TBD Meeting (3208-21)

Initiating treatment of polyarticular juvenile idiopathic arthritis (polyJIA) with both a conventional synthetic disease-modifying antirheumatic drug and a biologic DMARD resulted in more patients achieving clinical inactive disease 2 years later than did starting with only a csDMARD and stepping up to a biologic, according to data presented at the virtual annual meeting of the American College of Rheumatology.

“The 24-month results support the 12-month primary results that suggested that the early-combination group was superior and that, at 24 months, more early combination CTP [consensus treatment plan] patients achieve CID [clinical inactive disease], compared to step up,” Yukiko Kimura, MD, division chief of pediatric rheumatology at HMH Hackensack (N.J.) University Medical Center, told attendees. “This suggests that starting biologics early in polyJIA may lead to better long-term outcomes in many patients.”

Dr. Kimura noted that polyarticular JIA patients are already at risk for poor outcomes, and initial therapy can especially impact outcomes. Further, little evidence exists to suggest when the best time is to start biologics, a gap this study aimed to address.

Diane Brown, MD, PhD, a pediatric rheumatologist at Children’s Hospital Los Angeles who was not involved in the study, was pleased to see the results, which she said support her own preferences and practice patterns.

“Starting sooner with combination therapy, taking advantage of the advances with biologics and our long history with methotrexate at the same time, gives better outcomes for the long run,” Dr. Brown said in an interview. “Having studies like this to back up my own recommendations can be very powerful when talking to families, and it is absolutely invaluable when battling with insurance companies who always want you to take the cheapest road.”
 

Study details

The findings were an update of 12-month results in the CARRA STOP-JIA study that enrolled 400 untreated patients with polyJIA and compared three Childhood Arthritis and Rheumatology Research Alliance (CARRA) CTPs. Overall, 49.5% of participants received biologics within 3 months of starting the study. For these updated results, 275 participants had complete data at 24 months for the three CTPs:

• A step-up group of 177 patients who started therapy with a csDMARD and added a biologic if needed at least 3 months later
• An early-combination group of 73 patients who started therapy with a csDMARD and biologic together
• A biologic-first group of 25 patients who started with biologic monotherapy, adding a csDMARD only if needed at least 3 months later.

The primary outcome was the percentage of participants who reached CID without taking glucocorticoids at 24 months. Since the participants were not randomized, the researchers made adjustments to account for baseline differences between the groups, including differences in JIA categories, number of active joints, physician global assessment of disease activity, and the clinical Juvenile Arthritis Disease Activity Score based on 10 joints (cJADAS10).

At 24 months in an intention to treat analysis, 59.4% of the early-combination group had achieved CID, compared with 48% of the biologic-first group and 40.1% of the step-up group (P = .009 for early combination vs. step up). All three groups had improved since the 12-month time point, when 37% of the early-combination group, 24% of the biologic-first group, and 32% of the step-up group had reached CID.

There were no significant differences between the groups in secondary outcomes of achieving cJADAS10 inactive disease of 2.5 or less or 70% improvement in pediatric ACR response criteria at 24 months. All groups improved in PROMIS pain interference or mobility measures from baseline. Most of the 17 severe adverse events were infections.
 

Moving from step-up therapy to early-combination treatment

Dr. Brown said that she spent many years in her practice using the step-up therapy because it was difficult to get insurance companies to pay for biologics without first showing that methotrexate was insufficient.

”But methotrexate takes so long to control the disease that you need a lot of steroids, with all of their side effects, at least temporarily, or you must simply accept a longer period of active and symptomatic disease before you get to that desired state of clinically inactive disease,” Dr. Brown said. “And during that time, you can be accumulating what may be permanent damage to joints, as well as increase in risk of contractures and deconditioning for that child who is too uncomfortable to move and exercise and play normally.”

Dr. Brown is also wary of using a biologic as an initial therapy by itself because the actions of biologics are so specific. ”I like to back up the powerful, rapid, and specific actions of a biologic with the broader, if slower, action of methotrexate to minimize chances that the immune system is going to find a way around blockade of a single cytokine by your biologic,” she said.

While patient preference will also play a role in what CTP patients with polyJIA start with, Dr. Brown said that she believes more medication upfront can result in less medication and better outcomes in the long run, as the findings of this study suggest. The results here are helpful when speaking with families who are anxious about “so much medicine” or “such powerful medicines,” she said. ”I hope it will also help ease the fears of other providers who share the same concerns about ‘so much medicine.’ ”

The study’s biggest limitation is not being a randomized, controlled trial, but Dr. Brown said the researchers demonstrated effectively that the disease burden remains similar across the groups at baseline.

”It would also be useful to have a clear breakdown of adverse events and opportunistic infections because an excess of opportunistic infections would be a key concern with early combination therapy,” she said, although she added that the study overall was a ”beautiful example of the value of registry data.”

Dr. Kimura emphasized that polyJIA remains a challenging disease to treat, with 40%-60% of participants not reaching CID at 24 months. The registry follow-up will continue for up to 10 years to hopefully provide more information about longer-term outcomes from different treatments.

The research was funded by a grant from Genentech to CARRA. Dr. Kimura reported royalties from UpToDate and salary support from CARRA. Dr. Brown had no disclosures.

Initiating treatment of polyarticular juvenile idiopathic arthritis (polyJIA) with both a conventional synthetic disease-modifying antirheumatic drug and a biologic DMARD resulted in more patients achieving clinical inactive disease 2 years later than did starting with only a csDMARD and stepping up to a biologic, according to data presented at the virtual annual meeting of the American College of Rheumatology.

“The 24-month results support the 12-month primary results that suggested that the early-combination group was superior and that, at 24 months, more early combination CTP [consensus treatment plan] patients achieve CID [clinical inactive disease], compared to step up,” Yukiko Kimura, MD, division chief of pediatric rheumatology at HMH Hackensack (N.J.) University Medical Center, told attendees. “This suggests that starting biologics early in polyJIA may lead to better long-term outcomes in many patients.”

Dr. Kimura noted that polyarticular JIA patients are already at risk for poor outcomes, and initial therapy can especially impact outcomes. Further, little evidence exists to suggest when the best time is to start biologics, a gap this study aimed to address.

Diane Brown, MD, PhD, a pediatric rheumatologist at Children’s Hospital Los Angeles who was not involved in the study, was pleased to see the results, which she said support her own preferences and practice patterns.

“Starting sooner with combination therapy, taking advantage of the advances with biologics and our long history with methotrexate at the same time, gives better outcomes for the long run,” Dr. Brown said in an interview. “Having studies like this to back up my own recommendations can be very powerful when talking to families, and it is absolutely invaluable when battling with insurance companies who always want you to take the cheapest road.”
 

Study details

The findings were an update of 12-month results in the CARRA STOP-JIA study that enrolled 400 untreated patients with polyJIA and compared three Childhood Arthritis and Rheumatology Research Alliance (CARRA) CTPs. Overall, 49.5% of participants received biologics within 3 months of starting the study. For these updated results, 275 participants had complete data at 24 months for the three CTPs:

• A step-up group of 177 patients who started therapy with a csDMARD and added a biologic if needed at least 3 months later
• An early-combination group of 73 patients who started therapy with a csDMARD and biologic together
• A biologic-first group of 25 patients who started with biologic monotherapy, adding a csDMARD only if needed at least 3 months later.

The primary outcome was the percentage of participants who reached CID without taking glucocorticoids at 24 months. Since the participants were not randomized, the researchers made adjustments to account for baseline differences between the groups, including differences in JIA categories, number of active joints, physician global assessment of disease activity, and the clinical Juvenile Arthritis Disease Activity Score based on 10 joints (cJADAS10).

At 24 months in an intention to treat analysis, 59.4% of the early-combination group had achieved CID, compared with 48% of the biologic-first group and 40.1% of the step-up group (P = .009 for early combination vs. step up). All three groups had improved since the 12-month time point, when 37% of the early-combination group, 24% of the biologic-first group, and 32% of the step-up group had reached CID.

There were no significant differences between the groups in secondary outcomes of achieving cJADAS10 inactive disease of 2.5 or less or 70% improvement in pediatric ACR response criteria at 24 months. All groups improved in PROMIS pain interference or mobility measures from baseline. Most of the 17 severe adverse events were infections.
 

Moving from step-up therapy to early-combination treatment

Dr. Brown said that she spent many years in her practice using the step-up therapy because it was difficult to get insurance companies to pay for biologics without first showing that methotrexate was insufficient.

”But methotrexate takes so long to control the disease that you need a lot of steroids, with all of their side effects, at least temporarily, or you must simply accept a longer period of active and symptomatic disease before you get to that desired state of clinically inactive disease,” Dr. Brown said. “And during that time, you can be accumulating what may be permanent damage to joints, as well as increase in risk of contractures and deconditioning for that child who is too uncomfortable to move and exercise and play normally.”

Dr. Brown is also wary of using a biologic as an initial therapy by itself because the actions of biologics are so specific. ”I like to back up the powerful, rapid, and specific actions of a biologic with the broader, if slower, action of methotrexate to minimize chances that the immune system is going to find a way around blockade of a single cytokine by your biologic,” she said.

While patient preference will also play a role in what CTP patients with polyJIA start with, Dr. Brown said that she believes more medication upfront can result in less medication and better outcomes in the long run, as the findings of this study suggest. The results here are helpful when speaking with families who are anxious about “so much medicine” or “such powerful medicines,” she said. ”I hope it will also help ease the fears of other providers who share the same concerns about ‘so much medicine.’ ”

The study’s biggest limitation is not being a randomized, controlled trial, but Dr. Brown said the researchers demonstrated effectively that the disease burden remains similar across the groups at baseline.

”It would also be useful to have a clear breakdown of adverse events and opportunistic infections because an excess of opportunistic infections would be a key concern with early combination therapy,” she said, although she added that the study overall was a ”beautiful example of the value of registry data.”

Dr. Kimura emphasized that polyJIA remains a challenging disease to treat, with 40%-60% of participants not reaching CID at 24 months. The registry follow-up will continue for up to 10 years to hopefully provide more information about longer-term outcomes from different treatments.

The research was funded by a grant from Genentech to CARRA. Dr. Kimura reported royalties from UpToDate and salary support from CARRA. Dr. Brown had no disclosures.

Initiating treatment of polyarticular juvenile idiopathic arthritis (polyJIA) with both a conventional synthetic disease-modifying antirheumatic drug and a biologic DMARD resulted in more patients achieving clinical inactive disease 2 years later than did starting with only a csDMARD and stepping up to a biologic, according to data presented at the virtual annual meeting of the American College of Rheumatology.

“The 24-month results support the 12-month primary results that suggested that the early-combination group was superior and that, at 24 months, more early combination CTP [consensus treatment plan] patients achieve CID [clinical inactive disease], compared to step up,” Yukiko Kimura, MD, division chief of pediatric rheumatology at HMH Hackensack (N.J.) University Medical Center, told attendees. “This suggests that starting biologics early in polyJIA may lead to better long-term outcomes in many patients.”

Dr. Kimura noted that polyarticular JIA patients are already at risk for poor outcomes, and initial therapy can especially impact outcomes. Further, little evidence exists to suggest when the best time is to start biologics, a gap this study aimed to address.

Diane Brown, MD, PhD, a pediatric rheumatologist at Children’s Hospital Los Angeles who was not involved in the study, was pleased to see the results, which she said support her own preferences and practice patterns.

“Starting sooner with combination therapy, taking advantage of the advances with biologics and our long history with methotrexate at the same time, gives better outcomes for the long run,” Dr. Brown said in an interview. “Having studies like this to back up my own recommendations can be very powerful when talking to families, and it is absolutely invaluable when battling with insurance companies who always want you to take the cheapest road.”
 

Study details

The findings were an update of 12-month results in the CARRA STOP-JIA study that enrolled 400 untreated patients with polyJIA and compared three Childhood Arthritis and Rheumatology Research Alliance (CARRA) CTPs. Overall, 49.5% of participants received biologics within 3 months of starting the study. For these updated results, 275 participants had complete data at 24 months for the three CTPs:

• A step-up group of 177 patients who started therapy with a csDMARD and added a biologic if needed at least 3 months later
• An early-combination group of 73 patients who started therapy with a csDMARD and biologic together
• A biologic-first group of 25 patients who started with biologic monotherapy, adding a csDMARD only if needed at least 3 months later.

The primary outcome was the percentage of participants who reached CID without taking glucocorticoids at 24 months. Since the participants were not randomized, the researchers made adjustments to account for baseline differences between the groups, including differences in JIA categories, number of active joints, physician global assessment of disease activity, and the clinical Juvenile Arthritis Disease Activity Score based on 10 joints (cJADAS10).

At 24 months in an intention to treat analysis, 59.4% of the early-combination group had achieved CID, compared with 48% of the biologic-first group and 40.1% of the step-up group (P = .009 for early combination vs. step up). All three groups had improved since the 12-month time point, when 37% of the early-combination group, 24% of the biologic-first group, and 32% of the step-up group had reached CID.

There were no significant differences between the groups in secondary outcomes of achieving cJADAS10 inactive disease of 2.5 or less or 70% improvement in pediatric ACR response criteria at 24 months. All groups improved in PROMIS pain interference or mobility measures from baseline. Most of the 17 severe adverse events were infections.
 

Moving from step-up therapy to early-combination treatment

Dr. Brown said that she spent many years in her practice using the step-up therapy because it was difficult to get insurance companies to pay for biologics without first showing that methotrexate was insufficient.

”But methotrexate takes so long to control the disease that you need a lot of steroids, with all of their side effects, at least temporarily, or you must simply accept a longer period of active and symptomatic disease before you get to that desired state of clinically inactive disease,” Dr. Brown said. “And during that time, you can be accumulating what may be permanent damage to joints, as well as increase in risk of contractures and deconditioning for that child who is too uncomfortable to move and exercise and play normally.”

Dr. Brown is also wary of using a biologic as an initial therapy by itself because the actions of biologics are so specific. ”I like to back up the powerful, rapid, and specific actions of a biologic with the broader, if slower, action of methotrexate to minimize chances that the immune system is going to find a way around blockade of a single cytokine by your biologic,” she said.

While patient preference will also play a role in what CTP patients with polyJIA start with, Dr. Brown said that she believes more medication upfront can result in less medication and better outcomes in the long run, as the findings of this study suggest. The results here are helpful when speaking with families who are anxious about “so much medicine” or “such powerful medicines,” she said. ”I hope it will also help ease the fears of other providers who share the same concerns about ‘so much medicine.’ ”

The study’s biggest limitation is not being a randomized, controlled trial, but Dr. Brown said the researchers demonstrated effectively that the disease burden remains similar across the groups at baseline.

”It would also be useful to have a clear breakdown of adverse events and opportunistic infections because an excess of opportunistic infections would be a key concern with early combination therapy,” she said, although she added that the study overall was a ”beautiful example of the value of registry data.”

Dr. Kimura emphasized that polyJIA remains a challenging disease to treat, with 40%-60% of participants not reaching CID at 24 months. The registry follow-up will continue for up to 10 years to hopefully provide more information about longer-term outcomes from different treatments.

The research was funded by a grant from Genentech to CARRA. Dr. Kimura reported royalties from UpToDate and salary support from CARRA. Dr. Brown had no disclosures.

