Rheumatoid Arthritis

Key clinical point: Patients with rheumatoid arthritis (RA) did not show an increased risk for arthritis flare after completing 2 doses of mRNA (BNT162b2) or inactivated virus (CoronaVac) COVID-19 vaccination.

Major finding: There was no association between receiving 2 doses of mRNA vaccine (adjusted incidence rate ratio [aIRR], 0.86; 95% CI, 0.73-1.01) or inactivated virus vaccine (aIRR, 0.87; 95% CI, 0.74-1.02) and experiencing arthritis flares. The per-patient prescription and distribution of rheumatic drug prescriptions were similar for vaccinated and nonvaccinated patients (P > .1).

Study details: Findings are from a retrospective cohort study including 5,493 patients with RA, of which 653 patients received mRNA vaccine, 671 patients received inactivated virus vaccine, and the remaining were nonvaccinated.

Disclosures: This study was funded by the Food and Health Bureau (FHB), Hong Kong. The authors declared receiving research grants, consultancy fees, postdoctoral fellowship, speaker fees, and/ or honorarium from various sources including FHB.

Source: Li X et al. Ann Rheum Dis. 2021 Oct 22. doi: 10.1136/annrheumdis-2021-221571.

Key clinical point: Patients with rheumatoid arthritis (RA) did not show an increased risk for arthritis flare after completing 2 doses of mRNA (BNT162b2) or inactivated virus (CoronaVac) COVID-19 vaccination.

Major finding: There was no association between receiving 2 doses of mRNA vaccine (adjusted incidence rate ratio [aIRR], 0.86; 95% CI, 0.73-1.01) or inactivated virus vaccine (aIRR, 0.87; 95% CI, 0.74-1.02) and experiencing arthritis flares. The per-patient prescription and distribution of rheumatic drug prescriptions were similar for vaccinated and nonvaccinated patients (P > .1).

Study details: Findings are from a retrospective cohort study including 5,493 patients with RA, of which 653 patients received mRNA vaccine, 671 patients received inactivated virus vaccine, and the remaining were nonvaccinated.

Disclosures: This study was funded by the Food and Health Bureau (FHB), Hong Kong. The authors declared receiving research grants, consultancy fees, postdoctoral fellowship, speaker fees, and/ or honorarium from various sources including FHB.

Source: Li X et al. Ann Rheum Dis. 2021 Oct 22. doi: 10.1136/annrheumdis-2021-221571.

Key clinical point: Patients with rheumatoid arthritis (RA) did not show an increased risk for arthritis flare after completing 2 doses of mRNA (BNT162b2) or inactivated virus (CoronaVac) COVID-19 vaccination.

Major finding: There was no association between receiving 2 doses of mRNA vaccine (adjusted incidence rate ratio [aIRR], 0.86; 95% CI, 0.73-1.01) or inactivated virus vaccine (aIRR, 0.87; 95% CI, 0.74-1.02) and experiencing arthritis flares. The per-patient prescription and distribution of rheumatic drug prescriptions were similar for vaccinated and nonvaccinated patients (P > .1).

Study details: Findings are from a retrospective cohort study including 5,493 patients with RA, of which 653 patients received mRNA vaccine, 671 patients received inactivated virus vaccine, and the remaining were nonvaccinated.

Disclosures: This study was funded by the Food and Health Bureau (FHB), Hong Kong. The authors declared receiving research grants, consultancy fees, postdoctoral fellowship, speaker fees, and/ or honorarium from various sources including FHB.

Source: Li X et al. Ann Rheum Dis. 2021 Oct 22. doi: 10.1136/annrheumdis-2021-221571.

Rituximab doses as low as 200 mg reduced disease activity in patients with rheumatoid arthritis to an extent that’s similar to the standard 1,000-mg dose during more than 3 years of follow-up, according to results from an extension study of a clinical trial in the Netherlands.

“We could not formally statistically show that the lower doses were less effective than the higher dose,” study leader Nathan den Broeder, MSc, a PhD candidate at St. Maarten Clinic and the Radboud Institute for Health Sciences in Nijmegen, the Netherlands, said in a presentation at the virtual annual meeting of the American College of Rheumatology. “We concluded at this time that only 6% of patients needed to switch to another biologic or targeted disease-modifying antirheumatic drug and that mean disease activity remained very low,” he said of the patients treated with 200- and 500-mg doses of rituximab.

The extension study included 118 of 142 patients in the REDO trial, following them from the start of the trial in 2017-2018 through April 2021. They were randomized to three treatment arms: the standard 1,000-mg dose (24 patients), a 500-mg dose (n = 48), and the 200-mg dose (n = 46). The mean follow-up was 3.2 years.

The study evaluated disease activity by mean Disease Activity Score in 28 joints with C-reactive protein (DAS28-CRP), which during follow-up were 2.2-2.3 in the groups. Seven patients in the study cohort switched to a different DMARD, he said.

“On average, we saw a DAS28-CRP 0.15 points lower per 1,000 mg rituximab used in the past year,” Mr. den Broeder said in an interview. “For context, this is compared to a measurement error of about 0.6. A good response to a drug would be a reduction in DAS28-CRP of 1.2. This means we can just about get an effect that is bigger than the measurement error if we compare the highest dose in our study to the lowest one.” 

After a year, the median yearly rituximab dose was 978 mg, with an interquartile range of 704-1,425 mg. At the end of the study, 31% of patients took 200 mg every 6 months, 40% took 500 mg every 6.2 months, and 29% took 1,000 mg every 6.4 months.

“It’s important to note, though, this is in a situation where patients are given a dose based on disease activity,” Mr. den Broeder said. “That is, we try one dose; if the patient does well, we try a lower one; if not, we might go back up to a higher dose. We could expect somewhat larger differences if all patients were to be switched to a lower dose, regardless of whether that works well for them.”

The results were achieved without a high reliance on glucocorticoids (GCs), he said. Use of comedication in the extension study population was 0.38 GC injections per patient-year and starting or increasing an oral GC occurred at a rate of only 0.05 per patient-year.

“As a result of this study, we are now implementing a strategy of rituximab dose reduction in clinical practice at our center,” Mr. den Broeder said. Patients with RA start on a 1,000-mg dose for 6 months, and if they respond well they’re put on a 500-mg dose. If they respond well after 6 months on the 500-mg dose, they’re then moved to the 200-mg dose. “With this, we hope to gain that patients have fewer side effects,” he said. “We hope to reduce the cost of treatment, and also, what we instantly gain is that the infusion time for patients is also reduced.”

Future research considerations include evaluating the 200-mg dose as a subcutaneous injection. “Another thing you might think of as well: Are even lower doses possible?” he said.

Session moderator Maya Buch, MD, professor of rheumatology and director of Experimental Medicine at the Centre for Musculoskeletal Research at the University of Manchester (England), asked if the investigators used CD19 testing to measure B-cell levels or immunoglobulin G levels to determine dose escalation.

Mr. den Broeder said that CD19 wasn’t used in clinical practice but was used in the original trial. However, it wasn’t found to have any predictive ability, while immunoglobulin G levels were measured in patients who had multiple infections. “Sporadically, a lower dose might have been initiated because of that, but not systematically,” he said.

Mr. den Broeder had no relevant relationships to disclose. Dr. Buch reported financial relationships with AbbVie, Eli Lilly, Gilead Sciences, Merck-Serono, Pfizer, Roche, Sanofi, and UCB.

Rituximab doses as low as 200 mg reduced disease activity in patients with rheumatoid arthritis to an extent that’s similar to the standard 1,000-mg dose during more than 3 years of follow-up, according to results from an extension study of a clinical trial in the Netherlands.

“We could not formally statistically show that the lower doses were less effective than the higher dose,” study leader Nathan den Broeder, MSc, a PhD candidate at St. Maarten Clinic and the Radboud Institute for Health Sciences in Nijmegen, the Netherlands, said in a presentation at the virtual annual meeting of the American College of Rheumatology. “We concluded at this time that only 6% of patients needed to switch to another biologic or targeted disease-modifying antirheumatic drug and that mean disease activity remained very low,” he said of the patients treated with 200- and 500-mg doses of rituximab.

The extension study included 118 of 142 patients in the REDO trial, following them from the start of the trial in 2017-2018 through April 2021. They were randomized to three treatment arms: the standard 1,000-mg dose (24 patients), a 500-mg dose (n = 48), and the 200-mg dose (n = 46). The mean follow-up was 3.2 years.

The study evaluated disease activity by mean Disease Activity Score in 28 joints with C-reactive protein (DAS28-CRP), which during follow-up were 2.2-2.3 in the groups. Seven patients in the study cohort switched to a different DMARD, he said.

“On average, we saw a DAS28-CRP 0.15 points lower per 1,000 mg rituximab used in the past year,” Mr. den Broeder said in an interview. “For context, this is compared to a measurement error of about 0.6. A good response to a drug would be a reduction in DAS28-CRP of 1.2. This means we can just about get an effect that is bigger than the measurement error if we compare the highest dose in our study to the lowest one.” 

After a year, the median yearly rituximab dose was 978 mg, with an interquartile range of 704-1,425 mg. At the end of the study, 31% of patients took 200 mg every 6 months, 40% took 500 mg every 6.2 months, and 29% took 1,000 mg every 6.4 months.

“It’s important to note, though, this is in a situation where patients are given a dose based on disease activity,” Mr. den Broeder said. “That is, we try one dose; if the patient does well, we try a lower one; if not, we might go back up to a higher dose. We could expect somewhat larger differences if all patients were to be switched to a lower dose, regardless of whether that works well for them.”

The results were achieved without a high reliance on glucocorticoids (GCs), he said. Use of comedication in the extension study population was 0.38 GC injections per patient-year and starting or increasing an oral GC occurred at a rate of only 0.05 per patient-year.

“As a result of this study, we are now implementing a strategy of rituximab dose reduction in clinical practice at our center,” Mr. den Broeder said. Patients with RA start on a 1,000-mg dose for 6 months, and if they respond well they’re put on a 500-mg dose. If they respond well after 6 months on the 500-mg dose, they’re then moved to the 200-mg dose. “With this, we hope to gain that patients have fewer side effects,” he said. “We hope to reduce the cost of treatment, and also, what we instantly gain is that the infusion time for patients is also reduced.”

Future research considerations include evaluating the 200-mg dose as a subcutaneous injection. “Another thing you might think of as well: Are even lower doses possible?” he said.

Session moderator Maya Buch, MD, professor of rheumatology and director of Experimental Medicine at the Centre for Musculoskeletal Research at the University of Manchester (England), asked if the investigators used CD19 testing to measure B-cell levels or immunoglobulin G levels to determine dose escalation.

Mr. den Broeder said that CD19 wasn’t used in clinical practice but was used in the original trial. However, it wasn’t found to have any predictive ability, while immunoglobulin G levels were measured in patients who had multiple infections. “Sporadically, a lower dose might have been initiated because of that, but not systematically,” he said.

Mr. den Broeder had no relevant relationships to disclose. Dr. Buch reported financial relationships with AbbVie, Eli Lilly, Gilead Sciences, Merck-Serono, Pfizer, Roche, Sanofi, and UCB.

Rituximab doses as low as 200 mg reduced disease activity in patients with rheumatoid arthritis to an extent that’s similar to the standard 1,000-mg dose during more than 3 years of follow-up, according to results from an extension study of a clinical trial in the Netherlands.

“We could not formally statistically show that the lower doses were less effective than the higher dose,” study leader Nathan den Broeder, MSc, a PhD candidate at St. Maarten Clinic and the Radboud Institute for Health Sciences in Nijmegen, the Netherlands, said in a presentation at the virtual annual meeting of the American College of Rheumatology. “We concluded at this time that only 6% of patients needed to switch to another biologic or targeted disease-modifying antirheumatic drug and that mean disease activity remained very low,” he said of the patients treated with 200- and 500-mg doses of rituximab.

The extension study included 118 of 142 patients in the REDO trial, following them from the start of the trial in 2017-2018 through April 2021. They were randomized to three treatment arms: the standard 1,000-mg dose (24 patients), a 500-mg dose (n = 48), and the 200-mg dose (n = 46). The mean follow-up was 3.2 years.

The study evaluated disease activity by mean Disease Activity Score in 28 joints with C-reactive protein (DAS28-CRP), which during follow-up were 2.2-2.3 in the groups. Seven patients in the study cohort switched to a different DMARD, he said.

“On average, we saw a DAS28-CRP 0.15 points lower per 1,000 mg rituximab used in the past year,” Mr. den Broeder said in an interview. “For context, this is compared to a measurement error of about 0.6. A good response to a drug would be a reduction in DAS28-CRP of 1.2. This means we can just about get an effect that is bigger than the measurement error if we compare the highest dose in our study to the lowest one.” 

After a year, the median yearly rituximab dose was 978 mg, with an interquartile range of 704-1,425 mg. At the end of the study, 31% of patients took 200 mg every 6 months, 40% took 500 mg every 6.2 months, and 29% took 1,000 mg every 6.4 months.

“It’s important to note, though, this is in a situation where patients are given a dose based on disease activity,” Mr. den Broeder said. “That is, we try one dose; if the patient does well, we try a lower one; if not, we might go back up to a higher dose. We could expect somewhat larger differences if all patients were to be switched to a lower dose, regardless of whether that works well for them.”

