TBD Meeting (3208-21)

Patients with giant cell arteritis (GCA) remained in remission longer when they took secukinumab (Cosentyx) during a 6-month–long taper of glucocorticoids, a monoclonal antibody drug that inhibits interleukin-17A, compared with placebo, according to phase 2 trial results presented at the virtual annual meeting of the American College of Rheumatology.

The mainstay of GCA treatment is glucocorticoids, although IL-6 inhibition with tocilizumab (Actemra) has recently become another option, Jens Thiel, MD, vice director of the Clinic for Rheumatology and Clinical Immunology at University Hospital Freiburg (Germany), told attendees.

“Secukinumab has shown significant improvements in the signs and symptoms of IL-17A-driven medical conditions such as psoriasis and psoriatic arthritis, and it has a very favorable long-term safety profile,” Dr. Thiel said. “There is experimental and preclinical data that points toward the role of IL-17A in the pathogenesis of giant cell arteritis, and therefore IL-17A inhibition, blocking vascular inflammation, is potentially a new therapeutic target for GCA.”

Christopher R. Palma, MD, ScM, assistant professor in the division of allergy, immunology, and rheumatology at the University of Rochester (N.Y.), said in an interview that the trial’s preliminary findings were exciting because they suggest that IL-17A is likely to be an effective strategy for treating GCA. ”This aligns with known pathophysiology of GCA, where IL-17A is an important part of pathology of disease,” Dr. Palma said.

In the randomized, controlled, double-blind trial, researchers enrolled 52 patients, all at least 50 years old, who had never taken a biologic for GCA. Most of the participants (80.8%) had new-onset GCA, diagnosed within the previous 6 weeks, and 19.2% had relapsing GCA. The participants received either 300 mg of secukinumab or placebo every week for 5 weeks, and then every 4 weeks for 48 total weeks. At baseline, all participants also began a 26-week taper of prednisolone from a dose of 25-60 mg/day at baseline to 0 at week 27. The primary endpoint was the proportion of participants in sustained remission through week 28.

Among the 27 participants taking secukinumab and the 25 taking placebo, 37 completed the study treatment (71%). At week 28, those still in remission included 70.1% of participants taking secukinumab and 20.3% of those taking placebo (odds ratio [OR], 9.3). Through week 52, the proportion of participants in remission included 59.3% of the secukinumab group and 8% of the placebo group.

Determination of flare was based on signs and symptoms along with a C-reactive protein level of more than 10 mg/L or an increased erythrocyte sedimentation rate. Dr. Thiel did not provide more details on these parameters or on how flares were determined, but reported that participants taking secukinumab did not reach a median time to first flare, compared to a median 197 days in the placebo group.

All the participants taking secukinumab and 96% of those taking placebo experienced treatment-emergent adverse events, with serious adverse events occurring in 22.2% of those taking secukinumab and 44% of those taking placebo. Two patients in each group discontinued the treatment because of adverse events, and one participant in each group died from causes determined to be unrelated to the treatment.

The trial’s effect size was large, but Dr. Palma noted that the study’s generalizability is limited by prednisolone tapering in the placebo arm because that’s not reflective of most clinical practice for treatment of GCA.

“We would be unlikely to mimic this trial design as we know rates of disease flare and recurrence are high without long-term therapy of some kind,” Dr. Palma said. ”The real challenge will be in assessing relative benefit and risk among many possible therapies and how IL-17A–directed therapies fit in. Obviously, a head-to-head trial design would help answer many of these questions.”

Dr. Palma said it’s too early to recommend widespread off-label use of secukinumab for GCA, but he would encourage his patients with GCA to consider participating in a phase 3 trial of the drug.

Novartis, which markets secukinumab, funded the research. Dr. Thiel has received speaking and/or advising fees from AbbVie, Bristol-Myers Squibb, GlaxoSmithKline, and Novartis, and research grants from Bristol-Myers Squibb and Novartis. His coauthors had disclosures for a wide range of pharmaceutical companies. Dr. Palma has received research funding from AbbVie, Incyte, and Regeneron.

Patients with giant cell arteritis (GCA) remained in remission longer when they took secukinumab (Cosentyx) during a 6-month–long taper of glucocorticoids, a monoclonal antibody drug that inhibits interleukin-17A, compared with placebo, according to phase 2 trial results presented at the virtual annual meeting of the American College of Rheumatology.

The mainstay of GCA treatment is glucocorticoids, although IL-6 inhibition with tocilizumab (Actemra) has recently become another option, Jens Thiel, MD, vice director of the Clinic for Rheumatology and Clinical Immunology at University Hospital Freiburg (Germany), told attendees.

“Secukinumab has shown significant improvements in the signs and symptoms of IL-17A-driven medical conditions such as psoriasis and psoriatic arthritis, and it has a very favorable long-term safety profile,” Dr. Thiel said. “There is experimental and preclinical data that points toward the role of IL-17A in the pathogenesis of giant cell arteritis, and therefore IL-17A inhibition, blocking vascular inflammation, is potentially a new therapeutic target for GCA.”

Christopher R. Palma, MD, ScM, assistant professor in the division of allergy, immunology, and rheumatology at the University of Rochester (N.Y.), said in an interview that the trial’s preliminary findings were exciting because they suggest that IL-17A is likely to be an effective strategy for treating GCA. ”This aligns with known pathophysiology of GCA, where IL-17A is an important part of pathology of disease,” Dr. Palma said.

In the randomized, controlled, double-blind trial, researchers enrolled 52 patients, all at least 50 years old, who had never taken a biologic for GCA. Most of the participants (80.8%) had new-onset GCA, diagnosed within the previous 6 weeks, and 19.2% had relapsing GCA. The participants received either 300 mg of secukinumab or placebo every week for 5 weeks, and then every 4 weeks for 48 total weeks. At baseline, all participants also began a 26-week taper of prednisolone from a dose of 25-60 mg/day at baseline to 0 at week 27. The primary endpoint was the proportion of participants in sustained remission through week 28.

Among the 27 participants taking secukinumab and the 25 taking placebo, 37 completed the study treatment (71%). At week 28, those still in remission included 70.1% of participants taking secukinumab and 20.3% of those taking placebo (odds ratio [OR], 9.3). Through week 52, the proportion of participants in remission included 59.3% of the secukinumab group and 8% of the placebo group.

Determination of flare was based on signs and symptoms along with a C-reactive protein level of more than 10 mg/L or an increased erythrocyte sedimentation rate. Dr. Thiel did not provide more details on these parameters or on how flares were determined, but reported that participants taking secukinumab did not reach a median time to first flare, compared to a median 197 days in the placebo group.

All the participants taking secukinumab and 96% of those taking placebo experienced treatment-emergent adverse events, with serious adverse events occurring in 22.2% of those taking secukinumab and 44% of those taking placebo. Two patients in each group discontinued the treatment because of adverse events, and one participant in each group died from causes determined to be unrelated to the treatment.

The trial’s effect size was large, but Dr. Palma noted that the study’s generalizability is limited by prednisolone tapering in the placebo arm because that’s not reflective of most clinical practice for treatment of GCA.

“We would be unlikely to mimic this trial design as we know rates of disease flare and recurrence are high without long-term therapy of some kind,” Dr. Palma said. ”The real challenge will be in assessing relative benefit and risk among many possible therapies and how IL-17A–directed therapies fit in. Obviously, a head-to-head trial design would help answer many of these questions.”

Dr. Palma said it’s too early to recommend widespread off-label use of secukinumab for GCA, but he would encourage his patients with GCA to consider participating in a phase 3 trial of the drug.

Novartis, which markets secukinumab, funded the research. Dr. Thiel has received speaking and/or advising fees from AbbVie, Bristol-Myers Squibb, GlaxoSmithKline, and Novartis, and research grants from Bristol-Myers Squibb and Novartis. His coauthors had disclosures for a wide range of pharmaceutical companies. Dr. Palma has received research funding from AbbVie, Incyte, and Regeneron.

Patients with giant cell arteritis (GCA) remained in remission longer when they took secukinumab (Cosentyx) during a 6-month–long taper of glucocorticoids, a monoclonal antibody drug that inhibits interleukin-17A, compared with placebo, according to phase 2 trial results presented at the virtual annual meeting of the American College of Rheumatology.

The mainstay of GCA treatment is glucocorticoids, although IL-6 inhibition with tocilizumab (Actemra) has recently become another option, Jens Thiel, MD, vice director of the Clinic for Rheumatology and Clinical Immunology at University Hospital Freiburg (Germany), told attendees.