The use of statins by patients with rheumatoid arthritis appears to provide an overall net benefit on cardiovascular disease outcomes that outweighs the risk of type 2 diabetes mellitus (T2DM) seen with the drugs in the general population, according to evidence from a cohort study of more than 16,000 people in the United Kingdom that was presented at the virtual annual meeting of the American College of Rheumatology.

“Our study emphasizes that RA patients should be assessed for statin initiation to improve CVD risk,” lead study author Gulsen Ozen, MD, a third-year resident at the University of Nebraska, Omaha, said in an interview. Because the risk of T2DM with statin use is no worse in patients with RA than in the general population, statin initiation “is actually a great opportunity to address the risk factors for T2DM such as activity and exercise, obesity and weight loss, and [use of glucocorticoids], which have other important health effects,” she said.

“Also, importantly, even if [patients] develop T2DM, statins still work on CVD and mortality outcomes as in patients without diabetes,” Dr. Ozen added. “Given all, the benefits of statins way outweigh the hazards.”

Dr. Ozen said this was the first large cohort study to evaluate CVD mortality and T2DM risks with statins in patients with RA, a claim with which rheumatologist Elena Myasoedova, MD, PhD, of the Mayo Clinic in Rochester, Minn., concurred.

Dr. Myasoedova, professor of rheumatology and epidemiology at Mayo, said in an interview that the study was “methodologically rigorous” using time-conditional propensity score (TCPS) matching and a prevalent new-user design, “thus addressing the immortal time bias” found in the design of studies in which patients enter a cohort but do not start a treatment before developing the outcome of interest and are assigned to the untreated group or when the period of delay from when patients enter the cohort to when they are treated is excluded from the analysis. An earlier study from the same authors did not use TCPS matching, she said.

“The study findings suggest that patients with RA can benefit from statin use in terms of CVD outcomes and mortality but physicians should use vigilance regarding increased T2DM risk and discuss this possibility with patients,” Dr. Myasoedova said. “Identifying patients who are at higher risk of developing T2DM after statin initiation would be important to personalize the approach to statin therapy.”
 

Study details

The study accessed records from the U.K. Clinical Practice Research Datalink and linked Hospital Episode Statistics and Office of National Statistics databases. It analyzed adult patients with RA who were diagnosed during 1989-2018 in two cohorts: One for CVD and all-cause mortality, consisting of 1,768 statin initiators and 3,528 TCPS-matched nonusers; and a T2DM cohort with 3,608 statin initiators and 7,208 TCPS-matched nonusers.

In the entire cohort, statin use was associated with a 32% reduction in CV events (composite endpoint of the nonfatal or fatal MI, stroke, hospitalized heart failure, or CVD mortality), a 54% reduction in all-cause mortality, and a 33% increase in risk for T2DM, Dr. Ozen said. Results were similar in both sexes, although CV event reduction with statins in men did not reach statistical significance, likely because of a smaller sample size, she said.

Patients with and without a history of CVD had a similar reduction in CV events and all-cause mortality, and risk for T2DM increased with statins, but the latter reached statistical significance only in patients without a history of CVD, Dr. Ozen said.

Patients with RA who are at risk for T2DM and who are taking statins require blood glucose monitoring, which is typically done in patients with RA on disease-modifying antirheumatic drugs, and hemoglobin A1c testing when glucose levels are impaired, she said. “Any concerns for T2DM would be also communicated by the primary care providers of the patients to initiate further assessment and management,” she said.

But Dr. Ozen noted that confusion exists among primary care physicians and rheumatologists about who’s responsible for prescribing statins in these patients. “I would like to remind you that instead of assigning this role to a certain specialty, just good communication could improve this care gap of statin underutilization in RA,” she said. “Also, for rheumatologists, given that all-cause mortality reduction with statins was as high as CV event reduction, statins may be reducing other causes of mortality through improving disease activity.”

Bristol-Myers Squibb provided funding for the study. Dr. Ozen and Dr. Myasoedova have no relevant disclosures.

The use of statins by patients with rheumatoid arthritis appears to provide an overall net benefit on cardiovascular disease outcomes that outweighs the risk of type 2 diabetes mellitus (T2DM) seen with the drugs in the general population, according to evidence from a cohort study of more than 16,000 people in the United Kingdom that was presented at the virtual annual meeting of the American College of Rheumatology.

“Our study emphasizes that RA patients should be assessed for statin initiation to improve CVD risk,” lead study author Gulsen Ozen, MD, a third-year resident at the University of Nebraska, Omaha, said in an interview. Because the risk of T2DM with statin use is no worse in patients with RA than in the general population, statin initiation “is actually a great opportunity to address the risk factors for T2DM such as activity and exercise, obesity and weight loss, and [use of glucocorticoids], which have other important health effects,” she said.

“Also, importantly, even if [patients] develop T2DM, statins still work on CVD and mortality outcomes as in patients without diabetes,” Dr. Ozen added. “Given all, the benefits of statins way outweigh the hazards.”

Dr. Ozen said this was the first large cohort study to evaluate CVD mortality and T2DM risks with statins in patients with RA, a claim with which rheumatologist Elena Myasoedova, MD, PhD, of the Mayo Clinic in Rochester, Minn., concurred.

Dr. Myasoedova, professor of rheumatology and epidemiology at Mayo, said in an interview that the study was “methodologically rigorous” using time-conditional propensity score (TCPS) matching and a prevalent new-user design, “thus addressing the immortal time bias” found in the design of studies in which patients enter a cohort but do not start a treatment before developing the outcome of interest and are assigned to the untreated group or when the period of delay from when patients enter the cohort to when they are treated is excluded from the analysis. An earlier study from the same authors did not use TCPS matching, she said.

“The study findings suggest that patients with RA can benefit from statin use in terms of CVD outcomes and mortality but physicians should use vigilance regarding increased T2DM risk and discuss this possibility with patients,” Dr. Myasoedova said. “Identifying patients who are at higher risk of developing T2DM after statin initiation would be important to personalize the approach to statin therapy.”
 

Study details

The study accessed records from the U.K. Clinical Practice Research Datalink and linked Hospital Episode Statistics and Office of National Statistics databases. It analyzed adult patients with RA who were diagnosed during 1989-2018 in two cohorts: One for CVD and all-cause mortality, consisting of 1,768 statin initiators and 3,528 TCPS-matched nonusers; and a T2DM cohort with 3,608 statin initiators and 7,208 TCPS-matched nonusers.

In the entire cohort, statin use was associated with a 32% reduction in CV events (composite endpoint of the nonfatal or fatal MI, stroke, hospitalized heart failure, or CVD mortality), a 54% reduction in all-cause mortality, and a 33% increase in risk for T2DM, Dr. Ozen said. Results were similar in both sexes, although CV event reduction with statins in men did not reach statistical significance, likely because of a smaller sample size, she said.

Patients with and without a history of CVD had a similar reduction in CV events and all-cause mortality, and risk for T2DM increased with statins, but the latter reached statistical significance only in patients without a history of CVD, Dr. Ozen said.

Patients with RA who are at risk for T2DM and who are taking statins require blood glucose monitoring, which is typically done in patients with RA on disease-modifying antirheumatic drugs, and hemoglobin A1c testing when glucose levels are impaired, she said. “Any concerns for T2DM would be also communicated by the primary care providers of the patients to initiate further assessment and management,” she said.

But Dr. Ozen noted that confusion exists among primary care physicians and rheumatologists about who’s responsible for prescribing statins in these patients. “I would like to remind you that instead of assigning this role to a certain specialty, just good communication could improve this care gap of statin underutilization in RA,” she said. “Also, for rheumatologists, given that all-cause mortality reduction with statins was as high as CV event reduction, statins may be reducing other causes of mortality through improving disease activity.”

Bristol-Myers Squibb provided funding for the study. Dr. Ozen and Dr. Myasoedova have no relevant disclosures.

The use of statins by patients with rheumatoid arthritis appears to provide an overall net benefit on cardiovascular disease outcomes that outweighs the risk of type 2 diabetes mellitus (T2DM) seen with the drugs in the general population, according to evidence from a cohort study of more than 16,000 people in the United Kingdom that was presented at the virtual annual meeting of the American College of Rheumatology.

“Our study emphasizes that RA patients should be assessed for statin initiation to improve CVD risk,” lead study author Gulsen Ozen, MD, a third-year resident at the University of Nebraska, Omaha, said in an interview. Because the risk of T2DM with statin use is no worse in patients with RA than in the general population, statin initiation “is actually a great opportunity to address the risk factors for T2DM such as activity and exercise, obesity and weight loss, and [use of glucocorticoids], which have other important health effects,” she said.

“Also, importantly, even if [patients] develop T2DM, statins still work on CVD and mortality outcomes as in patients without diabetes,” Dr. Ozen added. “Given all, the benefits of statins way outweigh the hazards.”

Dr. Ozen said this was the first large cohort study to evaluate CVD mortality and T2DM risks with statins in patients with RA, a claim with which rheumatologist Elena Myasoedova, MD, PhD, of the Mayo Clinic in Rochester, Minn., concurred.

Dr. Myasoedova, professor of rheumatology and epidemiology at Mayo, said in an interview that the study was “methodologically rigorous” using time-conditional propensity score (TCPS) matching and a prevalent new-user design, “thus addressing the immortal time bias” found in the design of studies in which patients enter a cohort but do not start a treatment before developing the outcome of interest and are assigned to the untreated group or when the period of delay from when patients enter the cohort to when they are treated is excluded from the analysis. An earlier study from the same authors did not use TCPS matching, she said.

“The study findings suggest that patients with RA can benefit from statin use in terms of CVD outcomes and mortality but physicians should use vigilance regarding increased T2DM risk and discuss this possibility with patients,” Dr. Myasoedova said. “Identifying patients who are at higher risk of developing T2DM after statin initiation would be important to personalize the approach to statin therapy.”
 

Study details

The study accessed records from the U.K. Clinical Practice Research Datalink and linked Hospital Episode Statistics and Office of National Statistics databases. It analyzed adult patients with RA who were diagnosed during 1989-2018 in two cohorts: One for CVD and all-cause mortality, consisting of 1,768 statin initiators and 3,528 TCPS-matched nonusers; and a T2DM cohort with 3,608 statin initiators and 7,208 TCPS-matched nonusers.

In the entire cohort, statin use was associated with a 32% reduction in CV events (composite endpoint of the nonfatal or fatal MI, stroke, hospitalized heart failure, or CVD mortality), a 54% reduction in all-cause mortality, and a 33% increase in risk for T2DM, Dr. Ozen said. Results were similar in both sexes, although CV event reduction with statins in men did not reach statistical significance, likely because of a smaller sample size, she said.

Patients with and without a history of CVD had a similar reduction in CV events and all-cause mortality, and risk for T2DM increased with statins, but the latter reached statistical significance only in patients without a history of CVD, Dr. Ozen said.

Patients with RA who are at risk for T2DM and who are taking statins require blood glucose monitoring, which is typically done in patients with RA on disease-modifying antirheumatic drugs, and hemoglobin A1c testing when glucose levels are impaired, she said. “Any concerns for T2DM would be also communicated by the primary care providers of the patients to initiate further assessment and management,” she said.

But Dr. Ozen noted that confusion exists among primary care physicians and rheumatologists about who’s responsible for prescribing statins in these patients. “I would like to remind you that instead of assigning this role to a certain specialty, just good communication could improve this care gap of statin underutilization in RA,” she said. “Also, for rheumatologists, given that all-cause mortality reduction with statins was as high as CV event reduction, statins may be reducing other causes of mortality through improving disease activity.”

Bristol-Myers Squibb provided funding for the study. Dr. Ozen and Dr. Myasoedova have no relevant disclosures.

Among patients with the recently defined severe autoinflammatory syndrome VEXAS, those who are transfusion dependent or have a specific amino acid substitution are at highest risk for death, whereas those with ear chondritis are at significantly lower risk, a multinational team of investigators has found.

Courtesy Dr. Marcela Ferrada

Their study of mortality and predictors of survival among patients with genetically confirmed VEXAS showed that patients with a VEXAS variant resulting in an amino acid substitution of a methionine for a valine had a 3.5-fold higher risk for death, compared with patients with either a methionine-to-threonine substitution or a methionine-to-leucine swap.

Transfusion dependence was an independent predictor of mortality. Patients who became dependent on transfusions after symptom onset had a nearly threefold higher risk for death, reported Marcela A. Ferrada, MD, a clinical fellow at the National Institute of Arthritis and Musculoskeletal and Skin Diseases.

“These findings should inform risk assessment and clinical management in patients with VEXAS syndrome,” she said in an oral abstract presentation during the virtual annual meeting of the American College of Rheumatology.

“These genetic findings have proven right now to be not only diagnostic, but we have shown that they’re also prognostic, and we hope that this is going to help us identify patients who could have more aggressive treatment,” Dr. Ferrada said.

She also discussed her findings in a media briefing held 2 days prior to her plenary presentation. At that briefing, this news organization asked participating clinicians whether they had patients who they suspected may have had undiagnosed VEXAS.

“My answer to that is interesting,” replied moderator Vaneet Sandhu, MD, from Loma Linda (Calif.) University and Riverside University Health System.

“In the last couple of days, I’ve been reading about VEXAS, and actually texted one of my colleagues yesterday and said, ‘Hey, you know these patients we’ve been seeing who have these strange rashes and chondritis and have maybe a diagnosis of leukocytoclastic vasculitis or something else – are we not diagnosing these patients?’ ” she said.

“I think we are looking at every patient with chondritis and reexamining their phenotype. We had dismissed certain symptoms because they didn’t fit the archetype for relapsing polychondritis, for example, but it could be VEXAS,” said Alfred Kim, MD, PhD, of Washington University in St. Louis, who also presented data during the briefing.

Three variants

VEXAS is caused by somatic mutations in UBA1, a gene that initiates cytoplasmic ubiquitylation, a process by which misfolded proteins are tagged for degradation.

The syndrome’s name is an acronym descriptive of the major features:

• Vacuoles in bone marrow cells.
• E-1 activating enzyme that UBA1 encodes for.
• X-linked.
• Autoinflammatory.
• Somatic mutation featuring hematologic mosaicism.

VEXAS results in rheumatologic, dermatologic, and hematologic symptoms that are often misdiagnosed as being caused by treatment-refractory relapsing polychondritis, polyarteritis nodosa, Sweet syndrome, giant cell arteritis, or myelodysplastic syndrome (MDS).

VEXAS was identified as a distinct syndrome within the past year by Dr. Ferrada and other investigators at NIAMS, the National Human Genome Research Institute, and other institutions.

In the study reported at ACR 2021, Dr. Ferrada and colleagues assessed 83 men who had been referred for genetic testing for VEXAS at the National Institutes of Health, in Bethesda, Md., and at Leeds (England) Teaching Hospitals NHS Trust.

All patients were confirmed to have VEXAS-defining genetic mutations in UBA1 by Sanger sequencing of peripheral blood samples. Only those patients with mutations at codon p.Met41 were included in the investigators’ analysis. Mutations at that site account for nearly all cases of VEXAS that have been identified to date.

The most common clinical manifestation of VEXAS was skin involvement, which occurred in all but one of the 83 patients. Other common manifestations included arthritis (58 patients), pulmonary infiltrates (57 patients), and ear chondritis (54 patients).

Fifteen patients were found to have the leucine variant, 18 had the valine variant, and 50 had the threonine variant. The median age at disease onset was 66 years in the leucine and threonine variant groups and 65 in the valine variant group.