The results were achieved without a high reliance on glucocorticoids (GCs), he said. Use of comedication in the extension study population was 0.38 GC injections per patient-year and starting or increasing an oral GC occurred at a rate of only 0.05 per patient-year.

“As a result of this study, we are now implementing a strategy of rituximab dose reduction in clinical practice at our center,” Mr. den Broeder said. Patients with RA start on a 1,000-mg dose for 6 months, and if they respond well they’re put on a 500-mg dose. If they respond well after 6 months on the 500-mg dose, they’re then moved to the 200-mg dose. “With this, we hope to gain that patients have fewer side effects,” he said. “We hope to reduce the cost of treatment, and also, what we instantly gain is that the infusion time for patients is also reduced.”

Future research considerations include evaluating the 200-mg dose as a subcutaneous injection. “Another thing you might think of as well: Are even lower doses possible?” he said.

Session moderator Maya Buch, MD, professor of rheumatology and director of Experimental Medicine at the Centre for Musculoskeletal Research at the University of Manchester (England), asked if the investigators used CD19 testing to measure B-cell levels or immunoglobulin G levels to determine dose escalation.

Mr. den Broeder said that CD19 wasn’t used in clinical practice but was used in the original trial. However, it wasn’t found to have any predictive ability, while immunoglobulin G levels were measured in patients who had multiple infections. “Sporadically, a lower dose might have been initiated because of that, but not systematically,” he said.

Mr. den Broeder had no relevant relationships to disclose. Dr. Buch reported financial relationships with AbbVie, Eli Lilly, Gilead Sciences, Merck-Serono, Pfizer, Roche, Sanofi, and UCB.

Each month of glucocorticoid use in middle-aged patients with rheumatoid arthritis increases their odds of a major adverse cardiac event by 14%, independent of their baseline cardiovascular risk, according to a Veterans Administration study presented at the virtual annual meeting of the American College of Rheumatology. A similar study of Medicare and insurance claims data also presented at the meeting similarly found a dose-dependent increase in cardiovascular risk with long-term glucocorticoid use among patients with RA.

Up to half of patients with RA use long-term glucocorticoids, Beth Wallace, MD, an assistant professor of internal medicine at the University of Michigan, Ann Arbor, and a staff rheumatologist at the VA Ann Arbor Healthcare Center, told attendees in her presentation.

“Despite previous work suggesting they increase major [adverse] cardiovascular events, or MACE, in a dose-dependent way, prior work suggests long-term glucocorticoid use is common among RA patients with traditional basic risk factors like hyperlipidemia, diabetes, hypertension, and smoking,” Dr. Wallace said. “But we know little about the incremental effects of ongoing glucocorticoid use on MACE risk in RA, particularly as traditional predisposing comorbidities might confound its assessment.”

VA study details

The retrospective cohort study relied on VA administrative data for 26,239 patients with RA who had at least one rheumatology visit during 2013-2017. Only adults aged 40-90 were included (85% men), and none had other rheumatologic conditions, a previous MACE, or congestive heart failure in the preceding 5 years.

The researchers used pharmacy dispensing data to determine exposure to glucocorticoids, based on the number of days’ supply per 6 months and claims data to identify the primary outcome of MACE, defined as acute myocardial infarction, stroke, transient ischemic attack, cardiac arrest, or coronary revascularization, in the following 6 months. After a first MACE, a patient was removed from subsequent analysis so that only a participant’s initial event was considered.

The researchers adjusted their analysis for demographics, health care utilization, long-term glucocorticoid use (over 90 days), use of methotrexate or biologics, and baseline cardiac risk based on the Veterans Affairs Risk Score for Cardiovascular Disease (VARS-CVD). The VARS-CVD uses age, sex, race, tobacco use, systolic blood pressure, cholesterol, diabetes diagnosis, and use of antihypertensives to estimate the risk of a MACE in the next 5 years. A 5-year risk of less than 3% was considered low, 3%-9% medium, and above 9% high.

The population’s median 5-year MACE risk based on VARS-CVD was 5.7%, with nearly a quarter of participants (23%) having a high risk. During the first year of follow-up, 23% of patients overall, including 24% of those with high risk, received at least 90 days of glucocorticoids. An incident MACE occurred in 3.2% of overall patients and in 4.9% of high-risk patients. Median time until an incident MACE was 25 months.

After adjusting for confounders, the researchers calculated that each additional 30 days of glucocorticoid use per 6-month period was linked to a 14% increase in odds of a MACE in the subsequent 6-month period (odds ratio, 1.14). This finding remained independent of baseline cardiovascular risk, previous long-term exposure to glucocorticoids, baseline office visits, methotrexate or biologic use, and baseline Elixhauser Cormobidity Index (except rheumatoid arthritis, diabetes, hypertension, and congestive heart failure).

Dr. Wallace noted that the observational study could still include residual confounding because of factors such as rheumatic disease activity, glucocorticoid dose, and care outside the VA. They also did not distinguish between existing and incident RA and were missing some VARS-CVD data, and they did not adjust for hydroxychloroquine use, which can reduce cardiovascular risk.
 

Details of Medicare and private insurance claims study

In the second study, Brian Coburn, MD, a fourth-year internal medicine resident at the University of Pennsylvania, Philadelphia, presented findings on long-term glucocorticoid use and cardiovascular outcomes in patients with RA based on 2006-2015 claims data from Medicare and the Optum Clinformatics Data Mart. That study similarly found a dose-dependent increase in cardiovascular risk with increasing dosage of long-term glucocorticoids.

All the patients in the two databases had an RA diagnosis and remained on disease-modifying antirheumatic drugs (DMARDs) for at least 180 days without adding a new DMARD or stopping therapy for more than 90 days. Patients were not included if they had a history of myocardial infarction, stroke, coronary artery bypass grafting, or percutaneous coronary intervention.

Using the 180 days before and after starting DMARDs as baseline, the researchers assessed average dose of glucocorticoids during the last 90 days of the baseline period. Participants included 135,583 patients with Medicare, contributing 158,839 years at risk, and 39,272 patients in the Optum database, contributing 36,876 years at risk. The researchers then assessed composite cardiovascular events as a combination of strokes and myocardial infarctions.

A total of 2,067 cardiovascular events occurred among the Medicare patients, for a incidence of 1.3 events per 100 people per year, and 313 cardiovascular events occurred among Optum patients, for an incidence of 0.8 events per 100 people per year.

Over 1 year, a predicted 1.1% of Medicare patients not taking glucocorticoids would experience a stroke or heart attack, compared with 1.4% of those taking up to 5 mg/day of glucocorticoids, 1.7% of those taking 5-10 mg/day glucocorticoids, and 1.9% of those taking more than 10 mg/day glucocorticoids. The number needed to harm was 400 people for up to 5 mg/day, 192 people for 5-10 mg/day, and 137 people for more than 10 mg/day.

Among Optum patients, 0.7% not taking glucocorticoids would experience a stroke or heart attack over 1 year, compared with 0.9% of those taking up to 5 mg/day and 0.8% of those taking either 5-10 mg/day or more than 10 mg/day. The number needed to harm was 714 people for up to 5 mg/day of glucocorticoids, 5,000 people for 5-10 mg/day, and 1,667 for over 10 mg/day.

Dr. Bartels noted that this study “reported unadjusted rates, without controlling for traditional CVD risk factors, for instance, so it will be interesting to see that report after full analysis and peer review as well.” She added that the rates in the VA study may even be higher if there were uncounted cardiovascular events or deaths outside the VA.

“The key take away is that glucocorticoids have dose-related cardiovascular risk shown in both duration and dose of use now in these three large U.S. cohorts,” Dr. Bartels said. “Providers need to counsel patients in judicious use of glucocorticoids, favoring the role of biologic and nonbiologic DMARDs while balancing unique needs and quality-of-life considerations in our patients.”

The VA retrospective cohort study was funded by the National Institutes of Health, the American Autoimmune Related Diseases Association, the U.S. Department of Veterans Affairs, and the Michigan Institute for Clinical & Health Research. Dr. Wallace and seven other authors reported no disclosures. Several coauthors reported financial ties to multiple pharmaceutical companies. The Medicare/Optum retrospective cohort study was funded by the National Institutes of Health, the Patient-Centered Outcomes Research Institute, and the Rheumatology Research Foundation. Dr. Coburn and five coauthors had no disclosures, while several others reported financial ties to a variety of pharmaceutical companies. Dr. Bartels has received institutional grant support from Pfizer for tobacco cessation research

Each month of glucocorticoid use in middle-aged patients with rheumatoid arthritis increases their odds of a major adverse cardiac event by 14%, independent of their baseline cardiovascular risk, according to a Veterans Administration study presented at the virtual annual meeting of the American College of Rheumatology. A similar study of Medicare and insurance claims data also presented at the meeting similarly found a dose-dependent increase in cardiovascular risk with long-term glucocorticoid use among patients with RA.

Up to half of patients with RA use long-term glucocorticoids, Beth Wallace, MD, an assistant professor of internal medicine at the University of Michigan, Ann Arbor, and a staff rheumatologist at the VA Ann Arbor Healthcare Center, told attendees in her presentation.

“Despite previous work suggesting they increase major [adverse] cardiovascular events, or MACE, in a dose-dependent way, prior work suggests long-term glucocorticoid use is common among RA patients with traditional basic risk factors like hyperlipidemia, diabetes, hypertension, and smoking,” Dr. Wallace said. “But we know little about the incremental effects of ongoing glucocorticoid use on MACE risk in RA, particularly as traditional predisposing comorbidities might confound its assessment.”

VA study details

The retrospective cohort study relied on VA administrative data for 26,239 patients with RA who had at least one rheumatology visit during 2013-2017. Only adults aged 40-90 were included (85% men), and none had other rheumatologic conditions, a previous MACE, or congestive heart failure in the preceding 5 years.

The researchers used pharmacy dispensing data to determine exposure to glucocorticoids, based on the number of days’ supply per 6 months and claims data to identify the primary outcome of MACE, defined as acute myocardial infarction, stroke, transient ischemic attack, cardiac arrest, or coronary revascularization, in the following 6 months. After a first MACE, a patient was removed from subsequent analysis so that only a participant’s initial event was considered.

The researchers adjusted their analysis for demographics, health care utilization, long-term glucocorticoid use (over 90 days), use of methotrexate or biologics, and baseline cardiac risk based on the Veterans Affairs Risk Score for Cardiovascular Disease (VARS-CVD). The VARS-CVD uses age, sex, race, tobacco use, systolic blood pressure, cholesterol, diabetes diagnosis, and use of antihypertensives to estimate the risk of a MACE in the next 5 years. A 5-year risk of less than 3% was considered low, 3%-9% medium, and above 9% high.

The population’s median 5-year MACE risk based on VARS-CVD was 5.7%, with nearly a quarter of participants (23%) having a high risk. During the first year of follow-up, 23% of patients overall, including 24% of those with high risk, received at least 90 days of glucocorticoids. An incident MACE occurred in 3.2% of overall patients and in 4.9% of high-risk patients. Median time until an incident MACE was 25 months.

After adjusting for confounders, the researchers calculated that each additional 30 days of glucocorticoid use per 6-month period was linked to a 14% increase in odds of a MACE in the subsequent 6-month period (odds ratio, 1.14). This finding remained independent of baseline cardiovascular risk, previous long-term exposure to glucocorticoids, baseline office visits, methotrexate or biologic use, and baseline Elixhauser Cormobidity Index (except rheumatoid arthritis, diabetes, hypertension, and congestive heart failure).

Dr. Wallace noted that the observational study could still include residual confounding because of factors such as rheumatic disease activity, glucocorticoid dose, and care outside the VA. They also did not distinguish between existing and incident RA and were missing some VARS-CVD data, and they did not adjust for hydroxychloroquine use, which can reduce cardiovascular risk.
 

Details of Medicare and private insurance claims study

In the second study, Brian Coburn, MD, a fourth-year internal medicine resident at the University of Pennsylvania, Philadelphia, presented findings on long-term glucocorticoid use and cardiovascular outcomes in patients with RA based on 2006-2015 claims data from Medicare and the Optum Clinformatics Data Mart. That study similarly found a dose-dependent increase in cardiovascular risk with increasing dosage of long-term glucocorticoids.

All the patients in the two databases had an RA diagnosis and remained on disease-modifying antirheumatic drugs (DMARDs) for at least 180 days without adding a new DMARD or stopping therapy for more than 90 days. Patients were not included if they had a history of myocardial infarction, stroke, coronary artery bypass grafting, or percutaneous coronary intervention.

Using the 180 days before and after starting DMARDs as baseline, the researchers assessed average dose of glucocorticoids during the last 90 days of the baseline period. Participants included 135,583 patients with Medicare, contributing 158,839 years at risk, and 39,272 patients in the Optum database, contributing 36,876 years at risk. The researchers then assessed composite cardiovascular events as a combination of strokes and myocardial infarctions.

A total of 2,067 cardiovascular events occurred among the Medicare patients, for a incidence of 1.3 events per 100 people per year, and 313 cardiovascular events occurred among Optum patients, for an incidence of 0.8 events per 100 people per year.