“Secukinumab has shown significant improvements in the signs and symptoms of IL-17A-driven medical conditions such as psoriasis and psoriatic arthritis, and it has a very favorable long-term safety profile,” Dr. Thiel said. “There is experimental and preclinical data that points toward the role of IL-17A in the pathogenesis of giant cell arteritis, and therefore IL-17A inhibition, blocking vascular inflammation, is potentially a new therapeutic target for GCA.”

Christopher R. Palma, MD, ScM, assistant professor in the division of allergy, immunology, and rheumatology at the University of Rochester (N.Y.), said in an interview that the trial’s preliminary findings were exciting because they suggest that IL-17A is likely to be an effective strategy for treating GCA. ”This aligns with known pathophysiology of GCA, where IL-17A is an important part of pathology of disease,” Dr. Palma said.

In the randomized, controlled, double-blind trial, researchers enrolled 52 patients, all at least 50 years old, who had never taken a biologic for GCA. Most of the participants (80.8%) had new-onset GCA, diagnosed within the previous 6 weeks, and 19.2% had relapsing GCA. The participants received either 300 mg of secukinumab or placebo every week for 5 weeks, and then every 4 weeks for 48 total weeks. At baseline, all participants also began a 26-week taper of prednisolone from a dose of 25-60 mg/day at baseline to 0 at week 27. The primary endpoint was the proportion of participants in sustained remission through week 28.

Among the 27 participants taking secukinumab and the 25 taking placebo, 37 completed the study treatment (71%). At week 28, those still in remission included 70.1% of participants taking secukinumab and 20.3% of those taking placebo (odds ratio [OR], 9.3). Through week 52, the proportion of participants in remission included 59.3% of the secukinumab group and 8% of the placebo group.

Determination of flare was based on signs and symptoms along with a C-reactive protein level of more than 10 mg/L or an increased erythrocyte sedimentation rate. Dr. Thiel did not provide more details on these parameters or on how flares were determined, but reported that participants taking secukinumab did not reach a median time to first flare, compared to a median 197 days in the placebo group.

All the participants taking secukinumab and 96% of those taking placebo experienced treatment-emergent adverse events, with serious adverse events occurring in 22.2% of those taking secukinumab and 44% of those taking placebo. Two patients in each group discontinued the treatment because of adverse events, and one participant in each group died from causes determined to be unrelated to the treatment.

The trial’s effect size was large, but Dr. Palma noted that the study’s generalizability is limited by prednisolone tapering in the placebo arm because that’s not reflective of most clinical practice for treatment of GCA.

“We would be unlikely to mimic this trial design as we know rates of disease flare and recurrence are high without long-term therapy of some kind,” Dr. Palma said. ”The real challenge will be in assessing relative benefit and risk among many possible therapies and how IL-17A–directed therapies fit in. Obviously, a head-to-head trial design would help answer many of these questions.”

Dr. Palma said it’s too early to recommend widespread off-label use of secukinumab for GCA, but he would encourage his patients with GCA to consider participating in a phase 3 trial of the drug.

Novartis, which markets secukinumab, funded the research. Dr. Thiel has received speaking and/or advising fees from AbbVie, Bristol-Myers Squibb, GlaxoSmithKline, and Novartis, and research grants from Bristol-Myers Squibb and Novartis. His coauthors had disclosures for a wide range of pharmaceutical companies. Dr. Palma has received research funding from AbbVie, Incyte, and Regeneron.

The rate of U.S. hospitalizations for three types of serious infections in patients with psoriatic arthritis (PsA) appears to have declined from 2012 to 2017, according to research presented at the virtual annual meeting of the American College of Rheumatology.

Several of the standard treatments for PsA have an increased risk of infections, but the rates vary amongst conventional disease-modifying antirheumatic drugs (DMARDs), glucocorticoids, biologics, and other therapies.

“Given the uptake of biological therapies has increased over recent years, we sought to investigate the national trends in serious infections in patients with psoriatic arthritis from the years 2012 to 2017,” Vagishwari Murugesan, MBBS, a psoriatic arthritis clinical fellow at the University of Toronto, told attendees in a prerecorded poster presentation. Dr. Murugesan was a fellow at Boston University when she conducted the research.

The researchers analyzed data from 2012 to 2017 in the U.S. National Inpatient Sample (NIS), which includes approximately 20% of all discharges from U.S. community hospitals except rehabilitation and long-term acute care institutions. Using ICD-9 and ICD-10 codes, the researchers identified all discharge records containing a diagnosis of PsA as well as pneumonia, sepsis, urinary tract infection (UTI), and skin and soft-tissue infections. After making adjustments to match U.S. population age distributions over the years, they examined trends in serious infections among patients with PsA for that 6-year period.

Demographics over those years changed little: The average age of discharged patients was 59.5 in 2012 and 60.8 in 2017. Similarly, the patient population was 56% women and 88.5% Whites in 2012 and 57.7% women and 88.4% Whites in 2017. The average length of stay was also similar: 4.7 days in 2012, compared with 4.9 days in 2017.

Among 50,700 discharges of patients with PsA in 2012, the researchers identified 125 with pneumonia, 230 with sepsis, 312 with skin and soft-tissue infections, and 174 with a UTI. Among the 179,400 discharges in 2017 of patients with PsA, 344 had pneumonia, 374 had sepsis, 681 had skin and soft-tissue infections, and 348 had a UTI. After statistical analysis, the researchers found no significant differences in pneumonia diagnoses during the years studied, but they did find a statistically significant decline in sepsis, skin and soft tissue infections, and UTI discharges (P < .001).

A notable limitation of the study is the NIS database’s lack of data on treatments or outpatient data, making it impossible to determine if more infections were occurring but simply being treated in outpatient settings, although it’s not clear why such a substantial shift would occur in just 5 years. It’s also possible that coding practices differ across hospital, but, presumably, the ways they might differ in 2012 would be similar to any differences in 2017.

Bruce Jancin/MDedge News

Arthur Kavanaugh, MD, a professor of medicine and director of the Center for Innovative Therapy at the University of California, San Diego, found the results interesting for what he considers an important topic.

“What makes these data interesting is the same thing that limits their reliability: The authors note that infections decreased ‘despite the increase in use of biologics over this time,’ ” Dr. Kavanaugh said in an interview. “These are claims data, so there is no way to support any association between those serious infections and biologic use. Indeed, multiple factors could have also impacted these data. It is not possible to tell from claims data.”

Dr. Kavanaugh said the question is worth investigating further with data from other sources.

The research was funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases. One study coauthor reported ties to UCB; Dr. Murugesan and her other coauthors reported no disclosures. Dr. Kavanaugh had no disclosures.

The rate of U.S. hospitalizations for three types of serious infections in patients with psoriatic arthritis (PsA) appears to have declined from 2012 to 2017, according to research presented at the virtual annual meeting of the American College of Rheumatology.

Several of the standard treatments for PsA have an increased risk of infections, but the rates vary amongst conventional disease-modifying antirheumatic drugs (DMARDs), glucocorticoids, biologics, and other therapies.

“Given the uptake of biological therapies has increased over recent years, we sought to investigate the national trends in serious infections in patients with psoriatic arthritis from the years 2012 to 2017,” Vagishwari Murugesan, MBBS, a psoriatic arthritis clinical fellow at the University of Toronto, told attendees in a prerecorded poster presentation. Dr. Murugesan was a fellow at Boston University when she conducted the research.

The researchers analyzed data from 2012 to 2017 in the U.S. National Inpatient Sample (NIS), which includes approximately 20% of all discharges from U.S. community hospitals except rehabilitation and long-term acute care institutions. Using ICD-9 and ICD-10 codes, the researchers identified all discharge records containing a diagnosis of PsA as well as pneumonia, sepsis, urinary tract infection (UTI), and skin and soft-tissue infections. After making adjustments to match U.S. population age distributions over the years, they examined trends in serious infections among patients with PsA for that 6-year period.

Demographics over those years changed little: The average age of discharged patients was 59.5 in 2012 and 60.8 in 2017. Similarly, the patient population was 56% women and 88.5% Whites in 2012 and 57.7% women and 88.4% Whites in 2017. The average length of stay was also similar: 4.7 days in 2012, compared with 4.9 days in 2017.

Among 50,700 discharges of patients with PsA in 2012, the researchers identified 125 with pneumonia, 230 with sepsis, 312 with skin and soft-tissue infections, and 174 with a UTI. Among the 179,400 discharges in 2017 of patients with PsA, 344 had pneumonia, 374 had sepsis, 681 had skin and soft-tissue infections, and 348 had a UTI. After statistical analysis, the researchers found no significant differences in pneumonia diagnoses during the years studied, but they did find a statistically significant decline in sepsis, skin and soft tissue infections, and UTI discharges (P < .001).