The clinical diagnosis differed according to genotype: 4 of 18 patients (22%) with the valine variant were diagnosed with relapsing polychondritis, compared with 8 of 15 (53%) with the leucine variant and 31 of 50 (62%) with the threonine variant (P = .01).

In contrast, 55% of patients with valine genotype were diagnosed with undifferentiated fever, compared with 6% of those with the leucine and 16% with the threonine genotypes (P = .001). More patients with the leucine variant (60%) were diagnosed with Sweet syndrome, compared with 11% and 14% of patients with the valine and threonine variants, respectively (P = .001).

There was no significant difference among the three genotypes in the percentage of patients diagnosed with MDS.

The follow-up period ranged from 1 to 18 years (median, 4.7 years). The median survival time from disease onset for all patients was 10 years.

Among patients with the valine variant, median survival was 9 years, which was significantly less than among patients with the other two variants (P = .01).

In univariable analysis, independent predictors of mortality were ear chondritis (hazard ratio, 0.26; P = .005), transfusion dependence, a time-dependent variable (HR, 2.59; P = .03), and the valine variant (HR, 3.5; P = .008).

The association between VEXAS genotype and phenotype could be explained by the finding that, among patients with the valine variant, there was significantly less translation of the catalytically proficient UBA1b isoform than in patients with the other two variants, Dr. Ferrada said.

Therapeutic options

Dr. Ferrada noted that to date no drugs have been shown to provide consistent therapeutic benefits for patients with VEXAS, but evidence as to the etiology of the syndrome points to possible treatment approaches.

“All of these findings I think are extremely important to help us guide management of these patients, as we know that the mutation is located in the stem cells in the bone marrow. So we suspect that doing a bone marrow transplant in these patients is going to be curative,” Dr. Ferrada said during the briefing.

Investigators are planning a phase 2 trial of allogeneic hematopoietic stem cell transplant for patients with VEXAS.

The study was supported by the National Institutes of Health. Dr. Ferrada, Dr. Sandhu, and Dr. Kim have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Among patients with the recently defined severe autoinflammatory syndrome VEXAS, those who are transfusion dependent or have a specific amino acid substitution are at highest risk for death, whereas those with ear chondritis are at significantly lower risk, a multinational team of investigators has found.

Courtesy Dr. Marcela Ferrada

Their study of mortality and predictors of survival among patients with genetically confirmed VEXAS showed that patients with a VEXAS variant resulting in an amino acid substitution of a methionine for a valine had a 3.5-fold higher risk for death, compared with patients with either a methionine-to-threonine substitution or a methionine-to-leucine swap.

Transfusion dependence was an independent predictor of mortality. Patients who became dependent on transfusions after symptom onset had a nearly threefold higher risk for death, reported Marcela A. Ferrada, MD, a clinical fellow at the National Institute of Arthritis and Musculoskeletal and Skin Diseases.

“These findings should inform risk assessment and clinical management in patients with VEXAS syndrome,” she said in an oral abstract presentation during the virtual annual meeting of the American College of Rheumatology.

“These genetic findings have proven right now to be not only diagnostic, but we have shown that they’re also prognostic, and we hope that this is going to help us identify patients who could have more aggressive treatment,” Dr. Ferrada said.

She also discussed her findings in a media briefing held 2 days prior to her plenary presentation. At that briefing, this news organization asked participating clinicians whether they had patients who they suspected may have had undiagnosed VEXAS.

“My answer to that is interesting,” replied moderator Vaneet Sandhu, MD, from Loma Linda (Calif.) University and Riverside University Health System.

“In the last couple of days, I’ve been reading about VEXAS, and actually texted one of my colleagues yesterday and said, ‘Hey, you know these patients we’ve been seeing who have these strange rashes and chondritis and have maybe a diagnosis of leukocytoclastic vasculitis or something else – are we not diagnosing these patients?’ ” she said.

“I think we are looking at every patient with chondritis and reexamining their phenotype. We had dismissed certain symptoms because they didn’t fit the archetype for relapsing polychondritis, for example, but it could be VEXAS,” said Alfred Kim, MD, PhD, of Washington University in St. Louis, who also presented data during the briefing.

Three variants

VEXAS is caused by somatic mutations in UBA1, a gene that initiates cytoplasmic ubiquitylation, a process by which misfolded proteins are tagged for degradation.

The syndrome’s name is an acronym descriptive of the major features:

• Vacuoles in bone marrow cells.
• E-1 activating enzyme that UBA1 encodes for.
• X-linked.
• Autoinflammatory.
• Somatic mutation featuring hematologic mosaicism.

VEXAS results in rheumatologic, dermatologic, and hematologic symptoms that are often misdiagnosed as being caused by treatment-refractory relapsing polychondritis, polyarteritis nodosa, Sweet syndrome, giant cell arteritis, or myelodysplastic syndrome (MDS).

VEXAS was identified as a distinct syndrome within the past year by Dr. Ferrada and other investigators at NIAMS, the National Human Genome Research Institute, and other institutions.

In the study reported at ACR 2021, Dr. Ferrada and colleagues assessed 83 men who had been referred for genetic testing for VEXAS at the National Institutes of Health, in Bethesda, Md., and at Leeds (England) Teaching Hospitals NHS Trust.

All patients were confirmed to have VEXAS-defining genetic mutations in UBA1 by Sanger sequencing of peripheral blood samples. Only those patients with mutations at codon p.Met41 were included in the investigators’ analysis. Mutations at that site account for nearly all cases of VEXAS that have been identified to date.

The most common clinical manifestation of VEXAS was skin involvement, which occurred in all but one of the 83 patients. Other common manifestations included arthritis (58 patients), pulmonary infiltrates (57 patients), and ear chondritis (54 patients).

Fifteen patients were found to have the leucine variant, 18 had the valine variant, and 50 had the threonine variant. The median age at disease onset was 66 years in the leucine and threonine variant groups and 65 in the valine variant group.

The clinical diagnosis differed according to genotype: 4 of 18 patients (22%) with the valine variant were diagnosed with relapsing polychondritis, compared with 8 of 15 (53%) with the leucine variant and 31 of 50 (62%) with the threonine variant (P = .01).

In contrast, 55% of patients with valine genotype were diagnosed with undifferentiated fever, compared with 6% of those with the leucine and 16% with the threonine genotypes (P = .001). More patients with the leucine variant (60%) were diagnosed with Sweet syndrome, compared with 11% and 14% of patients with the valine and threonine variants, respectively (P = .001).

There was no significant difference among the three genotypes in the percentage of patients diagnosed with MDS.

The follow-up period ranged from 1 to 18 years (median, 4.7 years). The median survival time from disease onset for all patients was 10 years.

Among patients with the valine variant, median survival was 9 years, which was significantly less than among patients with the other two variants (P = .01).

In univariable analysis, independent predictors of mortality were ear chondritis (hazard ratio, 0.26; P = .005), transfusion dependence, a time-dependent variable (HR, 2.59; P = .03), and the valine variant (HR, 3.5; P = .008).

The association between VEXAS genotype and phenotype could be explained by the finding that, among patients with the valine variant, there was significantly less translation of the catalytically proficient UBA1b isoform than in patients with the other two variants, Dr. Ferrada said.

Therapeutic options

Dr. Ferrada noted that to date no drugs have been shown to provide consistent therapeutic benefits for patients with VEXAS, but evidence as to the etiology of the syndrome points to possible treatment approaches.

“All of these findings I think are extremely important to help us guide management of these patients, as we know that the mutation is located in the stem cells in the bone marrow. So we suspect that doing a bone marrow transplant in these patients is going to be curative,” Dr. Ferrada said during the briefing.

Investigators are planning a phase 2 trial of allogeneic hematopoietic stem cell transplant for patients with VEXAS.

The study was supported by the National Institutes of Health. Dr. Ferrada, Dr. Sandhu, and Dr. Kim have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Among patients with the recently defined severe autoinflammatory syndrome VEXAS, those who are transfusion dependent or have a specific amino acid substitution are at highest risk for death, whereas those with ear chondritis are at significantly lower risk, a multinational team of investigators has found.

Courtesy Dr. Marcela Ferrada

Their study of mortality and predictors of survival among patients with genetically confirmed VEXAS showed that patients with a VEXAS variant resulting in an amino acid substitution of a methionine for a valine had a 3.5-fold higher risk for death, compared with patients with either a methionine-to-threonine substitution or a methionine-to-leucine swap.

Transfusion dependence was an independent predictor of mortality. Patients who became dependent on transfusions after symptom onset had a nearly threefold higher risk for death, reported Marcela A. Ferrada, MD, a clinical fellow at the National Institute of Arthritis and Musculoskeletal and Skin Diseases.

“These findings should inform risk assessment and clinical management in patients with VEXAS syndrome,” she said in an oral abstract presentation during the virtual annual meeting of the American College of Rheumatology.

“These genetic findings have proven right now to be not only diagnostic, but we have shown that they’re also prognostic, and we hope that this is going to help us identify patients who could have more aggressive treatment,” Dr. Ferrada said.

She also discussed her findings in a media briefing held 2 days prior to her plenary presentation. At that briefing, this news organization asked participating clinicians whether they had patients who they suspected may have had undiagnosed VEXAS.

“My answer to that is interesting,” replied moderator Vaneet Sandhu, MD, from Loma Linda (Calif.) University and Riverside University Health System.

“In the last couple of days, I’ve been reading about VEXAS, and actually texted one of my colleagues yesterday and said, ‘Hey, you know these patients we’ve been seeing who have these strange rashes and chondritis and have maybe a diagnosis of leukocytoclastic vasculitis or something else – are we not diagnosing these patients?’ ” she said.

“I think we are looking at every patient with chondritis and reexamining their phenotype. We had dismissed certain symptoms because they didn’t fit the archetype for relapsing polychondritis, for example, but it could be VEXAS,” said Alfred Kim, MD, PhD, of Washington University in St. Louis, who also presented data during the briefing.

Three variants

VEXAS is caused by somatic mutations in UBA1, a gene that initiates cytoplasmic ubiquitylation, a process by which misfolded proteins are tagged for degradation.

The syndrome’s name is an acronym descriptive of the major features:

• Vacuoles in bone marrow cells.
• E-1 activating enzyme that UBA1 encodes for.
• X-linked.
• Autoinflammatory.
• Somatic mutation featuring hematologic mosaicism.

VEXAS results in rheumatologic, dermatologic, and hematologic symptoms that are often misdiagnosed as being caused by treatment-refractory relapsing polychondritis, polyarteritis nodosa, Sweet syndrome, giant cell arteritis, or myelodysplastic syndrome (MDS).

VEXAS was identified as a distinct syndrome within the past year by Dr. Ferrada and other investigators at NIAMS, the National Human Genome Research Institute, and other institutions.

In the study reported at ACR 2021, Dr. Ferrada and colleagues assessed 83 men who had been referred for genetic testing for VEXAS at the National Institutes of Health, in Bethesda, Md., and at Leeds (England) Teaching Hospitals NHS Trust.

All patients were confirmed to have VEXAS-defining genetic mutations in UBA1 by Sanger sequencing of peripheral blood samples. Only those patients with mutations at codon p.Met41 were included in the investigators’ analysis. Mutations at that site account for nearly all cases of VEXAS that have been identified to date.

The most common clinical manifestation of VEXAS was skin involvement, which occurred in all but one of the 83 patients. Other common manifestations included arthritis (58 patients), pulmonary infiltrates (57 patients), and ear chondritis (54 patients).

Fifteen patients were found to have the leucine variant, 18 had the valine variant, and 50 had the threonine variant. The median age at disease onset was 66 years in the leucine and threonine variant groups and 65 in the valine variant group.

The clinical diagnosis differed according to genotype: 4 of 18 patients (22%) with the valine variant were diagnosed with relapsing polychondritis, compared with 8 of 15 (53%) with the leucine variant and 31 of 50 (62%) with the threonine variant (P = .01).

In contrast, 55% of patients with valine genotype were diagnosed with undifferentiated fever, compared with 6% of those with the leucine and 16% with the threonine genotypes (P = .001). More patients with the leucine variant (60%) were diagnosed with Sweet syndrome, compared with 11% and 14% of patients with the valine and threonine variants, respectively (P = .001).

There was no significant difference among the three genotypes in the percentage of patients diagnosed with MDS.

The follow-up period ranged from 1 to 18 years (median, 4.7 years). The median survival time from disease onset for all patients was 10 years.

Among patients with the valine variant, median survival was 9 years, which was significantly less than among patients with the other two variants (P = .01).

In univariable analysis, independent predictors of mortality were ear chondritis (hazard ratio, 0.26; P = .005), transfusion dependence, a time-dependent variable (HR, 2.59; P = .03), and the valine variant (HR, 3.5; P = .008).

The association between VEXAS genotype and phenotype could be explained by the finding that, among patients with the valine variant, there was significantly less translation of the catalytically proficient UBA1b isoform than in patients with the other two variants, Dr. Ferrada said.

Therapeutic options

Dr. Ferrada noted that to date no drugs have been shown to provide consistent therapeutic benefits for patients with VEXAS, but evidence as to the etiology of the syndrome points to possible treatment approaches.

“All of these findings I think are extremely important to help us guide management of these patients, as we know that the mutation is located in the stem cells in the bone marrow. So we suspect that doing a bone marrow transplant in these patients is going to be curative,” Dr. Ferrada said during the briefing.

Investigators are planning a phase 2 trial of allogeneic hematopoietic stem cell transplant for patients with VEXAS.

The study was supported by the National Institutes of Health. Dr. Ferrada, Dr. Sandhu, and Dr. Kim have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Continuation of hydroxychloroquine (HCQ) when a patient’s systemic lupus erythematosus (SLE) is in remission or has very low disease activity is linked to a lower risk of flares than is reducing or stopping the antimalarial drug, according to new research presented at the virtual annual meeting of the American College of Rheumatology.

Marc Bruxelle/Getty Images

“Though HCQ is a cornerstone SLE drug, physicians and patients often consider lowering or stopping the drug during remission or low disease activity in order to limit long-term toxicity,” Sasha Bernatsky, MD, PhD, a professor of rheumatology at McGill University in Montreal, told attendees. Her group’s findings revealed a 20% increased risk of flares in those who reduced their HCQ dose and a 56% greater risk of flares in those who discontinued HCQ, compared with those who continued on a maintenance dose.

“I’m going to be using these results in discussions with my patients regarding what the potential implications are of lowering or stopping hydroxychloroquine,” Dr. Bernatsky told attendees. “I think, in the end, this information should be in their hands so that they can be the ones to make these decisions with us, and, of course, given the significant flare rates even in remission, we need to keep on working on optimizing lupus treatments.”
 

Study details

The researchers analyzed prospective data from 1,460 patients enrolled in the Systemic Lupus Erythematosus International Collaborating Clinics (SLICC) cohort, which includes 33 sites across Europe, Asia, and North America. Patients in this cohort undergo annual follow-ups after enrollment within 15 months of their diagnosis. The study population was 89% female and 52% white. All participants either had low disease activity, defined as a score of 4 or lower on the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) and/or as a prednisone dose no greater than 7.5 mg/day, or were in complete remission, defined as a 0 on SLEDAI-2K while receiving no therapy, including no prednisone or immunosuppressives in the past year.

