Lupus & Connective Tissue Diseases

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.

Treatment of antineutrophil cytoplasmic autoantibody (ANCA)–associated vasculitis and renal disease with the oral C5a receptor inhibitor avacopan (Tavneos, ChemoCentryx) provides significant recovery of kidney function, compared with prednisone, particularly in patients with severe kidney disease, novel research indicates.

The new analysis underscores that “the real value of avacopan is that we can now expect to get our patients steroid free,” said first author David R.W. Jayne, MD, a professor of clinical autoimmunity at the University of Cambridge (England), when presenting the findings at the American Society of Nephrology’s Kidney Week 2021.

“Whether or not we’re brave enough to initiate treatment without steroids, I think that will perhaps come with some patient experience,” he added.

The findings are from a subanalysis of renal effects in the phase 3 ADVOCATE trial, which was published in February 2021 in the New England Journal of Medicine and included 330 patients with ANCA-associated vasculitis.

The trial in large part led to the U.S. approval of avacopan by the Food and Drug Administration in October as an adjunctive treatment for adults with severe active ANCA-associated vasculitis in combination with standard therapy including glucocorticoids.

The approval was greeted with enthusiasm as suggesting a much-needed option to help reduce, or even potentially eliminate, the need for glucocorticoids and their side effects. Other agents included in treatment regimens for ANCA-associated vasculitis include cyclophosphamide and rituximab.

Dr. Jayne emphasized that, before avacopan, treatment options had been limited.

“There is nothing else new in the clinic apart from rituximab, which we have now been using for almost 20 years,” he said in an interview. “Avacopan is new, the mode of action is different from any drugs in use at the moment, and the speed of action is very quick.”

The need to more closely investigate the trial’s renal outcomes in this new analysis was important because the high mortality rates in ANCA-associated vasculitis – a rare systemic autoimmune disease causing overactivation of complement resulting in inflammation of small blood vessels – is largely driven by those with MPO and PR3 autoantibody renal vasculitis, Dr. Jayne explained.

Commenting on the study, J. Charles Jennette, MD, a professor of pathology and laboratory medicine and professor of medicine at the University of North Carolina at Chapel Hill, said the new findings on renal outcomes, such as proteinuria, may offer key insights on avacopan’s efficacy.

“To me, the most impressive outcome of the ADVOCATE Phase 3 trial was the more rapid reduction in hematuria and proteinuria with avacopan compared to conventional prednisone therapy,” he said in an interview.
 

Recovery of eGFR with avacopan best in those with severe renal disease

In the trial, patients with ANCA-associated vasculitis were randomized 1:1 to treatment with oral avacopan 30 mg twice daily or oral prednisone on a tapering schedule.

All patients also received background immunosuppression – about two-thirds received rituximab and a third received cyclophosphamide – followed by azathioprine.

The main study results showed similar rates of remission in both groups at week 26 and a superior remission rate with avacopan, in terms of sustained remission, at week 52 (65.7% vs. 54.9%; P < .001).

Approximately 80% of patients in the trial had renal involvement of ANCA vasculitis, the focus of the new analysis, and they had a baseline mean estimated glomerular filtration rate (eGFR) of 45 mL/min per 1.73 m2.

Among those with renal involvement, patients treated with avacopan had a significantly greater eGFR recovery, compared with the prednisone group at week 26 (P = .046) and week 52 (P < .029).

The strongest improvements were observed among patients with moderate to severe kidney damage, who had a mean eGFR of 21 mL/min per 1.73 m2 at baseline. Among those patients, the mean increase in eGFR was 13.7 mL/min per 1.73 m² in the avacopan-treated group (n = 52) versus 8.2 mL/min per 1.73 m² in the prednisone group (n = 48; P < .01) by week 52.

Improvements in urinary albumin:creatinine ratios (UACR) of as much as 40% were also observed in the avacopan group within the first 4 weeks of treatment, while no changes were observed in the same period in the prednisone group.

