA, said Margreet Kloppenburg, MD, of Leiden (the Netherlands) University Medical Center, even though the investigators obtained adequate pharmacodynamic results that suggested it was effectively blocking both IL-1 alpha and IL-1 beta.
The phase 2a, multicenter, randomized, double-blind, placebo-controlled study she reported followed on from a phase 1 trial showing that ABT-981 could dose-dependently reduce neutrophil counts and markers of joint inflammation in patients with knee OA. So it was perhaps natural to see if it could potentially have an effect in patients with erosive hand OA.
The aim of the phase 2a trial was to evaluate the safety and efficacy of ABT-981 in the treatment of 131 patients with erosive hand OA. After screening and a 45-day washout period, patients with confirmed erosive hand OA were randomized to receive ABT-981 200 mg injected every 2 weeks or matching placebo.
The primary endpoint was the change in Australian/Canadian Hand Osteoarthritis Index (AUSCAN) pain from baseline to 16 weeks, but no significant difference was observed. The mean change in AUSCAN pain was –9.2 for the 64 ABT-981-treated patients and –10.7 for placebo-treated patients (P = .039).
“There were similar results with AUSCAN function and tender and swollen joint counts,” Dr. Kloppenburg said.
There were also no differences seen in radiographic or MRI endpoints, such as the number of erosive joints, Kellgren and Lawrence scores, joint-space narrowing, or the presence of osteophytes.
Nevertheless, there was evidence that ABT-981 was decreasing inflammatory markers, such as high-sensitivity C-reactive protein and neutrophils. IL-1 alpha and IL-1 beta were difficult to measure, but data suggested that IL-1 was being blocked.
Disappointing results with cytokine targeting
Hand OA affects around 11% of the OA population and erosive hand OA is a very painful phenotype that affects multiple joints, Xavier Chevalier, MD, of Henri-Mondor Hospital, Paris XII University (France), said during a separate session at the congress.
While there is a rationale for using anti-inflammatory drugs for erosive hand OA, so far there just have not been many, if any, real successes. “The effect sizes are small,” Dr. Chevalier said. “There are not a lot of drugs when compared to hip and knee OA,” he observed.
His general conclusion was that targeting cytokines in hand OA had been “disappointing” with “small effect in subgroup of clinically inflamed IP [interphalangeal] joints.”
Dr. Chevalier questioned: “Is hand OA a real OA?” There are features of the disease that imply it could be more of a ligamentous or enthesitis disease, or perhaps a subchondral bone disorder.
Is erosive hand OA even an inflammatory disease? he asked. Are TNF and IL-1 the right targets? Perhaps not, given the research presented by Dr. Kloppenburg and others, he suggested. Further research needs to look for surrogate markers and try to quantify the structural evolution of the disease, he proposed.
It is important to talk about negative studies and to not make excuses for why they might be negative, Tonia Vincent, PhD, observed during the discussion that followed Dr. Chevalier’s presentation.
“If you do proper, randomized, controlled studies in decent numbers and you don’t see effect sizes, and the only times when you see things are when they are open-label, they are not randomized, you’re looking at small numbers, it just goes to show easy it is to over interpret the results of those small studies,” said Dr. Vincent, professor of musculoskeletal biology at the Kennedy Institute of Rheumatology in Oxford, England.
“My conclusion, from my own in vivo studies and from what you’ve [Dr. Chevalier] just said, is that these are the wrong targets. Just because we are rheumatologists does not mean to say everything is about cytokines,” she said.
AbbVie funded the study. Dr. Kloppenburg acknowledged receiving research support from Pfizer and consultancy fees from AbbVie, GlaxoSmithKline, Merck, and Levicept. Dr. Chevalier disclosed working as an advisor to IBSA [Institut Biochimique SA], Sanofi, and Flexion Therapeutics; as an advisory board member for Laboratoires Genevrier and Labpharma; and receiving travel and accommodation support to attend the meeting from Nordic Pharma. Dr. Vincent did not report her disclosures.
rhnews@frontlinemedcom.com
On Twitter @rheumnews1
MADRID – Treatment with the dual interleukin (IL) 1 blocker ABT-981 did not improve pain scores or erosive joint damage in patients with hand osteoarthritis (OA) in a phase 2a trial reported at the European Congress of Rheumatology.
The disappointing findings suggest that IL-1 may not be an effective target in erosive hand OA, said Margreet Kloppenburg, MD, of Leiden (the Netherlands) University Medical Center, even though the investigators obtained adequate pharmacodynamic results that suggested it was effectively blocking both IL-1 alpha and IL-1 beta.
The phase 2a, multicenter, randomized, double-blind, placebo-controlled study she reported followed on from a phase 1 trial showing that ABT-981 could dose-dependently reduce neutrophil counts and markers of joint inflammation in patients with knee OA. So it was perhaps natural to see if it could potentially have an effect in patients with erosive hand OA.
The aim of the phase 2a trial was to evaluate the safety and efficacy of ABT-981 in the treatment of 131 patients with erosive hand OA. After screening and a 45-day washout period, patients with confirmed erosive hand OA were randomized to receive ABT-981 200 mg injected every 2 weeks or matching placebo.
The primary endpoint was the change in Australian/Canadian Hand Osteoarthritis Index (AUSCAN) pain from baseline to 16 weeks, but no significant difference was observed. The mean change in AUSCAN pain was –9.2 for the 64 ABT-981-treated patients and –10.7 for placebo-treated patients (P = .039).
“There were similar results with AUSCAN function and tender and swollen joint counts,” Dr. Kloppenburg said.
There were also no differences seen in radiographic or MRI endpoints, such as the number of erosive joints, Kellgren and Lawrence scores, joint-space narrowing, or the presence of osteophytes.
Nevertheless, there was evidence that ABT-981 was decreasing inflammatory markers, such as high-sensitivity C-reactive protein and neutrophils. IL-1 alpha and IL-1 beta were difficult to measure, but data suggested that IL-1 was being blocked.
Disappointing results with cytokine targeting
Hand OA affects around 11% of the OA population and erosive hand OA is a very painful phenotype that affects multiple joints, Xavier Chevalier, MD, of Henri-Mondor Hospital, Paris XII University (France), said during a separate session at the congress.
While there is a rationale for using anti-inflammatory drugs for erosive hand OA, so far there just have not been many, if any, real successes. “The effect sizes are small,” Dr. Chevalier said. “There are not a lot of drugs when compared to hip and knee OA,” he observed.
His general conclusion was that targeting cytokines in hand OA had been “disappointing” with “small effect in subgroup of clinically inflamed IP [interphalangeal] joints.”
Dr. Chevalier questioned: “Is hand OA a real OA?” There are features of the disease that imply it could be more of a ligamentous or enthesitis disease, or perhaps a subchondral bone disorder.
Is erosive hand OA even an inflammatory disease? he asked. Are TNF and IL-1 the right targets? Perhaps not, given the research presented by Dr. Kloppenburg and others, he suggested. Further research needs to look for surrogate markers and try to quantify the structural evolution of the disease, he proposed.
It is important to talk about negative studies and to not make excuses for why they might be negative, Tonia Vincent, PhD, observed during the discussion that followed Dr. Chevalier’s presentation.
“If you do proper, randomized, controlled studies in decent numbers and you don’t see effect sizes, and the only times when you see things are when they are open-label, they are not randomized, you’re looking at small numbers, it just goes to show easy it is to over interpret the results of those small studies,” said Dr. Vincent, professor of musculoskeletal biology at the Kennedy Institute of Rheumatology in Oxford, England.
“My conclusion, from my own in vivo studies and from what you’ve [Dr. Chevalier] just said, is that these are the wrong targets. Just because we are rheumatologists does not mean to say everything is about cytokines,” she said.
AbbVie funded the study. Dr. Kloppenburg acknowledged receiving research support from Pfizer and consultancy fees from AbbVie, GlaxoSmithKline, Merck, and Levicept. Dr. Chevalier disclosed working as an advisor to IBSA [Institut Biochimique SA], Sanofi, and Flexion Therapeutics; as an advisory board member for Laboratoires Genevrier and Labpharma; and receiving travel and accommodation support to attend the meeting from Nordic Pharma. Dr. Vincent did not report her disclosures.
rhnews@frontlinemedcom.com
On Twitter @rheumnews1
MADRID – Treatment with the dual interleukin (IL) 1 blocker ABT-981 did not improve pain scores or erosive joint damage in patients with hand osteoarthritis (OA) in a phase 2a trial reported at the European Congress of Rheumatology.