In addition to adjusting for sex, race/ethnicity, age, education, and geographic residence, the researchers took into account baseline SLE duration, renal damage, body mass index, smoking status, and use of prednisone, immunosuppressives, and biologics. For the outcome of time to first flare, the researchers analyzed those who discontinued HCQ separately from those who reduced the dose, comparing each to those who continued HCQ maintenance therapy. The researchers defined first flare as either hospitalization because of SLE, increased disease activity (at least 4 points on the SLEDAI-2K), or therapy augmentation with steroids, immunosuppressives, antimalarials, or biologics.

Within each cohort, patients who reduced or stopped HCQ therapy were matched to patients who continued HCQ maintenance therapy based on duration of HCQ since time zero, the point at which participants were considered at risk for SLE flares. In the reduction cohort, time zero was the date of a participant’s first HCQ reduction; in the discontinuation cohort, time zero was the date a participant stopped the therapy. Because of the study’s design and reliance on person-years of exposure, it was possible for a single participant to contribute data to more than one cohort.
 

Results

The overall cohort examining reduction of HCQ dose included 564 patients who reduced their dose, contributing 1,063 person-years of data, and 778 matched patients who started HCQ at the same time but continued HCQ maintenance therapy without a dose reduction, contributing 1,242 person-years. The average duration of HCQ use since time zero in this cohort was 3.4 years.

Before stratifying for disease activity, the group who reduced their therapy experienced 40 first flares per 100 person-years, compared with 31.9 first flares per 100 person-years on maintenance therapy. Those who reduced HCQ had a 20% greater risk of flares than did those who continued it (adjusted hazard ratio, 1.2). However, when those in remission were compared with those not in remission – independent of disease activity level – patients in remission were twice as likely to experience a flare if they reduced their HCQ dose (aHR, 2.14).

In the discontinuation cohort, 389 patients who stopped HCQ therapy contributed 657 person-years, and 577 matched patients who continued HCQ maintenance therapy contributed 924 person-years. The average duration of HCQ use since time zero in this cohort was 4.2 years. Before stratifying for disease activity, the average number of first flares per 100 person-years was 41.3 in the HCQ discontinuation group and 30 in the HCQ maintenance group, resulting in a 56% higher risk of flares for those who stopped HCQ, compared with patients who continued HCQ (aHR, 1.56). Looking only at those in remission, patients were nearly three times more likely to experience a flare if they stopped HCQ than were patients not in remission who continued a maintenance dose (aHR, 2.77).
 

Patient age is an important consideration

Overall, these findings are not surprising, said Jill P. Buyon, MD, director of the division of rheumatology and of the Lupus Center at NYU-Langone Health in New York. Dr. Buyon is not involved in the current study but is studying discontinuation of HCQ in older adults with lupus.

“It has been already shown that when lupus patients discontinue HCQ, flares are more likely, but does this apply to all age groups?” Dr. Buyon asked in an interview. “Data are essential to more accurately weigh the balance between accumulating ocular exposure, the explosion of new tools to assess retinal injury, and the risk of disease flare in a population that may have more stable/quiescent disease than younger patients.”

Although HCQ’s track record with infection risk is consistently better than that of more immunosuppressive drugs and is very safe during pregnancy, Dr. Buyon said her “ophthalmology colleagues persistently emphasize the risk of retinal accumulation of drug and ocular toxicity over time.” She referenced a recent case-control study in which overall prevalence of HCQ retinopathy was 7.5%, and greater for patients taking more than 5 mg/kg of HCQ or who used HCQ for more than 10 years.

”Risk escalates with continued use, and evaluation by sensitive approaches such as multifocal electroretinography suggests nearly a third of patients accrue retinal damage,” Dr. Buyon said. “As the longevity of patients improves and comorbidities such as renal insufficiency (which affects HCQ clearance) may increase, the ratio of efficacy to toxicity would be expected to decrease.” Further, the fact that disease activity may wane as people age means that rheumatologists treating older adults need to address a critical question, she said: “Can HCQ be safely withdrawn? This question is important in the context of an even broader concern regarding management of SLE in the elderly population, a topic which has received minimal attention.”

The study is limited by its observational design and the fact that the intervention was not randomly allocated, although the researchers attempted to adjust for confounders. Dr. Bernatsky also noted that mild flares might have been missed, and the researchers did not evaluate HCQ levels or adherence, nor did the data set include physicians’ or patients’ explicitly stated reasons for HCQ reduction or discontinuation.

”We estimated that 5% of patients may have reduced HCQ therapy as result of the AAO [American Academy of Ophthalmology] guidelines, 55% because of low disease activity state, and the remainder (40%) for other reasons, possibly intolerance or patient preference,” the researchers noted in their abstract. “Among those who discontinued HCQ, 4% had retinal changes of concern, 15% were in clinical remission, and the remainder stopped for unknown reasons, possibly intolerance or patient preference.”

Dr. Buyon also pointed out that the cohort was initially intended for studying cardiovascular risk and not designed to capture all visits during each year of follow-up.

“Thus, while hospitalizations would be well captured, not all flares, particularly those not severe, would be captured, and thus we may not have the complete picture,” she said, reiterating Dr. Bernatsky’s point that mild flares may have been missed.

”Clearly, this is a very important topic for the management of our patients, particularly those who are elderly and may have already reaped the benefits of hydroxychloroquine,” Dr. Buyon said. “Of course, we have to be mindful of the potential benefit with regard to blood clotting and lipid lowering. Nevertheless, accumulated ocular toxicity and cardiac issues such as cardiomyopathy may emerge to tip the balance after years of accumulated drug exposure.”

The research was funded by the Canadian Institute of Health Research, the Singer Family Fund for Lupus Research, and the SLICC Group. Dr. Bernatsky had no disclosures. Dr. Buyon noted that she has an R34 NIH planning grant to study the safety of withdrawal of hydroxychloroquine in elderly lupus patients that is relevant to this study.

Continuation of hydroxychloroquine (HCQ) when a patient’s systemic lupus erythematosus (SLE) is in remission or has very low disease activity is linked to a lower risk of flares than is reducing or stopping the antimalarial drug, according to new research presented at the virtual annual meeting of the American College of Rheumatology.

Marc Bruxelle/Getty Images

“Though HCQ is a cornerstone SLE drug, physicians and patients often consider lowering or stopping the drug during remission or low disease activity in order to limit long-term toxicity,” Sasha Bernatsky, MD, PhD, a professor of rheumatology at McGill University in Montreal, told attendees. Her group’s findings revealed a 20% increased risk of flares in those who reduced their HCQ dose and a 56% greater risk of flares in those who discontinued HCQ, compared with those who continued on a maintenance dose.

“I’m going to be using these results in discussions with my patients regarding what the potential implications are of lowering or stopping hydroxychloroquine,” Dr. Bernatsky told attendees. “I think, in the end, this information should be in their hands so that they can be the ones to make these decisions with us, and, of course, given the significant flare rates even in remission, we need to keep on working on optimizing lupus treatments.”
 

Study details

The researchers analyzed prospective data from 1,460 patients enrolled in the Systemic Lupus Erythematosus International Collaborating Clinics (SLICC) cohort, which includes 33 sites across Europe, Asia, and North America. Patients in this cohort undergo annual follow-ups after enrollment within 15 months of their diagnosis. The study population was 89% female and 52% white. All participants either had low disease activity, defined as a score of 4 or lower on the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) and/or as a prednisone dose no greater than 7.5 mg/day, or were in complete remission, defined as a 0 on SLEDAI-2K while receiving no therapy, including no prednisone or immunosuppressives in the past year.

In addition to adjusting for sex, race/ethnicity, age, education, and geographic residence, the researchers took into account baseline SLE duration, renal damage, body mass index, smoking status, and use of prednisone, immunosuppressives, and biologics. For the outcome of time to first flare, the researchers analyzed those who discontinued HCQ separately from those who reduced the dose, comparing each to those who continued HCQ maintenance therapy. The researchers defined first flare as either hospitalization because of SLE, increased disease activity (at least 4 points on the SLEDAI-2K), or therapy augmentation with steroids, immunosuppressives, antimalarials, or biologics.

Within each cohort, patients who reduced or stopped HCQ therapy were matched to patients who continued HCQ maintenance therapy based on duration of HCQ since time zero, the point at which participants were considered at risk for SLE flares. In the reduction cohort, time zero was the date of a participant’s first HCQ reduction; in the discontinuation cohort, time zero was the date a participant stopped the therapy. Because of the study’s design and reliance on person-years of exposure, it was possible for a single participant to contribute data to more than one cohort.
 

Results

The overall cohort examining reduction of HCQ dose included 564 patients who reduced their dose, contributing 1,063 person-years of data, and 778 matched patients who started HCQ at the same time but continued HCQ maintenance therapy without a dose reduction, contributing 1,242 person-years. The average duration of HCQ use since time zero in this cohort was 3.4 years.

Before stratifying for disease activity, the group who reduced their therapy experienced 40 first flares per 100 person-years, compared with 31.9 first flares per 100 person-years on maintenance therapy. Those who reduced HCQ had a 20% greater risk of flares than did those who continued it (adjusted hazard ratio, 1.2). However, when those in remission were compared with those not in remission – independent of disease activity level – patients in remission were twice as likely to experience a flare if they reduced their HCQ dose (aHR, 2.14).

In the discontinuation cohort, 389 patients who stopped HCQ therapy contributed 657 person-years, and 577 matched patients who continued HCQ maintenance therapy contributed 924 person-years. The average duration of HCQ use since time zero in this cohort was 4.2 years. Before stratifying for disease activity, the average number of first flares per 100 person-years was 41.3 in the HCQ discontinuation group and 30 in the HCQ maintenance group, resulting in a 56% higher risk of flares for those who stopped HCQ, compared with patients who continued HCQ (aHR, 1.56). Looking only at those in remission, patients were nearly three times more likely to experience a flare if they stopped HCQ than were patients not in remission who continued a maintenance dose (aHR, 2.77).
 

Patient age is an important consideration

Overall, these findings are not surprising, said Jill P. Buyon, MD, director of the division of rheumatology and of the Lupus Center at NYU-Langone Health in New York. Dr. Buyon is not involved in the current study but is studying discontinuation of HCQ in older adults with lupus.

“It has been already shown that when lupus patients discontinue HCQ, flares are more likely, but does this apply to all age groups?” Dr. Buyon asked in an interview. “Data are essential to more accurately weigh the balance between accumulating ocular exposure, the explosion of new tools to assess retinal injury, and the risk of disease flare in a population that may have more stable/quiescent disease than younger patients.”

Although HCQ’s track record with infection risk is consistently better than that of more immunosuppressive drugs and is very safe during pregnancy, Dr. Buyon said her “ophthalmology colleagues persistently emphasize the risk of retinal accumulation of drug and ocular toxicity over time.” She referenced a recent case-control study in which overall prevalence of HCQ retinopathy was 7.5%, and greater for patients taking more than 5 mg/kg of HCQ or who used HCQ for more than 10 years.

”Risk escalates with continued use, and evaluation by sensitive approaches such as multifocal electroretinography suggests nearly a third of patients accrue retinal damage,” Dr. Buyon said. “As the longevity of patients improves and comorbidities such as renal insufficiency (which affects HCQ clearance) may increase, the ratio of efficacy to toxicity would be expected to decrease.” Further, the fact that disease activity may wane as people age means that rheumatologists treating older adults need to address a critical question, she said: “Can HCQ be safely withdrawn? This question is important in the context of an even broader concern regarding management of SLE in the elderly population, a topic which has received minimal attention.”

The study is limited by its observational design and the fact that the intervention was not randomly allocated, although the researchers attempted to adjust for confounders. Dr. Bernatsky also noted that mild flares might have been missed, and the researchers did not evaluate HCQ levels or adherence, nor did the data set include physicians’ or patients’ explicitly stated reasons for HCQ reduction or discontinuation.

”We estimated that 5% of patients may have reduced HCQ therapy as result of the AAO [American Academy of Ophthalmology] guidelines, 55% because of low disease activity state, and the remainder (40%) for other reasons, possibly intolerance or patient preference,” the researchers noted in their abstract. “Among those who discontinued HCQ, 4% had retinal changes of concern, 15% were in clinical remission, and the remainder stopped for unknown reasons, possibly intolerance or patient preference.”

Dr. Buyon also pointed out that the cohort was initially intended for studying cardiovascular risk and not designed to capture all visits during each year of follow-up.

“Thus, while hospitalizations would be well captured, not all flares, particularly those not severe, would be captured, and thus we may not have the complete picture,” she said, reiterating Dr. Bernatsky’s point that mild flares may have been missed.

”Clearly, this is a very important topic for the management of our patients, particularly those who are elderly and may have already reaped the benefits of hydroxychloroquine,” Dr. Buyon said. “Of course, we have to be mindful of the potential benefit with regard to blood clotting and lipid lowering. Nevertheless, accumulated ocular toxicity and cardiac issues such as cardiomyopathy may emerge to tip the balance after years of accumulated drug exposure.”

The research was funded by the Canadian Institute of Health Research, the Singer Family Fund for Lupus Research, and the SLICC Group. Dr. Bernatsky had no disclosures. Dr. Buyon noted that she has an R34 NIH planning grant to study the safety of withdrawal of hydroxychloroquine in elderly lupus patients that is relevant to this study.

Continuation of hydroxychloroquine (HCQ) when a patient’s systemic lupus erythematosus (SLE) is in remission or has very low disease activity is linked to a lower risk of flares than is reducing or stopping the antimalarial drug, according to new research presented at the virtual annual meeting of the American College of Rheumatology.

Marc Bruxelle/Getty Images

“Though HCQ is a cornerstone SLE drug, physicians and patients often consider lowering or stopping the drug during remission or low disease activity in order to limit long-term toxicity,” Sasha Bernatsky, MD, PhD, a professor of rheumatology at McGill University in Montreal, told attendees. Her group’s findings revealed a 20% increased risk of flares in those who reduced their HCQ dose and a 56% greater risk of flares in those who discontinued HCQ, compared with those who continued on a maintenance dose.

“I’m going to be using these results in discussions with my patients regarding what the potential implications are of lowering or stopping hydroxychloroquine,” Dr. Bernatsky told attendees. “I think, in the end, this information should be in their hands so that they can be the ones to make these decisions with us, and, of course, given the significant flare rates even in remission, we need to keep on working on optimizing lupus treatments.”
 

Study details

The researchers analyzed prospective data from 1,460 patients enrolled in the Systemic Lupus Erythematosus International Collaborating Clinics (SLICC) cohort, which includes 33 sites across Europe, Asia, and North America. Patients in this cohort undergo annual follow-ups after enrollment within 15 months of their diagnosis. The study population was 89% female and 52% white. All participants either had low disease activity, defined as a score of 4 or lower on the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) and/or as a prednisone dose no greater than 7.5 mg/day, or were in complete remission, defined as a 0 on SLEDAI-2K while receiving no therapy, including no prednisone or immunosuppressives in the past year.

In addition to adjusting for sex, race/ethnicity, age, education, and geographic residence, the researchers took into account baseline SLE duration, renal damage, body mass index, smoking status, and use of prednisone, immunosuppressives, and biologics. For the outcome of time to first flare, the researchers analyzed those who discontinued HCQ separately from those who reduced the dose, comparing each to those who continued HCQ maintenance therapy. The researchers defined first flare as either hospitalization because of SLE, increased disease activity (at least 4 points on the SLEDAI-2K), or therapy augmentation with steroids, immunosuppressives, antimalarials, or biologics.