Over 1 year, a predicted 1.1% of Medicare patients not taking glucocorticoids would experience a stroke or heart attack, compared with 1.4% of those taking up to 5 mg/day of glucocorticoids, 1.7% of those taking 5-10 mg/day glucocorticoids, and 1.9% of those taking more than 10 mg/day glucocorticoids. The number needed to harm was 400 people for up to 5 mg/day, 192 people for 5-10 mg/day, and 137 people for more than 10 mg/day.

Among Optum patients, 0.7% not taking glucocorticoids would experience a stroke or heart attack over 1 year, compared with 0.9% of those taking up to 5 mg/day and 0.8% of those taking either 5-10 mg/day or more than 10 mg/day. The number needed to harm was 714 people for up to 5 mg/day of glucocorticoids, 5,000 people for 5-10 mg/day, and 1,667 for over 10 mg/day.

Dr. Bartels noted that this study “reported unadjusted rates, without controlling for traditional CVD risk factors, for instance, so it will be interesting to see that report after full analysis and peer review as well.” She added that the rates in the VA study may even be higher if there were uncounted cardiovascular events or deaths outside the VA.

“The key take away is that glucocorticoids have dose-related cardiovascular risk shown in both duration and dose of use now in these three large U.S. cohorts,” Dr. Bartels said. “Providers need to counsel patients in judicious use of glucocorticoids, favoring the role of biologic and nonbiologic DMARDs while balancing unique needs and quality-of-life considerations in our patients.”

The VA retrospective cohort study was funded by the National Institutes of Health, the American Autoimmune Related Diseases Association, the U.S. Department of Veterans Affairs, and the Michigan Institute for Clinical & Health Research. Dr. Wallace and seven other authors reported no disclosures. Several coauthors reported financial ties to multiple pharmaceutical companies. The Medicare/Optum retrospective cohort study was funded by the National Institutes of Health, the Patient-Centered Outcomes Research Institute, and the Rheumatology Research Foundation. Dr. Coburn and five coauthors had no disclosures, while several others reported financial ties to a variety of pharmaceutical companies. Dr. Bartels has received institutional grant support from Pfizer for tobacco cessation research

Each month of glucocorticoid use in middle-aged patients with rheumatoid arthritis increases their odds of a major adverse cardiac event by 14%, independent of their baseline cardiovascular risk, according to a Veterans Administration study presented at the virtual annual meeting of the American College of Rheumatology. A similar study of Medicare and insurance claims data also presented at the meeting similarly found a dose-dependent increase in cardiovascular risk with long-term glucocorticoid use among patients with RA.

Up to half of patients with RA use long-term glucocorticoids, Beth Wallace, MD, an assistant professor of internal medicine at the University of Michigan, Ann Arbor, and a staff rheumatologist at the VA Ann Arbor Healthcare Center, told attendees in her presentation.

“Despite previous work suggesting they increase major [adverse] cardiovascular events, or MACE, in a dose-dependent way, prior work suggests long-term glucocorticoid use is common among RA patients with traditional basic risk factors like hyperlipidemia, diabetes, hypertension, and smoking,” Dr. Wallace said. “But we know little about the incremental effects of ongoing glucocorticoid use on MACE risk in RA, particularly as traditional predisposing comorbidities might confound its assessment.”

VA study details

The retrospective cohort study relied on VA administrative data for 26,239 patients with RA who had at least one rheumatology visit during 2013-2017. Only adults aged 40-90 were included (85% men), and none had other rheumatologic conditions, a previous MACE, or congestive heart failure in the preceding 5 years.

The researchers used pharmacy dispensing data to determine exposure to glucocorticoids, based on the number of days’ supply per 6 months and claims data to identify the primary outcome of MACE, defined as acute myocardial infarction, stroke, transient ischemic attack, cardiac arrest, or coronary revascularization, in the following 6 months. After a first MACE, a patient was removed from subsequent analysis so that only a participant’s initial event was considered.

The researchers adjusted their analysis for demographics, health care utilization, long-term glucocorticoid use (over 90 days), use of methotrexate or biologics, and baseline cardiac risk based on the Veterans Affairs Risk Score for Cardiovascular Disease (VARS-CVD). The VARS-CVD uses age, sex, race, tobacco use, systolic blood pressure, cholesterol, diabetes diagnosis, and use of antihypertensives to estimate the risk of a MACE in the next 5 years. A 5-year risk of less than 3% was considered low, 3%-9% medium, and above 9% high.

The population’s median 5-year MACE risk based on VARS-CVD was 5.7%, with nearly a quarter of participants (23%) having a high risk. During the first year of follow-up, 23% of patients overall, including 24% of those with high risk, received at least 90 days of glucocorticoids. An incident MACE occurred in 3.2% of overall patients and in 4.9% of high-risk patients. Median time until an incident MACE was 25 months.

After adjusting for confounders, the researchers calculated that each additional 30 days of glucocorticoid use per 6-month period was linked to a 14% increase in odds of a MACE in the subsequent 6-month period (odds ratio, 1.14). This finding remained independent of baseline cardiovascular risk, previous long-term exposure to glucocorticoids, baseline office visits, methotrexate or biologic use, and baseline Elixhauser Cormobidity Index (except rheumatoid arthritis, diabetes, hypertension, and congestive heart failure).

Dr. Wallace noted that the observational study could still include residual confounding because of factors such as rheumatic disease activity, glucocorticoid dose, and care outside the VA. They also did not distinguish between existing and incident RA and were missing some VARS-CVD data, and they did not adjust for hydroxychloroquine use, which can reduce cardiovascular risk.
 

Details of Medicare and private insurance claims study

In the second study, Brian Coburn, MD, a fourth-year internal medicine resident at the University of Pennsylvania, Philadelphia, presented findings on long-term glucocorticoid use and cardiovascular outcomes in patients with RA based on 2006-2015 claims data from Medicare and the Optum Clinformatics Data Mart. That study similarly found a dose-dependent increase in cardiovascular risk with increasing dosage of long-term glucocorticoids.

All the patients in the two databases had an RA diagnosis and remained on disease-modifying antirheumatic drugs (DMARDs) for at least 180 days without adding a new DMARD or stopping therapy for more than 90 days. Patients were not included if they had a history of myocardial infarction, stroke, coronary artery bypass grafting, or percutaneous coronary intervention.

Using the 180 days before and after starting DMARDs as baseline, the researchers assessed average dose of glucocorticoids during the last 90 days of the baseline period. Participants included 135,583 patients with Medicare, contributing 158,839 years at risk, and 39,272 patients in the Optum database, contributing 36,876 years at risk. The researchers then assessed composite cardiovascular events as a combination of strokes and myocardial infarctions.

A total of 2,067 cardiovascular events occurred among the Medicare patients, for a incidence of 1.3 events per 100 people per year, and 313 cardiovascular events occurred among Optum patients, for an incidence of 0.8 events per 100 people per year.

Over 1 year, a predicted 1.1% of Medicare patients not taking glucocorticoids would experience a stroke or heart attack, compared with 1.4% of those taking up to 5 mg/day of glucocorticoids, 1.7% of those taking 5-10 mg/day glucocorticoids, and 1.9% of those taking more than 10 mg/day glucocorticoids. The number needed to harm was 400 people for up to 5 mg/day, 192 people for 5-10 mg/day, and 137 people for more than 10 mg/day.

Among Optum patients, 0.7% not taking glucocorticoids would experience a stroke or heart attack over 1 year, compared with 0.9% of those taking up to 5 mg/day and 0.8% of those taking either 5-10 mg/day or more than 10 mg/day. The number needed to harm was 714 people for up to 5 mg/day of glucocorticoids, 5,000 people for 5-10 mg/day, and 1,667 for over 10 mg/day.

Dr. Bartels noted that this study “reported unadjusted rates, without controlling for traditional CVD risk factors, for instance, so it will be interesting to see that report after full analysis and peer review as well.” She added that the rates in the VA study may even be higher if there were uncounted cardiovascular events or deaths outside the VA.

“The key take away is that glucocorticoids have dose-related cardiovascular risk shown in both duration and dose of use now in these three large U.S. cohorts,” Dr. Bartels said. “Providers need to counsel patients in judicious use of glucocorticoids, favoring the role of biologic and nonbiologic DMARDs while balancing unique needs and quality-of-life considerations in our patients.”

The VA retrospective cohort study was funded by the National Institutes of Health, the American Autoimmune Related Diseases Association, the U.S. Department of Veterans Affairs, and the Michigan Institute for Clinical & Health Research. Dr. Wallace and seven other authors reported no disclosures. Several coauthors reported financial ties to multiple pharmaceutical companies. The Medicare/Optum retrospective cohort study was funded by the National Institutes of Health, the Patient-Centered Outcomes Research Institute, and the Rheumatology Research Foundation. Dr. Coburn and five coauthors had no disclosures, while several others reported financial ties to a variety of pharmaceutical companies. Dr. Bartels has received institutional grant support from Pfizer for tobacco cessation research

Additional analyses of a postmarketing trial that was required after the Food and Drug Administration’s approval of the Janus kinase inhibitor tofacitinib (Xeljanz, Xeljanz XR) has identified characteristics of older patients with rheumatoid arthritis with at least one cardiovascular risk factor who may be at higher risk for major adverse cardiovascular events (MACE) when taking the drug.

Results from the phase 3b/4 ORAL Surveillance trial presented at the virtual annual meeting of the American College of Rheumatology show that people taking tofacitinib for RA with at least one cardiovascular (CV) risk factor had a nonsignificant higher risk for MACE than did people taking tumor necrosis factor inhibitors (TNFi), with the risk from tofacitinib more pronounced in current smokers, aspirin users, people older than 65 years, and men, compared with women.

“It is the first large, randomized safety study of active RA patients with increased CV risk comparing tofacitinib to TNF inhibition,” study author Christina Charles-Schoeman, MD, said in an interview. “These data emphasize the importance of assessing baseline CV risk when treating patients with RA.” Dr. Charles-Schoeman is chief of rheumatology at the University of California, Los Angeles.

The results shed further light on the trial’s findings, which the FDA used in September 2021 to mandate boxed warnings about the risk of MI or stroke, cancer, venous thromboembolism, and death, as well as updated indications, for tofacitinib and other JAK inhibitors baricitinib (Olumiant) and upadacitinib (Rinvoq). The FDA limited all approved uses of these three medications to patients who have not responded well to TNFi to ensure their benefits outweigh their risks.

Tofacitinib is indicated for RA, psoriatic arthritis, ulcerative colitis, and polyarticular course juvenile idiopathic arthritis. Baricitinib and upadacitinib are approved only for RA.

While the overall results of the trial results show nonsignificant increased incidence rates for MACE in tofacitinib users versus TNFI users, Katherine Liao, MD, a rheumatologist at Brigham and Women’s Hospital in Boston, noted that more information is needed to determine who is at greatest risk. “Another thing to keep in mind is, while there was evidence of an elevated relative risk for MACE, compared to TNFi, the absolute risk, based on the numbers what we know so far, is small,” she said.

The trial compared two different doses of tofacitinib – 5 mg (1,455 patients) and 10 mg (n = 1,456) twice daily – and TNFi (n = 1,451) in people with moderate to severe RA over age 50. Patient characteristics were similar across all three treatment arms, Dr. Charles-Schoeman said. All patients had inadequate response to methotrexate, and about 57% in all three treatment groups were taking corticosteroids. The 10-mg tofacitinib patients switched to the 5-mg dose in February 2019 but represent the 10-mg group in the study analysis.

ORAL Surveillance demonstrated a 24% greater risk of MACE in the 5-mg tofacitinib patients and a 43% heightened risk the 10-mg group, compared with patients who received a TNFi.

The differentiating factor for MACE incidence was MI. The higher- and lower-dose tofacitinib groups had 69% and 80% greater risk for MI. While the risk for fatal MI were similar across all three treatment groups, the risk for nonfatal MI were more than doubled in the respective tofacitinib groups: hazard ratios of 2.32 and 2.08. The incidence of stroke was similar across all three arms, Dr. Charles-Schoeman said.

The study identified a number of baseline characteristics as independent overall risk factors for MACE across all treatment groups. Current smoking and aspirin use more than doubled the risk (HR, 2.18; P < .0001 and HR, 2.11; P = .004, respectively), while age greater than 65 years and male sex approached that level (HR, 1.81; P = .0011 and HR, 1.81; P = .0015) approached that level. Other factors that elevated the risk of MACE to a lesser extent were a history of diabetes, hypertension or coronary artery procedures, and a total cholesterol to HDL ratio greater than4.

Other ORAL Surveillance subanalyses and tofacitinib real-world data reported

This was one of several analyses presented at ACR 2021 that compared adverse event risks for tofacitinib versus TNFi drugs. A separate analysis of claims data from patients with RA in two U.S. insurance databases plus Medicare found a statistically nonsignificant increased risk of adverse CV outcomes (MI or stroke) with tofacitinib, compared with TNFi users, among patients who met the same inclusion and exclusion criteria of the ORAL Surveillance trial but not in a “real-world evidence” cohort of more than 102,000 patients with RA in routine care from the databases.

Two additional ORAL Surveillance analyses presented at ACR 2021 gave details about risk factors for higher rates of malignancies and venous thromboembolic events found in patients taking tofacitinib with at least one CV risk factor. As would be expected, older age (≥65 vs. 50-64 years) and current or past smoking (vs. never smoking) were independent risk factors for higher malignancy rates across all treatment arms. Pulmonary embolism events across treatment groups were independently associated with a history of venous thromboembolism, baseline use of oral contraceptives or hormone replacement therapy, baseline body mass index of at least 30 kg/m², age 65 or older, and history of hypertension.