The disappointing findings suggest that IL-1 may not be an effective target in erosive hand OA, said Margreet Kloppenburg, MD, of Leiden (the Netherlands) University Medical Center, even though the investigators obtained adequate pharmacodynamic results that suggested it was effectively blocking both IL-1 alpha and IL-1 beta.
The phase 2a, multicenter, randomized, double-blind, placebo-controlled study she reported followed on from a phase 1 trial showing that ABT-981 could dose-dependently reduce neutrophil counts and markers of joint inflammation in patients with knee OA. So it was perhaps natural to see if it could potentially have an effect in patients with erosive hand OA.
The aim of the phase 2a trial was to evaluate the safety and efficacy of ABT-981 in the treatment of 131 patients with erosive hand OA. After screening and a 45-day washout period, patients with confirmed erosive hand OA were randomized to receive ABT-981 200 mg injected every 2 weeks or matching placebo.
The primary endpoint was the change in Australian/Canadian Hand Osteoarthritis Index (AUSCAN) pain from baseline to 16 weeks, but no significant difference was observed. The mean change in AUSCAN pain was –9.2 for the 64 ABT-981-treated patients and –10.7 for placebo-treated patients (P = .039).
“There were similar results with AUSCAN function and tender and swollen joint counts,” Dr. Kloppenburg said.
There were also no differences seen in radiographic or MRI endpoints, such as the number of erosive joints, Kellgren and Lawrence scores, joint-space narrowing, or the presence of osteophytes.
Nevertheless, there was evidence that ABT-981 was decreasing inflammatory markers, such as high-sensitivity C-reactive protein and neutrophils. IL-1 alpha and IL-1 beta were difficult to measure, but data suggested that IL-1 was being blocked.
Disappointing results with cytokine targeting
Hand OA affects around 11% of the OA population and erosive hand OA is a very painful phenotype that affects multiple joints, Xavier Chevalier, MD, of Henri-Mondor Hospital, Paris XII University (France), said during a separate session at the congress.
While there is a rationale for using anti-inflammatory drugs for erosive hand OA, so far there just have not been many, if any, real successes. “The effect sizes are small,” Dr. Chevalier said. “There are not a lot of drugs when compared to hip and knee OA,” he observed.
His general conclusion was that targeting cytokines in hand OA had been “disappointing” with “small effect in subgroup of clinically inflamed IP [interphalangeal] joints.”
Dr. Chevalier questioned: “Is hand OA a real OA?” There are features of the disease that imply it could be more of a ligamentous or enthesitis disease, or perhaps a subchondral bone disorder.
Is erosive hand OA even an inflammatory disease? he asked. Are TNF and IL-1 the right targets? Perhaps not, given the research presented by Dr. Kloppenburg and others, he suggested. Further research needs to look for surrogate markers and try to quantify the structural evolution of the disease, he proposed.
It is important to talk about negative studies and to not make excuses for why they might be negative, Tonia Vincent, PhD, observed during the discussion that followed Dr. Chevalier’s presentation.
“If you do proper, randomized, controlled studies in decent numbers and you don’t see effect sizes, and the only times when you see things are when they are open-label, they are not randomized, you’re looking at small numbers, it just goes to show easy it is to over interpret the results of those small studies,” said Dr. Vincent, professor of musculoskeletal biology at the Kennedy Institute of Rheumatology in Oxford, England.
“My conclusion, from my own in vivo studies and from what you’ve [Dr. Chevalier] just said, is that these are the wrong targets. Just because we are rheumatologists does not mean to say everything is about cytokines,” she said.
AbbVie funded the study. Dr. Kloppenburg acknowledged receiving research support from Pfizer and consultancy fees from AbbVie, GlaxoSmithKline, Merck, and Levicept. Dr. Chevalier disclosed working as an advisor to IBSA [Institut Biochimique SA], Sanofi, and Flexion Therapeutics; as an advisory board member for Laboratoires Genevrier and Labpharma; and receiving travel and accommodation support to attend the meeting from Nordic Pharma. Dr. Vincent did not report her disclosures.
rhnews@frontlinemedcom.com
On Twitter @rheumnews1
AT THE EULAR 2017 CONGRESS
Key clinical point:
Major finding: The mean change in AUSCAN pain from baseline to week 16 was –9.2 and –10.7 comparing ABT-981 and placebo-treated patients (P = .039).
Data source: A phase 2a, multicenter, randomized, double-blind, placebo-controlled study evaluating the safety and efficacy of ABT-981 in the treatment of 131 patients with erosive hand OA.
Disclosures: AbbVie funded the study. The study presenter acknowledged receiving research support from Pfizer and consultancy fees from AbbVie, GlaxoSmithKline, Merck, and Levicept. The other speaker disclosed working as an adviser to IBSA [Institut Biochimique SA], Sanofi, and Flexion Therapeutics; as an advisory board member for Laboratoires Genevrier and Labpharma; and receiving travel and accommodation support to attend the meeting from Nordic Pharma.
Ixekizumab helps PsA patients who failed a TNFi
MADRID – The anti–interleukin-17 drug ixekizumab, already on the U.S. market for treating psoriasis, showed efficacy and safety for treating psoriatic arthritis in patients who previously failed to respond to or tolerate a tumor necrosis factor inhibitor in a pivotal, phase 3 trial with 363 patients.
Treatment of patients with psoriatic arthritis (PsA) with ixekizumab (Taltz) led to improvements, compared with placebo, in arthritis, physical function, and psoriasis. These patients were unresponsive to or intolerant of a tumor necrosis factor inhibitor (TNFi) at rates similar to previously reported response rates for PsA patients who were TNFi naive, Peter Nash, MD, said at the European Congress of Rheumatology.
A published report with the data presented by Dr. Nash also recently appeared (Lancet. 2017;389[10086]:2317-27).
Based in part on the results from this trial, as well as results from a companion phase 3 trial that enrolled PsA patients naive to a TNFi (Ann Rheum Dis. 2017 Jan; 6[1]:79-87), the company that markets ixekizumab, Eli Lilly, filed an application with the Food and Drug Administration in early 2017 to have a new label indication for PsA, said a company spokeswoman.
“At least half of PsA patients don’t get at least a 20% improvement [an ACR20 response] on a TNFi, and so they are looking for something else,” explained Mark C. Genovese, MD, professor of medicine and director of the Rheumatology Clinic at Stanford (Calif.) University and a coinvestigator on the trial reported by Dr. Nash. “There is pent up demand” for an alternative to a TNFi for treating PsA, Dr. Genovese said in an interview.
The finding also sets ixekizumab apart from secukinumab (Cosentyx), another interleukin-17 inhibitor that already has FDA approval for treating PsA but that has not been specifically tested in PsA patients who failed or didn’t tolerate a TNFi, he noted.
The SPIRIT-P2 results also showed superior outcomes for patients treated with an ixekizumab injection once every 2 or 4 weeks, compared with placebo, by several secondary measures, including ACR50 and ACR70 rates and minimal disease activity. The ACR70 rate after 24 weeks on treatment was 23% with a dose of ixekizumab every 4 weeks and none with placebo. Minimal disease activity was reached by about a quarter of patients on either dosage of the active drug and by 3% of patients on placebo.
Despite the apparent role for ixekizumab when TNFi treatment fails, the TNFi drug class remains the clear first-line choice for PsA patients who are starting a biological drug for the first time. Not only do the TNFis have a much longer and more extensive track record but they also generally receive better insurance coverage that minimizes out-of-pocket expenses for patients, Dr. Genovese said.
SPIRIT-P2 was sponsored by Eli Lilly, the company that markets ixekizumab. Dr. Nash has been a speaker for or consultant to and has received research funding from Eli Lily and for several other companies. Dr. Genovese has been a consultant to and has received research funding from Eli Lilly, AbbVie, Astellas, Galapagos, Pfizer, and Vertex.
mzoler@frontlinemedcom.com
On Twitter @mitchelzoler
MADRID – The anti–interleukin-17 drug ixekizumab, already on the U.S. market for treating psoriasis, showed efficacy and safety for treating psoriatic arthritis in patients who previously failed to respond to or tolerate a tumor necrosis factor inhibitor in a pivotal, phase 3 trial with 363 patients.