Within each cohort, patients who reduced or stopped HCQ therapy were matched to patients who continued HCQ maintenance therapy based on duration of HCQ since time zero, the point at which participants were considered at risk for SLE flares. In the reduction cohort, time zero was the date of a participant’s first HCQ reduction; in the discontinuation cohort, time zero was the date a participant stopped the therapy. Because of the study’s design and reliance on person-years of exposure, it was possible for a single participant to contribute data to more than one cohort.
 

Results

The overall cohort examining reduction of HCQ dose included 564 patients who reduced their dose, contributing 1,063 person-years of data, and 778 matched patients who started HCQ at the same time but continued HCQ maintenance therapy without a dose reduction, contributing 1,242 person-years. The average duration of HCQ use since time zero in this cohort was 3.4 years.

Before stratifying for disease activity, the group who reduced their therapy experienced 40 first flares per 100 person-years, compared with 31.9 first flares per 100 person-years on maintenance therapy. Those who reduced HCQ had a 20% greater risk of flares than did those who continued it (adjusted hazard ratio, 1.2). However, when those in remission were compared with those not in remission – independent of disease activity level – patients in remission were twice as likely to experience a flare if they reduced their HCQ dose (aHR, 2.14).

In the discontinuation cohort, 389 patients who stopped HCQ therapy contributed 657 person-years, and 577 matched patients who continued HCQ maintenance therapy contributed 924 person-years. The average duration of HCQ use since time zero in this cohort was 4.2 years. Before stratifying for disease activity, the average number of first flares per 100 person-years was 41.3 in the HCQ discontinuation group and 30 in the HCQ maintenance group, resulting in a 56% higher risk of flares for those who stopped HCQ, compared with patients who continued HCQ (aHR, 1.56). Looking only at those in remission, patients were nearly three times more likely to experience a flare if they stopped HCQ than were patients not in remission who continued a maintenance dose (aHR, 2.77).
 

Patient age is an important consideration

Overall, these findings are not surprising, said Jill P. Buyon, MD, director of the division of rheumatology and of the Lupus Center at NYU-Langone Health in New York. Dr. Buyon is not involved in the current study but is studying discontinuation of HCQ in older adults with lupus.

“It has been already shown that when lupus patients discontinue HCQ, flares are more likely, but does this apply to all age groups?” Dr. Buyon asked in an interview. “Data are essential to more accurately weigh the balance between accumulating ocular exposure, the explosion of new tools to assess retinal injury, and the risk of disease flare in a population that may have more stable/quiescent disease than younger patients.”

Although HCQ’s track record with infection risk is consistently better than that of more immunosuppressive drugs and is very safe during pregnancy, Dr. Buyon said her “ophthalmology colleagues persistently emphasize the risk of retinal accumulation of drug and ocular toxicity over time.” She referenced a recent case-control study in which overall prevalence of HCQ retinopathy was 7.5%, and greater for patients taking more than 5 mg/kg of HCQ or who used HCQ for more than 10 years.

”Risk escalates with continued use, and evaluation by sensitive approaches such as multifocal electroretinography suggests nearly a third of patients accrue retinal damage,” Dr. Buyon said. “As the longevity of patients improves and comorbidities such as renal insufficiency (which affects HCQ clearance) may increase, the ratio of efficacy to toxicity would be expected to decrease.” Further, the fact that disease activity may wane as people age means that rheumatologists treating older adults need to address a critical question, she said: “Can HCQ be safely withdrawn? This question is important in the context of an even broader concern regarding management of SLE in the elderly population, a topic which has received minimal attention.”

The study is limited by its observational design and the fact that the intervention was not randomly allocated, although the researchers attempted to adjust for confounders. Dr. Bernatsky also noted that mild flares might have been missed, and the researchers did not evaluate HCQ levels or adherence, nor did the data set include physicians’ or patients’ explicitly stated reasons for HCQ reduction or discontinuation.

”We estimated that 5% of patients may have reduced HCQ therapy as result of the AAO [American Academy of Ophthalmology] guidelines, 55% because of low disease activity state, and the remainder (40%) for other reasons, possibly intolerance or patient preference,” the researchers noted in their abstract. “Among those who discontinued HCQ, 4% had retinal changes of concern, 15% were in clinical remission, and the remainder stopped for unknown reasons, possibly intolerance or patient preference.”

Dr. Buyon also pointed out that the cohort was initially intended for studying cardiovascular risk and not designed to capture all visits during each year of follow-up.

“Thus, while hospitalizations would be well captured, not all flares, particularly those not severe, would be captured, and thus we may not have the complete picture,” she said, reiterating Dr. Bernatsky’s point that mild flares may have been missed.

”Clearly, this is a very important topic for the management of our patients, particularly those who are elderly and may have already reaped the benefits of hydroxychloroquine,” Dr. Buyon said. “Of course, we have to be mindful of the potential benefit with regard to blood clotting and lipid lowering. Nevertheless, accumulated ocular toxicity and cardiac issues such as cardiomyopathy may emerge to tip the balance after years of accumulated drug exposure.”

The research was funded by the Canadian Institute of Health Research, the Singer Family Fund for Lupus Research, and the SLICC Group. Dr. Bernatsky had no disclosures. Dr. Buyon noted that she has an R34 NIH planning grant to study the safety of withdrawal of hydroxychloroquine in elderly lupus patients that is relevant to this study.

Rituximab effectively reduced skin sclerosis and appeared to have a beneficial effect on interstitial lung disease (ILD) for patients with systemic sclerosis (SSc) in a randomized, clinical trial.

Courtesy Charlotte E. LaSenna and Dr. Andrea Maderal, University of Miami

At 24 weeks’ follow-up, there was significant improvement in total skin thickness scores among patients who received four once-weekly rituximab infusions, compared with patients who received placebo infusions. Among patients who received rituximab, there were also small but significant improvements in percentage of forced vital capacity (FVC). Among patients who received placebo, FVC worsened, reported Ayumi Yoshizaki, MD, of the University of Tokyo and colleagues.

“Systemic sclerosis is considered to have high unmet medical needs because of its poor prognosis and the lack of satisfactory and effective treatments,” he said at the virtual annual meeting of the American College of Rheumatology.

“Several clinical studies have suggested that B-cell depletion therapy with rituximab anti-CD20 antibody is effective in treating skin and lung fibrosis of SSc. However, no randomized, placebo-controlled trial has been able to confirm the efficacy of rituximab in SSc,” Dr. Yoshizaki said.

A rheumatologist who is currently conducting an investigator-initiated trial in which patients with SSC are undergoing treatment with rituximab followed by belimumab (Benlysta) said in an interview that he found the data to be “super interesting.”

“There are a lot of reasons to think that B cells might be important in systemic sclerosis, and actually that’s why our group had previously done an investigator-initiated trial with belimumab years ago,” said Robert Spiera, MD, director of the Scleroderma, Vasculitis, and Myositis Center at the Hospital for Special Surgery in New York.

Randomized trial

Dr. Yoshizaki and colleagues conducted the randomized, placebo-controlled DESIRES trial in four hospitals in Japan to evaluate the safety and efficacy of rituximab for the treatment of SSc.

In the investigator-initiated trial, patients aged 20-79 years who fulfilled ACR and European Alliance of Associations for Rheumatology classification criteria for systemic sclerosis and who had a modified Rodnan Skin Score (mRSS) of 10 or more and a life expectancy of at least 6 months were randomly assigned to receive infusions with either rituximab 375 mg/m² or placebo once weekly for 4 weeks. Patients and clinicians were masked to treatment allocation.

The trial included 56 patients (51 women, 5 men). Of all patients enrolled, 27 of 28 who were allocated to receive rituximab and 22 of 28 who were allocated to receive placebo underwent at least one infusion and completed 24 weeks of follow-up.

The absolute change in mRSS at 24 weeks after the start of therapy, the primary endpoint, was –6.30 in the rituximab group, compared with +2.14 in the placebo group, a difference of –8.44 (P < .0001).

In a subgroup analysis, rituximab was superior to placebo regardless of disease duration, disease type (diffuse cutaneous or limited cutaneous SSc), prior receipt of systemic corticosteroids or immunosuppressants, or having C-reactive protein levels less than 0.3 mg/dL or at least 0.3 mg/dL.

However, there was no significant benefit with rituximab for patients with baseline mRSS of at least 20 or for those without ILD at baseline.

There was also evidence that rituximab reduced lung fibrosis. For patients assigned to the active drug, the absolute change in FVC at 24 weeks was +0.09% of the predicted value, compared with –3.56% for patients who received placebo (P = .044).

The researchers also observed radiographic evidence of lung improvement. The absolute change in the percentage of lung field occupied with interstitial shadows was –0.32% in the rituximab arm versus +2.39% in the placebo arm (P = .034). There was no significant between-group difference in the absolute change in diffusing capacity of lung for carbon monoxide, however.

Adverse events that occurred more frequently with rituximab included oral mucositis, diarrhea, and decreased neutrophil and white blood cell counts.

Convincing results

“What I thought the Japanese study did was to give a much more convincing proof of concept than has been out there,” Dr. Spiera said in an interview.

“There have been some preliminary experiences that have been encouraging with rituximab in scleroderma, most of which has been open label,” he said.

He also referred to a retrospective study by EUSTAR, the European Scleroderma Trials and Research group, which indicated that patients who had previously received rituximab seemed to have had better outcomes than patients who had been treated with other therapies.

Dr. Spiera added that, although he was glad to see the data from a randomized, placebo-controlled trial in this population, he was uncomfortable with the idea of leaving patients untreated for 6 months.

“From the standpoint of somebody wanting to know what strategies might be promising, this is great for us, but I would not have designed the trial that way,” he said.

The study results were previously published in the Lancet Rheumatology.

The study was supported by grants from the Japan Agency for Medical Research and Development and Zenyaku Kogyo. Dr. Yoshizaki disclosed no relevant financial relationships. Dr. Spiera has received grant/research support from and has consulted for Roche/Genentech, maker of rituximab, and has received compensation from other companies.

A version of this article first appeared on Medscape.com.

Rituximab effectively reduced skin sclerosis and appeared to have a beneficial effect on interstitial lung disease (ILD) for patients with systemic sclerosis (SSc) in a randomized, clinical trial.

Courtesy Charlotte E. LaSenna and Dr. Andrea Maderal, University of Miami

At 24 weeks’ follow-up, there was significant improvement in total skin thickness scores among patients who received four once-weekly rituximab infusions, compared with patients who received placebo infusions. Among patients who received rituximab, there were also small but significant improvements in percentage of forced vital capacity (FVC). Among patients who received placebo, FVC worsened, reported Ayumi Yoshizaki, MD, of the University of Tokyo and colleagues.

“Systemic sclerosis is considered to have high unmet medical needs because of its poor prognosis and the lack of satisfactory and effective treatments,” he said at the virtual annual meeting of the American College of Rheumatology.

“Several clinical studies have suggested that B-cell depletion therapy with rituximab anti-CD20 antibody is effective in treating skin and lung fibrosis of SSc. However, no randomized, placebo-controlled trial has been able to confirm the efficacy of rituximab in SSc,” Dr. Yoshizaki said.

A rheumatologist who is currently conducting an investigator-initiated trial in which patients with SSC are undergoing treatment with rituximab followed by belimumab (Benlysta) said in an interview that he found the data to be “super interesting.”

“There are a lot of reasons to think that B cells might be important in systemic sclerosis, and actually that’s why our group had previously done an investigator-initiated trial with belimumab years ago,” said Robert Spiera, MD, director of the Scleroderma, Vasculitis, and Myositis Center at the Hospital for Special Surgery in New York.

Randomized trial

Dr. Yoshizaki and colleagues conducted the randomized, placebo-controlled DESIRES trial in four hospitals in Japan to evaluate the safety and efficacy of rituximab for the treatment of SSc.

In the investigator-initiated trial, patients aged 20-79 years who fulfilled ACR and European Alliance of Associations for Rheumatology classification criteria for systemic sclerosis and who had a modified Rodnan Skin Score (mRSS) of 10 or more and a life expectancy of at least 6 months were randomly assigned to receive infusions with either rituximab 375 mg/m² or placebo once weekly for 4 weeks. Patients and clinicians were masked to treatment allocation.

The trial included 56 patients (51 women, 5 men). Of all patients enrolled, 27 of 28 who were allocated to receive rituximab and 22 of 28 who were allocated to receive placebo underwent at least one infusion and completed 24 weeks of follow-up.

The absolute change in mRSS at 24 weeks after the start of therapy, the primary endpoint, was –6.30 in the rituximab group, compared with +2.14 in the placebo group, a difference of –8.44 (P < .0001).

In a subgroup analysis, rituximab was superior to placebo regardless of disease duration, disease type (diffuse cutaneous or limited cutaneous SSc), prior receipt of systemic corticosteroids or immunosuppressants, or having C-reactive protein levels less than 0.3 mg/dL or at least 0.3 mg/dL.

However, there was no significant benefit with rituximab for patients with baseline mRSS of at least 20 or for those without ILD at baseline.

There was also evidence that rituximab reduced lung fibrosis. For patients assigned to the active drug, the absolute change in FVC at 24 weeks was +0.09% of the predicted value, compared with –3.56% for patients who received placebo (P = .044).

The researchers also observed radiographic evidence of lung improvement. The absolute change in the percentage of lung field occupied with interstitial shadows was –0.32% in the rituximab arm versus +2.39% in the placebo arm (P = .034). There was no significant between-group difference in the absolute change in diffusing capacity of lung for carbon monoxide, however.

Adverse events that occurred more frequently with rituximab included oral mucositis, diarrhea, and decreased neutrophil and white blood cell counts.

Convincing results

“What I thought the Japanese study did was to give a much more convincing proof of concept than has been out there,” Dr. Spiera said in an interview.

“There have been some preliminary experiences that have been encouraging with rituximab in scleroderma, most of which has been open label,” he said.

He also referred to a retrospective study by EUSTAR, the European Scleroderma Trials and Research group, which indicated that patients who had previously received rituximab seemed to have had better outcomes than patients who had been treated with other therapies.

Dr. Spiera added that, although he was glad to see the data from a randomized, placebo-controlled trial in this population, he was uncomfortable with the idea of leaving patients untreated for 6 months.

“From the standpoint of somebody wanting to know what strategies might be promising, this is great for us, but I would not have designed the trial that way,” he said.

The study results were previously published in the Lancet Rheumatology.

The study was supported by grants from the Japan Agency for Medical Research and Development and Zenyaku Kogyo. Dr. Yoshizaki disclosed no relevant financial relationships. Dr. Spiera has received grant/research support from and has consulted for Roche/Genentech, maker of rituximab, and has received compensation from other companies.

A version of this article first appeared on Medscape.com.

Rituximab effectively reduced skin sclerosis and appeared to have a beneficial effect on interstitial lung disease (ILD) for patients with systemic sclerosis (SSc) in a randomized, clinical trial.

Courtesy Charlotte E. LaSenna and Dr. Andrea Maderal, University of Miami

At 24 weeks’ follow-up, there was significant improvement in total skin thickness scores among patients who received four once-weekly rituximab infusions, compared with patients who received placebo infusions. Among patients who received rituximab, there were also small but significant improvements in percentage of forced vital capacity (FVC). Among patients who received placebo, FVC worsened, reported Ayumi Yoshizaki, MD, of the University of Tokyo and colleagues.