A notable limitation of the study is the NIS database’s lack of data on treatments or outpatient data, making it impossible to determine if more infections were occurring but simply being treated in outpatient settings, although it’s not clear why such a substantial shift would occur in just 5 years. It’s also possible that coding practices differ across hospital, but, presumably, the ways they might differ in 2012 would be similar to any differences in 2017.

Bruce Jancin/MDedge News

Arthur Kavanaugh, MD, a professor of medicine and director of the Center for Innovative Therapy at the University of California, San Diego, found the results interesting for what he considers an important topic.

“What makes these data interesting is the same thing that limits their reliability: The authors note that infections decreased ‘despite the increase in use of biologics over this time,’ ” Dr. Kavanaugh said in an interview. “These are claims data, so there is no way to support any association between those serious infections and biologic use. Indeed, multiple factors could have also impacted these data. It is not possible to tell from claims data.”

Dr. Kavanaugh said the question is worth investigating further with data from other sources.

The research was funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases. One study coauthor reported ties to UCB; Dr. Murugesan and her other coauthors reported no disclosures. Dr. Kavanaugh had no disclosures.

The rate of U.S. hospitalizations for three types of serious infections in patients with psoriatic arthritis (PsA) appears to have declined from 2012 to 2017, according to research presented at the virtual annual meeting of the American College of Rheumatology.

Several of the standard treatments for PsA have an increased risk of infections, but the rates vary amongst conventional disease-modifying antirheumatic drugs (DMARDs), glucocorticoids, biologics, and other therapies.

“Given the uptake of biological therapies has increased over recent years, we sought to investigate the national trends in serious infections in patients with psoriatic arthritis from the years 2012 to 2017,” Vagishwari Murugesan, MBBS, a psoriatic arthritis clinical fellow at the University of Toronto, told attendees in a prerecorded poster presentation. Dr. Murugesan was a fellow at Boston University when she conducted the research.

The researchers analyzed data from 2012 to 2017 in the U.S. National Inpatient Sample (NIS), which includes approximately 20% of all discharges from U.S. community hospitals except rehabilitation and long-term acute care institutions. Using ICD-9 and ICD-10 codes, the researchers identified all discharge records containing a diagnosis of PsA as well as pneumonia, sepsis, urinary tract infection (UTI), and skin and soft-tissue infections. After making adjustments to match U.S. population age distributions over the years, they examined trends in serious infections among patients with PsA for that 6-year period.

Demographics over those years changed little: The average age of discharged patients was 59.5 in 2012 and 60.8 in 2017. Similarly, the patient population was 56% women and 88.5% Whites in 2012 and 57.7% women and 88.4% Whites in 2017. The average length of stay was also similar: 4.7 days in 2012, compared with 4.9 days in 2017.

Among 50,700 discharges of patients with PsA in 2012, the researchers identified 125 with pneumonia, 230 with sepsis, 312 with skin and soft-tissue infections, and 174 with a UTI. Among the 179,400 discharges in 2017 of patients with PsA, 344 had pneumonia, 374 had sepsis, 681 had skin and soft-tissue infections, and 348 had a UTI. After statistical analysis, the researchers found no significant differences in pneumonia diagnoses during the years studied, but they did find a statistically significant decline in sepsis, skin and soft tissue infections, and UTI discharges (P < .001).

A notable limitation of the study is the NIS database’s lack of data on treatments or outpatient data, making it impossible to determine if more infections were occurring but simply being treated in outpatient settings, although it’s not clear why such a substantial shift would occur in just 5 years. It’s also possible that coding practices differ across hospital, but, presumably, the ways they might differ in 2012 would be similar to any differences in 2017.

Bruce Jancin/MDedge News

Arthur Kavanaugh, MD, a professor of medicine and director of the Center for Innovative Therapy at the University of California, San Diego, found the results interesting for what he considers an important topic.

“What makes these data interesting is the same thing that limits their reliability: The authors note that infections decreased ‘despite the increase in use of biologics over this time,’ ” Dr. Kavanaugh said in an interview. “These are claims data, so there is no way to support any association between those serious infections and biologic use. Indeed, multiple factors could have also impacted these data. It is not possible to tell from claims data.”

Dr. Kavanaugh said the question is worth investigating further with data from other sources.

The research was funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases. One study coauthor reported ties to UCB; Dr. Murugesan and her other coauthors reported no disclosures. Dr. Kavanaugh had no disclosures.

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

Adding a single cycle of rituximab to belimumab (Benlysta) did not improve disease control for patients with systemic lupus erythematosus (SLE) in comparison with belimumab alone in a phase 3, randomized, controlled trial.

Among patients with SLE who were randomly assigned to receive belimumab with either rituximab, placebo, or standard care, there were no statistically significant differences between the rituximab and placebo arms for the primary endpoint of the proportion of patients with disease control at week 52 or in the secondary endpoints of clinical remission at week 64 or disease control at week 104, Cynthia Aranow, MD, reported in a late-breaking poster session presented during the virtual annual meeting of the American College of Rheumatology.

“Using a new, clinically meaningful endpoint underscores the efficacy of belimumab for disease control, with some patients maintaining disease control with considerable reductions in steroids, and no immunosuppressants,” said Dr. Aranow, a rheumatologist specializing in SLE and RA in New York and director of the Clinical Autoimmunity Center of Excellence at Feinstein Institutes for Medical Research, Manhasset, N.Y.

Use of the combination of belimumab and rituximab was, however, associated with significant improvement over belimumab and placebo in several secondary efficacy endpoints.

Investigators in the randomized, controlled trial, dubbed BLISS-BELIEVE, had previously published a rationale for sequential therapy with belimumab, a human monoclonal antibody that binds to soluble B-lymphocyte stimulator, and rituximab, a B-cell–depleting anti-CD20 monoclonal antibody.

“These biologics, which operate through complementary mechanisms, might result in an enhanced depletion of circulating and tissue-resident autoreactive B lymphocytes when administered together. Thus, belimumab and rituximab combination may be a highly effective treatment of SLE,” they wrote in an article published in 2019 in BMJ Open.
 

Three-arm trial

The investigators screened 396 patients, of whom 292 were randomly assigned in a 1:2:1 ratio to receive either subcutaneous belimumab 200 mg/wk plus intravenous placebo at weeks 4 and 6 (BEL/PBO, 72 patients), belimumab plus IV rituximab 1,000 mg at weeks 4 and 6 (BEL/RTX, 144 patients), or open-label belimumab plus standard therapy. Patients were allowed to continue taking antimalarial and nonsteroidal anti-inflammatory drugs throughout the study.

The primary disease-control endpoint was defined as a Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score of 2 or less, achieved without other immunosuppression, equivalent to that achieved with prednisone 5 mg/day or less.

As noted before, there were no significant differences between the BEL/RTX and BEL/PBO arms in either disease control at week 52 or in the secondary endpoints of clinical remission at week 64 (SLEDAI-2K score, 0) or in the proportion of patients with disease control at week 104.

However, use of BEL/RTX was associated with a significantly longer duration of disease control through 52 weeks than was BEL/PBO (mean, 105.4 days vs. 60.1 days; P = .0188) and with a large SLEDAI-2K mean change from baseline at week 104 (–7.2 vs 5.1; P = .0033).

In addition, there was a trend toward a shift in proteinuria from baseline high (>0.5 g/24 h) to normal in the BEL/RTX group at week 52 and a significantly greater shift at week 104 (P = .0085).

The overall adverse event profiles were generally consistent with those of the individual agents, although serious infections and infestations occurred more frequently with BEL/RTX than BEL/PBO.
 

Further analyses planned to look for subgroups that benefit

In a poster discussion session, Akshat Khanna, PhD, of Newtown, Pa., a consultant with Effimed Life Sciences Research, asked Dr. Aranow about the rationale for giving rituximab and belimumab concurrently and noted that, in the BEAT-LUPUS and CALIBRATE trials, anti-CD20 agents were given first, followed by belimumab, to prevent activation of humoral immunity.

“The two B-cell agents were given sequentially. Belimumab was given first to maximize the effect of peripheral B-cell depletion and [was] then continued after rituximab to suppress the elevation [of B-lymphocyte stimulator] that occurs after rituximab monotherapy. We used this approach (instead of that used in CALIBRATE and BEAT LUPUS), as we thought this might be more efficacious,” she explained.