Treatment of patients with psoriatic arthritis (PsA) with ixekizumab (Taltz) led to improvements, compared with placebo, in arthritis, physical function, and psoriasis. These patients were unresponsive to or intolerant of a tumor necrosis factor inhibitor (TNFi) at rates similar to previously reported response rates for PsA patients who were TNFi naive, Peter Nash, MD, said at the European Congress of Rheumatology.
A published report with the data presented by Dr. Nash also recently appeared (Lancet. 2017;389[10086]:2317-27).
Based in part on the results from this trial, as well as results from a companion phase 3 trial that enrolled PsA patients naive to a TNFi (Ann Rheum Dis. 2017 Jan; 6[1]:79-87), the company that markets ixekizumab, Eli Lilly, filed an application with the Food and Drug Administration in early 2017 to have a new label indication for PsA, said a company spokeswoman.
“At least half of PsA patients don’t get at least a 20% improvement [an ACR20 response] on a TNFi, and so they are looking for something else,” explained Mark C. Genovese, MD, professor of medicine and director of the Rheumatology Clinic at Stanford (Calif.) University and a coinvestigator on the trial reported by Dr. Nash. “There is pent up demand” for an alternative to a TNFi for treating PsA, Dr. Genovese said in an interview.
The finding also sets ixekizumab apart from secukinumab (Cosentyx), another interleukin-17 inhibitor that already has FDA approval for treating PsA but that has not been specifically tested in PsA patients who failed or didn’t tolerate a TNFi, he noted.
The SPIRIT-P2 results also showed superior outcomes for patients treated with an ixekizumab injection once every 2 or 4 weeks, compared with placebo, by several secondary measures, including ACR50 and ACR70 rates and minimal disease activity. The ACR70 rate after 24 weeks on treatment was 23% with a dose of ixekizumab every 4 weeks and none with placebo. Minimal disease activity was reached by about a quarter of patients on either dosage of the active drug and by 3% of patients on placebo.
Despite the apparent role for ixekizumab when TNFi treatment fails, the TNFi drug class remains the clear first-line choice for PsA patients who are starting a biological drug for the first time. Not only do the TNFis have a much longer and more extensive track record but they also generally receive better insurance coverage that minimizes out-of-pocket expenses for patients, Dr. Genovese said.
SPIRIT-P2 was sponsored by Eli Lilly, the company that markets ixekizumab. Dr. Nash has been a speaker for or consultant to and has received research funding from Eli Lily and for several other companies. Dr. Genovese has been a consultant to and has received research funding from Eli Lilly, AbbVie, Astellas, Galapagos, Pfizer, and Vertex.
mzoler@frontlinemedcom.com
On Twitter @mitchelzoler
MADRID – The anti–interleukin-17 drug ixekizumab, already on the U.S. market for treating psoriasis, showed efficacy and safety for treating psoriatic arthritis in patients who previously failed to respond to or tolerate a tumor necrosis factor inhibitor in a pivotal, phase 3 trial with 363 patients.
Treatment of patients with psoriatic arthritis (PsA) with ixekizumab (Taltz) led to improvements, compared with placebo, in arthritis, physical function, and psoriasis. These patients were unresponsive to or intolerant of a tumor necrosis factor inhibitor (TNFi) at rates similar to previously reported response rates for PsA patients who were TNFi naive, Peter Nash, MD, said at the European Congress of Rheumatology.
A published report with the data presented by Dr. Nash also recently appeared (Lancet. 2017;389[10086]:2317-27).
Based in part on the results from this trial, as well as results from a companion phase 3 trial that enrolled PsA patients naive to a TNFi (Ann Rheum Dis. 2017 Jan; 6[1]:79-87), the company that markets ixekizumab, Eli Lilly, filed an application with the Food and Drug Administration in early 2017 to have a new label indication for PsA, said a company spokeswoman.
“At least half of PsA patients don’t get at least a 20% improvement [an ACR20 response] on a TNFi, and so they are looking for something else,” explained Mark C. Genovese, MD, professor of medicine and director of the Rheumatology Clinic at Stanford (Calif.) University and a coinvestigator on the trial reported by Dr. Nash. “There is pent up demand” for an alternative to a TNFi for treating PsA, Dr. Genovese said in an interview.
The finding also sets ixekizumab apart from secukinumab (Cosentyx), another interleukin-17 inhibitor that already has FDA approval for treating PsA but that has not been specifically tested in PsA patients who failed or didn’t tolerate a TNFi, he noted.
The SPIRIT-P2 results also showed superior outcomes for patients treated with an ixekizumab injection once every 2 or 4 weeks, compared with placebo, by several secondary measures, including ACR50 and ACR70 rates and minimal disease activity. The ACR70 rate after 24 weeks on treatment was 23% with a dose of ixekizumab every 4 weeks and none with placebo. Minimal disease activity was reached by about a quarter of patients on either dosage of the active drug and by 3% of patients on placebo.
Despite the apparent role for ixekizumab when TNFi treatment fails, the TNFi drug class remains the clear first-line choice for PsA patients who are starting a biological drug for the first time. Not only do the TNFis have a much longer and more extensive track record but they also generally receive better insurance coverage that minimizes out-of-pocket expenses for patients, Dr. Genovese said.
SPIRIT-P2 was sponsored by Eli Lilly, the company that markets ixekizumab. Dr. Nash has been a speaker for or consultant to and has received research funding from Eli Lily and for several other companies. Dr. Genovese has been a consultant to and has received research funding from Eli Lilly, AbbVie, Astellas, Galapagos, Pfizer, and Vertex.
mzoler@frontlinemedcom.com
On Twitter @mitchelzoler
AT THE EULAR 2017 CONGRESS
Key clinical point:
Major finding: The ACR20 rate after 24 weeks of treatment was 53% with monthly ixekizumab and 20% on placebo.
Data source: The SPIRIT-P2 trial, a phase 3 multicenter trial with 363 patients.
Disclosures: SPIRIT-P2 was sponsored by Eli Lilly, the company that markets ixekizumab (Taltz). Dr. Nash has been a speaker for or consultant to and has received research funding from Eli Lily and for several other companies. Dr. Genovese has been a consultant to and has received research funding from Eli Lilly, AbbVie, Astellas, Galapagos, Pfizer, and Vertex.
Selection of strategy for high-risk early RA remission induction hinges on safety
MADRID – Two-year results from the Care in early RA (CareRA) trial demonstrated the sustained effectiveness of a treat-to-target approach in patients with early rheumatoid arthritis at high risk for progression.
The percentage of patients who achieved clinical remission with one of three disease-modifying antirheumatic drug (DMARD) and glucocorticoid-containing regimens ranged from 60% to 65% at 1 year, and the percentage of those patients who were able to maintain their remission at all time points in year 2 ranged from 55% to 70%, none of which were significantly different from each other.
Ms. Stouten added that, according to international guidelines, achieving clinical remission means treating patients early, as soon as possible after the diagnosis of rheumatoid arthritis is made; intensively, with a DMARD, preferably methotrexate if not contraindicated, combined with short-term glucocorticoids; and to target, meaning treatment should be targeted at achieving remission or at least low disease activity in every patient.
The CareRA trial was a prospective, randomized, multicenter trial set up to see which of three methotrexate-based, steroid-containing intensive regimens would be best for inducing remission in patients with high-risk RA. The pragmatic trial was conducted in 13 Belgian rheumatology practices recruiting 400 patients, 300 of whom were designated as high risk for progression based on factors such as their antibody status and presence of joint erosions. CareRA trial investigators defined clinical remission as less than 2.6 on the 28-joint Disease Activity Score using C-reactive protein (DAS28-CRP).
The three regimens all contained a weekly 15-mg dose of methotrexate and prednisone 30 mg or 60 mg that was then tapered weekly after the first 6-7 weeks.
In the COBRA Classic regimen, methotrexate was partnered with sulfasalazine, given as a 2-g daily dose. Prednisone was initially given at a dose of 60 mg and then taped to 5.7 mg starting at week 7.
For the COBRA Slim regimen, just methotrexate and prednisone were used, with the latter started at a dose of 30 mg and then tapered to 5 mg starting at week 6.
Lastly, the COBRA Avant-Garde regimen saw methotrexate combined with leflunomide, 10 mg daily, and the same step-down prednisone regimen as COBRA Slim.
In the first year, treatment in each group was adjusted to achieve a target of low disease activity (DAS28-CRP of 3.2 or lower), with measurements taken every 3 months. The steroid component was stepped down further after 28 weeks and stopped altogether by 34 weeks. The aim was also to reduce the number of DMARDs used, such that everyone was on DMARD monotherapy if possible. In the second year, rheumatologists could treat patients at their own discretion, with adjustments to treatment made according to DAS28-CRP at visits every 3 months.