The ORAL Surveillance findings are worth considering when determining treatments for RA patients with CV risk factors, Dr. Charles-Schoeman said. “Tofacitinib remains an effective RA treatment,” she said. “The choice of specific RA treatment for any patient remains an individual decision between the patient and physician, which is decided based on a number of different factors. This new study provides additional information regarding both tofacitinib as well as traditional CV risk factors for discussion with the patient.”

The ORAL Surveillance results may give rheumatologists reason to rethink use of tofacitinib in some patients with CV risk, said Dr. Liao of Brigham and Women’s Hospital in Boston. “Currently, we have limited data and are still awaiting a report of the full trial results,” she said in an interview. “Based on the data available, I can think of a few patients in my clinic where I would reconsider use of these drugs, i.e., history of heart attack with stable angina, especially if there are other options.” However, she noted that many patients on tofacitinib have already failed on older treatments.

These data emphasize the importance of addressing CV risk with patients, said Brittany N. Weber, MD, PhD, a cardio-rheumatologist at Brigham and Women’s Hospital who works with Dr. Liao. “It is also an opportunity to discuss modification of risk factors and to discuss primary prevention therapies, such as statin therapy, where appropriate,” she added. “Based on the individual’s cardiovascular risk, there may be a role for further risk stratification to further understand an individual’s risk, which can also inform primary prevention cardiovascular therapies and help guide these discussions.” Risk stratification could include cardiac CT for calcium scoring or cardiac coronary CT angiography for determining atherosclerotic burden.

The study was sponsored by Pfizer. Dr. Charles-Schoeman disclosed relationships with AbbVie, Bristol-Myers Squibb, Gilead Sciences, Pfizer, and Regeneron-Sanofi. Dr. Liao and Dr. Weber have no relevant disclosures.

Additional analyses of a postmarketing trial that was required after the Food and Drug Administration’s approval of the Janus kinase inhibitor tofacitinib (Xeljanz, Xeljanz XR) has identified characteristics of older patients with rheumatoid arthritis with at least one cardiovascular risk factor who may be at higher risk for major adverse cardiovascular events (MACE) when taking the drug.

Results from the phase 3b/4 ORAL Surveillance trial presented at the virtual annual meeting of the American College of Rheumatology show that people taking tofacitinib for RA with at least one cardiovascular (CV) risk factor had a nonsignificant higher risk for MACE than did people taking tumor necrosis factor inhibitors (TNFi), with the risk from tofacitinib more pronounced in current smokers, aspirin users, people older than 65 years, and men, compared with women.

“It is the first large, randomized safety study of active RA patients with increased CV risk comparing tofacitinib to TNF inhibition,” study author Christina Charles-Schoeman, MD, said in an interview. “These data emphasize the importance of assessing baseline CV risk when treating patients with RA.” Dr. Charles-Schoeman is chief of rheumatology at the University of California, Los Angeles.

The results shed further light on the trial’s findings, which the FDA used in September 2021 to mandate boxed warnings about the risk of MI or stroke, cancer, venous thromboembolism, and death, as well as updated indications, for tofacitinib and other JAK inhibitors baricitinib (Olumiant) and upadacitinib (Rinvoq). The FDA limited all approved uses of these three medications to patients who have not responded well to TNFi to ensure their benefits outweigh their risks.

Tofacitinib is indicated for RA, psoriatic arthritis, ulcerative colitis, and polyarticular course juvenile idiopathic arthritis. Baricitinib and upadacitinib are approved only for RA.

While the overall results of the trial results show nonsignificant increased incidence rates for MACE in tofacitinib users versus TNFI users, Katherine Liao, MD, a rheumatologist at Brigham and Women’s Hospital in Boston, noted that more information is needed to determine who is at greatest risk. “Another thing to keep in mind is, while there was evidence of an elevated relative risk for MACE, compared to TNFi, the absolute risk, based on the numbers what we know so far, is small,” she said.

The trial compared two different doses of tofacitinib – 5 mg (1,455 patients) and 10 mg (n = 1,456) twice daily – and TNFi (n = 1,451) in people with moderate to severe RA over age 50. Patient characteristics were similar across all three treatment arms, Dr. Charles-Schoeman said. All patients had inadequate response to methotrexate, and about 57% in all three treatment groups were taking corticosteroids. The 10-mg tofacitinib patients switched to the 5-mg dose in February 2019 but represent the 10-mg group in the study analysis.

ORAL Surveillance demonstrated a 24% greater risk of MACE in the 5-mg tofacitinib patients and a 43% heightened risk the 10-mg group, compared with patients who received a TNFi.

The differentiating factor for MACE incidence was MI. The higher- and lower-dose tofacitinib groups had 69% and 80% greater risk for MI. While the risk for fatal MI were similar across all three treatment groups, the risk for nonfatal MI were more than doubled in the respective tofacitinib groups: hazard ratios of 2.32 and 2.08. The incidence of stroke was similar across all three arms, Dr. Charles-Schoeman said.

The study identified a number of baseline characteristics as independent overall risk factors for MACE across all treatment groups. Current smoking and aspirin use more than doubled the risk (HR, 2.18; P < .0001 and HR, 2.11; P = .004, respectively), while age greater than 65 years and male sex approached that level (HR, 1.81; P = .0011 and HR, 1.81; P = .0015) approached that level. Other factors that elevated the risk of MACE to a lesser extent were a history of diabetes, hypertension or coronary artery procedures, and a total cholesterol to HDL ratio greater than4.

Other ORAL Surveillance subanalyses and tofacitinib real-world data reported

This was one of several analyses presented at ACR 2021 that compared adverse event risks for tofacitinib versus TNFi drugs. A separate analysis of claims data from patients with RA in two U.S. insurance databases plus Medicare found a statistically nonsignificant increased risk of adverse CV outcomes (MI or stroke) with tofacitinib, compared with TNFi users, among patients who met the same inclusion and exclusion criteria of the ORAL Surveillance trial but not in a “real-world evidence” cohort of more than 102,000 patients with RA in routine care from the databases.

Two additional ORAL Surveillance analyses presented at ACR 2021 gave details about risk factors for higher rates of malignancies and venous thromboembolic events found in patients taking tofacitinib with at least one CV risk factor. As would be expected, older age (≥65 vs. 50-64 years) and current or past smoking (vs. never smoking) were independent risk factors for higher malignancy rates across all treatment arms. Pulmonary embolism events across treatment groups were independently associated with a history of venous thromboembolism, baseline use of oral contraceptives or hormone replacement therapy, baseline body mass index of at least 30 kg/m², age 65 or older, and history of hypertension.

The ORAL Surveillance findings are worth considering when determining treatments for RA patients with CV risk factors, Dr. Charles-Schoeman said. “Tofacitinib remains an effective RA treatment,” she said. “The choice of specific RA treatment for any patient remains an individual decision between the patient and physician, which is decided based on a number of different factors. This new study provides additional information regarding both tofacitinib as well as traditional CV risk factors for discussion with the patient.”

The ORAL Surveillance results may give rheumatologists reason to rethink use of tofacitinib in some patients with CV risk, said Dr. Liao of Brigham and Women’s Hospital in Boston. “Currently, we have limited data and are still awaiting a report of the full trial results,” she said in an interview. “Based on the data available, I can think of a few patients in my clinic where I would reconsider use of these drugs, i.e., history of heart attack with stable angina, especially if there are other options.” However, she noted that many patients on tofacitinib have already failed on older treatments.

These data emphasize the importance of addressing CV risk with patients, said Brittany N. Weber, MD, PhD, a cardio-rheumatologist at Brigham and Women’s Hospital who works with Dr. Liao. “It is also an opportunity to discuss modification of risk factors and to discuss primary prevention therapies, such as statin therapy, where appropriate,” she added. “Based on the individual’s cardiovascular risk, there may be a role for further risk stratification to further understand an individual’s risk, which can also inform primary prevention cardiovascular therapies and help guide these discussions.” Risk stratification could include cardiac CT for calcium scoring or cardiac coronary CT angiography for determining atherosclerotic burden.

The study was sponsored by Pfizer. Dr. Charles-Schoeman disclosed relationships with AbbVie, Bristol-Myers Squibb, Gilead Sciences, Pfizer, and Regeneron-Sanofi. Dr. Liao and Dr. Weber have no relevant disclosures.

Additional analyses of a postmarketing trial that was required after the Food and Drug Administration’s approval of the Janus kinase inhibitor tofacitinib (Xeljanz, Xeljanz XR) has identified characteristics of older patients with rheumatoid arthritis with at least one cardiovascular risk factor who may be at higher risk for major adverse cardiovascular events (MACE) when taking the drug.

Results from the phase 3b/4 ORAL Surveillance trial presented at the virtual annual meeting of the American College of Rheumatology show that people taking tofacitinib for RA with at least one cardiovascular (CV) risk factor had a nonsignificant higher risk for MACE than did people taking tumor necrosis factor inhibitors (TNFi), with the risk from tofacitinib more pronounced in current smokers, aspirin users, people older than 65 years, and men, compared with women.

“It is the first large, randomized safety study of active RA patients with increased CV risk comparing tofacitinib to TNF inhibition,” study author Christina Charles-Schoeman, MD, said in an interview. “These data emphasize the importance of assessing baseline CV risk when treating patients with RA.” Dr. Charles-Schoeman is chief of rheumatology at the University of California, Los Angeles.

The results shed further light on the trial’s findings, which the FDA used in September 2021 to mandate boxed warnings about the risk of MI or stroke, cancer, venous thromboembolism, and death, as well as updated indications, for tofacitinib and other JAK inhibitors baricitinib (Olumiant) and upadacitinib (Rinvoq). The FDA limited all approved uses of these three medications to patients who have not responded well to TNFi to ensure their benefits outweigh their risks.

Tofacitinib is indicated for RA, psoriatic arthritis, ulcerative colitis, and polyarticular course juvenile idiopathic arthritis. Baricitinib and upadacitinib are approved only for RA.

While the overall results of the trial results show nonsignificant increased incidence rates for MACE in tofacitinib users versus TNFI users, Katherine Liao, MD, a rheumatologist at Brigham and Women’s Hospital in Boston, noted that more information is needed to determine who is at greatest risk. “Another thing to keep in mind is, while there was evidence of an elevated relative risk for MACE, compared to TNFi, the absolute risk, based on the numbers what we know so far, is small,” she said.

The trial compared two different doses of tofacitinib – 5 mg (1,455 patients) and 10 mg (n = 1,456) twice daily – and TNFi (n = 1,451) in people with moderate to severe RA over age 50. Patient characteristics were similar across all three treatment arms, Dr. Charles-Schoeman said. All patients had inadequate response to methotrexate, and about 57% in all three treatment groups were taking corticosteroids. The 10-mg tofacitinib patients switched to the 5-mg dose in February 2019 but represent the 10-mg group in the study analysis.

ORAL Surveillance demonstrated a 24% greater risk of MACE in the 5-mg tofacitinib patients and a 43% heightened risk the 10-mg group, compared with patients who received a TNFi.

The differentiating factor for MACE incidence was MI. The higher- and lower-dose tofacitinib groups had 69% and 80% greater risk for MI. While the risk for fatal MI were similar across all three treatment groups, the risk for nonfatal MI were more than doubled in the respective tofacitinib groups: hazard ratios of 2.32 and 2.08. The incidence of stroke was similar across all three arms, Dr. Charles-Schoeman said.

The study identified a number of baseline characteristics as independent overall risk factors for MACE across all treatment groups. Current smoking and aspirin use more than doubled the risk (HR, 2.18; P < .0001 and HR, 2.11; P = .004, respectively), while age greater than 65 years and male sex approached that level (HR, 1.81; P = .0011 and HR, 1.81; P = .0015) approached that level. Other factors that elevated the risk of MACE to a lesser extent were a history of diabetes, hypertension or coronary artery procedures, and a total cholesterol to HDL ratio greater than4.

Other ORAL Surveillance subanalyses and tofacitinib real-world data reported

This was one of several analyses presented at ACR 2021 that compared adverse event risks for tofacitinib versus TNFi drugs. A separate analysis of claims data from patients with RA in two U.S. insurance databases plus Medicare found a statistically nonsignificant increased risk of adverse CV outcomes (MI or stroke) with tofacitinib, compared with TNFi users, among patients who met the same inclusion and exclusion criteria of the ORAL Surveillance trial but not in a “real-world evidence” cohort of more than 102,000 patients with RA in routine care from the databases.

Two additional ORAL Surveillance analyses presented at ACR 2021 gave details about risk factors for higher rates of malignancies and venous thromboembolic events found in patients taking tofacitinib with at least one CV risk factor. As would be expected, older age (≥65 vs. 50-64 years) and current or past smoking (vs. never smoking) were independent risk factors for higher malignancy rates across all treatment arms. Pulmonary embolism events across treatment groups were independently associated with a history of venous thromboembolism, baseline use of oral contraceptives or hormone replacement therapy, baseline body mass index of at least 30 kg/m², age 65 or older, and history of hypertension.