When asked whether there were subgroups of patients who might still benefit from the combination, compared with belimumab alone, Dr. Aranow replied: “There may be individual patients in which it might be considered. Further analyses of the data are ongoing/planned.”

The study was supported by GlaxoSmithKline. Dr. Aranow has received grant/research support from GlaxoSmithKline and has consulted for Bristol-Myers Squibb. Dr. Khanna has disclosed no relevant financial relationships.

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

Adding a single cycle of rituximab to belimumab (Benlysta) did not improve disease control for patients with systemic lupus erythematosus (SLE) in comparison with belimumab alone in a phase 3, randomized, controlled trial.

Among patients with SLE who were randomly assigned to receive belimumab with either rituximab, placebo, or standard care, there were no statistically significant differences between the rituximab and placebo arms for the primary endpoint of the proportion of patients with disease control at week 52 or in the secondary endpoints of clinical remission at week 64 or disease control at week 104, Cynthia Aranow, MD, reported in a late-breaking poster session presented during the virtual annual meeting of the American College of Rheumatology.

“Using a new, clinically meaningful endpoint underscores the efficacy of belimumab for disease control, with some patients maintaining disease control with considerable reductions in steroids, and no immunosuppressants,” said Dr. Aranow, a rheumatologist specializing in SLE and RA in New York and director of the Clinical Autoimmunity Center of Excellence at Feinstein Institutes for Medical Research, Manhasset, N.Y.

Use of the combination of belimumab and rituximab was, however, associated with significant improvement over belimumab and placebo in several secondary efficacy endpoints.

Investigators in the randomized, controlled trial, dubbed BLISS-BELIEVE, had previously published a rationale for sequential therapy with belimumab, a human monoclonal antibody that binds to soluble B-lymphocyte stimulator, and rituximab, a B-cell–depleting anti-CD20 monoclonal antibody.

“These biologics, which operate through complementary mechanisms, might result in an enhanced depletion of circulating and tissue-resident autoreactive B lymphocytes when administered together. Thus, belimumab and rituximab combination may be a highly effective treatment of SLE,” they wrote in an article published in 2019 in BMJ Open.
 

Three-arm trial

The investigators screened 396 patients, of whom 292 were randomly assigned in a 1:2:1 ratio to receive either subcutaneous belimumab 200 mg/wk plus intravenous placebo at weeks 4 and 6 (BEL/PBO, 72 patients), belimumab plus IV rituximab 1,000 mg at weeks 4 and 6 (BEL/RTX, 144 patients), or open-label belimumab plus standard therapy. Patients were allowed to continue taking antimalarial and nonsteroidal anti-inflammatory drugs throughout the study.

The primary disease-control endpoint was defined as a Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score of 2 or less, achieved without other immunosuppression, equivalent to that achieved with prednisone 5 mg/day or less.

As noted before, there were no significant differences between the BEL/RTX and BEL/PBO arms in either disease control at week 52 or in the secondary endpoints of clinical remission at week 64 (SLEDAI-2K score, 0) or in the proportion of patients with disease control at week 104.

However, use of BEL/RTX was associated with a significantly longer duration of disease control through 52 weeks than was BEL/PBO (mean, 105.4 days vs. 60.1 days; P = .0188) and with a large SLEDAI-2K mean change from baseline at week 104 (–7.2 vs 5.1; P = .0033).

In addition, there was a trend toward a shift in proteinuria from baseline high (>0.5 g/24 h) to normal in the BEL/RTX group at week 52 and a significantly greater shift at week 104 (P = .0085).

The overall adverse event profiles were generally consistent with those of the individual agents, although serious infections and infestations occurred more frequently with BEL/RTX than BEL/PBO.
 

Further analyses planned to look for subgroups that benefit

In a poster discussion session, Akshat Khanna, PhD, of Newtown, Pa., a consultant with Effimed Life Sciences Research, asked Dr. Aranow about the rationale for giving rituximab and belimumab concurrently and noted that, in the BEAT-LUPUS and CALIBRATE trials, anti-CD20 agents were given first, followed by belimumab, to prevent activation of humoral immunity.

“The two B-cell agents were given sequentially. Belimumab was given first to maximize the effect of peripheral B-cell depletion and [was] then continued after rituximab to suppress the elevation [of B-lymphocyte stimulator] that occurs after rituximab monotherapy. We used this approach (instead of that used in CALIBRATE and BEAT LUPUS), as we thought this might be more efficacious,” she explained.

When asked whether there were subgroups of patients who might still benefit from the combination, compared with belimumab alone, Dr. Aranow replied: “There may be individual patients in which it might be considered. Further analyses of the data are ongoing/planned.”

The study was supported by GlaxoSmithKline. Dr. Aranow has received grant/research support from GlaxoSmithKline and has consulted for Bristol-Myers Squibb. Dr. Khanna has disclosed no relevant financial relationships.

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

Adding a single cycle of rituximab to belimumab (Benlysta) did not improve disease control for patients with systemic lupus erythematosus (SLE) in comparison with belimumab alone in a phase 3, randomized, controlled trial.

Among patients with SLE who were randomly assigned to receive belimumab with either rituximab, placebo, or standard care, there were no statistically significant differences between the rituximab and placebo arms for the primary endpoint of the proportion of patients with disease control at week 52 or in the secondary endpoints of clinical remission at week 64 or disease control at week 104, Cynthia Aranow, MD, reported in a late-breaking poster session presented during the virtual annual meeting of the American College of Rheumatology.

“Using a new, clinically meaningful endpoint underscores the efficacy of belimumab for disease control, with some patients maintaining disease control with considerable reductions in steroids, and no immunosuppressants,” said Dr. Aranow, a rheumatologist specializing in SLE and RA in New York and director of the Clinical Autoimmunity Center of Excellence at Feinstein Institutes for Medical Research, Manhasset, N.Y.

Use of the combination of belimumab and rituximab was, however, associated with significant improvement over belimumab and placebo in several secondary efficacy endpoints.

Investigators in the randomized, controlled trial, dubbed BLISS-BELIEVE, had previously published a rationale for sequential therapy with belimumab, a human monoclonal antibody that binds to soluble B-lymphocyte stimulator, and rituximab, a B-cell–depleting anti-CD20 monoclonal antibody.

“These biologics, which operate through complementary mechanisms, might result in an enhanced depletion of circulating and tissue-resident autoreactive B lymphocytes when administered together. Thus, belimumab and rituximab combination may be a highly effective treatment of SLE,” they wrote in an article published in 2019 in BMJ Open.
 

Three-arm trial

The investigators screened 396 patients, of whom 292 were randomly assigned in a 1:2:1 ratio to receive either subcutaneous belimumab 200 mg/wk plus intravenous placebo at weeks 4 and 6 (BEL/PBO, 72 patients), belimumab plus IV rituximab 1,000 mg at weeks 4 and 6 (BEL/RTX, 144 patients), or open-label belimumab plus standard therapy. Patients were allowed to continue taking antimalarial and nonsteroidal anti-inflammatory drugs throughout the study.

The primary disease-control endpoint was defined as a Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score of 2 or less, achieved without other immunosuppression, equivalent to that achieved with prednisone 5 mg/day or less.

As noted before, there were no significant differences between the BEL/RTX and BEL/PBO arms in either disease control at week 52 or in the secondary endpoints of clinical remission at week 64 (SLEDAI-2K score, 0) or in the proportion of patients with disease control at week 104.

However, use of BEL/RTX was associated with a significantly longer duration of disease control through 52 weeks than was BEL/PBO (mean, 105.4 days vs. 60.1 days; P = .0188) and with a large SLEDAI-2K mean change from baseline at week 104 (–7.2 vs 5.1; P = .0033).

In addition, there was a trend toward a shift in proteinuria from baseline high (>0.5 g/24 h) to normal in the BEL/RTX group at week 52 and a significantly greater shift at week 104 (P = .0085).

The overall adverse event profiles were generally consistent with those of the individual agents, although serious infections and infestations occurred more frequently with BEL/RTX than BEL/PBO.
 

Further analyses planned to look for subgroups that benefit

In a poster discussion session, Akshat Khanna, PhD, of Newtown, Pa., a consultant with Effimed Life Sciences Research, asked Dr. Aranow about the rationale for giving rituximab and belimumab concurrently and noted that, in the BEAT-LUPUS and CALIBRATE trials, anti-CD20 agents were given first, followed by belimumab, to prevent activation of humoral immunity.