Ms. Stouten reported that all three of the intensive induction regimens “were very effective in our high-risk population and that they showed persistently high remission rates at year 2.”
The percentage of patients with a DAS28-CRP of less than 2.6 at 2 years was 65.3% for the COBRA Classic regimen, 73.5% for COBRA Slim, and 73.1% for COBRA Avant-Garde.
For inducing remission, however, she suggested that the COBRA Slim regimen might have the edge from a benefit-to-risk perspective.
A total of 60.2% of COBRA Slim patients were in remission at year 1, and 67.8% of them remained in remission throughout year 2. Also, fewer COBRA Slim patients needed biologic therapy, both overall (n = 11) and in the first year (n = 2), when compared with the other two regimens. However, in the COBRA Classic arm, 65.3% were in remission at year 1, and 54.7% of those patients maintained it throughout year 2, whereas in the COBRA Avant-Garde arm the rates were 61.3% at year 1, with 70.2% of those maintaining remission throughout year 2. A total of 18 patients in the COBRA Classic group started biologics, including 10 in the first year, compared with 15 in the COBRA Avant-Garde group, 7 of those in the first year.
“For maintaining remission, there were no statistically significant differences observed in remission rates at year 2 between treatment groups,” Ms. Stouten observed. “However, COBRA Avant-Garde had numerically better CDAI [clinical disease activity index] remission rates at year 2 [48.2% vs. 33.7% for COBRA Slim and 34.7% for COBRA Classic; P = .068].”
The total numbers of patients reporting adverse events related to treatment were lower with the COBRA Slim regimen (n = 164) than with COBRA Classic (n = 209) and COBRA Avant-Garde (n = 208). Fewer COBRA Slim patients also had to stop treatment (5 vs. 9 with COBRA Classic and 12 with COBRA Avant-Garde) or have interrupted treatment (12 vs. 17 and 19, respectively) because of adverse events.
Ms. Stouten had no personal disclosures. The study was supported by a Flemish governmental grant provided by IWT (Innovatie door Wetenschap en Technologie).
rhnews@frontlinemedcom.com
On Twitter @rheumnews1
MADRID – Two-year results from the Care in early RA (CareRA) trial demonstrated the sustained effectiveness of a treat-to-target approach in patients with early rheumatoid arthritis at high risk for progression.
The percentage of patients who achieved clinical remission with one of three disease-modifying antirheumatic drug (DMARD) and glucocorticoid-containing regimens ranged from 60% to 65% at 1 year, and the percentage of those patients who were able to maintain their remission at all time points in year 2 ranged from 55% to 70%, none of which were significantly different from each other.
Ms. Stouten added that, according to international guidelines, achieving clinical remission means treating patients early, as soon as possible after the diagnosis of rheumatoid arthritis is made; intensively, with a DMARD, preferably methotrexate if not contraindicated, combined with short-term glucocorticoids; and to target, meaning treatment should be targeted at achieving remission or at least low disease activity in every patient.
The CareRA trial was a prospective, randomized, multicenter trial set up to see which of three methotrexate-based, steroid-containing intensive regimens would be best for inducing remission in patients with high-risk RA. The pragmatic trial was conducted in 13 Belgian rheumatology practices recruiting 400 patients, 300 of whom were designated as high risk for progression based on factors such as their antibody status and presence of joint erosions. CareRA trial investigators defined clinical remission as less than 2.6 on the 28-joint Disease Activity Score using C-reactive protein (DAS28-CRP).
The three regimens all contained a weekly 15-mg dose of methotrexate and prednisone 30 mg or 60 mg that was then tapered weekly after the first 6-7 weeks.
In the COBRA Classic regimen, methotrexate was partnered with sulfasalazine, given as a 2-g daily dose. Prednisone was initially given at a dose of 60 mg and then taped to 5.7 mg starting at week 7.
For the COBRA Slim regimen, just methotrexate and prednisone were used, with the latter started at a dose of 30 mg and then tapered to 5 mg starting at week 6.
Lastly, the COBRA Avant-Garde regimen saw methotrexate combined with leflunomide, 10 mg daily, and the same step-down prednisone regimen as COBRA Slim.
In the first year, treatment in each group was adjusted to achieve a target of low disease activity (DAS28-CRP of 3.2 or lower), with measurements taken every 3 months. The steroid component was stepped down further after 28 weeks and stopped altogether by 34 weeks. The aim was also to reduce the number of DMARDs used, such that everyone was on DMARD monotherapy if possible. In the second year, rheumatologists could treat patients at their own discretion, with adjustments to treatment made according to DAS28-CRP at visits every 3 months.
Ms. Stouten reported that all three of the intensive induction regimens “were very effective in our high-risk population and that they showed persistently high remission rates at year 2.”
The percentage of patients with a DAS28-CRP of less than 2.6 at 2 years was 65.3% for the COBRA Classic regimen, 73.5% for COBRA Slim, and 73.1% for COBRA Avant-Garde.
For inducing remission, however, she suggested that the COBRA Slim regimen might have the edge from a benefit-to-risk perspective.
A total of 60.2% of COBRA Slim patients were in remission at year 1, and 67.8% of them remained in remission throughout year 2. Also, fewer COBRA Slim patients needed biologic therapy, both overall (n = 11) and in the first year (n = 2), when compared with the other two regimens. However, in the COBRA Classic arm, 65.3% were in remission at year 1, and 54.7% of those patients maintained it throughout year 2, whereas in the COBRA Avant-Garde arm the rates were 61.3% at year 1, with 70.2% of those maintaining remission throughout year 2. A total of 18 patients in the COBRA Classic group started biologics, including 10 in the first year, compared with 15 in the COBRA Avant-Garde group, 7 of those in the first year.
“For maintaining remission, there were no statistically significant differences observed in remission rates at year 2 between treatment groups,” Ms. Stouten observed. “However, COBRA Avant-Garde had numerically better CDAI [clinical disease activity index] remission rates at year 2 [48.2% vs. 33.7% for COBRA Slim and 34.7% for COBRA Classic; P = .068].”
The total numbers of patients reporting adverse events related to treatment were lower with the COBRA Slim regimen (n = 164) than with COBRA Classic (n = 209) and COBRA Avant-Garde (n = 208). Fewer COBRA Slim patients also had to stop treatment (5 vs. 9 with COBRA Classic and 12 with COBRA Avant-Garde) or have interrupted treatment (12 vs. 17 and 19, respectively) because of adverse events.
Ms. Stouten had no personal disclosures. The study was supported by a Flemish governmental grant provided by IWT (Innovatie door Wetenschap en Technologie).
rhnews@frontlinemedcom.com
On Twitter @rheumnews1
MADRID – Two-year results from the Care in early RA (CareRA) trial demonstrated the sustained effectiveness of a treat-to-target approach in patients with early rheumatoid arthritis at high risk for progression.
The percentage of patients who achieved clinical remission with one of three disease-modifying antirheumatic drug (DMARD) and glucocorticoid-containing regimens ranged from 60% to 65% at 1 year, and the percentage of those patients who were able to maintain their remission at all time points in year 2 ranged from 55% to 70%, none of which were significantly different from each other.
Ms. Stouten added that, according to international guidelines, achieving clinical remission means treating patients early, as soon as possible after the diagnosis of rheumatoid arthritis is made; intensively, with a DMARD, preferably methotrexate if not contraindicated, combined with short-term glucocorticoids; and to target, meaning treatment should be targeted at achieving remission or at least low disease activity in every patient.
The CareRA trial was a prospective, randomized, multicenter trial set up to see which of three methotrexate-based, steroid-containing intensive regimens would be best for inducing remission in patients with high-risk RA. The pragmatic trial was conducted in 13 Belgian rheumatology practices recruiting 400 patients, 300 of whom were designated as high risk for progression based on factors such as their antibody status and presence of joint erosions. CareRA trial investigators defined clinical remission as less than 2.6 on the 28-joint Disease Activity Score using C-reactive protein (DAS28-CRP).
The three regimens all contained a weekly 15-mg dose of methotrexate and prednisone 30 mg or 60 mg that was then tapered weekly after the first 6-7 weeks.
In the COBRA Classic regimen, methotrexate was partnered with sulfasalazine, given as a 2-g daily dose. Prednisone was initially given at a dose of 60 mg and then taped to 5.7 mg starting at week 7.