In other findings, the study also showed more rapid declines in proteinuria within 4 weeks in the avacopan group, and fewer patients had hematuria and there were greater reductions in MCP-1 in avacopan-treated patients at week 52, Dr. Jayne reported.

In terms of safety, there were no differences between the groups, with trends of fewer deaths and severe adverse events in the avacopan group.

“We found that the improved recovery of eGFR with avacopan was accentuated among those with more severe renal disease,” Dr. Jayne said.

He noted that, while the study’s aim was for the avacopan group to be steroid free, the patients received brief, reduced doses of about a third of the normal oral steroid dose early in the trial. However, using a Glucocorticoid Toxicity Index, the authors found those in the avacopan group did have fewer glucocorticoid-related adverse events.

Future issues to be examined include what happens when avacopan is discontinued and whether there will be a high relapse rate, Dr. Jayne noted.

Overall, however, “we anticipate that with longer-term follow-up, this better eGFR recovery will have a [favorable] effect on kidney failure and potentially mortality risk in these patients,” he concluded.

Targeted therapy is good for patients and doctors

Expanding upon his comments regarding the new drug, Dr. Jennette said it implies “that the C5a receptor inhibitor was targeting an event that blocks injury more quickly and effectively than prednisone.”

“This may be because prednisone has more complex pharmacodynamics and less targeted effects than a C5a receptor inhibitor,” he said.

Overall, the findings bode well for a potentially beneficial therapy, he added. “We have entered a new era of more targeted therapies, for example, targeted B-cell therapy using an anti-CD20 antibody, and targeted complement-mediated injury therapy using C5a receptor inhibitor.”

“The validation of this targeted therapy to block complement-mediated autoimmune inflammatory injury is another advance toward targeted precision therapy versus empirical therapy. This will be good for the doctors and good for the patients,” Dr. Jennette concluded.

The study was funded by ChemoCentryx. Dr. Jayne has reported receiving grants and/or consulting for AstraZeneca, ChemoCentryx, GlaxoSmithKline, MiroBio, Vifor, and Roche/Genentech. Dr. Jennette has received funding from ChemoCentryx for preclinical validation studies of avacopan in a mouse model of ANCA glomerulonephritis.

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

Treatment of antineutrophil cytoplasmic autoantibody (ANCA)–associated vasculitis and renal disease with the oral C5a receptor inhibitor avacopan (Tavneos, ChemoCentryx) provides significant recovery of kidney function, compared with prednisone, particularly in patients with severe kidney disease, novel research indicates.

The new analysis underscores that “the real value of avacopan is that we can now expect to get our patients steroid free,” said first author David R.W. Jayne, MD, a professor of clinical autoimmunity at the University of Cambridge (England), when presenting the findings at the American Society of Nephrology’s Kidney Week 2021.

“Whether or not we’re brave enough to initiate treatment without steroids, I think that will perhaps come with some patient experience,” he added.

The findings are from a subanalysis of renal effects in the phase 3 ADVOCATE trial, which was published in February 2021 in the New England Journal of Medicine and included 330 patients with ANCA-associated vasculitis.

The trial in large part led to the U.S. approval of avacopan by the Food and Drug Administration in October as an adjunctive treatment for adults with severe active ANCA-associated vasculitis in combination with standard therapy including glucocorticoids.

The approval was greeted with enthusiasm as suggesting a much-needed option to help reduce, or even potentially eliminate, the need for glucocorticoids and their side effects. Other agents included in treatment regimens for ANCA-associated vasculitis include cyclophosphamide and rituximab.

Dr. Jayne emphasized that, before avacopan, treatment options had been limited.

“There is nothing else new in the clinic apart from rituximab, which we have now been using for almost 20 years,” he said in an interview. “Avacopan is new, the mode of action is different from any drugs in use at the moment, and the speed of action is very quick.”