“The two B-cell agents were given sequentially. Belimumab was given first to maximize the effect of peripheral B-cell depletion and [was] then continued after rituximab to suppress the elevation [of B-lymphocyte stimulator] that occurs after rituximab monotherapy. We used this approach (instead of that used in CALIBRATE and BEAT LUPUS), as we thought this might be more efficacious,” she explained.

When asked whether there were subgroups of patients who might still benefit from the combination, compared with belimumab alone, Dr. Aranow replied: “There may be individual patients in which it might be considered. Further analyses of the data are ongoing/planned.”

The study was supported by GlaxoSmithKline. Dr. Aranow has received grant/research support from GlaxoSmithKline and has consulted for Bristol-Myers Squibb. Dr. Khanna has disclosed no relevant financial relationships.

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

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.

Rituximab didn’t perform any worse or better at inducing remission after a year in patients with eosinophilic granulomatosis with polyangiitis (EGPA) than did conventional treatment with cyclophosphamide in the phase 3 REOVAS trial conducted in France.

The B-cell–depleting agent also had a safety profile similar to cyclophosphamide during that window of time, Benjamin Terrier, MD, PhD, said in presenting results of the trial at the virtual annual meeting of the American College of Rheumatology. He is a professor of rheumatology at Cochin Hospital in Paris, the University of Paris, and vice president of the French Vasculitis Study Group.

“So some of the major adverse events that we can consider with this treatment, especially with cyclophosphamide and specifically the fertility issues and the cancer issues, the follow-up of this study does not allow us to evaluate the potential benefit of rituximab over cyclophosphamide,” Dr. Terrier said in an interview.

“But on the short-term study of 1 year, for which the major adverse events are infections, there is almost no difference between the two treatments,” he said. A total of 11 patients taking rituximab and 9 patients taking cyclophosphamide had infections in the study period.

The REOVAS trial randomly assigned 105 adult patients with EPGA, otherwise known as Churg-Strauss syndrome, to either rituximab (52 patients) or the conventional strategy using cyclophosphamide (53). The patients had either newly diagnosed or relapsing disease. There was no significant differences in average daily glucocorticoid use between the two arms.

Patient characteristics were similar in both arms, including the percentages of patients with severe disease. Overall, 60% in each group had a Five-Factor Score (FFS) of 0, while the remainder had an FFS greater than 1. The FFS is calculated by giving 1 point for the presence of each of the following: proteinuria greater than 1 g/day, serum creatinine greater than 140 micromol/L, GI involvement, cardiomyopathy, and CNS involvement. The presence of each FFS component was similar between the groups at baseline, although 25% of the rituximab group and 30.2% of the conventional arm had myeloperoxidase-positive antineutrophilic cytoplasmic antibodies, and the absolute eosinophil count was 180 per mm³ in the former and 300 per mm³ in the latter.

Treatment outcomes at 6 months and 1 year were similar in both groups. At 1 year, remission occurred in 59.6% with rituximab and 64.2% with cyclophosphamide, Birmingham Vasculitis Activity Score equaled 0 in 85.7% with rituximab and 86.5% with cyclophosphamide, and prednisone dose was less than 7.5 mg/day in 77.1% with rituximab and 71.2% with cyclophosphamide.

The cumulative total weeks of complete remission was about 16 weeks in each group. Relapse-free survival, prednisone dosage, quality of life, and disease sequelae patterns also were similar.

Tailor treatment choice to the patient

Despite the equivocal findings between the two treatments, Dr. Terrier said there may be individual patients for whom rituximab would be preferred to cyclophosphamide. “It’s not dependent on the disease by itself but more on the patients we want to treat,” he said. “And clearly if there is a young female patient who wants to get pregnant, knowing that rituximab is not superior but does not appear to be inferior to cyclophosphamide can be interesting.”

The researchers opted to test the superiority rather than noninferiority of rituximab versus cyclophosphamide because a noninferiority design would have required a larger patient population, “which is not possible for a disease like this one,” he said.

“Ostensibly, [the trial] failed to show superiority, but given its favorable side-effect profile, it may be sufficient to show it’s more or less the same,” Michael Putman, MD, MSc, an associate professor and director of the vasculitis program at the Medical College of Wisconsin, Milwaukee, said in an interview. However, he noted that the study didn’t include some phenotypes seen in patients with EGPA, “in particular patients with neurological involvement.”

Dr. Putman added that the French REOVAS findings support recommendations in the 2021 ACR/Vasculitis Foundation guideline for using rituximab as a possible first-line agent to induce remission in severe granulomatosis with polyangiitis and microscopic polyangiitis. “I was somewhat surprised by that,” he said of the ACR/VF recommendation. “These are the best data to date comparing rituximab to cyclophosphamide in EGPA. I would feel more comfortable using rituximab in cases where previously I would have reached for cyclophosphamide.”

He also concurred with Dr. Terrier’s comment that rituximab may be preferred in people of child-bearing age, even extending that to men. “Cyclophosphamide can be quite toxic in terms of ovarian toxicity and premature ovarian failure,” he said. “Young men or women of child-bearing age are a group in whom I would strongly consider using rituximab.”

The French REOVAS investigators’ future research into rituximab for EGPA will include long-term follow-up for relapse and the induction of remission, Dr. Terrier said.

Dr. Terrier disclosed relationships with Roche, Chugai, Vifor, LFB, Grifols, GlaxoSmithKline, AstraZeneca, Bristol-Myers Squibb, Octapharma, and Janssen. Dr. Putnam has no relevant relationships to disclose

Rituximab didn’t perform any worse or better at inducing remission after a year in patients with eosinophilic granulomatosis with polyangiitis (EGPA) than did conventional treatment with cyclophosphamide in the phase 3 REOVAS trial conducted in France.

The B-cell–depleting agent also had a safety profile similar to cyclophosphamide during that window of time, Benjamin Terrier, MD, PhD, said in presenting results of the trial at the virtual annual meeting of the American College of Rheumatology. He is a professor of rheumatology at Cochin Hospital in Paris, the University of Paris, and vice president of the French Vasculitis Study Group.

“So some of the major adverse events that we can consider with this treatment, especially with cyclophosphamide and specifically the fertility issues and the cancer issues, the follow-up of this study does not allow us to evaluate the potential benefit of rituximab over cyclophosphamide,” Dr. Terrier said in an interview.

“But on the short-term study of 1 year, for which the major adverse events are infections, there is almost no difference between the two treatments,” he said. A total of 11 patients taking rituximab and 9 patients taking cyclophosphamide had infections in the study period.

The REOVAS trial randomly assigned 105 adult patients with EPGA, otherwise known as Churg-Strauss syndrome, to either rituximab (52 patients) or the conventional strategy using cyclophosphamide (53). The patients had either newly diagnosed or relapsing disease. There was no significant differences in average daily glucocorticoid use between the two arms.

Patient characteristics were similar in both arms, including the percentages of patients with severe disease. Overall, 60% in each group had a Five-Factor Score (FFS) of 0, while the remainder had an FFS greater than 1. The FFS is calculated by giving 1 point for the presence of each of the following: proteinuria greater than 1 g/day, serum creatinine greater than 140 micromol/L, GI involvement, cardiomyopathy, and CNS involvement. The presence of each FFS component was similar between the groups at baseline, although 25% of the rituximab group and 30.2% of the conventional arm had myeloperoxidase-positive antineutrophilic cytoplasmic antibodies, and the absolute eosinophil count was 180 per mm³ in the former and 300 per mm³ in the latter.

Treatment outcomes at 6 months and 1 year were similar in both groups. At 1 year, remission occurred in 59.6% with rituximab and 64.2% with cyclophosphamide, Birmingham Vasculitis Activity Score equaled 0 in 85.7% with rituximab and 86.5% with cyclophosphamide, and prednisone dose was less than 7.5 mg/day in 77.1% with rituximab and 71.2% with cyclophosphamide.

The cumulative total weeks of complete remission was about 16 weeks in each group. Relapse-free survival, prednisone dosage, quality of life, and disease sequelae patterns also were similar.

Tailor treatment choice to the patient

Despite the equivocal findings between the two treatments, Dr. Terrier said there may be individual patients for whom rituximab would be preferred to cyclophosphamide. “It’s not dependent on the disease by itself but more on the patients we want to treat,” he said. “And clearly if there is a young female patient who wants to get pregnant, knowing that rituximab is not superior but does not appear to be inferior to cyclophosphamide can be interesting.”

The researchers opted to test the superiority rather than noninferiority of rituximab versus cyclophosphamide because a noninferiority design would have required a larger patient population, “which is not possible for a disease like this one,” he said.