For the COBRA Slim regimen, just methotrexate and prednisone were used, with the latter started at a dose of 30 mg and then tapered to 5 mg starting at week 6.
Lastly, the COBRA Avant-Garde regimen saw methotrexate combined with leflunomide, 10 mg daily, and the same step-down prednisone regimen as COBRA Slim.
In the first year, treatment in each group was adjusted to achieve a target of low disease activity (DAS28-CRP of 3.2 or lower), with measurements taken every 3 months. The steroid component was stepped down further after 28 weeks and stopped altogether by 34 weeks. The aim was also to reduce the number of DMARDs used, such that everyone was on DMARD monotherapy if possible. In the second year, rheumatologists could treat patients at their own discretion, with adjustments to treatment made according to DAS28-CRP at visits every 3 months.
Ms. Stouten reported that all three of the intensive induction regimens “were very effective in our high-risk population and that they showed persistently high remission rates at year 2.”
The percentage of patients with a DAS28-CRP of less than 2.6 at 2 years was 65.3% for the COBRA Classic regimen, 73.5% for COBRA Slim, and 73.1% for COBRA Avant-Garde.
For inducing remission, however, she suggested that the COBRA Slim regimen might have the edge from a benefit-to-risk perspective.
A total of 60.2% of COBRA Slim patients were in remission at year 1, and 67.8% of them remained in remission throughout year 2. Also, fewer COBRA Slim patients needed biologic therapy, both overall (n = 11) and in the first year (n = 2), when compared with the other two regimens. However, in the COBRA Classic arm, 65.3% were in remission at year 1, and 54.7% of those patients maintained it throughout year 2, whereas in the COBRA Avant-Garde arm the rates were 61.3% at year 1, with 70.2% of those maintaining remission throughout year 2. A total of 18 patients in the COBRA Classic group started biologics, including 10 in the first year, compared with 15 in the COBRA Avant-Garde group, 7 of those in the first year.
“For maintaining remission, there were no statistically significant differences observed in remission rates at year 2 between treatment groups,” Ms. Stouten observed. “However, COBRA Avant-Garde had numerically better CDAI [clinical disease activity index] remission rates at year 2 [48.2% vs. 33.7% for COBRA Slim and 34.7% for COBRA Classic; P = .068].”
The total numbers of patients reporting adverse events related to treatment were lower with the COBRA Slim regimen (n = 164) than with COBRA Classic (n = 209) and COBRA Avant-Garde (n = 208). Fewer COBRA Slim patients also had to stop treatment (5 vs. 9 with COBRA Classic and 12 with COBRA Avant-Garde) or have interrupted treatment (12 vs. 17 and 19, respectively) because of adverse events.
Ms. Stouten had no personal disclosures. The study was supported by a Flemish governmental grant provided by IWT (Innovatie door Wetenschap en Technologie).
rhnews@frontlinemedcom.com
On Twitter @rheumnews1
AT THE EULAR 2017 CONGRESS
Key clinical point:
Major finding: The percentage of patients with a DAS28-CRP of less than 2.6 at 2 years was 73.5% for the COBRA Slim regimen, 73.1% for COBRA Avant-Garde, and 65.3% for COBRA Classic.
Data source: The Care in early RA (CareRA) trial, a prospective, randomized, multicenter trial of 379 patients with treatment-naive, early rheumatoid arthritis.
Disclosures: The presenter had no personal disclosures. The study was supported by a Flemish governmental grant provided by IWT (Innovatie door Wetenschap en Technologie).
ANCA-associated vasculitis appears to increase risk of stroke, death
MADRID – Small-vessel vasculitis associated with antineutrophil cytoplasmic autoantibodies (ANCAs) appears to increase the risk of stroke and overall mortality, results of a French retrospective study suggest.
Patients with ANCA-associated vasculitis (AAV) were twice as likely as those without to experience a stroke over 7.5 years, Grégory Pugnet, MD, reported at the European Congress of Rheumatology. Their all-cause mortality was also significantly higher, with 30% of the deaths attributed to cardiovascular causes, said Dr. Pugnet of the Internal Medicine Service at Purpan Hospital in Toulouse, France.
“We think this [shows that it] is very important to monitor [these patients] and to be vigilant in our search for cardiovascular complications and cardiovascular risk factors in this population,” he said.
Dr. Pugnet and his colleagues conducted a retrospective study of 125 patients with AAV who were diagnosed in a teaching hospital between 1981 and 2015. He compared cardiovascular outcomes and mortality between this cohort and two French regional registries: the Midi-Pyrénées County Mortality and Acute Myocardial Infarction Registry and the Dijon Stroke Registry. Outcomes were the date of first acute myocardial infarction, date of first stroke, and date of death; the mean follow-up was about 90 months.
Of the 125 patients with AAV, 99 had granulomatosis with polyangiitis, and 26 had microscopic polyangiitis. Preexisting cardiovascular disease was present in 23. Patients were a mean of 61 years old. Hypertension, peripheral artery disease, and coronary artery disease were all more common among those with cardiovascular disease. These patients were also more likely to smoke.
Over the follow-up period, there were 10 acute myocardial infarctions for an incidence of 8.5 per 1,000 person-years. The MI incidence in the Midi-Pyrénées registry was 2.2 per 1,000 person-years, which was a significant difference in an unadjusted analysis. But after adjusting for age, AAV patients were not significantly more likely to experience a heart attack than were those in the registry.
There were nine strokes during the follow-up period for an incidence of 10.2 per 1,000 person-years. After adjusting for age, this was more than three times higher than the rate of 1.9 per 1,000 person-year in the Dijon Stroke Registry – a significant difference.
A total of 22 AAV patients died during the follow-up period, translating to a mortality of 22.5 per 1,000 person-years. Mortality in the stroke registry was 1.9 per 1,000 person-years. An age-adjusted analysis found that AAV patients were about 1.6 times more likely to die than were those in the Midi-Pyrénées registry.
A multivariate regression analysis identified some factors that were independently associated with the outcomes. Smoking almost quadrupled the risk of having any cardiovascular event (hazard ratio, 3.7), and having had a plasma exchange tripled it (HR, 2.9). Smoking and a history of coronary artery disease were significant risk factors for myocardial infarction (HRs of 8.8 and 10.3, respectively). Dr. Pugnet and his associates didn’t find any significant independent risk factors for stroke. Age was not independently associated with any of the outcomes.
Dr. Pugnet reported receiving travel support from AbbVie and Actelion, fees for serving on an advisory board from Grifols, and lecture fees from AbbVie.
msullivan@frontlinemedcom.com
On Twitter @alz_gal
MADRID – Small-vessel vasculitis associated with antineutrophil cytoplasmic autoantibodies (ANCAs) appears to increase the risk of stroke and overall mortality, results of a French retrospective study suggest.
Patients with ANCA-associated vasculitis (AAV) were twice as likely as those without to experience a stroke over 7.5 years, Grégory Pugnet, MD, reported at the European Congress of Rheumatology. Their all-cause mortality was also significantly higher, with 30% of the deaths attributed to cardiovascular causes, said Dr. Pugnet of the Internal Medicine Service at Purpan Hospital in Toulouse, France.
“We think this [shows that it] is very important to monitor [these patients] and to be vigilant in our search for cardiovascular complications and cardiovascular risk factors in this population,” he said.
Dr. Pugnet and his colleagues conducted a retrospective study of 125 patients with AAV who were diagnosed in a teaching hospital between 1981 and 2015. He compared cardiovascular outcomes and mortality between this cohort and two French regional registries: the Midi-Pyrénées County Mortality and Acute Myocardial Infarction Registry and the Dijon Stroke Registry. Outcomes were the date of first acute myocardial infarction, date of first stroke, and date of death; the mean follow-up was about 90 months.
Of the 125 patients with AAV, 99 had granulomatosis with polyangiitis, and 26 had microscopic polyangiitis. Preexisting cardiovascular disease was present in 23. Patients were a mean of 61 years old. Hypertension, peripheral artery disease, and coronary artery disease were all more common among those with cardiovascular disease. These patients were also more likely to smoke.
Over the follow-up period, there were 10 acute myocardial infarctions for an incidence of 8.5 per 1,000 person-years. The MI incidence in the Midi-Pyrénées registry was 2.2 per 1,000 person-years, which was a significant difference in an unadjusted analysis. But after adjusting for age, AAV patients were not significantly more likely to experience a heart attack than were those in the registry.