The ORAL Surveillance findings are worth considering when determining treatments for RA patients with CV risk factors, Dr. Charles-Schoeman said. “Tofacitinib remains an effective RA treatment,” she said. “The choice of specific RA treatment for any patient remains an individual decision between the patient and physician, which is decided based on a number of different factors. This new study provides additional information regarding both tofacitinib as well as traditional CV risk factors for discussion with the patient.”

The ORAL Surveillance results may give rheumatologists reason to rethink use of tofacitinib in some patients with CV risk, said Dr. Liao of Brigham and Women’s Hospital in Boston. “Currently, we have limited data and are still awaiting a report of the full trial results,” she said in an interview. “Based on the data available, I can think of a few patients in my clinic where I would reconsider use of these drugs, i.e., history of heart attack with stable angina, especially if there are other options.” However, she noted that many patients on tofacitinib have already failed on older treatments.

These data emphasize the importance of addressing CV risk with patients, said Brittany N. Weber, MD, PhD, a cardio-rheumatologist at Brigham and Women’s Hospital who works with Dr. Liao. “It is also an opportunity to discuss modification of risk factors and to discuss primary prevention therapies, such as statin therapy, where appropriate,” she added. “Based on the individual’s cardiovascular risk, there may be a role for further risk stratification to further understand an individual’s risk, which can also inform primary prevention cardiovascular therapies and help guide these discussions.” Risk stratification could include cardiac CT for calcium scoring or cardiac coronary CT angiography for determining atherosclerotic burden.

The study was sponsored by Pfizer. Dr. Charles-Schoeman disclosed relationships with AbbVie, Bristol-Myers Squibb, Gilead Sciences, Pfizer, and Regeneron-Sanofi. Dr. Liao and Dr. Weber have no relevant disclosures.

Immunosuppressed patients with autoimmune diseases who received the Moderna mRNA-1273 SARS-CoV-2 two-dose vaccine series had a frequency of adverse events similar to the general population albeit with a somewhat reduced, but still significant, antibody response with no severe vaccine-related disease flares, results of a prospective, nonrandomized open-label comparative trial in Canada demonstrated.

At the same time, patients with RA who were taking rituximab and patients with systemic lupus erythematosus (SLE) who were taking mycophenolate mofetil seemed to have reduced humoral responses after receiving the vaccine, said Ines Colmegna, MD, reporting results of the COVID-19 Vaccine in Immunosuppressed Adults with Autoimmune Disease (COVIAAD) study as a late-breaking poster abstract at the virtual annual meeting of the American College of Rheumatology. Dr. Colmegna is an associate professor of rheumatology in the division of experimental medicine at McGill University, Montreal.

“The frequency of adverse events, specifically the reactogenicity in people with comorbid conditions regardless of their diagnosis, was similar to healthy controls in this study, and their frequency was similar also the initial studies in the general population,” Dr. Colmegna said.

COVIAAD prospectively enrolled 220 fully vaccinated patients, 162 with rheumatic disease (131 with RA, 23 with SLE, and 8 with other diseases) and 58 controls. Adverse events a week and a month after each dose was the primary outcome. The postvaccine presence of the IgG antibody against the SARS-CoV-2 spike protein and the receptor binding domain (IgG-RBD) was the secondary outcome. Dr. Colmegna said that the study will continue evaluating participants after they get a third dose.

The Canadian trial appears to validate the ACR’s COVID-19 vaccine guidance, the fourth version of which was issued in October, said Jeffrey Curtis, MD, MS, MPH, professor of immunology and rheumatology at the University of Alabama at Birmingham and lead of the ACR COVID-19 Vaccine Guidance Task Force. Specifically, the guidance recommends that patients on rituximab or other anti-CD20 B-cell–depleting agents discuss vaccine timing with their rheumatologist.

“A few things changed over time when there was a paucity of evidence for any vaccine, but as time has gone on, mostly we were more correct than we weren’t,” Dr. Curtis said of the task force’s work. “The evidence that now is in this poster with regard to systemic lupus erythematosus and mycophenolate mofetil is [that] you have impaired vaccine response. If you’re on a B-cell drug like rituximab, you really have impaired vaccine response.”

In the study, 100% of controls had immunogenicity in terms of anti-spike and anti-RBD levels after the first and second dose. The rate of immunogenicity after the first and second dose were 67% and 88% in all patients with RA, and 35% and 78% in patients with SLE who were taking mycophenolate mofetil. The subset of patients with RA on rituximab (n = 17) had rates of immunogenicity of 5.9% and 17.6%, respectively.

“Measured antibody response is not the only way in which people develop a response to a vaccine, and there are also similar responses that occur even in people who are on rituximab and have not developed antibodies,” Dr. Colmegna said. “That’s a very important message also that we need to convey to patients: The immune response really extends beyond antibody protection.”

Overall, disease activity in both patients with RA and SLE did not appreciably change from baseline within 7 days and 28 days of each vaccine dose.

The study raises important questions about the timing of the vaccine, particularly in patients on rituximab, Dr. Colmegna said in an interview. “In theory, there is no element to suggest that, if you would schedule the vaccine a month prior to the next dose of rituximab, the effect of the drug would have decreased the number of B cells, and that the possibility of developing antibodies in response to the vaccine might be better if you give rituximab a month later when the amount of the drug and the effect of the drug is maximal,” she said. The average interval between patients receiving rituximab and vaccines was 4.5 months, Dr. Colmegna said in answering a question after her presentation.

Dr. Curtis said that the effect of holding rituximab or the vaccine to boost antibodies “is somewhat yet unknown. We think it will help, but that’s not a guarantee,” he said. “We don’t have direct evidence that just because the drug impairs vaccine response, that holding that drug for a week or 2 is going to take care of the problem.”

The study does arm rheumatologists with more information for discussing COVID vaccines with vaccine-hesitant patients with autoimmune diseases, Dr. Curtis said.

“It gives them evidence that for most of our immunomodulatory drugs the vaccine works pretty well,” he said. “The poster provides evidence that, compared to healthy controls, the vaccine doesn’t work quite as well in some patients, but for most people it actually did work pretty well. That reinforces the message: Go get vaccinated because [you] will mount [an immune] response, even, if that response isn’t quite as brisk as it is in healthy people.”

Dr. Colmegna and Dr. Curtis have no relevant relationships to disclose. The study received funding from Health and Social Services Quebec.

Immunosuppressed patients with autoimmune diseases who received the Moderna mRNA-1273 SARS-CoV-2 two-dose vaccine series had a frequency of adverse events similar to the general population albeit with a somewhat reduced, but still significant, antibody response with no severe vaccine-related disease flares, results of a prospective, nonrandomized open-label comparative trial in Canada demonstrated.

At the same time, patients with RA who were taking rituximab and patients with systemic lupus erythematosus (SLE) who were taking mycophenolate mofetil seemed to have reduced humoral responses after receiving the vaccine, said Ines Colmegna, MD, reporting results of the COVID-19 Vaccine in Immunosuppressed Adults with Autoimmune Disease (COVIAAD) study as a late-breaking poster abstract at the virtual annual meeting of the American College of Rheumatology. Dr. Colmegna is an associate professor of rheumatology in the division of experimental medicine at McGill University, Montreal.

“The frequency of adverse events, specifically the reactogenicity in people with comorbid conditions regardless of their diagnosis, was similar to healthy controls in this study, and their frequency was similar also the initial studies in the general population,” Dr. Colmegna said.

COVIAAD prospectively enrolled 220 fully vaccinated patients, 162 with rheumatic disease (131 with RA, 23 with SLE, and 8 with other diseases) and 58 controls. Adverse events a week and a month after each dose was the primary outcome. The postvaccine presence of the IgG antibody against the SARS-CoV-2 spike protein and the receptor binding domain (IgG-RBD) was the secondary outcome. Dr. Colmegna said that the study will continue evaluating participants after they get a third dose.

The Canadian trial appears to validate the ACR’s COVID-19 vaccine guidance, the fourth version of which was issued in October, said Jeffrey Curtis, MD, MS, MPH, professor of immunology and rheumatology at the University of Alabama at Birmingham and lead of the ACR COVID-19 Vaccine Guidance Task Force. Specifically, the guidance recommends that patients on rituximab or other anti-CD20 B-cell–depleting agents discuss vaccine timing with their rheumatologist.

“A few things changed over time when there was a paucity of evidence for any vaccine, but as time has gone on, mostly we were more correct than we weren’t,” Dr. Curtis said of the task force’s work. “The evidence that now is in this poster with regard to systemic lupus erythematosus and mycophenolate mofetil is [that] you have impaired vaccine response. If you’re on a B-cell drug like rituximab, you really have impaired vaccine response.”

In the study, 100% of controls had immunogenicity in terms of anti-spike and anti-RBD levels after the first and second dose. The rate of immunogenicity after the first and second dose were 67% and 88% in all patients with RA, and 35% and 78% in patients with SLE who were taking mycophenolate mofetil. The subset of patients with RA on rituximab (n = 17) had rates of immunogenicity of 5.9% and 17.6%, respectively.

“Measured antibody response is not the only way in which people develop a response to a vaccine, and there are also similar responses that occur even in people who are on rituximab and have not developed antibodies,” Dr. Colmegna said. “That’s a very important message also that we need to convey to patients: The immune response really extends beyond antibody protection.”

Overall, disease activity in both patients with RA and SLE did not appreciably change from baseline within 7 days and 28 days of each vaccine dose.

The study raises important questions about the timing of the vaccine, particularly in patients on rituximab, Dr. Colmegna said in an interview. “In theory, there is no element to suggest that, if you would schedule the vaccine a month prior to the next dose of rituximab, the effect of the drug would have decreased the number of B cells, and that the possibility of developing antibodies in response to the vaccine might be better if you give rituximab a month later when the amount of the drug and the effect of the drug is maximal,” she said. The average interval between patients receiving rituximab and vaccines was 4.5 months, Dr. Colmegna said in answering a question after her presentation.

Dr. Curtis said that the effect of holding rituximab or the vaccine to boost antibodies “is somewhat yet unknown. We think it will help, but that’s not a guarantee,” he said. “We don’t have direct evidence that just because the drug impairs vaccine response, that holding that drug for a week or 2 is going to take care of the problem.”

The study does arm rheumatologists with more information for discussing COVID vaccines with vaccine-hesitant patients with autoimmune diseases, Dr. Curtis said.

“It gives them evidence that for most of our immunomodulatory drugs the vaccine works pretty well,” he said. “The poster provides evidence that, compared to healthy controls, the vaccine doesn’t work quite as well in some patients, but for most people it actually did work pretty well. That reinforces the message: Go get vaccinated because [you] will mount [an immune] response, even, if that response isn’t quite as brisk as it is in healthy people.”

Dr. Colmegna and Dr. Curtis have no relevant relationships to disclose. The study received funding from Health and Social Services Quebec.

Immunosuppressed patients with autoimmune diseases who received the Moderna mRNA-1273 SARS-CoV-2 two-dose vaccine series had a frequency of adverse events similar to the general population albeit with a somewhat reduced, but still significant, antibody response with no severe vaccine-related disease flares, results of a prospective, nonrandomized open-label comparative trial in Canada demonstrated.

At the same time, patients with RA who were taking rituximab and patients with systemic lupus erythematosus (SLE) who were taking mycophenolate mofetil seemed to have reduced humoral responses after receiving the vaccine, said Ines Colmegna, MD, reporting results of the COVID-19 Vaccine in Immunosuppressed Adults with Autoimmune Disease (COVIAAD) study as a late-breaking poster abstract at the virtual annual meeting of the American College of Rheumatology. Dr. Colmegna is an associate professor of rheumatology in the division of experimental medicine at McGill University, Montreal.

“The frequency of adverse events, specifically the reactogenicity in people with comorbid conditions regardless of their diagnosis, was similar to healthy controls in this study, and their frequency was similar also the initial studies in the general population,” Dr. Colmegna said.

COVIAAD prospectively enrolled 220 fully vaccinated patients, 162 with rheumatic disease (131 with RA, 23 with SLE, and 8 with other diseases) and 58 controls. Adverse events a week and a month after each dose was the primary outcome. The postvaccine presence of the IgG antibody against the SARS-CoV-2 spike protein and the receptor binding domain (IgG-RBD) was the secondary outcome. Dr. Colmegna said that the study will continue evaluating participants after they get a third dose.

The Canadian trial appears to validate the ACR’s COVID-19 vaccine guidance, the fourth version of which was issued in October, said Jeffrey Curtis, MD, MS, MPH, professor of immunology and rheumatology at the University of Alabama at Birmingham and lead of the ACR COVID-19 Vaccine Guidance Task Force. Specifically, the guidance recommends that patients on rituximab or other anti-CD20 B-cell–depleting agents discuss vaccine timing with their rheumatologist.

“A few things changed over time when there was a paucity of evidence for any vaccine, but as time has gone on, mostly we were more correct than we weren’t,” Dr. Curtis said of the task force’s work. “The evidence that now is in this poster with regard to systemic lupus erythematosus and mycophenolate mofetil is [that] you have impaired vaccine response. If you’re on a B-cell drug like rituximab, you really have impaired vaccine response.”

In the study, 100% of controls had immunogenicity in terms of anti-spike and anti-RBD levels after the first and second dose. The rate of immunogenicity after the first and second dose were 67% and 88% in all patients with RA, and 35% and 78% in patients with SLE who were taking mycophenolate mofetil. The subset of patients with RA on rituximab (n = 17) had rates of immunogenicity of 5.9% and 17.6%, respectively.