“Ostensibly, [the trial] failed to show superiority, but given its favorable side-effect profile, it may be sufficient to show it’s more or less the same,” Michael Putman, MD, MSc, an associate professor and director of the vasculitis program at the Medical College of Wisconsin, Milwaukee, said in an interview. However, he noted that the study didn’t include some phenotypes seen in patients with EGPA, “in particular patients with neurological involvement.”

Dr. Putman added that the French REOVAS findings support recommendations in the 2021 ACR/Vasculitis Foundation guideline for using rituximab as a possible first-line agent to induce remission in severe granulomatosis with polyangiitis and microscopic polyangiitis. “I was somewhat surprised by that,” he said of the ACR/VF recommendation. “These are the best data to date comparing rituximab to cyclophosphamide in EGPA. I would feel more comfortable using rituximab in cases where previously I would have reached for cyclophosphamide.”

He also concurred with Dr. Terrier’s comment that rituximab may be preferred in people of child-bearing age, even extending that to men. “Cyclophosphamide can be quite toxic in terms of ovarian toxicity and premature ovarian failure,” he said. “Young men or women of child-bearing age are a group in whom I would strongly consider using rituximab.”

The French REOVAS investigators’ future research into rituximab for EGPA will include long-term follow-up for relapse and the induction of remission, Dr. Terrier said.

Dr. Terrier disclosed relationships with Roche, Chugai, Vifor, LFB, Grifols, GlaxoSmithKline, AstraZeneca, Bristol-Myers Squibb, Octapharma, and Janssen. Dr. Putnam has no relevant relationships to disclose

Rituximab didn’t perform any worse or better at inducing remission after a year in patients with eosinophilic granulomatosis with polyangiitis (EGPA) than did conventional treatment with cyclophosphamide in the phase 3 REOVAS trial conducted in France.

The B-cell–depleting agent also had a safety profile similar to cyclophosphamide during that window of time, Benjamin Terrier, MD, PhD, said in presenting results of the trial at the virtual annual meeting of the American College of Rheumatology. He is a professor of rheumatology at Cochin Hospital in Paris, the University of Paris, and vice president of the French Vasculitis Study Group.

“So some of the major adverse events that we can consider with this treatment, especially with cyclophosphamide and specifically the fertility issues and the cancer issues, the follow-up of this study does not allow us to evaluate the potential benefit of rituximab over cyclophosphamide,” Dr. Terrier said in an interview.

“But on the short-term study of 1 year, for which the major adverse events are infections, there is almost no difference between the two treatments,” he said. A total of 11 patients taking rituximab and 9 patients taking cyclophosphamide had infections in the study period.

The REOVAS trial randomly assigned 105 adult patients with EPGA, otherwise known as Churg-Strauss syndrome, to either rituximab (52 patients) or the conventional strategy using cyclophosphamide (53). The patients had either newly diagnosed or relapsing disease. There was no significant differences in average daily glucocorticoid use between the two arms.

Patient characteristics were similar in both arms, including the percentages of patients with severe disease. Overall, 60% in each group had a Five-Factor Score (FFS) of 0, while the remainder had an FFS greater than 1. The FFS is calculated by giving 1 point for the presence of each of the following: proteinuria greater than 1 g/day, serum creatinine greater than 140 micromol/L, GI involvement, cardiomyopathy, and CNS involvement. The presence of each FFS component was similar between the groups at baseline, although 25% of the rituximab group and 30.2% of the conventional arm had myeloperoxidase-positive antineutrophilic cytoplasmic antibodies, and the absolute eosinophil count was 180 per mm³ in the former and 300 per mm³ in the latter.

Treatment outcomes at 6 months and 1 year were similar in both groups. At 1 year, remission occurred in 59.6% with rituximab and 64.2% with cyclophosphamide, Birmingham Vasculitis Activity Score equaled 0 in 85.7% with rituximab and 86.5% with cyclophosphamide, and prednisone dose was less than 7.5 mg/day in 77.1% with rituximab and 71.2% with cyclophosphamide.

The cumulative total weeks of complete remission was about 16 weeks in each group. Relapse-free survival, prednisone dosage, quality of life, and disease sequelae patterns also were similar.

Tailor treatment choice to the patient

Despite the equivocal findings between the two treatments, Dr. Terrier said there may be individual patients for whom rituximab would be preferred to cyclophosphamide. “It’s not dependent on the disease by itself but more on the patients we want to treat,” he said. “And clearly if there is a young female patient who wants to get pregnant, knowing that rituximab is not superior but does not appear to be inferior to cyclophosphamide can be interesting.”

The researchers opted to test the superiority rather than noninferiority of rituximab versus cyclophosphamide because a noninferiority design would have required a larger patient population, “which is not possible for a disease like this one,” he said.

“Ostensibly, [the trial] failed to show superiority, but given its favorable side-effect profile, it may be sufficient to show it’s more or less the same,” Michael Putman, MD, MSc, an associate professor and director of the vasculitis program at the Medical College of Wisconsin, Milwaukee, said in an interview. However, he noted that the study didn’t include some phenotypes seen in patients with EGPA, “in particular patients with neurological involvement.”

Dr. Putman added that the French REOVAS findings support recommendations in the 2021 ACR/Vasculitis Foundation guideline for using rituximab as a possible first-line agent to induce remission in severe granulomatosis with polyangiitis and microscopic polyangiitis. “I was somewhat surprised by that,” he said of the ACR/VF recommendation. “These are the best data to date comparing rituximab to cyclophosphamide in EGPA. I would feel more comfortable using rituximab in cases where previously I would have reached for cyclophosphamide.”

He also concurred with Dr. Terrier’s comment that rituximab may be preferred in people of child-bearing age, even extending that to men. “Cyclophosphamide can be quite toxic in terms of ovarian toxicity and premature ovarian failure,” he said. “Young men or women of child-bearing age are a group in whom I would strongly consider using rituximab.”

The French REOVAS investigators’ future research into rituximab for EGPA will include long-term follow-up for relapse and the induction of remission, Dr. Terrier said.

Dr. Terrier disclosed relationships with Roche, Chugai, Vifor, LFB, Grifols, GlaxoSmithKline, AstraZeneca, Bristol-Myers Squibb, Octapharma, and Janssen. Dr. Putnam has no relevant relationships to disclose

Allopurinol may finally start to get the respect that many rheumatologists feel it deserves as a first-line urate-lowering treatment for gout, following results of a randomized trial showing that it was noninferior to febuxostat both in the overall trial population and in patients with stage 3 chronic kidney disease (CKD).

Sirisak Boakaew/Getty Images

In the multicenter, randomized, double-blinded comparison trial that used a treat-to-target strategy, allopurinol met the primary outcome of noninferiority to febuxostat for preventing gout flare during the observation phase of therapy, reported James O’Dell, MD, chief of the division of rheumatology and vice chair for education in the department of internal medicine at the University of Nebraska Medical Center in Omaha.

“Both agents were well tolerated, with or without CKD. Most importantly, both agents were highly effective when used in a treat-to-target protocol in getting patients to target urate levels,” he said in an oral abstract presentation during the American College of Rheumatology (ACR) 2021 Annual Meeting, which was held online.

And although febuxostat contains a boxed warning about the risks of cardiovascular adverse events with its use, there were no signals for increased cardiovascular toxicity with febuxostat compared with allopurinol, the investigators found.

The trial is the first to compare allopurinol, a decades-old drug, with febuxostat, approved in 2009, in a treat-to-target approach, Dr. O’Dell said.
 

American College of Physicians’ guideline ‘antiquated’

The results of the study “will hopefully teach doctors how to treat gout better by encouraging them to use higher doses of gout medications safely than they’re actually using at this time,” said Donald Thomas Jr., MD, in private practice in Greenbelt, Md., and associate professor of medicine at the Uniformed Services University of the Health Sciences in Bethesda, Md.

Dr. Thomas, who moderated a media briefing where Dr. O’Dell discussed the results of the trial, said that he had recently read the 2017 gout guideline by the American College of Physicians (ACP), which he called “antiquated.”

The ACP recommends the use of corticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDs), or low-dose colchicine to treat patients with acute gout. The ACP also recommends “against initiating long-term urate-lowering therapy in most patients after a first gout attack or in patients with infrequent attacks.”

The guideline recommends that clinicians discuss potential benefits, risks, costs, and personal preferences before starting patients on urate-lowering therapy in patients with recurrent gout attacks.

The 2017 guidelines also state, however, that “[e]vidence was insufficient to conclude whether the benefits of escalating urate-lowering therapy to reach a serum urate target (‘treat to target’) outweigh the harms associated with repeated monitoring and medication escalation.”