There were nine strokes during the follow-up period for an incidence of 10.2 per 1,000 person-years. After adjusting for age, this was more than three times higher than the rate of 1.9 per 1,000 person-year in the Dijon Stroke Registry – a significant difference.
A total of 22 AAV patients died during the follow-up period, translating to a mortality of 22.5 per 1,000 person-years. Mortality in the stroke registry was 1.9 per 1,000 person-years. An age-adjusted analysis found that AAV patients were about 1.6 times more likely to die than were those in the Midi-Pyrénées registry.
A multivariate regression analysis identified some factors that were independently associated with the outcomes. Smoking almost quadrupled the risk of having any cardiovascular event (hazard ratio, 3.7), and having had a plasma exchange tripled it (HR, 2.9). Smoking and a history of coronary artery disease were significant risk factors for myocardial infarction (HRs of 8.8 and 10.3, respectively). Dr. Pugnet and his associates didn’t find any significant independent risk factors for stroke. Age was not independently associated with any of the outcomes.
Dr. Pugnet reported receiving travel support from AbbVie and Actelion, fees for serving on an advisory board from Grifols, and lecture fees from AbbVie.
msullivan@frontlinemedcom.com
On Twitter @alz_gal
MADRID – Small-vessel vasculitis associated with antineutrophil cytoplasmic autoantibodies (ANCAs) appears to increase the risk of stroke and overall mortality, results of a French retrospective study suggest.
Patients with ANCA-associated vasculitis (AAV) were twice as likely as those without to experience a stroke over 7.5 years, Grégory Pugnet, MD, reported at the European Congress of Rheumatology. Their all-cause mortality was also significantly higher, with 30% of the deaths attributed to cardiovascular causes, said Dr. Pugnet of the Internal Medicine Service at Purpan Hospital in Toulouse, France.
“We think this [shows that it] is very important to monitor [these patients] and to be vigilant in our search for cardiovascular complications and cardiovascular risk factors in this population,” he said.
Dr. Pugnet and his colleagues conducted a retrospective study of 125 patients with AAV who were diagnosed in a teaching hospital between 1981 and 2015. He compared cardiovascular outcomes and mortality between this cohort and two French regional registries: the Midi-Pyrénées County Mortality and Acute Myocardial Infarction Registry and the Dijon Stroke Registry. Outcomes were the date of first acute myocardial infarction, date of first stroke, and date of death; the mean follow-up was about 90 months.
Of the 125 patients with AAV, 99 had granulomatosis with polyangiitis, and 26 had microscopic polyangiitis. Preexisting cardiovascular disease was present in 23. Patients were a mean of 61 years old. Hypertension, peripheral artery disease, and coronary artery disease were all more common among those with cardiovascular disease. These patients were also more likely to smoke.
Over the follow-up period, there were 10 acute myocardial infarctions for an incidence of 8.5 per 1,000 person-years. The MI incidence in the Midi-Pyrénées registry was 2.2 per 1,000 person-years, which was a significant difference in an unadjusted analysis. But after adjusting for age, AAV patients were not significantly more likely to experience a heart attack than were those in the registry.
There were nine strokes during the follow-up period for an incidence of 10.2 per 1,000 person-years. After adjusting for age, this was more than three times higher than the rate of 1.9 per 1,000 person-year in the Dijon Stroke Registry – a significant difference.
A total of 22 AAV patients died during the follow-up period, translating to a mortality of 22.5 per 1,000 person-years. Mortality in the stroke registry was 1.9 per 1,000 person-years. An age-adjusted analysis found that AAV patients were about 1.6 times more likely to die than were those in the Midi-Pyrénées registry.
A multivariate regression analysis identified some factors that were independently associated with the outcomes. Smoking almost quadrupled the risk of having any cardiovascular event (hazard ratio, 3.7), and having had a plasma exchange tripled it (HR, 2.9). Smoking and a history of coronary artery disease were significant risk factors for myocardial infarction (HRs of 8.8 and 10.3, respectively). Dr. Pugnet and his associates didn’t find any significant independent risk factors for stroke. Age was not independently associated with any of the outcomes.
Dr. Pugnet reported receiving travel support from AbbVie and Actelion, fees for serving on an advisory board from Grifols, and lecture fees from AbbVie.
msullivan@frontlinemedcom.com
On Twitter @alz_gal
AT THE EULAR 2017 CONGRESS
Key clinical point:
Major finding: AAV patients were twice as likely as those without the vasculitis to experience a stroke over 7.5 years.
Data source: A retrospective comparison of 125 AAV patients and patients from two French regional registries: the Midi-Pyrénées County Mortality and Acute Myocardial Infarction Registry and the Dijon Stroke Registry.
Disclosures: Dr. Pugnet reported receiving travel support from AbbVie and Actelion, fees for serving on an advisory board from Grifols, and lecture fees from AbbVie.
Studies examine methotrexate starting dose for RA in monotherapy and combinations
MADRID – A low versus high starting dose of methotrexate given as monotherapy or in combination with glucocorticoids or conventional synthetic disease-modifying antirheumatic drugs to newly diagnosed rheumatoid arthritis patients doesn’t seem to make a difference in short-term disease activity and physical functioning responses, but a higher starting dose of at least 15 mg/week may provide a better chance at achieving a good response at 6 months, according to two separate observational studies presented at the European Congress of Rheumatology.
One of the studies looked at 3- to 6-month disease activity and physical functioning responses to methotrexate used as mono- or combination therapy and the other assessed EULAR clinical responses at 6 months in mostly monotherapy-treated patients.
Low vs. high dose in combination treatments
“Methotrexate is the anchor drug in the treatment of rheumatoid arthritis patients. Current guidelines for methotrexate monotherapy recommend initiating 15 mg/week orally then escalating to 25-30 mg/week or the highest tolerable dose, but no recommendations exist for the drug’s use in combination therapy,” said Sytske Anne Bergstra, first author of a study using the international, observational METEOR database, a cohort with real-world clinical data.
The investigators selected 1,404 RA patients from the METEOR database who had a symptom duration of less than 5 years, had less than 2 months between diagnosis and first visit, and did not change medications (only dose adjustments were allowed). They were divided into three groups: methotrexate monotherapy, methotrexate plus conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), and methotrexate plus glucocorticoids (and possibly csDMARDs). The investigators defined initial starting doses of methotrexate as low (10 mg/week or less) or high (15 mg/week or more) based on the last reported dose of methotrexate at no later than 8 weeks of follow-up.
In each group, females comprised about 80% of patients, and the mean age was 45-48 years. The group that received methotrexate plus csDMARDs had a median symptom duration nearly twice that of the other groups (730 days vs. 365 for monotherapy and 458 for methotrexate plus glucocorticoids). Rheumatoid factor positivity ranged from 77% to 84% and anticitrullinated peptide autoantibody positivity from 72% to 85%.
The use of a high methotrexate starting dose generally trended upward in patients enrolled in the database through 2015, whereas the high point for use of a low dose was 2010 and declined thereafter. Overall, a high starting dose was used in 28% of monotherapy patients, 14% with methotrexate plus csDMARDs, and 46% with methotrexate plus glucocorticoids.
In propensity score–adjusted analyses that helped to control for confounding by indication, there were no differences in the effectiveness of low or high methotrexate starting doses for all three groups after follow-up between 3 and 6 months on Disease Activity Score (DAS), 28-joint DAS, or the Health Assessment Questionnaire (HAQ).
“Our findings seem to contradict the general trend of starting with high methotrexate doses. They indicate that higher doses did not provide better short-term clinical outcome in either monotherapy or combination therapy,” Ms. Bergstra observed.
She continued: “For the moment, we suggest that rheumatologists consider starting with a lower initial methotrexate dose, especially when prescribing in combination with other synthetic DMARDS or glucocorticoids.”
Effect of initial dose on EULAR response
Rebecca Davies of the Centre for Musculoskeletal Research at the University of Manchester (England) presented data from a separate study that examined the effect of giving a low versus a high dose of methotrexate on patients’ rate of response to EULAR criteria at 6 months.
“Methotrexate is the recommended first line treatment for rheumatoid arthritis; however, we have not yet established [a] clear optimal strategy for the starting dose of this therapy,” Ms. Davies said.
The aim of the study was therefore to assess the two most commonly used methotrexate starting doses used in the United Kingdom (7.5 mg/week or less vs. 15 mg/week or more) and how they affected the DAS28 of patients.