“Measured antibody response is not the only way in which people develop a response to a vaccine, and there are also similar responses that occur even in people who are on rituximab and have not developed antibodies,” Dr. Colmegna said. “That’s a very important message also that we need to convey to patients: The immune response really extends beyond antibody protection.”

Overall, disease activity in both patients with RA and SLE did not appreciably change from baseline within 7 days and 28 days of each vaccine dose.

The study raises important questions about the timing of the vaccine, particularly in patients on rituximab, Dr. Colmegna said in an interview. “In theory, there is no element to suggest that, if you would schedule the vaccine a month prior to the next dose of rituximab, the effect of the drug would have decreased the number of B cells, and that the possibility of developing antibodies in response to the vaccine might be better if you give rituximab a month later when the amount of the drug and the effect of the drug is maximal,” she said. The average interval between patients receiving rituximab and vaccines was 4.5 months, Dr. Colmegna said in answering a question after her presentation.

Dr. Curtis said that the effect of holding rituximab or the vaccine to boost antibodies “is somewhat yet unknown. We think it will help, but that’s not a guarantee,” he said. “We don’t have direct evidence that just because the drug impairs vaccine response, that holding that drug for a week or 2 is going to take care of the problem.”

The study does arm rheumatologists with more information for discussing COVID vaccines with vaccine-hesitant patients with autoimmune diseases, Dr. Curtis said.

“It gives them evidence that for most of our immunomodulatory drugs the vaccine works pretty well,” he said. “The poster provides evidence that, compared to healthy controls, the vaccine doesn’t work quite as well in some patients, but for most people it actually did work pretty well. That reinforces the message: Go get vaccinated because [you] will mount [an immune] response, even, if that response isn’t quite as brisk as it is in healthy people.”

Dr. Colmegna and Dr. Curtis have no relevant relationships to disclose. The study received funding from Health and Social Services Quebec.

For patients with rheumatoid arthritis (RA) for whom a first Janus kinase inhibitor (JAKi) has failed, there appears to be no difference in treatment effectiveness whether the patient is cycled to a second JAKi or receives a biologic disease-modifying antirheumatic drug (bDMARD), a study of international patient registry data suggests.

However, patients who are prescribed a different JAKi after the first has failed them tend to have conditions that are more difficult to treat than do patients who are switched to a bDMARD after JAKi failure. In addition, adverse events that occur with the first JAKi are likely to occur again if a different agent in the same class is used, reported Manuel Pombo-Suarez, MD, PhD, adjunct professor of medicine at the University Hospital of Santiago de Compostela, Spain.

“When the first JAK inhibitor was stopped due to an adverse event, it was also more likely that the second JAK inhibitor would be stopped for the same reason,” he said in an oral abstract presentation during the American College of Rheumatology (ACR) 2021 Annual Meeting, which was held online.

The 2019 update of the European Alliance of Associations for Rheumatology (EULAR) guidelines for RA recommend that for patients for whom a first JAKi has failed, clinicians can consider a different JAKi or switch to a bDMARD. But at the time the guidelines were published, no data were available from studies in which a second JAKi was used after the failure of a first JAKi, Dr. Pombo-Suarez noted.

“We are trying to shed a light on this growing population of patients, as prescription of these drugs is increasing and new JAK inhibitors come into play, meaning that this scenario, we propose, is becoming more and more frequent in real life. We must provide a solution for these patients,” he said.
 

Pooled registry data

The investigators compared the effectiveness of the two approaches with respect to rates of drug retention and Disease Activity Score in 28 joints (DAS28).

They conducted a nested cohort study using data from 14 national registries that are part of the JAK-pot collaboration.

They pooled data from each registry on patients with RA for whom a first JAKi had failed and who were then treated with either a second JAKi or a bDMARD.

They identified a total of 708 patients for whom a JAKi had failed initially. Of these patients, 154 were given a different JAKi, and 554 were switched to a bDMARD. In each group, women accounted for a large majority of patients.

The mean age was slightly older among those who received a second JAKi (58.41 years vs. 54.74 years for patients who were given a bDMARD). The mean disease duration was 13.95 years and 11.37 years, respectively.

In each group, approximately 77% of patients received tofacitinib (Xeljanz).

At baseline, the mean DAS28 scores were similar between the groups: 4.10 in the group that received a second JAKi, and 4.17 in the group given a bDMARD.

Reasons for initially stopping use of a JAKi were as follows: adverse events (27.3% of those who took a second JAKi after they had stopped taking one initially, and 17.9% of patients who received a bDMARD); lack of efficacy (61% and 65%, respectively), and other reasons (11.7% and 17.1%, respectively).

At 2 years’ follow-up, drug survival rates were similar between the two treatment arms, although there was a nonsignificant trend toward a higher rate of discontinuation among patients who were given a second JAKi after they stopped taking the first JAKi because of adverse events. In contrast, there was also a nonsignificant trend toward lower discontinuation rates among patients who were given a second JAKi after they had stopped taking the first JAKi because of lack of efficacy.

As noted before, patients who stopped taking the first JAKi because of an adverse event were more likely to stop taking the second JAKi because of they experienced either the same or a different adverse event, whereas patients who started taking a bDMARD were equally likely to stop taking the second therapy because of either adverse events or lack of efficacy.

The treatment strategies were virtually identical with respect to improvement of DAS28 at 7 months after the start of therapy.

Dr. Pombo-Suarez acknowledged that the study was limited by the fact that heterogeneity between countries could not be assessed, owing to the small sample sizes in each nation’s registry. Other limitations include short follow-up and the fact that tofacitinib was used as the first JAKi by the large majority of patients.

What’s your practice?

In a media briefing during which Dr. Pombo-Suarez discussed the study findings, this news organization polled other speakers who were not involved in the study about their go-to strategies when JAKi therapy fails.

Silje Watterdal Syversen, MD, PhD, a consultant rheumatologist and researcher at Diakonhjemmet Hospital, Oslo, said that she would choose to switch to a tumor necrosis factor [TNF] inhibitor.

“I think it would depend on what prior treatment the patient had received,” said April Jorge, MD, a rheumatologist at Massachusetts General Hospital, Boston. “In my practice, patients receiving a JAK inhibitor typically failed on their biologics. I haven’t had many fail a JAK inhibitor – a small sample size.”

“That’s what we see in our study,” Dr. Pombo-Suarez said. “Most of the patients that cycled JAK inhibitors had higher numbers of biologics compared with switchers.”

“I can share my experience, which is a greater comfort level with cycling a TNF antagonist. I agree with Dr Jorge: I don’t use JAK inhibitors in the first line for rheumatoid arthritis, but based on the work that’s been described here and future data, I might have a greater comfort level cycling JAK inhibitors once the data support such an approach,” commented H. Michael Belmont, MD, professor of medicine at New York University, co-director of the NYU Lupus Center, and medical director of Bellevue Hospital Lupus Center, New York.

The JAK-pot study is supported by unrestricted research grants from AbbVie and Galapagos. Dr. Pombo-Suarez has received adviser and speaker honoraria from several companies other than the funders. Dr. Syversen has received honoraria from Thermo Fisher. Dr. Jorge has disclosed no relevant financial relationships. Dr. Belmont has received honoraria from Alexion.

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

For patients with rheumatoid arthritis (RA) for whom a first Janus kinase inhibitor (JAKi) has failed, there appears to be no difference in treatment effectiveness whether the patient is cycled to a second JAKi or receives a biologic disease-modifying antirheumatic drug (bDMARD), a study of international patient registry data suggests.

However, patients who are prescribed a different JAKi after the first has failed them tend to have conditions that are more difficult to treat than do patients who are switched to a bDMARD after JAKi failure. In addition, adverse events that occur with the first JAKi are likely to occur again if a different agent in the same class is used, reported Manuel Pombo-Suarez, MD, PhD, adjunct professor of medicine at the University Hospital of Santiago de Compostela, Spain.

“When the first JAK inhibitor was stopped due to an adverse event, it was also more likely that the second JAK inhibitor would be stopped for the same reason,” he said in an oral abstract presentation during the American College of Rheumatology (ACR) 2021 Annual Meeting, which was held online.

The 2019 update of the European Alliance of Associations for Rheumatology (EULAR) guidelines for RA recommend that for patients for whom a first JAKi has failed, clinicians can consider a different JAKi or switch to a bDMARD. But at the time the guidelines were published, no data were available from studies in which a second JAKi was used after the failure of a first JAKi, Dr. Pombo-Suarez noted.

“We are trying to shed a light on this growing population of patients, as prescription of these drugs is increasing and new JAK inhibitors come into play, meaning that this scenario, we propose, is becoming more and more frequent in real life. We must provide a solution for these patients,” he said.
 

Pooled registry data

The investigators compared the effectiveness of the two approaches with respect to rates of drug retention and Disease Activity Score in 28 joints (DAS28).

They conducted a nested cohort study using data from 14 national registries that are part of the JAK-pot collaboration.

They pooled data from each registry on patients with RA for whom a first JAKi had failed and who were then treated with either a second JAKi or a bDMARD.

They identified a total of 708 patients for whom a JAKi had failed initially. Of these patients, 154 were given a different JAKi, and 554 were switched to a bDMARD. In each group, women accounted for a large majority of patients.

The mean age was slightly older among those who received a second JAKi (58.41 years vs. 54.74 years for patients who were given a bDMARD). The mean disease duration was 13.95 years and 11.37 years, respectively.

In each group, approximately 77% of patients received tofacitinib (Xeljanz).

At baseline, the mean DAS28 scores were similar between the groups: 4.10 in the group that received a second JAKi, and 4.17 in the group given a bDMARD.

Reasons for initially stopping use of a JAKi were as follows: adverse events (27.3% of those who took a second JAKi after they had stopped taking one initially, and 17.9% of patients who received a bDMARD); lack of efficacy (61% and 65%, respectively), and other reasons (11.7% and 17.1%, respectively).

At 2 years’ follow-up, drug survival rates were similar between the two treatment arms, although there was a nonsignificant trend toward a higher rate of discontinuation among patients who were given a second JAKi after they stopped taking the first JAKi because of adverse events. In contrast, there was also a nonsignificant trend toward lower discontinuation rates among patients who were given a second JAKi after they had stopped taking the first JAKi because of lack of efficacy.

As noted before, patients who stopped taking the first JAKi because of an adverse event were more likely to stop taking the second JAKi because of they experienced either the same or a different adverse event, whereas patients who started taking a bDMARD were equally likely to stop taking the second therapy because of either adverse events or lack of efficacy.

The treatment strategies were virtually identical with respect to improvement of DAS28 at 7 months after the start of therapy.

Dr. Pombo-Suarez acknowledged that the study was limited by the fact that heterogeneity between countries could not be assessed, owing to the small sample sizes in each nation’s registry. Other limitations include short follow-up and the fact that tofacitinib was used as the first JAKi by the large majority of patients.

What’s your practice?

In a media briefing during which Dr. Pombo-Suarez discussed the study findings, this news organization polled other speakers who were not involved in the study about their go-to strategies when JAKi therapy fails.

Silje Watterdal Syversen, MD, PhD, a consultant rheumatologist and researcher at Diakonhjemmet Hospital, Oslo, said that she would choose to switch to a tumor necrosis factor [TNF] inhibitor.

“I think it would depend on what prior treatment the patient had received,” said April Jorge, MD, a rheumatologist at Massachusetts General Hospital, Boston. “In my practice, patients receiving a JAK inhibitor typically failed on their biologics. I haven’t had many fail a JAK inhibitor – a small sample size.”

“That’s what we see in our study,” Dr. Pombo-Suarez said. “Most of the patients that cycled JAK inhibitors had higher numbers of biologics compared with switchers.”

“I can share my experience, which is a greater comfort level with cycling a TNF antagonist. I agree with Dr Jorge: I don’t use JAK inhibitors in the first line for rheumatoid arthritis, but based on the work that’s been described here and future data, I might have a greater comfort level cycling JAK inhibitors once the data support such an approach,” commented H. Michael Belmont, MD, professor of medicine at New York University, co-director of the NYU Lupus Center, and medical director of Bellevue Hospital Lupus Center, New York.

The JAK-pot study is supported by unrestricted research grants from AbbVie and Galapagos. Dr. Pombo-Suarez has received adviser and speaker honoraria from several companies other than the funders. Dr. Syversen has received honoraria from Thermo Fisher. Dr. Jorge has disclosed no relevant financial relationships. Dr. Belmont has received honoraria from Alexion.

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

For patients with rheumatoid arthritis (RA) for whom a first Janus kinase inhibitor (JAKi) has failed, there appears to be no difference in treatment effectiveness whether the patient is cycled to a second JAKi or receives a biologic disease-modifying antirheumatic drug (bDMARD), a study of international patient registry data suggests.

However, patients who are prescribed a different JAKi after the first has failed them tend to have conditions that are more difficult to treat than do patients who are switched to a bDMARD after JAKi failure. In addition, adverse events that occur with the first JAKi are likely to occur again if a different agent in the same class is used, reported Manuel Pombo-Suarez, MD, PhD, adjunct professor of medicine at the University Hospital of Santiago de Compostela, Spain.

“When the first JAK inhibitor was stopped due to an adverse event, it was also more likely that the second JAK inhibitor would be stopped for the same reason,” he said in an oral abstract presentation during the American College of Rheumatology (ACR) 2021 Annual Meeting, which was held online.