“Systemic sclerosis is considered to have high unmet medical needs because of its poor prognosis and the lack of satisfactory and effective treatments,” he said at the virtual annual meeting of the American College of Rheumatology.

“Several clinical studies have suggested that B-cell depletion therapy with rituximab anti-CD20 antibody is effective in treating skin and lung fibrosis of SSc. However, no randomized, placebo-controlled trial has been able to confirm the efficacy of rituximab in SSc,” Dr. Yoshizaki said.

A rheumatologist who is currently conducting an investigator-initiated trial in which patients with SSC are undergoing treatment with rituximab followed by belimumab (Benlysta) said in an interview that he found the data to be “super interesting.”

“There are a lot of reasons to think that B cells might be important in systemic sclerosis, and actually that’s why our group had previously done an investigator-initiated trial with belimumab years ago,” said Robert Spiera, MD, director of the Scleroderma, Vasculitis, and Myositis Center at the Hospital for Special Surgery in New York.

Randomized trial

Dr. Yoshizaki and colleagues conducted the randomized, placebo-controlled DESIRES trial in four hospitals in Japan to evaluate the safety and efficacy of rituximab for the treatment of SSc.

In the investigator-initiated trial, patients aged 20-79 years who fulfilled ACR and European Alliance of Associations for Rheumatology classification criteria for systemic sclerosis and who had a modified Rodnan Skin Score (mRSS) of 10 or more and a life expectancy of at least 6 months were randomly assigned to receive infusions with either rituximab 375 mg/m² or placebo once weekly for 4 weeks. Patients and clinicians were masked to treatment allocation.

The trial included 56 patients (51 women, 5 men). Of all patients enrolled, 27 of 28 who were allocated to receive rituximab and 22 of 28 who were allocated to receive placebo underwent at least one infusion and completed 24 weeks of follow-up.

The absolute change in mRSS at 24 weeks after the start of therapy, the primary endpoint, was –6.30 in the rituximab group, compared with +2.14 in the placebo group, a difference of –8.44 (P < .0001).

In a subgroup analysis, rituximab was superior to placebo regardless of disease duration, disease type (diffuse cutaneous or limited cutaneous SSc), prior receipt of systemic corticosteroids or immunosuppressants, or having C-reactive protein levels less than 0.3 mg/dL or at least 0.3 mg/dL.

However, there was no significant benefit with rituximab for patients with baseline mRSS of at least 20 or for those without ILD at baseline.

There was also evidence that rituximab reduced lung fibrosis. For patients assigned to the active drug, the absolute change in FVC at 24 weeks was +0.09% of the predicted value, compared with –3.56% for patients who received placebo (P = .044).

The researchers also observed radiographic evidence of lung improvement. The absolute change in the percentage of lung field occupied with interstitial shadows was –0.32% in the rituximab arm versus +2.39% in the placebo arm (P = .034). There was no significant between-group difference in the absolute change in diffusing capacity of lung for carbon monoxide, however.

Adverse events that occurred more frequently with rituximab included oral mucositis, diarrhea, and decreased neutrophil and white blood cell counts.

Convincing results

“What I thought the Japanese study did was to give a much more convincing proof of concept than has been out there,” Dr. Spiera said in an interview.

“There have been some preliminary experiences that have been encouraging with rituximab in scleroderma, most of which has been open label,” he said.

He also referred to a retrospective study by EUSTAR, the European Scleroderma Trials and Research group, which indicated that patients who had previously received rituximab seemed to have had better outcomes than patients who had been treated with other therapies.

Dr. Spiera added that, although he was glad to see the data from a randomized, placebo-controlled trial in this population, he was uncomfortable with the idea of leaving patients untreated for 6 months.

“From the standpoint of somebody wanting to know what strategies might be promising, this is great for us, but I would not have designed the trial that way,” he said.

The study results were previously published in the Lancet Rheumatology.

The study was supported by grants from the Japan Agency for Medical Research and Development and Zenyaku Kogyo. Dr. Yoshizaki disclosed no relevant financial relationships. Dr. Spiera has received grant/research support from and has consulted for Roche/Genentech, maker of rituximab, and has received compensation from other companies.

A version of this article first appeared on Medscape.com.

Patients with psoriatic arthritis (PsA) showed more improvement in symptoms at 6 months with risankizumab (Skyrizi) than with placebo in combined phase 3, randomized, controlled trials, according to data presented at the virtual annual meeting of the American College of Rheumatology.

“Risankizumab was well tolerated and showed no new safety signals over those seen in the trial program for psoriasis,” reported Andrew Östör, MD, of Monash University and Cabrini Hospital, both in Melbourne. The results included pooled data that added KEEPsAKE 1 data to KEEPsAKE 2 results, which were presented at the 2021 congress of the European Alliance of Associations for Rheumatology.

Risankizumab received Food and Drug Administration approval in 2019 for moderate to severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy. The humanized monoclonal antibody inhibits interleukin-23, which is believed to be involved in the development of PsA. The FDA updated its approval in August 2021 to make it available as a 150-mg single-dose injection instead of two 75-mg doses for psoriasis treatment, but it is not yet approved for PsA.

The trials included adults with active PsA, active plaque psoriasis or nail psoriasis, and at least five swollen joints and five tender joints. All the participants had an inadequate response or intolerance to at least one conventional synthetic disease-modifying antirheumatic drug (csDMARD), and KEEPsAKE 2 included participants who had an inadequate response or intolerance to at least one biologic therapy.

The majority of patients in both groups were taking anti-inflammatory drugs (58.8% with risankizumab vs. 62.1% with placebo) and methotrexate (60% vs. 59.1%, respectively), but a minority were taking oral glucocorticoids (18.2% with risankizumab vs. 15.6% with placebo). A small proportion in both groups were also taking a csDMARD besides methotrexate (11.9% with risankizumab vs. 11.3% with placebo).

Participants were randomly assigned to receive either 150 mg of subcutaneous risankizumab or placebo at baseline, 4 weeks, and 16 weeks with a double-blind protocol. The proportion of patients with 20% improvement in ACR response criteria (ACR 20) at 24 weeks was the primary endpoint. The trial is currently continuing with all participants receiving open-label risankizumab.

The 1,407 patients initially enrolled included 707 receiving risankizumab and 700 receiving placebo across both trials, with similar baseline demographic and disease characteristics in both groups. A total of 1,354 participants completed the 24-week assessments, including 688 receiving risankizumab and 666 receiving placebo. In an intent-to-treat analysis, 55.5% of patients receiving risankizumab and 31.3% of those receiving placebo achieved ACR 20 at week 24 (P < .001). Participants who received risankizumab also had more improvement in secondary clinical and patient-reported outcomes than did those who received placebo. A quarter (25.2%) of risankizumab patients versus 10.6% of placebo patients showed minimal disease activity, and significantly more participants receiving risankizumab than placebo saw resolution of enthesitis, dactylitis, and fatigue.

Adverse events of any kind occurred in 45.5% of risankizumab and 43.9% of placebo participants, with similar numbers of serious adverse events (3% vs. 4.4%, respectively). One death caused by urosepsis in an 81-year-old participant with dementia occurred in the risankizumab group and was determined to be unrelated to the drug.

David Karp, MD, PhD, chief of division of rheumatic diseases at the University of Texas Southwestern Medical Center in Dallas and ACR president, conducted a question-and-answer session with Dr. Östör following his presentation and asked whether a difference in responses was seen between patients who had failed biologic DMARDs. Dr. Östör said the response rates were similar independent of which previous therapies the participants had failed.

Regarding where risankizumab, as an IL-23 inhibitor, fits among the options for treating PsA, Dr. Östör said “the data speaks for itself” in terms of efficacy with arthritic, musculoskeletal manifestations and the patient-reported outcomes.

“One of the major benefits of these medications is their remarkable effect on skin with psoriasis,” Dr. Östör told Dr. Karp. Regarding axial response to the drug, Dr. Östör noted the statistically significant improvement in Bath Ankylosing Spondylitis Disease Activity Index, appearing to show a clinical benefit with spinal inflammatory disease. Radiologic data, however, are not currently available for the trials.

Dr. Karp noted the recent findings of a phase 2a trial published in the New England Journal of Medicine regarding risankizumab’s poor performance in patients with severe asthma, who experienced worsening symptoms sooner and more rapidly than did those who received placebo. It’s unclear whether any patients in the KEEPsAKE 1 or 2 trials had an asthma diagnosis, but any people with unstable, severe asthma would have been excluded from participation, Dr. Östör said.

The research was funded by AbbVie. Dr. Östör and colleagues have a range of financial ties to numerous pharmaceutical companies.

Patients with psoriatic arthritis (PsA) showed more improvement in symptoms at 6 months with risankizumab (Skyrizi) than with placebo in combined phase 3, randomized, controlled trials, according to data presented at the virtual annual meeting of the American College of Rheumatology.

“Risankizumab was well tolerated and showed no new safety signals over those seen in the trial program for psoriasis,” reported Andrew Östör, MD, of Monash University and Cabrini Hospital, both in Melbourne. The results included pooled data that added KEEPsAKE 1 data to KEEPsAKE 2 results, which were presented at the 2021 congress of the European Alliance of Associations for Rheumatology.

Risankizumab received Food and Drug Administration approval in 2019 for moderate to severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy. The humanized monoclonal antibody inhibits interleukin-23, which is believed to be involved in the development of PsA. The FDA updated its approval in August 2021 to make it available as a 150-mg single-dose injection instead of two 75-mg doses for psoriasis treatment, but it is not yet approved for PsA.

The trials included adults with active PsA, active plaque psoriasis or nail psoriasis, and at least five swollen joints and five tender joints. All the participants had an inadequate response or intolerance to at least one conventional synthetic disease-modifying antirheumatic drug (csDMARD), and KEEPsAKE 2 included participants who had an inadequate response or intolerance to at least one biologic therapy.

The majority of patients in both groups were taking anti-inflammatory drugs (58.8% with risankizumab vs. 62.1% with placebo) and methotrexate (60% vs. 59.1%, respectively), but a minority were taking oral glucocorticoids (18.2% with risankizumab vs. 15.6% with placebo). A small proportion in both groups were also taking a csDMARD besides methotrexate (11.9% with risankizumab vs. 11.3% with placebo).

Participants were randomly assigned to receive either 150 mg of subcutaneous risankizumab or placebo at baseline, 4 weeks, and 16 weeks with a double-blind protocol. The proportion of patients with 20% improvement in ACR response criteria (ACR 20) at 24 weeks was the primary endpoint. The trial is currently continuing with all participants receiving open-label risankizumab.

The 1,407 patients initially enrolled included 707 receiving risankizumab and 700 receiving placebo across both trials, with similar baseline demographic and disease characteristics in both groups. A total of 1,354 participants completed the 24-week assessments, including 688 receiving risankizumab and 666 receiving placebo. In an intent-to-treat analysis, 55.5% of patients receiving risankizumab and 31.3% of those receiving placebo achieved ACR 20 at week 24 (P < .001). Participants who received risankizumab also had more improvement in secondary clinical and patient-reported outcomes than did those who received placebo. A quarter (25.2%) of risankizumab patients versus 10.6% of placebo patients showed minimal disease activity, and significantly more participants receiving risankizumab than placebo saw resolution of enthesitis, dactylitis, and fatigue.

Adverse events of any kind occurred in 45.5% of risankizumab and 43.9% of placebo participants, with similar numbers of serious adverse events (3% vs. 4.4%, respectively). One death caused by urosepsis in an 81-year-old participant with dementia occurred in the risankizumab group and was determined to be unrelated to the drug.

David Karp, MD, PhD, chief of division of rheumatic diseases at the University of Texas Southwestern Medical Center in Dallas and ACR president, conducted a question-and-answer session with Dr. Östör following his presentation and asked whether a difference in responses was seen between patients who had failed biologic DMARDs. Dr. Östör said the response rates were similar independent of which previous therapies the participants had failed.

Regarding where risankizumab, as an IL-23 inhibitor, fits among the options for treating PsA, Dr. Östör said “the data speaks for itself” in terms of efficacy with arthritic, musculoskeletal manifestations and the patient-reported outcomes.

“One of the major benefits of these medications is their remarkable effect on skin with psoriasis,” Dr. Östör told Dr. Karp. Regarding axial response to the drug, Dr. Östör noted the statistically significant improvement in Bath Ankylosing Spondylitis Disease Activity Index, appearing to show a clinical benefit with spinal inflammatory disease. Radiologic data, however, are not currently available for the trials.

Dr. Karp noted the recent findings of a phase 2a trial published in the New England Journal of Medicine regarding risankizumab’s poor performance in patients with severe asthma, who experienced worsening symptoms sooner and more rapidly than did those who received placebo. It’s unclear whether any patients in the KEEPsAKE 1 or 2 trials had an asthma diagnosis, but any people with unstable, severe asthma would have been excluded from participation, Dr. Östör said.

The research was funded by AbbVie. Dr. Östör and colleagues have a range of financial ties to numerous pharmaceutical companies.

Patients with psoriatic arthritis (PsA) showed more improvement in symptoms at 6 months with risankizumab (Skyrizi) than with placebo in combined phase 3, randomized, controlled trials, according to data presented at the virtual annual meeting of the American College of Rheumatology.

“Risankizumab was well tolerated and showed no new safety signals over those seen in the trial program for psoriasis,” reported Andrew Östör, MD, of Monash University and Cabrini Hospital, both in Melbourne. The results included pooled data that added KEEPsAKE 1 data to KEEPsAKE 2 results, which were presented at the 2021 congress of the European Alliance of Associations for Rheumatology.

Risankizumab received Food and Drug Administration approval in 2019 for moderate to severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy. The humanized monoclonal antibody inhibits interleukin-23, which is believed to be involved in the development of PsA. The FDA updated its approval in August 2021 to make it available as a 150-mg single-dose injection instead of two 75-mg doses for psoriasis treatment, but it is not yet approved for PsA.

The trials included adults with active PsA, active plaque psoriasis or nail psoriasis, and at least five swollen joints and five tender joints. All the participants had an inadequate response or intolerance to at least one conventional synthetic disease-modifying antirheumatic drug (csDMARD), and KEEPsAKE 2 included participants who had an inadequate response or intolerance to at least one biologic therapy.

The majority of patients in both groups were taking anti-inflammatory drugs (58.8% with risankizumab vs. 62.1% with placebo) and methotrexate (60% vs. 59.1%, respectively), but a minority were taking oral glucocorticoids (18.2% with risankizumab vs. 15.6% with placebo). A small proportion in both groups were also taking a csDMARD besides methotrexate (11.9% with risankizumab vs. 11.3% with placebo).

Participants were randomly assigned to receive either 150 mg of subcutaneous risankizumab or placebo at baseline, 4 weeks, and 16 weeks with a double-blind protocol. The proportion of patients with 20% improvement in ACR response criteria (ACR 20) at 24 weeks was the primary endpoint. The trial is currently continuing with all participants receiving open-label risankizumab.