A total of 810 patients with rheumatoid arthritis who were starting methotrexate were recruited from the U.K. national, multicenter, longitudinal, observational Rheumatoid Arthritis Medication Study. For inclusion in the study, patients had to have complete DAS28 data at baseline and at 6 months.
The median age of patients was similar among the low- and high-dose groups, at 58 and 61 years, respectively. Most of the participants were female (70% vs. 60%), with a median disease duration of 6 years. Median baseline DAS28 scores were 4.2 in low- and 4.1 in high-dose groups, and baseline HAQ scores were 1.3 and 0.9, respectively.
Ms. Davies noted that 627 (77%) of the patients newly initiated on methotrexate received 15 mg/week, 10 received 20 mg, and 2 received 25 mg. The low dose of 7.5 mg/week was started by 165 patients (20%), 4 started on 5 mg, and 2 started on 2.5 mg. In more than 90% of patients, methotrexate was given orally in both the low- and high-dose groups.
Patients who were initiated on the lower methotrexate dose were more often prescribed concomitant nonbiologic DMARDs (17% vs. 10% of those in the high-dose group). Half of patients in both high- and low-dose groups used oral steroids, and a quarter used intramuscular steroids.
According to the EULAR response criteria, a good response is seen if the final DAS28 drops to 3.2 or below and there is also an improvement of 1.2 or more from baseline values. This was achieved in 23% of patients in the low-dose group and in 33% of patients in the high-dose group. Moderate EULAR clinical responses were seen in 32% and 25%, and nonresponses seen in a respective 45% and 42%.
However, findings on a multinomial logistic regression model “showed that RA patients starting methotrexate on a higher dose have a higher probability of having a good EULAR clinical response, as opposed to nonresponse, at 6 months,” Ms. Davies said.
The unadjusted relative risk ratio in patients starting a high versus low dose was 0.8 for a moderate EULAR response and 1.5 for a good EULAR response. The respective adjusted RRR was 1.0 and 2.7, suggesting that there is no difference between the doses in achieving a moderate response, but the higher dose has the edge at helping patients achieve a good EULAR response by 6 months.
During the discussion following Ms. Davies’ presentation, Roy Fleischmann, MD, of the department of internal medicine at the University of Texas Southwestern Medical Center, Dallas, asked whether a high dose had actually been used at all in the study. Dr. Fleischmann observed that both 7.5 mg/week and 15 mg/week could be considered low doses.
However, one of the chairs of the session, Peter Taylor, PhD , of the University of Oxford (England) noted that the bioavailability of methotrexate does not change much when the dose is above 15 mg via the oral route.
Kimme Hyrich, MD, of the University of Manchester (England) and senior author on the study, pointed out that the point of the analysis was to compare the starting doses of methotrexate among patients, and there might have been patients who received higher doses (25 mg or more) during the 6-month follow-up period. It is expected that future work will look at the change in the dose response over the 6-month time period, she said.
Ms. Bergstra and Ms. Davies reported that they had no relevant financial disclosures. Several coauthors for the METEOR database study disclosed financial relationships with numerous companies that market drugs for RA.
MADRID – A low versus high starting dose of methotrexate given as monotherapy or in combination with glucocorticoids or conventional synthetic disease-modifying antirheumatic drugs to newly diagnosed rheumatoid arthritis patients doesn’t seem to make a difference in short-term disease activity and physical functioning responses, but a higher starting dose of at least 15 mg/week may provide a better chance at achieving a good response at 6 months, according to two separate observational studies presented at the European Congress of Rheumatology.
One of the studies looked at 3- to 6-month disease activity and physical functioning responses to methotrexate used as mono- or combination therapy and the other assessed EULAR clinical responses at 6 months in mostly monotherapy-treated patients.
Low vs. high dose in combination treatments
“Methotrexate is the anchor drug in the treatment of rheumatoid arthritis patients. Current guidelines for methotrexate monotherapy recommend initiating 15 mg/week orally then escalating to 25-30 mg/week or the highest tolerable dose, but no recommendations exist for the drug’s use in combination therapy,” said Sytske Anne Bergstra, first author of a study using the international, observational METEOR database, a cohort with real-world clinical data.
The investigators selected 1,404 RA patients from the METEOR database who had a symptom duration of less than 5 years, had less than 2 months between diagnosis and first visit, and did not change medications (only dose adjustments were allowed). They were divided into three groups: methotrexate monotherapy, methotrexate plus conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), and methotrexate plus glucocorticoids (and possibly csDMARDs). The investigators defined initial starting doses of methotrexate as low (10 mg/week or less) or high (15 mg/week or more) based on the last reported dose of methotrexate at no later than 8 weeks of follow-up.
In each group, females comprised about 80% of patients, and the mean age was 45-48 years. The group that received methotrexate plus csDMARDs had a median symptom duration nearly twice that of the other groups (730 days vs. 365 for monotherapy and 458 for methotrexate plus glucocorticoids). Rheumatoid factor positivity ranged from 77% to 84% and anticitrullinated peptide autoantibody positivity from 72% to 85%.
The use of a high methotrexate starting dose generally trended upward in patients enrolled in the database through 2015, whereas the high point for use of a low dose was 2010 and declined thereafter. Overall, a high starting dose was used in 28% of monotherapy patients, 14% with methotrexate plus csDMARDs, and 46% with methotrexate plus glucocorticoids.
In propensity score–adjusted analyses that helped to control for confounding by indication, there were no differences in the effectiveness of low or high methotrexate starting doses for all three groups after follow-up between 3 and 6 months on Disease Activity Score (DAS), 28-joint DAS, or the Health Assessment Questionnaire (HAQ).
“Our findings seem to contradict the general trend of starting with high methotrexate doses. They indicate that higher doses did not provide better short-term clinical outcome in either monotherapy or combination therapy,” Ms. Bergstra observed.
She continued: “For the moment, we suggest that rheumatologists consider starting with a lower initial methotrexate dose, especially when prescribing in combination with other synthetic DMARDS or glucocorticoids.”
Effect of initial dose on EULAR response
Rebecca Davies of the Centre for Musculoskeletal Research at the University of Manchester (England) presented data from a separate study that examined the effect of giving a low versus a high dose of methotrexate on patients’ rate of response to EULAR criteria at 6 months.
“Methotrexate is the recommended first line treatment for rheumatoid arthritis; however, we have not yet established [a] clear optimal strategy for the starting dose of this therapy,” Ms. Davies said.
The aim of the study was therefore to assess the two most commonly used methotrexate starting doses used in the United Kingdom (7.5 mg/week or less vs. 15 mg/week or more) and how they affected the DAS28 of patients.
A total of 810 patients with rheumatoid arthritis who were starting methotrexate were recruited from the U.K. national, multicenter, longitudinal, observational Rheumatoid Arthritis Medication Study. For inclusion in the study, patients had to have complete DAS28 data at baseline and at 6 months.
The median age of patients was similar among the low- and high-dose groups, at 58 and 61 years, respectively. Most of the participants were female (70% vs. 60%), with a median disease duration of 6 years. Median baseline DAS28 scores were 4.2 in low- and 4.1 in high-dose groups, and baseline HAQ scores were 1.3 and 0.9, respectively.
Ms. Davies noted that 627 (77%) of the patients newly initiated on methotrexate received 15 mg/week, 10 received 20 mg, and 2 received 25 mg. The low dose of 7.5 mg/week was started by 165 patients (20%), 4 started on 5 mg, and 2 started on 2.5 mg. In more than 90% of patients, methotrexate was given orally in both the low- and high-dose groups.
Patients who were initiated on the lower methotrexate dose were more often prescribed concomitant nonbiologic DMARDs (17% vs. 10% of those in the high-dose group). Half of patients in both high- and low-dose groups used oral steroids, and a quarter used intramuscular steroids.
According to the EULAR response criteria, a good response is seen if the final DAS28 drops to 3.2 or below and there is also an improvement of 1.2 or more from baseline values. This was achieved in 23% of patients in the low-dose group and in 33% of patients in the high-dose group. Moderate EULAR clinical responses were seen in 32% and 25%, and nonresponses seen in a respective 45% and 42%.
However, findings on a multinomial logistic regression model “showed that RA patients starting methotrexate on a higher dose have a higher probability of having a good EULAR clinical response, as opposed to nonresponse, at 6 months,” Ms. Davies said.