The 2019 update of the European Alliance of Associations for Rheumatology (EULAR) guidelines for RA recommend that for patients for whom a first JAKi has failed, clinicians can consider a different JAKi or switch to a bDMARD. But at the time the guidelines were published, no data were available from studies in which a second JAKi was used after the failure of a first JAKi, Dr. Pombo-Suarez noted.

“We are trying to shed a light on this growing population of patients, as prescription of these drugs is increasing and new JAK inhibitors come into play, meaning that this scenario, we propose, is becoming more and more frequent in real life. We must provide a solution for these patients,” he said.
 

Pooled registry data

The investigators compared the effectiveness of the two approaches with respect to rates of drug retention and Disease Activity Score in 28 joints (DAS28).

They conducted a nested cohort study using data from 14 national registries that are part of the JAK-pot collaboration.

They pooled data from each registry on patients with RA for whom a first JAKi had failed and who were then treated with either a second JAKi or a bDMARD.

They identified a total of 708 patients for whom a JAKi had failed initially. Of these patients, 154 were given a different JAKi, and 554 were switched to a bDMARD. In each group, women accounted for a large majority of patients.

The mean age was slightly older among those who received a second JAKi (58.41 years vs. 54.74 years for patients who were given a bDMARD). The mean disease duration was 13.95 years and 11.37 years, respectively.

In each group, approximately 77% of patients received tofacitinib (Xeljanz).

At baseline, the mean DAS28 scores were similar between the groups: 4.10 in the group that received a second JAKi, and 4.17 in the group given a bDMARD.

Reasons for initially stopping use of a JAKi were as follows: adverse events (27.3% of those who took a second JAKi after they had stopped taking one initially, and 17.9% of patients who received a bDMARD); lack of efficacy (61% and 65%, respectively), and other reasons (11.7% and 17.1%, respectively).

At 2 years’ follow-up, drug survival rates were similar between the two treatment arms, although there was a nonsignificant trend toward a higher rate of discontinuation among patients who were given a second JAKi after they stopped taking the first JAKi because of adverse events. In contrast, there was also a nonsignificant trend toward lower discontinuation rates among patients who were given a second JAKi after they had stopped taking the first JAKi because of lack of efficacy.

As noted before, patients who stopped taking the first JAKi because of an adverse event were more likely to stop taking the second JAKi because of they experienced either the same or a different adverse event, whereas patients who started taking a bDMARD were equally likely to stop taking the second therapy because of either adverse events or lack of efficacy.

The treatment strategies were virtually identical with respect to improvement of DAS28 at 7 months after the start of therapy.

Dr. Pombo-Suarez acknowledged that the study was limited by the fact that heterogeneity between countries could not be assessed, owing to the small sample sizes in each nation’s registry. Other limitations include short follow-up and the fact that tofacitinib was used as the first JAKi by the large majority of patients.

What’s your practice?

In a media briefing during which Dr. Pombo-Suarez discussed the study findings, this news organization polled other speakers who were not involved in the study about their go-to strategies when JAKi therapy fails.

Silje Watterdal Syversen, MD, PhD, a consultant rheumatologist and researcher at Diakonhjemmet Hospital, Oslo, said that she would choose to switch to a tumor necrosis factor [TNF] inhibitor.

“I think it would depend on what prior treatment the patient had received,” said April Jorge, MD, a rheumatologist at Massachusetts General Hospital, Boston. “In my practice, patients receiving a JAK inhibitor typically failed on their biologics. I haven’t had many fail a JAK inhibitor – a small sample size.”

“That’s what we see in our study,” Dr. Pombo-Suarez said. “Most of the patients that cycled JAK inhibitors had higher numbers of biologics compared with switchers.”

“I can share my experience, which is a greater comfort level with cycling a TNF antagonist. I agree with Dr Jorge: I don’t use JAK inhibitors in the first line for rheumatoid arthritis, but based on the work that’s been described here and future data, I might have a greater comfort level cycling JAK inhibitors once the data support such an approach,” commented H. Michael Belmont, MD, professor of medicine at New York University, co-director of the NYU Lupus Center, and medical director of Bellevue Hospital Lupus Center, New York.

The JAK-pot study is supported by unrestricted research grants from AbbVie and Galapagos. Dr. Pombo-Suarez has received adviser and speaker honoraria from several companies other than the funders. Dr. Syversen has received honoraria from Thermo Fisher. Dr. Jorge has disclosed no relevant financial relationships. Dr. Belmont has received honoraria from Alexion.

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

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.

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.

Patients with rheumatoid arthritis who are treated with methotrexate (MTX) are more than twice as likely to develop venous thromboembolism (VTE) when compared with patients who use hydroxychloroquine, according to data from a propensity score–matched cohort study.

“As the effect of these medications on the risk of VTE is largely unknown, we aimed to compare the rate of incident VTE after initiating MTX versus hydroxychloroquine among older patients with RA,” wrote Mengdong He, MHS, and coauthors from Brigham and Women’s Hospital and Harvard Medical School, both in Boston. Ms. At the time of the study, Ms. He was a research specialist but is now a medical student at the University of California, Los Angeles.

The results were published in Seminars in Arthritis and Rheumatism.

Using U.S. Medicare claims data from 2008 to 2017, the researchers identified patients with RA aged 65 years and older who initiated MTX or hydroxychloroquine without prior use of any immunomodulators for at least 365 days (that is, index date). Patients who used any conventional (other than methotrexate and hydroxychloroquine), biologic, or targeted synthetic disease-modifying antirheumatic drugs (DMARDs) any time prior to the index date were excluded.

The primary outcome of interest was incident VTE, a composite endpoint of pulmonary embolism (PE) or deep vein thrombosis (DVT). Secondary outcomes were PE, DVT, and all-cause mortality.

Results

After applying the eligibility criteria, a total of 68,648 RA patients who initiated either MTX (n = 41,197) or hydroxychloroquine (n = 27,451) as their first DMARD were identified and included in the analysis.

After 1:1 propensity score matching, the cohort consisted of 26,534 matched pairs of MTX and hydroxychloroquine initiators. The mean age was 74 years (standard deviation, 7 years), and 79% of the patients were female.

During a total of 56,686 person-years of follow-up, VTE occurred in 208 MTX (incidence, 6.94 per 1,000 person-years) and 83 hydroxychloroquine initiators (incidence, 3.11 per 1,000 person-years).

Patients who initiated MTX without prior use of any DMARDs had a higher risk of PE (hazard ratio, 3.30; 95% confidence interval, 2.28-4.77) and DVT (HR, 1.53; 95% CI, 1.07-2.19) than hydroxychloroquine initiators. However, all-cause mortality did not differ between the two groups (HR, 0.91; 95% CI, 0.83-1.00).

“MTX initiators had a relative risk of VTE higher than 2 and an absolute risk increase of about 4 per 1,000 person-years, compared with hydroxychloroquine initiators,” the authors wrote. “Results from the secondary outcome analyses were consistent and subgroup analyses found no meaningful treatment effect heterogeneity.”

The researchers acknowledged that a key limitation of the study was the use of claims-based algorithms to define outcomes. As a result, outcome misclassification is possible.

“While the study methodology was sound, patients with RA who receive hydroxychloroquine are very different than those who receive MTX, and it’s difficult to fully account for these differences using an administrative data set,” commented Kaleb Michaud, PhD, professor of internal medicine at the University of Nebraska, Omaha.

“Most clinicians are more interested in understanding the differences in VTE risk between MTX and Jakinibs [Janus kinase inhibitors] or MTX and biologics,” Dr. Michaud said.

“More research, particularly with randomized trials including the placebo arm, is needed to determine the causal relationships between the study drugs and VTE and whether MTX elevates or hydroxychloroquine reduces the risk of VTE,” the authors concluded.

The study was funded by internal resources in the division of pharmacoepidemiology and pharmacoeconomics at Brigham and Women’s Hospital and Harvard Medical School. Several authors reported financial relationships with the pharmaceutical industry.

Patients with rheumatoid arthritis who are treated with methotrexate (MTX) are more than twice as likely to develop venous thromboembolism (VTE) when compared with patients who use hydroxychloroquine, according to data from a propensity score–matched cohort study.

“As the effect of these medications on the risk of VTE is largely unknown, we aimed to compare the rate of incident VTE after initiating MTX versus hydroxychloroquine among older patients with RA,” wrote Mengdong He, MHS, and coauthors from Brigham and Women’s Hospital and Harvard Medical School, both in Boston. Ms. At the time of the study, Ms. He was a research specialist but is now a medical student at the University of California, Los Angeles.

The results were published in Seminars in Arthritis and Rheumatism.

Using U.S. Medicare claims data from 2008 to 2017, the researchers identified patients with RA aged 65 years and older who initiated MTX or hydroxychloroquine without prior use of any immunomodulators for at least 365 days (that is, index date). Patients who used any conventional (other than methotrexate and hydroxychloroquine), biologic, or targeted synthetic disease-modifying antirheumatic drugs (DMARDs) any time prior to the index date were excluded.

The primary outcome of interest was incident VTE, a composite endpoint of pulmonary embolism (PE) or deep vein thrombosis (DVT). Secondary outcomes were PE, DVT, and all-cause mortality.

Results

After applying the eligibility criteria, a total of 68,648 RA patients who initiated either MTX (n = 41,197) or hydroxychloroquine (n = 27,451) as their first DMARD were identified and included in the analysis.

After 1:1 propensity score matching, the cohort consisted of 26,534 matched pairs of MTX and hydroxychloroquine initiators. The mean age was 74 years (standard deviation, 7 years), and 79% of the patients were female.

During a total of 56,686 person-years of follow-up, VTE occurred in 208 MTX (incidence, 6.94 per 1,000 person-years) and 83 hydroxychloroquine initiators (incidence, 3.11 per 1,000 person-years).

Patients who initiated MTX without prior use of any DMARDs had a higher risk of PE (hazard ratio, 3.30; 95% confidence interval, 2.28-4.77) and DVT (HR, 1.53; 95% CI, 1.07-2.19) than hydroxychloroquine initiators. However, all-cause mortality did not differ between the two groups (HR, 0.91; 95% CI, 0.83-1.00).

“MTX initiators had a relative risk of VTE higher than 2 and an absolute risk increase of about 4 per 1,000 person-years, compared with hydroxychloroquine initiators,” the authors wrote. “Results from the secondary outcome analyses were consistent and subgroup analyses found no meaningful treatment effect heterogeneity.”

The researchers acknowledged that a key limitation of the study was the use of claims-based algorithms to define outcomes. As a result, outcome misclassification is possible.

“While the study methodology was sound, patients with RA who receive hydroxychloroquine are very different than those who receive MTX, and it’s difficult to fully account for these differences using an administrative data set,” commented Kaleb Michaud, PhD, professor of internal medicine at the University of Nebraska, Omaha.

“Most clinicians are more interested in understanding the differences in VTE risk between MTX and Jakinibs [Janus kinase inhibitors] or MTX and biologics,” Dr. Michaud said.

“More research, particularly with randomized trials including the placebo arm, is needed to determine the causal relationships between the study drugs and VTE and whether MTX elevates or hydroxychloroquine reduces the risk of VTE,” the authors concluded.

The study was funded by internal resources in the division of pharmacoepidemiology and pharmacoeconomics at Brigham and Women’s Hospital and Harvard Medical School. Several authors reported financial relationships with the pharmaceutical industry.

Patients with rheumatoid arthritis who are treated with methotrexate (MTX) are more than twice as likely to develop venous thromboembolism (VTE) when compared with patients who use hydroxychloroquine, according to data from a propensity score–matched cohort study.

“As the effect of these medications on the risk of VTE is largely unknown, we aimed to compare the rate of incident VTE after initiating MTX versus hydroxychloroquine among older patients with RA,” wrote Mengdong He, MHS, and coauthors from Brigham and Women’s Hospital and Harvard Medical School, both in Boston. Ms. At the time of the study, Ms. He was a research specialist but is now a medical student at the University of California, Los Angeles.

The results were published in Seminars in Arthritis and Rheumatism.

Using U.S. Medicare claims data from 2008 to 2017, the researchers identified patients with RA aged 65 years and older who initiated MTX or hydroxychloroquine without prior use of any immunomodulators for at least 365 days (that is, index date). Patients who used any conventional (other than methotrexate and hydroxychloroquine), biologic, or targeted synthetic disease-modifying antirheumatic drugs (DMARDs) any time prior to the index date were excluded.

The primary outcome of interest was incident VTE, a composite endpoint of pulmonary embolism (PE) or deep vein thrombosis (DVT). Secondary outcomes were PE, DVT, and all-cause mortality.

Results

After applying the eligibility criteria, a total of 68,648 RA patients who initiated either MTX (n = 41,197) or hydroxychloroquine (n = 27,451) as their first DMARD were identified and included in the analysis.

After 1:1 propensity score matching, the cohort consisted of 26,534 matched pairs of MTX and hydroxychloroquine initiators. The mean age was 74 years (standard deviation, 7 years), and 79% of the patients were female.

During a total of 56,686 person-years of follow-up, VTE occurred in 208 MTX (incidence, 6.94 per 1,000 person-years) and 83 hydroxychloroquine initiators (incidence, 3.11 per 1,000 person-years).