The need to more closely investigate the trial’s renal outcomes in this new analysis was important because the high mortality rates in ANCA-associated vasculitis – a rare systemic autoimmune disease causing overactivation of complement resulting in inflammation of small blood vessels – is largely driven by those with MPO and PR3 autoantibody renal vasculitis, Dr. Jayne explained.

Commenting on the study, J. Charles Jennette, MD, a professor of pathology and laboratory medicine and professor of medicine at the University of North Carolina at Chapel Hill, said the new findings on renal outcomes, such as proteinuria, may offer key insights on avacopan’s efficacy.

“To me, the most impressive outcome of the ADVOCATE Phase 3 trial was the more rapid reduction in hematuria and proteinuria with avacopan compared to conventional prednisone therapy,” he said in an interview.
 

Recovery of eGFR with avacopan best in those with severe renal disease

In the trial, patients with ANCA-associated vasculitis were randomized 1:1 to treatment with oral avacopan 30 mg twice daily or oral prednisone on a tapering schedule.

All patients also received background immunosuppression – about two-thirds received rituximab and a third received cyclophosphamide – followed by azathioprine.

The main study results showed similar rates of remission in both groups at week 26 and a superior remission rate with avacopan, in terms of sustained remission, at week 52 (65.7% vs. 54.9%; P < .001).

Approximately 80% of patients in the trial had renal involvement of ANCA vasculitis, the focus of the new analysis, and they had a baseline mean estimated glomerular filtration rate (eGFR) of 45 mL/min per 1.73 m2.

Among those with renal involvement, patients treated with avacopan had a significantly greater eGFR recovery, compared with the prednisone group at week 26 (P = .046) and week 52 (P < .029).

The strongest improvements were observed among patients with moderate to severe kidney damage, who had a mean eGFR of 21 mL/min per 1.73 m2 at baseline. Among those patients, the mean increase in eGFR was 13.7 mL/min per 1.73 m² in the avacopan-treated group (n = 52) versus 8.2 mL/min per 1.73 m² in the prednisone group (n = 48; P < .01) by week 52.

Improvements in urinary albumin:creatinine ratios (UACR) of as much as 40% were also observed in the avacopan group within the first 4 weeks of treatment, while no changes were observed in the same period in the prednisone group.

In other findings, the study also showed more rapid declines in proteinuria within 4 weeks in the avacopan group, and fewer patients had hematuria and there were greater reductions in MCP-1 in avacopan-treated patients at week 52, Dr. Jayne reported.

In terms of safety, there were no differences between the groups, with trends of fewer deaths and severe adverse events in the avacopan group.

“We found that the improved recovery of eGFR with avacopan was accentuated among those with more severe renal disease,” Dr. Jayne said.

He noted that, while the study’s aim was for the avacopan group to be steroid free, the patients received brief, reduced doses of about a third of the normal oral steroid dose early in the trial. However, using a Glucocorticoid Toxicity Index, the authors found those in the avacopan group did have fewer glucocorticoid-related adverse events.

Future issues to be examined include what happens when avacopan is discontinued and whether there will be a high relapse rate, Dr. Jayne noted.

Overall, however, “we anticipate that with longer-term follow-up, this better eGFR recovery will have a [favorable] effect on kidney failure and potentially mortality risk in these patients,” he concluded.

Targeted therapy is good for patients and doctors

Expanding upon his comments regarding the new drug, Dr. Jennette said it implies “that the C5a receptor inhibitor was targeting an event that blocks injury more quickly and effectively than prednisone.”

“This may be because prednisone has more complex pharmacodynamics and less targeted effects than a C5a receptor inhibitor,” he said.

Overall, the findings bode well for a potentially beneficial therapy, he added. “We have entered a new era of more targeted therapies, for example, targeted B-cell therapy using an anti-CD20 antibody, and targeted complement-mediated injury therapy using C5a receptor inhibitor.”

“The validation of this targeted therapy to block complement-mediated autoimmune inflammatory injury is another advance toward targeted precision therapy versus empirical therapy. This will be good for the doctors and good for the patients,” Dr. Jennette concluded.