The unadjusted relative risk ratio in patients starting a high versus low dose was 0.8 for a moderate EULAR response and 1.5 for a good EULAR response. The respective adjusted RRR was 1.0 and 2.7, suggesting that there is no difference between the doses in achieving a moderate response, but the higher dose has the edge at helping patients achieve a good EULAR response by 6 months.
During the discussion following Ms. Davies’ presentation, Roy Fleischmann, MD, of the department of internal medicine at the University of Texas Southwestern Medical Center, Dallas, asked whether a high dose had actually been used at all in the study. Dr. Fleischmann observed that both 7.5 mg/week and 15 mg/week could be considered low doses.
However, one of the chairs of the session, Peter Taylor, PhD , of the University of Oxford (England) noted that the bioavailability of methotrexate does not change much when the dose is above 15 mg via the oral route.
Kimme Hyrich, MD, of the University of Manchester (England) and senior author on the study, pointed out that the point of the analysis was to compare the starting doses of methotrexate among patients, and there might have been patients who received higher doses (25 mg or more) during the 6-month follow-up period. It is expected that future work will look at the change in the dose response over the 6-month time period, she said.
Ms. Bergstra and Ms. Davies reported that they had no relevant financial disclosures. Several coauthors for the METEOR database study disclosed financial relationships with numerous companies that market drugs for RA.
MADRID – A low versus high starting dose of methotrexate given as monotherapy or in combination with glucocorticoids or conventional synthetic disease-modifying antirheumatic drugs to newly diagnosed rheumatoid arthritis patients doesn’t seem to make a difference in short-term disease activity and physical functioning responses, but a higher starting dose of at least 15 mg/week may provide a better chance at achieving a good response at 6 months, according to two separate observational studies presented at the European Congress of Rheumatology.
One of the studies looked at 3- to 6-month disease activity and physical functioning responses to methotrexate used as mono- or combination therapy and the other assessed EULAR clinical responses at 6 months in mostly monotherapy-treated patients.
Low vs. high dose in combination treatments
“Methotrexate is the anchor drug in the treatment of rheumatoid arthritis patients. Current guidelines for methotrexate monotherapy recommend initiating 15 mg/week orally then escalating to 25-30 mg/week or the highest tolerable dose, but no recommendations exist for the drug’s use in combination therapy,” said Sytske Anne Bergstra, first author of a study using the international, observational METEOR database, a cohort with real-world clinical data.
The investigators selected 1,404 RA patients from the METEOR database who had a symptom duration of less than 5 years, had less than 2 months between diagnosis and first visit, and did not change medications (only dose adjustments were allowed). They were divided into three groups: methotrexate monotherapy, methotrexate plus conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), and methotrexate plus glucocorticoids (and possibly csDMARDs). The investigators defined initial starting doses of methotrexate as low (10 mg/week or less) or high (15 mg/week or more) based on the last reported dose of methotrexate at no later than 8 weeks of follow-up.
In each group, females comprised about 80% of patients, and the mean age was 45-48 years. The group that received methotrexate plus csDMARDs had a median symptom duration nearly twice that of the other groups (730 days vs. 365 for monotherapy and 458 for methotrexate plus glucocorticoids). Rheumatoid factor positivity ranged from 77% to 84% and anticitrullinated peptide autoantibody positivity from 72% to 85%.
The use of a high methotrexate starting dose generally trended upward in patients enrolled in the database through 2015, whereas the high point for use of a low dose was 2010 and declined thereafter. Overall, a high starting dose was used in 28% of monotherapy patients, 14% with methotrexate plus csDMARDs, and 46% with methotrexate plus glucocorticoids.
In propensity score–adjusted analyses that helped to control for confounding by indication, there were no differences in the effectiveness of low or high methotrexate starting doses for all three groups after follow-up between 3 and 6 months on Disease Activity Score (DAS), 28-joint DAS, or the Health Assessment Questionnaire (HAQ).
“Our findings seem to contradict the general trend of starting with high methotrexate doses. They indicate that higher doses did not provide better short-term clinical outcome in either monotherapy or combination therapy,” Ms. Bergstra observed.
She continued: “For the moment, we suggest that rheumatologists consider starting with a lower initial methotrexate dose, especially when prescribing in combination with other synthetic DMARDS or glucocorticoids.”
Effect of initial dose on EULAR response
Rebecca Davies of the Centre for Musculoskeletal Research at the University of Manchester (England) presented data from a separate study that examined the effect of giving a low versus a high dose of methotrexate on patients’ rate of response to EULAR criteria at 6 months.
“Methotrexate is the recommended first line treatment for rheumatoid arthritis; however, we have not yet established [a] clear optimal strategy for the starting dose of this therapy,” Ms. Davies said.
The aim of the study was therefore to assess the two most commonly used methotrexate starting doses used in the United Kingdom (7.5 mg/week or less vs. 15 mg/week or more) and how they affected the DAS28 of patients.
A total of 810 patients with rheumatoid arthritis who were starting methotrexate were recruited from the U.K. national, multicenter, longitudinal, observational Rheumatoid Arthritis Medication Study. For inclusion in the study, patients had to have complete DAS28 data at baseline and at 6 months.
The median age of patients was similar among the low- and high-dose groups, at 58 and 61 years, respectively. Most of the participants were female (70% vs. 60%), with a median disease duration of 6 years. Median baseline DAS28 scores were 4.2 in low- and 4.1 in high-dose groups, and baseline HAQ scores were 1.3 and 0.9, respectively.
Ms. Davies noted that 627 (77%) of the patients newly initiated on methotrexate received 15 mg/week, 10 received 20 mg, and 2 received 25 mg. The low dose of 7.5 mg/week was started by 165 patients (20%), 4 started on 5 mg, and 2 started on 2.5 mg. In more than 90% of patients, methotrexate was given orally in both the low- and high-dose groups.
Patients who were initiated on the lower methotrexate dose were more often prescribed concomitant nonbiologic DMARDs (17% vs. 10% of those in the high-dose group). Half of patients in both high- and low-dose groups used oral steroids, and a quarter used intramuscular steroids.
According to the EULAR response criteria, a good response is seen if the final DAS28 drops to 3.2 or below and there is also an improvement of 1.2 or more from baseline values. This was achieved in 23% of patients in the low-dose group and in 33% of patients in the high-dose group. Moderate EULAR clinical responses were seen in 32% and 25%, and nonresponses seen in a respective 45% and 42%.
However, findings on a multinomial logistic regression model “showed that RA patients starting methotrexate on a higher dose have a higher probability of having a good EULAR clinical response, as opposed to nonresponse, at 6 months,” Ms. Davies said.
The unadjusted relative risk ratio in patients starting a high versus low dose was 0.8 for a moderate EULAR response and 1.5 for a good EULAR response. The respective adjusted RRR was 1.0 and 2.7, suggesting that there is no difference between the doses in achieving a moderate response, but the higher dose has the edge at helping patients achieve a good EULAR response by 6 months.
During the discussion following Ms. Davies’ presentation, Roy Fleischmann, MD, of the department of internal medicine at the University of Texas Southwestern Medical Center, Dallas, asked whether a high dose had actually been used at all in the study. Dr. Fleischmann observed that both 7.5 mg/week and 15 mg/week could be considered low doses.
However, one of the chairs of the session, Peter Taylor, PhD , of the University of Oxford (England) noted that the bioavailability of methotrexate does not change much when the dose is above 15 mg via the oral route.
Kimme Hyrich, MD, of the University of Manchester (England) and senior author on the study, pointed out that the point of the analysis was to compare the starting doses of methotrexate among patients, and there might have been patients who received higher doses (25 mg or more) during the 6-month follow-up period. It is expected that future work will look at the change in the dose response over the 6-month time period, she said.
Ms. Bergstra and Ms. Davies reported that they had no relevant financial disclosures. Several coauthors for the METEOR database study disclosed financial relationships with numerous companies that market drugs for RA.
AT THE EULAR 2017 CONGRESS
Key clinical point: For newly diagnosed RA, consider using a lower methotrexate starting dose with combination therapy and a higher dose of 15 mg/week or more in monotherapy.
Major finding: In one study, 23% and 33% of patients taking low-dose or high-dose methotrexate, respectively, achieved a good EULAR clinical response.
Data source: Two studies (METEOR and RAMS) evaluating the comparative effects of initiating low versus high doses of methotrexate for newly diagnosed rheumatoid arthritis.
Disclosures: The presenters reported they had no relevant financial disclosures. Several coauthors for the METEOR database study disclosed financial relationships with numerous companies that market drugs for RA.