Patients who initiated MTX without prior use of any DMARDs had a higher risk of PE (hazard ratio, 3.30; 95% confidence interval, 2.28-4.77) and DVT (HR, 1.53; 95% CI, 1.07-2.19) than hydroxychloroquine initiators. However, all-cause mortality did not differ between the two groups (HR, 0.91; 95% CI, 0.83-1.00).

“MTX initiators had a relative risk of VTE higher than 2 and an absolute risk increase of about 4 per 1,000 person-years, compared with hydroxychloroquine initiators,” the authors wrote. “Results from the secondary outcome analyses were consistent and subgroup analyses found no meaningful treatment effect heterogeneity.”

The researchers acknowledged that a key limitation of the study was the use of claims-based algorithms to define outcomes. As a result, outcome misclassification is possible.

“While the study methodology was sound, patients with RA who receive hydroxychloroquine are very different than those who receive MTX, and it’s difficult to fully account for these differences using an administrative data set,” commented Kaleb Michaud, PhD, professor of internal medicine at the University of Nebraska, Omaha.

“Most clinicians are more interested in understanding the differences in VTE risk between MTX and Jakinibs [Janus kinase inhibitors] or MTX and biologics,” Dr. Michaud said.

“More research, particularly with randomized trials including the placebo arm, is needed to determine the causal relationships between the study drugs and VTE and whether MTX elevates or hydroxychloroquine reduces the risk of VTE,” the authors concluded.

The study was funded by internal resources in the division of pharmacoepidemiology and pharmacoeconomics at Brigham and Women’s Hospital and Harvard Medical School. Several authors reported financial relationships with the pharmaceutical industry.

Biosimilar medications have received significant attention recently in the treatment of rheumatoid arthritis (RA), though the effects of switching from the reference drug to a biosimilar is not known. The study by Fleischmann et al¹ looks at the safety and efficacy, as well as immunogenicity, of biosimilar adalimumab (ADL-PF) compared to the reference ADL-EU (European Union sourced adalimumab) in a randomized double-blind study. Patients were randomized to start and continue ADL-PF or start ADL-EU and switch to ADL-PF at week 26 or 52. Immunogenicity was measured using anti-drug antibodies (ADA). American College of Rheumatology (ACR20) response rates were similar among all groups, while ACR50 and ACR70 response rates were numerically lower in the week 52 switch group. ADA development was comparable between groups. Data were analyzed using descriptive statistics, but overall, safety, efficacy, and immunogenicity were similar between patients maintained on ADL-PF and those switched from ADL-EU at week 26 or 52.

Statins have long been associated with musculoskeletal symptoms in patients, but have also been postulated to have anti-inflammatory and immunomodulatory effects. Complicating the relationship is the knowledge that inflammation increases cardiovascular risk in RA patients. In a case-control study, Peterson et al² used an administrative database to examine the influence of statin use on development of RA. Cases were identified based on ICD-9 coding as well as a prescription for methotrexate after diagnosis. They were matched 1:1 with controls based on demographics and year of diagnosis. Statin use was evaluated. Statin use was associated with a small increase in risk of RA, which was diminished after adjusting for hyperlipidemia; a trend towards increase in risk with higher dose and duration of statin use was not statistically significant. Beyond this, the reduced risk after adjustment for hyperlipidemia is hard to interpret as an explanation of cause or effect of autoimmunity, and, given the small magnitude of increases and decreases in risk, may not be clinically meaningful.

In addition to patients with RA having a higher burden of cardiovascular disease necessitating use of statins, they also have a high risk of progressive secondary osteoarthritis requiring joint replacement surgery. Chang et al³ used a national claims-based dataset from China to examine risk of total knee or hip replacement (TKR and THR, respectively) in patients with RA. From 2000-2013 (ie, the onset of the biologic era), TKR and THR rates were examined in a cohort of biologic disease-modifying antirheumatic drug (bDMARD) users compared to conventional synthetic DMARD (csDMARD) users. Adjusted hazard ratios (HR) were lower for both TKD and THR in bDMARD users. Though RA activity was not examined, combined with the knowledge of the association of disease severity with bDMARD use, this study lends evidence to the benefits of more aggressive treatment.

Finally, much is made of the link between bDMARD and targeted synthetic DMARD use and malignancy due to reduced immunosurveillance, but concrete evidence is conflicting. Wetzman et al⁴ performed a systematic review of studies of patients with inflammatory arthritis (RA, psoriatic arthritis, and Ankylosing spondylitis) looking at cancer relapse or occurrence of new cancer. An increase in skin cancers (HR 1.32) was noted, but reassuringly no other increase in risk of recurrent or new cancer was seen.

References

1. Fleischmann R et al. Long-term efficacy, safety, and immunogenicity of the adalimumab biosimilar, PF-06410293, in patients with rheumatoid arthritis after switching from reference adalimumab (Humira®) or continuing biosimilar therapy: week 52–92 data from a randomized, double-blind, phase 3 trialArthritis Res Ther. 2021(Sep 25);23:248.
2. Peterson MN et al. Risk of rheumatoid arthritis diagnosis in statin users in a large nationwide US study. Arthritis Res Ther. 2021(Sep 18):23:244.
3. Chang YS et al. Effects of biologics on reducing the risks of total knee replacement and total hip replacement in rheumatoid arthritis. Rheumatology (Oxford). 2021(Sep 17):keab671.
4. Wetzman A et al. Risk of cancer after initiation of targeted therapies in patients with rheumatoid arthritis and a prior cancer: systematic review with meta-analysis. Arthritis Care Res (Hoboken). 2021(Sep 21): acr.24784.

Biosimilar medications have received significant attention recently in the treatment of rheumatoid arthritis (RA), though the effects of switching from the reference drug to a biosimilar is not known. The study by Fleischmann et al¹ looks at the safety and efficacy, as well as immunogenicity, of biosimilar adalimumab (ADL-PF) compared to the reference ADL-EU (European Union sourced adalimumab) in a randomized double-blind study. Patients were randomized to start and continue ADL-PF or start ADL-EU and switch to ADL-PF at week 26 or 52. Immunogenicity was measured using anti-drug antibodies (ADA). American College of Rheumatology (ACR20) response rates were similar among all groups, while ACR50 and ACR70 response rates were numerically lower in the week 52 switch group. ADA development was comparable between groups. Data were analyzed using descriptive statistics, but overall, safety, efficacy, and immunogenicity were similar between patients maintained on ADL-PF and those switched from ADL-EU at week 26 or 52.

Statins have long been associated with musculoskeletal symptoms in patients, but have also been postulated to have anti-inflammatory and immunomodulatory effects. Complicating the relationship is the knowledge that inflammation increases cardiovascular risk in RA patients. In a case-control study, Peterson et al² used an administrative database to examine the influence of statin use on development of RA. Cases were identified based on ICD-9 coding as well as a prescription for methotrexate after diagnosis. They were matched 1:1 with controls based on demographics and year of diagnosis. Statin use was evaluated. Statin use was associated with a small increase in risk of RA, which was diminished after adjusting for hyperlipidemia; a trend towards increase in risk with higher dose and duration of statin use was not statistically significant. Beyond this, the reduced risk after adjustment for hyperlipidemia is hard to interpret as an explanation of cause or effect of autoimmunity, and, given the small magnitude of increases and decreases in risk, may not be clinically meaningful.

In addition to patients with RA having a higher burden of cardiovascular disease necessitating use of statins, they also have a high risk of progressive secondary osteoarthritis requiring joint replacement surgery. Chang et al³ used a national claims-based dataset from China to examine risk of total knee or hip replacement (TKR and THR, respectively) in patients with RA. From 2000-2013 (ie, the onset of the biologic era), TKR and THR rates were examined in a cohort of biologic disease-modifying antirheumatic drug (bDMARD) users compared to conventional synthetic DMARD (csDMARD) users. Adjusted hazard ratios (HR) were lower for both TKD and THR in bDMARD users. Though RA activity was not examined, combined with the knowledge of the association of disease severity with bDMARD use, this study lends evidence to the benefits of more aggressive treatment.

Finally, much is made of the link between bDMARD and targeted synthetic DMARD use and malignancy due to reduced immunosurveillance, but concrete evidence is conflicting. Wetzman et al⁴ performed a systematic review of studies of patients with inflammatory arthritis (RA, psoriatic arthritis, and Ankylosing spondylitis) looking at cancer relapse or occurrence of new cancer. An increase in skin cancers (HR 1.32) was noted, but reassuringly no other increase in risk of recurrent or new cancer was seen.

References

1. Fleischmann R et al. Long-term efficacy, safety, and immunogenicity of the adalimumab biosimilar, PF-06410293, in patients with rheumatoid arthritis after switching from reference adalimumab (Humira®) or continuing biosimilar therapy: week 52–92 data from a randomized, double-blind, phase 3 trialArthritis Res Ther. 2021(Sep 25);23:248.
2. Peterson MN et al. Risk of rheumatoid arthritis diagnosis in statin users in a large nationwide US study. Arthritis Res Ther. 2021(Sep 18):23:244.
3. Chang YS et al. Effects of biologics on reducing the risks of total knee replacement and total hip replacement in rheumatoid arthritis. Rheumatology (Oxford). 2021(Sep 17):keab671.
4. Wetzman A et al. Risk of cancer after initiation of targeted therapies in patients with rheumatoid arthritis and a prior cancer: systematic review with meta-analysis. Arthritis Care Res (Hoboken). 2021(Sep 21): acr.24784.

Biosimilar medications have received significant attention recently in the treatment of rheumatoid arthritis (RA), though the effects of switching from the reference drug to a biosimilar is not known. The study by Fleischmann et al¹ looks at the safety and efficacy, as well as immunogenicity, of biosimilar adalimumab (ADL-PF) compared to the reference ADL-EU (European Union sourced adalimumab) in a randomized double-blind study. Patients were randomized to start and continue ADL-PF or start ADL-EU and switch to ADL-PF at week 26 or 52. Immunogenicity was measured using anti-drug antibodies (ADA). American College of Rheumatology (ACR20) response rates were similar among all groups, while ACR50 and ACR70 response rates were numerically lower in the week 52 switch group. ADA development was comparable between groups. Data were analyzed using descriptive statistics, but overall, safety, efficacy, and immunogenicity were similar between patients maintained on ADL-PF and those switched from ADL-EU at week 26 or 52.

Statins have long been associated with musculoskeletal symptoms in patients, but have also been postulated to have anti-inflammatory and immunomodulatory effects. Complicating the relationship is the knowledge that inflammation increases cardiovascular risk in RA patients. In a case-control study, Peterson et al² used an administrative database to examine the influence of statin use on development of RA. Cases were identified based on ICD-9 coding as well as a prescription for methotrexate after diagnosis. They were matched 1:1 with controls based on demographics and year of diagnosis. Statin use was evaluated. Statin use was associated with a small increase in risk of RA, which was diminished after adjusting for hyperlipidemia; a trend towards increase in risk with higher dose and duration of statin use was not statistically significant. Beyond this, the reduced risk after adjustment for hyperlipidemia is hard to interpret as an explanation of cause or effect of autoimmunity, and, given the small magnitude of increases and decreases in risk, may not be clinically meaningful.

In addition to patients with RA having a higher burden of cardiovascular disease necessitating use of statins, they also have a high risk of progressive secondary osteoarthritis requiring joint replacement surgery. Chang et al³ used a national claims-based dataset from China to examine risk of total knee or hip replacement (TKR and THR, respectively) in patients with RA. From 2000-2013 (ie, the onset of the biologic era), TKR and THR rates were examined in a cohort of biologic disease-modifying antirheumatic drug (bDMARD) users compared to conventional synthetic DMARD (csDMARD) users. Adjusted hazard ratios (HR) were lower for both TKD and THR in bDMARD users. Though RA activity was not examined, combined with the knowledge of the association of disease severity with bDMARD use, this study lends evidence to the benefits of more aggressive treatment.

Finally, much is made of the link between bDMARD and targeted synthetic DMARD use and malignancy due to reduced immunosurveillance, but concrete evidence is conflicting. Wetzman et al⁴ performed a systematic review of studies of patients with inflammatory arthritis (RA, psoriatic arthritis, and Ankylosing spondylitis) looking at cancer relapse or occurrence of new cancer. An increase in skin cancers (HR 1.32) was noted, but reassuringly no other increase in risk of recurrent or new cancer was seen.

References

1. Fleischmann R et al. Long-term efficacy, safety, and immunogenicity of the adalimumab biosimilar, PF-06410293, in patients with rheumatoid arthritis after switching from reference adalimumab (Humira®) or continuing biosimilar therapy: week 52–92 data from a randomized, double-blind, phase 3 trialArthritis Res Ther. 2021(Sep 25);23:248.
2. Peterson MN et al. Risk of rheumatoid arthritis diagnosis in statin users in a large nationwide US study. Arthritis Res Ther. 2021(Sep 18):23:244.
3. Chang YS et al. Effects of biologics on reducing the risks of total knee replacement and total hip replacement in rheumatoid arthritis. Rheumatology (Oxford). 2021(Sep 17):keab671.
4. Wetzman A et al. Risk of cancer after initiation of targeted therapies in patients with rheumatoid arthritis and a prior cancer: systematic review with meta-analysis. Arthritis Care Res (Hoboken). 2021(Sep 21): acr.24784.