The study was funded by ChemoCentryx. Dr. Jayne has reported receiving grants and/or consulting for AstraZeneca, ChemoCentryx, GlaxoSmithKline, MiroBio, Vifor, and Roche/Genentech. Dr. Jennette has received funding from ChemoCentryx for preclinical validation studies of avacopan in a mouse model of ANCA glomerulonephritis.

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

Treatment of antineutrophil cytoplasmic autoantibody (ANCA)–associated vasculitis and renal disease with the oral C5a receptor inhibitor avacopan (Tavneos, ChemoCentryx) provides significant recovery of kidney function, compared with prednisone, particularly in patients with severe kidney disease, novel research indicates.

The new analysis underscores that “the real value of avacopan is that we can now expect to get our patients steroid free,” said first author David R.W. Jayne, MD, a professor of clinical autoimmunity at the University of Cambridge (England), when presenting the findings at the American Society of Nephrology’s Kidney Week 2021.

“Whether or not we’re brave enough to initiate treatment without steroids, I think that will perhaps come with some patient experience,” he added.

The findings are from a subanalysis of renal effects in the phase 3 ADVOCATE trial, which was published in February 2021 in the New England Journal of Medicine and included 330 patients with ANCA-associated vasculitis.

The trial in large part led to the U.S. approval of avacopan by the Food and Drug Administration in October as an adjunctive treatment for adults with severe active ANCA-associated vasculitis in combination with standard therapy including glucocorticoids.

The approval was greeted with enthusiasm as suggesting a much-needed option to help reduce, or even potentially eliminate, the need for glucocorticoids and their side effects. Other agents included in treatment regimens for ANCA-associated vasculitis include cyclophosphamide and rituximab.

Dr. Jayne emphasized that, before avacopan, treatment options had been limited.

“There is nothing else new in the clinic apart from rituximab, which we have now been using for almost 20 years,” he said in an interview. “Avacopan is new, the mode of action is different from any drugs in use at the moment, and the speed of action is very quick.”

The need to more closely investigate the trial’s renal outcomes in this new analysis was important because the high mortality rates in ANCA-associated vasculitis – a rare systemic autoimmune disease causing overactivation of complement resulting in inflammation of small blood vessels – is largely driven by those with MPO and PR3 autoantibody renal vasculitis, Dr. Jayne explained.

Commenting on the study, J. Charles Jennette, MD, a professor of pathology and laboratory medicine and professor of medicine at the University of North Carolina at Chapel Hill, said the new findings on renal outcomes, such as proteinuria, may offer key insights on avacopan’s efficacy.

“To me, the most impressive outcome of the ADVOCATE Phase 3 trial was the more rapid reduction in hematuria and proteinuria with avacopan compared to conventional prednisone therapy,” he said in an interview.
 

Recovery of eGFR with avacopan best in those with severe renal disease

In the trial, patients with ANCA-associated vasculitis were randomized 1:1 to treatment with oral avacopan 30 mg twice daily or oral prednisone on a tapering schedule.

All patients also received background immunosuppression – about two-thirds received rituximab and a third received cyclophosphamide – followed by azathioprine.

The main study results showed similar rates of remission in both groups at week 26 and a superior remission rate with avacopan, in terms of sustained remission, at week 52 (65.7% vs. 54.9%; P < .001).

Approximately 80% of patients in the trial had renal involvement of ANCA vasculitis, the focus of the new analysis, and they had a baseline mean estimated glomerular filtration rate (eGFR) of 45 mL/min per 1.73 m2.

Among those with renal involvement, patients treated with avacopan had a significantly greater eGFR recovery, compared with the prednisone group at week 26 (P = .046) and week 52 (P < .029).