The 1,407 patients initially enrolled included 707 receiving risankizumab and 700 receiving placebo across both trials, with similar baseline demographic and disease characteristics in both groups. A total of 1,354 participants completed the 24-week assessments, including 688 receiving risankizumab and 666 receiving placebo. In an intent-to-treat analysis, 55.5% of patients receiving risankizumab and 31.3% of those receiving placebo achieved ACR 20 at week 24 (P < .001). Participants who received risankizumab also had more improvement in secondary clinical and patient-reported outcomes than did those who received placebo. A quarter (25.2%) of risankizumab patients versus 10.6% of placebo patients showed minimal disease activity, and significantly more participants receiving risankizumab than placebo saw resolution of enthesitis, dactylitis, and fatigue.

Adverse events of any kind occurred in 45.5% of risankizumab and 43.9% of placebo participants, with similar numbers of serious adverse events (3% vs. 4.4%, respectively). One death caused by urosepsis in an 81-year-old participant with dementia occurred in the risankizumab group and was determined to be unrelated to the drug.

David Karp, MD, PhD, chief of division of rheumatic diseases at the University of Texas Southwestern Medical Center in Dallas and ACR president, conducted a question-and-answer session with Dr. Östör following his presentation and asked whether a difference in responses was seen between patients who had failed biologic DMARDs. Dr. Östör said the response rates were similar independent of which previous therapies the participants had failed.

Regarding where risankizumab, as an IL-23 inhibitor, fits among the options for treating PsA, Dr. Östör said “the data speaks for itself” in terms of efficacy with arthritic, musculoskeletal manifestations and the patient-reported outcomes.

“One of the major benefits of these medications is their remarkable effect on skin with psoriasis,” Dr. Östör told Dr. Karp. Regarding axial response to the drug, Dr. Östör noted the statistically significant improvement in Bath Ankylosing Spondylitis Disease Activity Index, appearing to show a clinical benefit with spinal inflammatory disease. Radiologic data, however, are not currently available for the trials.

Dr. Karp noted the recent findings of a phase 2a trial published in the New England Journal of Medicine regarding risankizumab’s poor performance in patients with severe asthma, who experienced worsening symptoms sooner and more rapidly than did those who received placebo. It’s unclear whether any patients in the KEEPsAKE 1 or 2 trials had an asthma diagnosis, but any people with unstable, severe asthma would have been excluded from participation, Dr. Östör said.

The research was funded by AbbVie. Dr. Östör and colleagues have a range of financial ties to numerous pharmaceutical companies.

Early intervention with the immunomodulator abatacept (Orencia) may enable people at risk for rheumatoid arthritis but who don’t yet manifest symptomatic inflammation to either avoid or delay the onset of full-blown, symptomatic rheumatoid arthritis, early results of a European clinical trial have shown.

Early results of the ARIAA study, presented at the virtual annual meeting of the American College of Rheumatology, showed that among patients considered at-risk for RA and having arthralgia and subclinical inflammation – considered symptomatic but not having full-blown RA – 61% of those who received a 6-month course of abatacept versus 31% of the placebo group had an improvement in MRI inflammation score (P = .0043), said Juergen Rech, MD, a rheumatologist at Friedrich-Alexander University of Erlangen-Nuremberg (Germany) and University Clinic Erlangen.

“When we actually talk about early treatment, this may be not early enough or at least could be improved,” Dr. Rech said in an interview when asked what the findings add to the evidence for treating at-risk RA patients before disease onset. “It seems as if we were in the situation of delaying the development of disease or possibly even preventing it in some patients, and in our trial this approach was safe with abatacept.”

ARIAA randomized 100 patients to abatacept or placebo at 14 study sites between November 2014 and December 2019. The goal is to treat at-risk patients for 6 months with abatacept, then follow them for 12 months to determine their progression to RA. Dr. Rech noted that 8% of patients in the treatment group and 35% in the placebo group developed arthritis (P = .0025).

He noted that the safety profile of abatacept in this patient population was similar to previous trials. “No safety issues emerged,” Dr. Rech said.

The investigators used MRI to determine the patients’ status for arthralgia and subclinical inflammation before enrollment. They had no history of clinically obvious inflammation fulfilling the criteria for RA and no previous treatment with glucocorticoids or disease-modifying antirheumatic drugs.

The results showed that abatacept is superior to placebo in improving subclinical inflammation and in inhibiting the progression to RA in at-risk patients at 6 months, Dr. Rech said, but early clinical results of patients in the study who’ve had 18 months of follow-up, which were not part of the dataset he presented, revealed that time-limited treatment with the immunomodulator has a significant sustained effect on progression to RA. That “means 6 months of treatment with abatacept will delay the development of RA after 18 months,” he said.

After the complete 18-month dataset is analyzed, the next step for investigators will be to re-evaluate the ARIAA population, perhaps for genetic markers, Dr. Rech said. What would then follow, he said, could be to conduct a larger phase 3 trial, determine the risk factors that drive RA autoimmunity, see if disease progression varies among ethnic groups and people in different geographic regions, and perhaps start a head-to-head trial with rituximab (Rituxan) or an evaluation of combined time-limited abatacept and rituximab in at-risk patients.

“We should think about new strategies, new life-quality questionnaires, new biomarkers and tools for covering and understanding these RA patients at-risk in a better way,” Dr. Rech said, noting that a European Alliance of Associations for Rheumatology task force has already addressed this topic.

John D. Isaacs, MBBS, PhD, professor of rheumatology at Newcastle (England) University, said in an interview that ARIAA is the first readout from a number of studies evaluating preemptive treatment to prevent or delay RA onset. “You have to ask a question: Is this just suppressing what’s going on?” Dr. Isaacs said. “In other words, now that the treatment has been stopped, there’s great interest in what happens over the next 12 months of this study. Have we delayed the onset of rheumatoid arthritis or have we actually prevented it? I think that’s the $10 billion dollar question of this and similar studies.”

Answering that question may be difficult without a known blood biomarker. “That’s not a criticism of the trial; we just don’t have that scientifically at the moment,” Dr. Isaacs said. “Until then, it will be difficult to say we have delayed or we have prevented rheumatoid arthritis. My feeling is, even if we delay it 6 months or even a year with safe treatment, that would be worth it.”

Bristol-Myers Squibb sponsored the trial. Dr. Rech and Dr. Isaacs disclosed having financial relationships with Bristol-Myers Squibb and other pharmaceutical companies.

Early intervention with the immunomodulator abatacept (Orencia) may enable people at risk for rheumatoid arthritis but who don’t yet manifest symptomatic inflammation to either avoid or delay the onset of full-blown, symptomatic rheumatoid arthritis, early results of a European clinical trial have shown.

Early results of the ARIAA study, presented at the virtual annual meeting of the American College of Rheumatology, showed that among patients considered at-risk for RA and having arthralgia and subclinical inflammation – considered symptomatic but not having full-blown RA – 61% of those who received a 6-month course of abatacept versus 31% of the placebo group had an improvement in MRI inflammation score (P = .0043), said Juergen Rech, MD, a rheumatologist at Friedrich-Alexander University of Erlangen-Nuremberg (Germany) and University Clinic Erlangen.

“When we actually talk about early treatment, this may be not early enough or at least could be improved,” Dr. Rech said in an interview when asked what the findings add to the evidence for treating at-risk RA patients before disease onset. “It seems as if we were in the situation of delaying the development of disease or possibly even preventing it in some patients, and in our trial this approach was safe with abatacept.”

ARIAA randomized 100 patients to abatacept or placebo at 14 study sites between November 2014 and December 2019. The goal is to treat at-risk patients for 6 months with abatacept, then follow them for 12 months to determine their progression to RA. Dr. Rech noted that 8% of patients in the treatment group and 35% in the placebo group developed arthritis (P = .0025).

He noted that the safety profile of abatacept in this patient population was similar to previous trials. “No safety issues emerged,” Dr. Rech said.

The investigators used MRI to determine the patients’ status for arthralgia and subclinical inflammation before enrollment. They had no history of clinically obvious inflammation fulfilling the criteria for RA and no previous treatment with glucocorticoids or disease-modifying antirheumatic drugs.

The results showed that abatacept is superior to placebo in improving subclinical inflammation and in inhibiting the progression to RA in at-risk patients at 6 months, Dr. Rech said, but early clinical results of patients in the study who’ve had 18 months of follow-up, which were not part of the dataset he presented, revealed that time-limited treatment with the immunomodulator has a significant sustained effect on progression to RA. That “means 6 months of treatment with abatacept will delay the development of RA after 18 months,” he said.

After the complete 18-month dataset is analyzed, the next step for investigators will be to re-evaluate the ARIAA population, perhaps for genetic markers, Dr. Rech said. What would then follow, he said, could be to conduct a larger phase 3 trial, determine the risk factors that drive RA autoimmunity, see if disease progression varies among ethnic groups and people in different geographic regions, and perhaps start a head-to-head trial with rituximab (Rituxan) or an evaluation of combined time-limited abatacept and rituximab in at-risk patients.

“We should think about new strategies, new life-quality questionnaires, new biomarkers and tools for covering and understanding these RA patients at-risk in a better way,” Dr. Rech said, noting that a European Alliance of Associations for Rheumatology task force has already addressed this topic.

John D. Isaacs, MBBS, PhD, professor of rheumatology at Newcastle (England) University, said in an interview that ARIAA is the first readout from a number of studies evaluating preemptive treatment to prevent or delay RA onset. “You have to ask a question: Is this just suppressing what’s going on?” Dr. Isaacs said. “In other words, now that the treatment has been stopped, there’s great interest in what happens over the next 12 months of this study. Have we delayed the onset of rheumatoid arthritis or have we actually prevented it? I think that’s the $10 billion dollar question of this and similar studies.”

Answering that question may be difficult without a known blood biomarker. “That’s not a criticism of the trial; we just don’t have that scientifically at the moment,” Dr. Isaacs said. “Until then, it will be difficult to say we have delayed or we have prevented rheumatoid arthritis. My feeling is, even if we delay it 6 months or even a year with safe treatment, that would be worth it.”

Bristol-Myers Squibb sponsored the trial. Dr. Rech and Dr. Isaacs disclosed having financial relationships with Bristol-Myers Squibb and other pharmaceutical companies.

Early intervention with the immunomodulator abatacept (Orencia) may enable people at risk for rheumatoid arthritis but who don’t yet manifest symptomatic inflammation to either avoid or delay the onset of full-blown, symptomatic rheumatoid arthritis, early results of a European clinical trial have shown.

Early results of the ARIAA study, presented at the virtual annual meeting of the American College of Rheumatology, showed that among patients considered at-risk for RA and having arthralgia and subclinical inflammation – considered symptomatic but not having full-blown RA – 61% of those who received a 6-month course of abatacept versus 31% of the placebo group had an improvement in MRI inflammation score (P = .0043), said Juergen Rech, MD, a rheumatologist at Friedrich-Alexander University of Erlangen-Nuremberg (Germany) and University Clinic Erlangen.

“When we actually talk about early treatment, this may be not early enough or at least could be improved,” Dr. Rech said in an interview when asked what the findings add to the evidence for treating at-risk RA patients before disease onset. “It seems as if we were in the situation of delaying the development of disease or possibly even preventing it in some patients, and in our trial this approach was safe with abatacept.”

ARIAA randomized 100 patients to abatacept or placebo at 14 study sites between November 2014 and December 2019. The goal is to treat at-risk patients for 6 months with abatacept, then follow them for 12 months to determine their progression to RA. Dr. Rech noted that 8% of patients in the treatment group and 35% in the placebo group developed arthritis (P = .0025).

He noted that the safety profile of abatacept in this patient population was similar to previous trials. “No safety issues emerged,” Dr. Rech said.

The investigators used MRI to determine the patients’ status for arthralgia and subclinical inflammation before enrollment. They had no history of clinically obvious inflammation fulfilling the criteria for RA and no previous treatment with glucocorticoids or disease-modifying antirheumatic drugs.

The results showed that abatacept is superior to placebo in improving subclinical inflammation and in inhibiting the progression to RA in at-risk patients at 6 months, Dr. Rech said, but early clinical results of patients in the study who’ve had 18 months of follow-up, which were not part of the dataset he presented, revealed that time-limited treatment with the immunomodulator has a significant sustained effect on progression to RA. That “means 6 months of treatment with abatacept will delay the development of RA after 18 months,” he said.

After the complete 18-month dataset is analyzed, the next step for investigators will be to re-evaluate the ARIAA population, perhaps for genetic markers, Dr. Rech said. What would then follow, he said, could be to conduct a larger phase 3 trial, determine the risk factors that drive RA autoimmunity, see if disease progression varies among ethnic groups and people in different geographic regions, and perhaps start a head-to-head trial with rituximab (Rituxan) or an evaluation of combined time-limited abatacept and rituximab in at-risk patients.

“We should think about new strategies, new life-quality questionnaires, new biomarkers and tools for covering and understanding these RA patients at-risk in a better way,” Dr. Rech said, noting that a European Alliance of Associations for Rheumatology task force has already addressed this topic.

John D. Isaacs, MBBS, PhD, professor of rheumatology at Newcastle (England) University, said in an interview that ARIAA is the first readout from a number of studies evaluating preemptive treatment to prevent or delay RA onset. “You have to ask a question: Is this just suppressing what’s going on?” Dr. Isaacs said. “In other words, now that the treatment has been stopped, there’s great interest in what happens over the next 12 months of this study. Have we delayed the onset of rheumatoid arthritis or have we actually prevented it? I think that’s the $10 billion dollar question of this and similar studies.”

Answering that question may be difficult without a known blood biomarker. “That’s not a criticism of the trial; we just don’t have that scientifically at the moment,” Dr. Isaacs said. “Until then, it will be difficult to say we have delayed or we have prevented rheumatoid arthritis. My feeling is, even if we delay it 6 months or even a year with safe treatment, that would be worth it.”

Bristol-Myers Squibb sponsored the trial. Dr. Rech and Dr. Isaacs disclosed having financial relationships with Bristol-Myers Squibb and other pharmaceutical companies.

For those of us who cannot sit in the sun and fish all day, the next best thing for preventing autoimmune diseases may be supplementation with vitamin D and fish oil-derived omega-3 fatty acids, results of a large prospective randomized trial suggest.

Ziga Plahutar

Among nearly 26,000 adults enrolled in a randomized trial designed primarily to study the effects of vitamin D and omega-3 supplementation on incident cancer and cardiovascular disease, 5 years of vitamin D supplementation was associated with a 22% reduction in risk for confirmed autoimmune diseases, and 5 years of omega-3 fatty acid supplementation was associated with an 18% reduction in confirmed and probable incident autoimmune diseases, reported Karen H. Costenbader, MD, MPH, of Brigham & Women’s Hospital in Boston.

“The clinical importance of these results is very high, given that these are nontoxic, well-tolerated supplements, and that there are no other known effective therapies to reduce the incidence of autoimmune diseases,” she said during the virtual annual meeting of the American College of Rheumatology.

“People do have to take the supplements a long time to start to see the reduction in risk, especially for vitamin D, but they make biological sense, and autoimmune diseases develop slowly over time, so taking it today isn’t going to reduce risk of developing something tomorrow,” Dr. Costenbader said in an interview.

“These supplements have other health benefits. Obviously, fish oil is anti-inflammatory, and vitamin D is good for osteoporosis prevention, especially in our patients who take glucocorticoids. People who are otherwise healthy and have a family history of autoimmune disease might also consider starting to take these supplements,” she said.

After watching her presentation, session co-moderator Gregg Silverman, MD, from the NYU Langone School of Medicine in New York, who was not involved in the study, commented “I’m going to [nutrition store] GNC to get some vitamins.”