“I’ve been a proud member of the American College of Physicians for years, I’m a master of the ACP, and they do a lot of great things, but this is one case where their insistence that they’re not going to have a guideline that isn’t completely based in evidence from studies is getting in the way of common sense,” Dr. O’Dell said.

“Their contention is that what matters to a gout patient is a gout flare, and how do we know that gout flares are less if you treat to target or not – and that’s a fair question,” he continued, “except for the fact that in uric acid metabolism we know physiologically that there’s a magic number and that’s 6.8 mg/dL, and anything above that, every day uric acid is above 6.8, you are literally putting crystal out into all places in your body.”

In contrast, the ACR’s 2020 guideline for the management of gout strongly recommends starting urate-lowering therapy for all patients with tophaceous gout, radiographic damage because of gout, or frequent gout flares. It also advises using allopurinol as the preferred first-line urate-lowering therapy, including for those with stage 3 or greater CKD, and using a low starting dose of allopurinol of 100 mg/day or less (lower in CKD) or febuxostat at 40 mg/day or less. It endorses a treat-to-target management strategy that aims for serum urate < 6 mg/dL with dose titration of urate-lowering agents guided by serial serum urate measurements.

Dr. Thomas and Dr. O’Dell expressed hope that the results of this clinical trial will put the issue to rest, and that the ACP will update its guideline accordingly.

VA-sponsored trial

The study was conducted at 19 Veterans Affairs medical centers and two non-VA sites. The trial was divided into dose-titration, maintenance, and observation phases, each lasting 24 weeks.

A total of 950 participants with gout and a serum urate concentration 6.8 mg/dL or greater were randomly assigned on a 1:1 basis to receive allopurinol 100-800 mg or febuxostat 40 mg to 80/120 mg daily. In 2019, the Food and Drug Administration requested that the maximum titrated dose of febuxostat in the trial be capped at 80 mg daily. All patients stopped prophylaxis with NSAIDs, colchicine, or prednisone before the observation phase.

Patients with persistent hyperuricemia despite treatment with allopurinol were eligible, and these patients were started in the titration phase at their current dose.

The mean patient age was 62.9 years in the allopurinol arm and 61.3 years in the febuxostat arm. Men comprised 98% of patients in each study arm.

The racial/ethnic distribution of patients was similar between the groups. In all, 38.7% of patients assigned to allopurinol and 36% assigned to febuxostat had CKD stages 1-3. (Patients with stage 4 or 5 CKD were excluded from the study.)

A gout flare occurred if a participants reported three or more symptoms of tender, warm, swollen joints, or gout flare, or if the participant reported use of medication for gout flare in the observation phase during weeks 49-72.

As noted before, the trial met its primary endpoint, with 36.5% of patients on allopurinol reporting gout flare in the observation phase, compared with 43.5% on febuxostat (P for noninferiority < .001).

Among patients with CKD stage 3, the respective percentages of patients reporting at least one gout flare in the observation phase were 31.9% and 45.3% (P for noninferiority < .001).

Approximately 80% of patients in each arm had mean serum urate concentrations less than 6.0 mg/dL during the maintenance phase (weeks 36, 42, and 48).

In each arm, about 20% of patients left the study before completing 72 weeks of follow-up. Serious adverse events occurred in 26.7% of patients assigned to allopurinol and 26.1% of patients assigned to febuxostat.

Cardiovascular adverse events occurred in 8.1% and 6.8%, respectively. There were three cases of cardiovascular death in the allopurinol arm and one in the febuxostat arm. Nonfatal myocardial infarction occurred in two and four patients, respectively, stroke in one and two, and unstable angina requiring urgent revascularization in four and three patients.

In the question-and-answer session of the briefing, this news organization asked Dr. Thomas whether he would use the agents interchangeably in his practice. He replied “no, I start off with allopurinol in all of my patients, even those with chronic kidney disease, because it has been shown to be safe. I start off at a very low dose, go up slowly, [and] if they have a reaction, I change it to febuxostat.”

The study was supported by the U.S. Department of Veterans Affairs. Dr. O’Dell and Dr. Thomas have disclosed no relevant financial relationships.

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

Allopurinol may finally start to get the respect that many rheumatologists feel it deserves as a first-line urate-lowering treatment for gout, following results of a randomized trial showing that it was noninferior to febuxostat both in the overall trial population and in patients with stage 3 chronic kidney disease (CKD).

Sirisak Boakaew/Getty Images

In the multicenter, randomized, double-blinded comparison trial that used a treat-to-target strategy, allopurinol met the primary outcome of noninferiority to febuxostat for preventing gout flare during the observation phase of therapy, reported James O’Dell, MD, chief of the division of rheumatology and vice chair for education in the department of internal medicine at the University of Nebraska Medical Center in Omaha.

“Both agents were well tolerated, with or without CKD. Most importantly, both agents were highly effective when used in a treat-to-target protocol in getting patients to target urate levels,” he said in an oral abstract presentation during the American College of Rheumatology (ACR) 2021 Annual Meeting, which was held online.

And although febuxostat contains a boxed warning about the risks of cardiovascular adverse events with its use, there were no signals for increased cardiovascular toxicity with febuxostat compared with allopurinol, the investigators found.

The trial is the first to compare allopurinol, a decades-old drug, with febuxostat, approved in 2009, in a treat-to-target approach, Dr. O’Dell said.
 

American College of Physicians’ guideline ‘antiquated’

The results of the study “will hopefully teach doctors how to treat gout better by encouraging them to use higher doses of gout medications safely than they’re actually using at this time,” said Donald Thomas Jr., MD, in private practice in Greenbelt, Md., and associate professor of medicine at the Uniformed Services University of the Health Sciences in Bethesda, Md.

Dr. Thomas, who moderated a media briefing where Dr. O’Dell discussed the results of the trial, said that he had recently read the 2017 gout guideline by the American College of Physicians (ACP), which he called “antiquated.”

The ACP recommends the use of corticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDs), or low-dose colchicine to treat patients with acute gout. The ACP also recommends “against initiating long-term urate-lowering therapy in most patients after a first gout attack or in patients with infrequent attacks.”

The guideline recommends that clinicians discuss potential benefits, risks, costs, and personal preferences before starting patients on urate-lowering therapy in patients with recurrent gout attacks.

The 2017 guidelines also state, however, that “[e]vidence was insufficient to conclude whether the benefits of escalating urate-lowering therapy to reach a serum urate target (‘treat to target’) outweigh the harms associated with repeated monitoring and medication escalation.”

“I’ve been a proud member of the American College of Physicians for years, I’m a master of the ACP, and they do a lot of great things, but this is one case where their insistence that they’re not going to have a guideline that isn’t completely based in evidence from studies is getting in the way of common sense,” Dr. O’Dell said.

“Their contention is that what matters to a gout patient is a gout flare, and how do we know that gout flares are less if you treat to target or not – and that’s a fair question,” he continued, “except for the fact that in uric acid metabolism we know physiologically that there’s a magic number and that’s 6.8 mg/dL, and anything above that, every day uric acid is above 6.8, you are literally putting crystal out into all places in your body.”

In contrast, the ACR’s 2020 guideline for the management of gout strongly recommends starting urate-lowering therapy for all patients with tophaceous gout, radiographic damage because of gout, or frequent gout flares. It also advises using allopurinol as the preferred first-line urate-lowering therapy, including for those with stage 3 or greater CKD, and using a low starting dose of allopurinol of 100 mg/day or less (lower in CKD) or febuxostat at 40 mg/day or less. It endorses a treat-to-target management strategy that aims for serum urate < 6 mg/dL with dose titration of urate-lowering agents guided by serial serum urate measurements.

Dr. Thomas and Dr. O’Dell expressed hope that the results of this clinical trial will put the issue to rest, and that the ACP will update its guideline accordingly.

VA-sponsored trial

The study was conducted at 19 Veterans Affairs medical centers and two non-VA sites. The trial was divided into dose-titration, maintenance, and observation phases, each lasting 24 weeks.

A total of 950 participants with gout and a serum urate concentration 6.8 mg/dL or greater were randomly assigned on a 1:1 basis to receive allopurinol 100-800 mg or febuxostat 40 mg to 80/120 mg daily. In 2019, the Food and Drug Administration requested that the maximum titrated dose of febuxostat in the trial be capped at 80 mg daily. All patients stopped prophylaxis with NSAIDs, colchicine, or prednisone before the observation phase.

Patients with persistent hyperuricemia despite treatment with allopurinol were eligible, and these patients were started in the titration phase at their current dose.