The strongest improvements were observed among patients with moderate to severe kidney damage, who had a mean eGFR of 21 mL/min per 1.73 m2 at baseline. Among those patients, the mean increase in eGFR was 13.7 mL/min per 1.73 m² in the avacopan-treated group (n = 52) versus 8.2 mL/min per 1.73 m² in the prednisone group (n = 48; P < .01) by week 52.

Improvements in urinary albumin:creatinine ratios (UACR) of as much as 40% were also observed in the avacopan group within the first 4 weeks of treatment, while no changes were observed in the same period in the prednisone group.

In other findings, the study also showed more rapid declines in proteinuria within 4 weeks in the avacopan group, and fewer patients had hematuria and there were greater reductions in MCP-1 in avacopan-treated patients at week 52, Dr. Jayne reported.

In terms of safety, there were no differences between the groups, with trends of fewer deaths and severe adverse events in the avacopan group.

“We found that the improved recovery of eGFR with avacopan was accentuated among those with more severe renal disease,” Dr. Jayne said.

He noted that, while the study’s aim was for the avacopan group to be steroid free, the patients received brief, reduced doses of about a third of the normal oral steroid dose early in the trial. However, using a Glucocorticoid Toxicity Index, the authors found those in the avacopan group did have fewer glucocorticoid-related adverse events.

Future issues to be examined include what happens when avacopan is discontinued and whether there will be a high relapse rate, Dr. Jayne noted.

Overall, however, “we anticipate that with longer-term follow-up, this better eGFR recovery will have a [favorable] effect on kidney failure and potentially mortality risk in these patients,” he concluded.

Targeted therapy is good for patients and doctors

Expanding upon his comments regarding the new drug, Dr. Jennette said it implies “that the C5a receptor inhibitor was targeting an event that blocks injury more quickly and effectively than prednisone.”

“This may be because prednisone has more complex pharmacodynamics and less targeted effects than a C5a receptor inhibitor,” he said.

Overall, the findings bode well for a potentially beneficial therapy, he added. “We have entered a new era of more targeted therapies, for example, targeted B-cell therapy using an anti-CD20 antibody, and targeted complement-mediated injury therapy using C5a receptor inhibitor.”

“The validation of this targeted therapy to block complement-mediated autoimmune inflammatory injury is another advance toward targeted precision therapy versus empirical therapy. This will be good for the doctors and good for the patients,” Dr. Jennette concluded.

The study was funded by ChemoCentryx. Dr. Jayne has reported receiving grants and/or consulting for AstraZeneca, ChemoCentryx, GlaxoSmithKline, MiroBio, Vifor, and Roche/Genentech. Dr. Jennette has received funding from ChemoCentryx for preclinical validation studies of avacopan in a mouse model of ANCA glomerulonephritis.

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.

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.

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

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.

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

Courtesy Dr. Marcela Ferrada

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

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

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

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

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

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

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

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

Three variants

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Therapeutic options

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

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

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

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

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

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

Courtesy Dr. Marcela Ferrada

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

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

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

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

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

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

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

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

Three variants

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Therapeutic options

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

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

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

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

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

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

Courtesy Dr. Marcela Ferrada

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

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

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

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

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

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

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

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

Three variants

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Therapeutic options

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

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

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

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

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

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

Marc Bruxelle/Getty Images

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

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

Study details

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

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

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

Results

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

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

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

Patient age is an important consideration

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

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

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

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

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

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

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

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

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

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

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

Marc Bruxelle/Getty Images

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

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

Study details

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

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

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

Results

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

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

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

Patient age is an important consideration

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

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

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

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

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

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

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

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

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

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

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

Marc Bruxelle/Getty Images

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

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

Study details

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

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

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

Results

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

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

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

Patient age is an important consideration

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Randomized trial

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

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

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

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

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

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

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

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

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

Convincing results

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

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

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

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

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

The study results were previously published in the Lancet Rheumatology.

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

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

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

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

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

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

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

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

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

Randomized trial

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

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

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

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

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

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

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

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

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

Convincing results

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

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

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

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

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

The study results were previously published in the Lancet Rheumatology.