When asked for comment, the other session moderator, Tracy Frech, MD, of Vanderbilt University, Nashville, said, “I think Dr. Costenbader’s work is very important and her presentation excellent. My current practice is replacement of vitamin D in all autoimmune disease patients with low levels and per bone health guidelines. Additionally, I discuss omega-3 supplementation with Sjögren’s [syndrome] patients as a consideration.”

Evidence base

Dr. Costenbader noted that in a 2013 observational study from France, vitamin D derived through ultraviolet (UV) light exposure was associated with a lower risk for incident Crohn’s disease but not ulcerative colitis, and in two analyses of data in 2014 from the Nurses’ Health Study, both high plasma levels of 25-OH vitamin D and geographic residence in areas of high UV exposure were associated with a decreased incidence of rheumatoid arthritis (RA).

Other observational studies have supported omega-3 fatty acids for their anti-inflammatory properties, including a 2005 Danish prospective cohort study showing a lower risk for RA in participants who reported higher levels of fatty fish intake. In a separate study conducted in 2017, healthy volunteers with higher omega-3 fatty acid/total lipid proportions in red blood cell membranes had a lower prevalence of anti-cyclic citrullinated peptide (anti-CCP) antibodies and rheumatoid factor and a lower incidence of progression to inflammatory arthritis, she said.

Ancillary study

Despite the evidence, however, there have been no prospective randomized trials to test the effects of either vitamin D or omega-3 fatty acid supplementation on the incidence of autoimmune disease over time.

To rectify this, Dr. Costenbader and colleagues piggybacked an ancillary study onto the Vitamin D and Omega-3 Trial (VITAL), which had primary outcomes of cancer and cardiovascular disease incidence.

A total of 25,871 participants were enrolled, including 12,786 men aged 50 and older, and 13,085 women aged 55 and older.

The study had a 2 x 2 factorial design, with patients randomly assigned to vitamin D 2,000 IU/day or placebo, and then further randomized to either 1 g/day omega-3 fatty acids or placebo in both the vitamin D and placebo primary randomization arms.

At baseline 16,956 participants were assayed for 25-OH vitamin D and plasma omega 3 index, the ratio of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) to total fatty acids. Participants self-reported baseline and all incident autoimmune diseases annually, with the reports confirmed by medical record review and disease criteria whenever possible.

Results

At 5 years of follow-up, confirmed incident autoimmune diseases had occurred in 123 patients in the active vitamin D group, compared with 155 in the placebo vitamin D group, translating into a hazard ratio (HR) for vitamin D of 0.78 (P = .045).

In the active omega-3 arm, 130 participants developed an autoimmune disease, compared with 148 in the placebo omega-3 arm, which translated into a nonsignificant HR of 0.85.

There was no statistical interaction between the two supplements. The investigators did observe an interaction between vitamin D and body mass index, with the effect stronger among participants with low BMI (P = .02). There also was an interaction between omega-3 fatty acids with a family history of autoimmune disease (P = .03).

In multivariate analysis adjusted for age, sex, race, and other supplement arm, vitamin D alone was associated with an HR for incident autoimmune disease of 0.68 (P = .02), omega-3 alone was associated with a nonsignificant HR of 0.74, and the combination was associated with an HR of 0.69 (P = .03).

Dr. Costenbader and colleagues acknowledged that the study was limited by the lack of a high-risk or nutritionally-deficient population, where the effects of supplementation might be larger; the restriction of the sample to older adults; and to the difficulty of confirming incident autoimmune thyroid disease from patient reports.

Cheryl Koehn, an arthritis patient advocate from Vancouver, Canada, who was not involved in the study, commented in the “chat” section of the presentation that her rheumatologist “has recommended vitamin D for years now. Says basically everyone north of Boston is vitamin D deficient. I take 1,000 IU per day. Been taking it for years.” Ms. Koehn is the founder and president of Arthritis Consumer Experts, a website that provides education to those with arthritis.

“Agreed. I tell every patient to take vitamin D supplement,” commented Fatma Dedeoglu, MD, a rheumatologist at Boston Children’s Hospital.



A version of this article first appeared on Medscape.com.

For those of us who cannot sit in the sun and fish all day, the next best thing for preventing autoimmune diseases may be supplementation with vitamin D and fish oil-derived omega-3 fatty acids, results of a large prospective randomized trial suggest.

Ziga Plahutar

Among nearly 26,000 adults enrolled in a randomized trial designed primarily to study the effects of vitamin D and omega-3 supplementation on incident cancer and cardiovascular disease, 5 years of vitamin D supplementation was associated with a 22% reduction in risk for confirmed autoimmune diseases, and 5 years of omega-3 fatty acid supplementation was associated with an 18% reduction in confirmed and probable incident autoimmune diseases, reported Karen H. Costenbader, MD, MPH, of Brigham & Women’s Hospital in Boston.

“The clinical importance of these results is very high, given that these are nontoxic, well-tolerated supplements, and that there are no other known effective therapies to reduce the incidence of autoimmune diseases,” she said during the virtual annual meeting of the American College of Rheumatology.

“People do have to take the supplements a long time to start to see the reduction in risk, especially for vitamin D, but they make biological sense, and autoimmune diseases develop slowly over time, so taking it today isn’t going to reduce risk of developing something tomorrow,” Dr. Costenbader said in an interview.

“These supplements have other health benefits. Obviously, fish oil is anti-inflammatory, and vitamin D is good for osteoporosis prevention, especially in our patients who take glucocorticoids. People who are otherwise healthy and have a family history of autoimmune disease might also consider starting to take these supplements,” she said.

After watching her presentation, session co-moderator Gregg Silverman, MD, from the NYU Langone School of Medicine in New York, who was not involved in the study, commented “I’m going to [nutrition store] GNC to get some vitamins.”

When asked for comment, the other session moderator, Tracy Frech, MD, of Vanderbilt University, Nashville, said, “I think Dr. Costenbader’s work is very important and her presentation excellent. My current practice is replacement of vitamin D in all autoimmune disease patients with low levels and per bone health guidelines. Additionally, I discuss omega-3 supplementation with Sjögren’s [syndrome] patients as a consideration.”

Evidence base

Dr. Costenbader noted that in a 2013 observational study from France, vitamin D derived through ultraviolet (UV) light exposure was associated with a lower risk for incident Crohn’s disease but not ulcerative colitis, and in two analyses of data in 2014 from the Nurses’ Health Study, both high plasma levels of 25-OH vitamin D and geographic residence in areas of high UV exposure were associated with a decreased incidence of rheumatoid arthritis (RA).

Other observational studies have supported omega-3 fatty acids for their anti-inflammatory properties, including a 2005 Danish prospective cohort study showing a lower risk for RA in participants who reported higher levels of fatty fish intake. In a separate study conducted in 2017, healthy volunteers with higher omega-3 fatty acid/total lipid proportions in red blood cell membranes had a lower prevalence of anti-cyclic citrullinated peptide (anti-CCP) antibodies and rheumatoid factor and a lower incidence of progression to inflammatory arthritis, she said.

Ancillary study

Despite the evidence, however, there have been no prospective randomized trials to test the effects of either vitamin D or omega-3 fatty acid supplementation on the incidence of autoimmune disease over time.

To rectify this, Dr. Costenbader and colleagues piggybacked an ancillary study onto the Vitamin D and Omega-3 Trial (VITAL), which had primary outcomes of cancer and cardiovascular disease incidence.

A total of 25,871 participants were enrolled, including 12,786 men aged 50 and older, and 13,085 women aged 55 and older.

The study had a 2 x 2 factorial design, with patients randomly assigned to vitamin D 2,000 IU/day or placebo, and then further randomized to either 1 g/day omega-3 fatty acids or placebo in both the vitamin D and placebo primary randomization arms.

At baseline 16,956 participants were assayed for 25-OH vitamin D and plasma omega 3 index, the ratio of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) to total fatty acids. Participants self-reported baseline and all incident autoimmune diseases annually, with the reports confirmed by medical record review and disease criteria whenever possible.

Results

At 5 years of follow-up, confirmed incident autoimmune diseases had occurred in 123 patients in the active vitamin D group, compared with 155 in the placebo vitamin D group, translating into a hazard ratio (HR) for vitamin D of 0.78 (P = .045).

In the active omega-3 arm, 130 participants developed an autoimmune disease, compared with 148 in the placebo omega-3 arm, which translated into a nonsignificant HR of 0.85.

There was no statistical interaction between the two supplements. The investigators did observe an interaction between vitamin D and body mass index, with the effect stronger among participants with low BMI (P = .02). There also was an interaction between omega-3 fatty acids with a family history of autoimmune disease (P = .03).

In multivariate analysis adjusted for age, sex, race, and other supplement arm, vitamin D alone was associated with an HR for incident autoimmune disease of 0.68 (P = .02), omega-3 alone was associated with a nonsignificant HR of 0.74, and the combination was associated with an HR of 0.69 (P = .03).

Dr. Costenbader and colleagues acknowledged that the study was limited by the lack of a high-risk or nutritionally-deficient population, where the effects of supplementation might be larger; the restriction of the sample to older adults; and to the difficulty of confirming incident autoimmune thyroid disease from patient reports.

Cheryl Koehn, an arthritis patient advocate from Vancouver, Canada, who was not involved in the study, commented in the “chat” section of the presentation that her rheumatologist “has recommended vitamin D for years now. Says basically everyone north of Boston is vitamin D deficient. I take 1,000 IU per day. Been taking it for years.” Ms. Koehn is the founder and president of Arthritis Consumer Experts, a website that provides education to those with arthritis.

“Agreed. I tell every patient to take vitamin D supplement,” commented Fatma Dedeoglu, MD, a rheumatologist at Boston Children’s Hospital.



A version of this article first appeared on Medscape.com.

For those of us who cannot sit in the sun and fish all day, the next best thing for preventing autoimmune diseases may be supplementation with vitamin D and fish oil-derived omega-3 fatty acids, results of a large prospective randomized trial suggest.

Ziga Plahutar

Among nearly 26,000 adults enrolled in a randomized trial designed primarily to study the effects of vitamin D and omega-3 supplementation on incident cancer and cardiovascular disease, 5 years of vitamin D supplementation was associated with a 22% reduction in risk for confirmed autoimmune diseases, and 5 years of omega-3 fatty acid supplementation was associated with an 18% reduction in confirmed and probable incident autoimmune diseases, reported Karen H. Costenbader, MD, MPH, of Brigham & Women’s Hospital in Boston.

“The clinical importance of these results is very high, given that these are nontoxic, well-tolerated supplements, and that there are no other known effective therapies to reduce the incidence of autoimmune diseases,” she said during the virtual annual meeting of the American College of Rheumatology.

“People do have to take the supplements a long time to start to see the reduction in risk, especially for vitamin D, but they make biological sense, and autoimmune diseases develop slowly over time, so taking it today isn’t going to reduce risk of developing something tomorrow,” Dr. Costenbader said in an interview.

“These supplements have other health benefits. Obviously, fish oil is anti-inflammatory, and vitamin D is good for osteoporosis prevention, especially in our patients who take glucocorticoids. People who are otherwise healthy and have a family history of autoimmune disease might also consider starting to take these supplements,” she said.

After watching her presentation, session co-moderator Gregg Silverman, MD, from the NYU Langone School of Medicine in New York, who was not involved in the study, commented “I’m going to [nutrition store] GNC to get some vitamins.”

When asked for comment, the other session moderator, Tracy Frech, MD, of Vanderbilt University, Nashville, said, “I think Dr. Costenbader’s work is very important and her presentation excellent. My current practice is replacement of vitamin D in all autoimmune disease patients with low levels and per bone health guidelines. Additionally, I discuss omega-3 supplementation with Sjögren’s [syndrome] patients as a consideration.”

Evidence base

Dr. Costenbader noted that in a 2013 observational study from France, vitamin D derived through ultraviolet (UV) light exposure was associated with a lower risk for incident Crohn’s disease but not ulcerative colitis, and in two analyses of data in 2014 from the Nurses’ Health Study, both high plasma levels of 25-OH vitamin D and geographic residence in areas of high UV exposure were associated with a decreased incidence of rheumatoid arthritis (RA).

Other observational studies have supported omega-3 fatty acids for their anti-inflammatory properties, including a 2005 Danish prospective cohort study showing a lower risk for RA in participants who reported higher levels of fatty fish intake. In a separate study conducted in 2017, healthy volunteers with higher omega-3 fatty acid/total lipid proportions in red blood cell membranes had a lower prevalence of anti-cyclic citrullinated peptide (anti-CCP) antibodies and rheumatoid factor and a lower incidence of progression to inflammatory arthritis, she said.

Ancillary study

Despite the evidence, however, there have been no prospective randomized trials to test the effects of either vitamin D or omega-3 fatty acid supplementation on the incidence of autoimmune disease over time.

To rectify this, Dr. Costenbader and colleagues piggybacked an ancillary study onto the Vitamin D and Omega-3 Trial (VITAL), which had primary outcomes of cancer and cardiovascular disease incidence.

A total of 25,871 participants were enrolled, including 12,786 men aged 50 and older, and 13,085 women aged 55 and older.

The study had a 2 x 2 factorial design, with patients randomly assigned to vitamin D 2,000 IU/day or placebo, and then further randomized to either 1 g/day omega-3 fatty acids or placebo in both the vitamin D and placebo primary randomization arms.

At baseline 16,956 participants were assayed for 25-OH vitamin D and plasma omega 3 index, the ratio of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) to total fatty acids. Participants self-reported baseline and all incident autoimmune diseases annually, with the reports confirmed by medical record review and disease criteria whenever possible.

Results

At 5 years of follow-up, confirmed incident autoimmune diseases had occurred in 123 patients in the active vitamin D group, compared with 155 in the placebo vitamin D group, translating into a hazard ratio (HR) for vitamin D of 0.78 (P = .045).

In the active omega-3 arm, 130 participants developed an autoimmune disease, compared with 148 in the placebo omega-3 arm, which translated into a nonsignificant HR of 0.85.

There was no statistical interaction between the two supplements. The investigators did observe an interaction between vitamin D and body mass index, with the effect stronger among participants with low BMI (P = .02). There also was an interaction between omega-3 fatty acids with a family history of autoimmune disease (P = .03).

In multivariate analysis adjusted for age, sex, race, and other supplement arm, vitamin D alone was associated with an HR for incident autoimmune disease of 0.68 (P = .02), omega-3 alone was associated with a nonsignificant HR of 0.74, and the combination was associated with an HR of 0.69 (P = .03).

Dr. Costenbader and colleagues acknowledged that the study was limited by the lack of a high-risk or nutritionally-deficient population, where the effects of supplementation might be larger; the restriction of the sample to older adults; and to the difficulty of confirming incident autoimmune thyroid disease from patient reports.

Cheryl Koehn, an arthritis patient advocate from Vancouver, Canada, who was not involved in the study, commented in the “chat” section of the presentation that her rheumatologist “has recommended vitamin D for years now. Says basically everyone north of Boston is vitamin D deficient. I take 1,000 IU per day. Been taking it for years.” Ms. Koehn is the founder and president of Arthritis Consumer Experts, a website that provides education to those with arthritis.

“Agreed. I tell every patient to take vitamin D supplement,” commented Fatma Dedeoglu, MD, a rheumatologist at Boston Children’s Hospital.



A version of this article first appeared on Medscape.com.