The mean patient age was 62.9 years in the allopurinol arm and 61.3 years in the febuxostat arm. Men comprised 98% of patients in each study arm.

The racial/ethnic distribution of patients was similar between the groups. In all, 38.7% of patients assigned to allopurinol and 36% assigned to febuxostat had CKD stages 1-3. (Patients with stage 4 or 5 CKD were excluded from the study.)

A gout flare occurred if a participants reported three or more symptoms of tender, warm, swollen joints, or gout flare, or if the participant reported use of medication for gout flare in the observation phase during weeks 49-72.

As noted before, the trial met its primary endpoint, with 36.5% of patients on allopurinol reporting gout flare in the observation phase, compared with 43.5% on febuxostat (P for noninferiority < .001).

Among patients with CKD stage 3, the respective percentages of patients reporting at least one gout flare in the observation phase were 31.9% and 45.3% (P for noninferiority < .001).

Approximately 80% of patients in each arm had mean serum urate concentrations less than 6.0 mg/dL during the maintenance phase (weeks 36, 42, and 48).

In each arm, about 20% of patients left the study before completing 72 weeks of follow-up. Serious adverse events occurred in 26.7% of patients assigned to allopurinol and 26.1% of patients assigned to febuxostat.

Cardiovascular adverse events occurred in 8.1% and 6.8%, respectively. There were three cases of cardiovascular death in the allopurinol arm and one in the febuxostat arm. Nonfatal myocardial infarction occurred in two and four patients, respectively, stroke in one and two, and unstable angina requiring urgent revascularization in four and three patients.

In the question-and-answer session of the briefing, this news organization asked Dr. Thomas whether he would use the agents interchangeably in his practice. He replied “no, I start off with allopurinol in all of my patients, even those with chronic kidney disease, because it has been shown to be safe. I start off at a very low dose, go up slowly, [and] if they have a reaction, I change it to febuxostat.”

The study was supported by the U.S. Department of Veterans Affairs. Dr. O’Dell and Dr. Thomas have disclosed no relevant financial relationships.

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

Allopurinol may finally start to get the respect that many rheumatologists feel it deserves as a first-line urate-lowering treatment for gout, following results of a randomized trial showing that it was noninferior to febuxostat both in the overall trial population and in patients with stage 3 chronic kidney disease (CKD).

Sirisak Boakaew/Getty Images

In the multicenter, randomized, double-blinded comparison trial that used a treat-to-target strategy, allopurinol met the primary outcome of noninferiority to febuxostat for preventing gout flare during the observation phase of therapy, reported James O’Dell, MD, chief of the division of rheumatology and vice chair for education in the department of internal medicine at the University of Nebraska Medical Center in Omaha.

“Both agents were well tolerated, with or without CKD. Most importantly, both agents were highly effective when used in a treat-to-target protocol in getting patients to target urate levels,” he said in an oral abstract presentation during the American College of Rheumatology (ACR) 2021 Annual Meeting, which was held online.

And although febuxostat contains a boxed warning about the risks of cardiovascular adverse events with its use, there were no signals for increased cardiovascular toxicity with febuxostat compared with allopurinol, the investigators found.

The trial is the first to compare allopurinol, a decades-old drug, with febuxostat, approved in 2009, in a treat-to-target approach, Dr. O’Dell said.
 

American College of Physicians’ guideline ‘antiquated’

The results of the study “will hopefully teach doctors how to treat gout better by encouraging them to use higher doses of gout medications safely than they’re actually using at this time,” said Donald Thomas Jr., MD, in private practice in Greenbelt, Md., and associate professor of medicine at the Uniformed Services University of the Health Sciences in Bethesda, Md.

Dr. Thomas, who moderated a media briefing where Dr. O’Dell discussed the results of the trial, said that he had recently read the 2017 gout guideline by the American College of Physicians (ACP), which he called “antiquated.”

The ACP recommends the use of corticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDs), or low-dose colchicine to treat patients with acute gout. The ACP also recommends “against initiating long-term urate-lowering therapy in most patients after a first gout attack or in patients with infrequent attacks.”

The guideline recommends that clinicians discuss potential benefits, risks, costs, and personal preferences before starting patients on urate-lowering therapy in patients with recurrent gout attacks.

The 2017 guidelines also state, however, that “[e]vidence was insufficient to conclude whether the benefits of escalating urate-lowering therapy to reach a serum urate target (‘treat to target’) outweigh the harms associated with repeated monitoring and medication escalation.”

“I’ve been a proud member of the American College of Physicians for years, I’m a master of the ACP, and they do a lot of great things, but this is one case where their insistence that they’re not going to have a guideline that isn’t completely based in evidence from studies is getting in the way of common sense,” Dr. O’Dell said.

“Their contention is that what matters to a gout patient is a gout flare, and how do we know that gout flares are less if you treat to target or not – and that’s a fair question,” he continued, “except for the fact that in uric acid metabolism we know physiologically that there’s a magic number and that’s 6.8 mg/dL, and anything above that, every day uric acid is above 6.8, you are literally putting crystal out into all places in your body.”

In contrast, the ACR’s 2020 guideline for the management of gout strongly recommends starting urate-lowering therapy for all patients with tophaceous gout, radiographic damage because of gout, or frequent gout flares. It also advises using allopurinol as the preferred first-line urate-lowering therapy, including for those with stage 3 or greater CKD, and using a low starting dose of allopurinol of 100 mg/day or less (lower in CKD) or febuxostat at 40 mg/day or less. It endorses a treat-to-target management strategy that aims for serum urate < 6 mg/dL with dose titration of urate-lowering agents guided by serial serum urate measurements.

Dr. Thomas and Dr. O’Dell expressed hope that the results of this clinical trial will put the issue to rest, and that the ACP will update its guideline accordingly.

VA-sponsored trial

The study was conducted at 19 Veterans Affairs medical centers and two non-VA sites. The trial was divided into dose-titration, maintenance, and observation phases, each lasting 24 weeks.

A total of 950 participants with gout and a serum urate concentration 6.8 mg/dL or greater were randomly assigned on a 1:1 basis to receive allopurinol 100-800 mg or febuxostat 40 mg to 80/120 mg daily. In 2019, the Food and Drug Administration requested that the maximum titrated dose of febuxostat in the trial be capped at 80 mg daily. All patients stopped prophylaxis with NSAIDs, colchicine, or prednisone before the observation phase.

Patients with persistent hyperuricemia despite treatment with allopurinol were eligible, and these patients were started in the titration phase at their current dose.

The mean patient age was 62.9 years in the allopurinol arm and 61.3 years in the febuxostat arm. Men comprised 98% of patients in each study arm.

The racial/ethnic distribution of patients was similar between the groups. In all, 38.7% of patients assigned to allopurinol and 36% assigned to febuxostat had CKD stages 1-3. (Patients with stage 4 or 5 CKD were excluded from the study.)

A gout flare occurred if a participants reported three or more symptoms of tender, warm, swollen joints, or gout flare, or if the participant reported use of medication for gout flare in the observation phase during weeks 49-72.

As noted before, the trial met its primary endpoint, with 36.5% of patients on allopurinol reporting gout flare in the observation phase, compared with 43.5% on febuxostat (P for noninferiority < .001).

Among patients with CKD stage 3, the respective percentages of patients reporting at least one gout flare in the observation phase were 31.9% and 45.3% (P for noninferiority < .001).

Approximately 80% of patients in each arm had mean serum urate concentrations less than 6.0 mg/dL during the maintenance phase (weeks 36, 42, and 48).

In each arm, about 20% of patients left the study before completing 72 weeks of follow-up. Serious adverse events occurred in 26.7% of patients assigned to allopurinol and 26.1% of patients assigned to febuxostat.

Cardiovascular adverse events occurred in 8.1% and 6.8%, respectively. There were three cases of cardiovascular death in the allopurinol arm and one in the febuxostat arm. Nonfatal myocardial infarction occurred in two and four patients, respectively, stroke in one and two, and unstable angina requiring urgent revascularization in four and three patients.

In the question-and-answer session of the briefing, this news organization asked Dr. Thomas whether he would use the agents interchangeably in his practice. He replied “no, I start off with allopurinol in all of my patients, even those with chronic kidney disease, because it has been shown to be safe. I start off at a very low dose, go up slowly, [and] if they have a reaction, I change it to febuxostat.”

The study was supported by the U.S. Department of Veterans Affairs. Dr. O’Dell and Dr. Thomas have disclosed no relevant financial relationships.

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

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.