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

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

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

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

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

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

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

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

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

Randomized trial

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

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

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

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

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

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

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

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

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

Convincing results

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

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

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

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

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

The study results were previously published in the Lancet Rheumatology.

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

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

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

Ziga Plahutar

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

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

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

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

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

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

Evidence base

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

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

Ancillary study

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

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

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

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

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

Results

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

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

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

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

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

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

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



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

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

Ziga Plahutar

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

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

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

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

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

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

Evidence base

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

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

Ancillary study

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

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

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

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

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

Results

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

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

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

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

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

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

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



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

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

Ziga Plahutar

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

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

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

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

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

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

Evidence base

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

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

Ancillary study

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

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

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

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

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

Results

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

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

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

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

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

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

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



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

Women with systemic lupus erythematous (SLE) who are at risk for preeclampsia may benefit from timely treatment with low-dose aspirin and perhaps hydroxychloroquine, according to German researchers.

©American Heart Association

In a prospective, real-world study of 190 pregnancies in 148 women (average age, 30 years), the use of low-dose aspirin starting around the 16th week of gestation was associated with a lower risk for preeclampsia than was no aspirin use (adjusted odds ratio [aOR], 0.21; P < .05).

The use of hydroxychloroquine starting in the first trimester had a “moderating effect,” said Isabell Haase, MD, a senior clinician scientist in the department of rheumatology at Hiller-Research Unit, Düsseldorf, Germany. Although this was not a statistically significant effect (aOR, 0.47; P = .21), the association strengthened if only high-risk pregnancies were considered (aOR, 0.28; P = .075).

“I think this once more shows us that counseling and risk assessment in our lupus patients is very important to find out those with the highest risk and treat them as good as possible,” Dr. Haase said at an international congress on systemic lupus erythematosus.

Preeclampsia and lupus

“Women with SLE face a high risk of preeclampsia because of their autoimmune disease,” Dr. Haase explained. “This [risk] can be further increased if a woman carries additional risk factors, like hypertension or lupus nephritis.”

Low-dose aspirin is known to protect against the development of preeclampsia in women without autoimmune disease if started before the 16th gestational week of pregnancy, Dr. Haase added. That is why it’s recommended by both the American College of Rheumatology and the European Alliance of Associations for Rheumatology.

“For hydroxychloroquine, we only have some small studies and its mechanism of action that lead us to the idea that it could also have a beneficial effect on preeclampsia in lupus patients,” she said.
 

Study design and results

The aim of the study was to see in a real-world cohort whether there was any beneficial effect of either aspirin or hydroxychloroquine regarding the development of preeclampsia.

The researchers used prospectively collected data from pregnancies seen at an outpatient pregnancy clinic during 1995-2019. They used multiple logistic regression to determine whether there was any effect of four treatments on the development of preeclampsia: aspirin (n = 39 patients) or hydroxychloroquine (n = 39) alone, in combination (n = 43), or neither drug (n = 69).

Overall, 56% of the women had significant risk factors for preeclampsia, including a prior history, multifetal gestation, chronic hypertension, lupus nephritis, or antiphospholipid antibodies (aPL). A further 28% had moderate risk factors, including not having had children, a body mass index >30 kg/m², and being older than 35 years.

The overall rate of preeclampsia in the study population was 13.2%, “which is in line with other studies in lupus pregnancies,” Dr. Haase said. Rates in each of the four treatment groups were 15.4% with aspirin alone, 7.7% with hydroxychloroquine alone, 14% with both drugs, and 14.5% with neither.

The odds of developing preeclampsia were lower with both aspirin and hydroxychloroquine. Factors that raised the odds were high disease activity in the first trimester (aOR, 4.55), a BMI of >30 kg/m² (aOR, 6.14), having high-risk aPL or antiphospholipid syndrome (aOR, 8.02), and a history of preeclampsia (aOR, 9.78).

Only high disease activity in the first trimester and BMI >30 kg/m² remained independent predictors of preeclampsia when the researchers considered only high-risk pregnancies (aOR, 7.74 for high disease activity in first trimester and 10.04 for a high BMI).

The results are “really impressive,” said Angela Tincani, MD, senior consultant at the Rheumatology and Clinical Immunology Unit of ASST–Spedali Civili di Brescia, in Italy.

Dr. Tincani observed that the study had covered a “large number of years” (1995-2020).

“I think that our attitude in looking after lupus patients [changed] during this time,” she said.

“As an example, I think that we probably use less corticosteroids now than in the 90s,” she said.

When asked whether changes in practices have influenced the findings, she acknowledged, “You can see that the prescription of the different medications has changed a lot. We also thought that we have to take into account the years as a confounder, but we haven’t statistically analyzed that, but it’s definitely something that we are going to do next.”

The study received no outside funding. Dr. Haase has received travel fees from AbbVie, Celgene, Chugai, Janssen-Cilag, Eli Lilly, and Medac. Dr. Tincani has disclosed no relevant financial relationships.

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

Women with systemic lupus erythematous (SLE) who are at risk for preeclampsia may benefit from timely treatment with low-dose aspirin and perhaps hydroxychloroquine, according to German researchers.

©American Heart Association

In a prospective, real-world study of 190 pregnancies in 148 women (average age, 30 years), the use of low-dose aspirin starting around the 16th week of gestation was associated with a lower risk for preeclampsia than was no aspirin use (adjusted odds ratio [aOR], 0.21; P < .05).

The use of hydroxychloroquine starting in the first trimester had a “moderating effect,” said Isabell Haase, MD, a senior clinician scientist in the department of rheumatology at Hiller-Research Unit, Düsseldorf, Germany. Although this was not a statistically significant effect (aOR, 0.47; P = .21), the association strengthened if only high-risk pregnancies were considered (aOR, 0.28; P = .075).

“I think this once more shows us that counseling and risk assessment in our lupus patients is very important to find out those with the highest risk and treat them as good as possible,” Dr. Haase said at an international congress on systemic lupus erythematosus.

Preeclampsia and lupus

“Women with SLE face a high risk of preeclampsia because of their autoimmune disease,” Dr. Haase explained. “This [risk] can be further increased if a woman carries additional risk factors, like hypertension or lupus nephritis.”

Low-dose aspirin is known to protect against the development of preeclampsia in women without autoimmune disease if started before the 16th gestational week of pregnancy, Dr. Haase added. That is why it’s recommended by both the American College of Rheumatology and the European Alliance of Associations for Rheumatology.

“For hydroxychloroquine, we only have some small studies and its mechanism of action that lead us to the idea that it could also have a beneficial effect on preeclampsia in lupus patients,” she said.
 

Study design and results

The aim of the study was to see in a real-world cohort whether there was any beneficial effect of either aspirin or hydroxychloroquine regarding the development of preeclampsia.

The researchers used prospectively collected data from pregnancies seen at an outpatient pregnancy clinic during 1995-2019. They used multiple logistic regression to determine whether there was any effect of four treatments on the development of preeclampsia: aspirin (n = 39 patients) or hydroxychloroquine (n = 39) alone, in combination (n = 43), or neither drug (n = 69).

Overall, 56% of the women had significant risk factors for preeclampsia, including a prior history, multifetal gestation, chronic hypertension, lupus nephritis, or antiphospholipid antibodies (aPL). A further 28% had moderate risk factors, including not having had children, a body mass index >30 kg/m², and being older than 35 years.

The overall rate of preeclampsia in the study population was 13.2%, “which is in line with other studies in lupus pregnancies,” Dr. Haase said. Rates in each of the four treatment groups were 15.4% with aspirin alone, 7.7% with hydroxychloroquine alone, 14% with both drugs, and 14.5% with neither.

The odds of developing preeclampsia were lower with both aspirin and hydroxychloroquine. Factors that raised the odds were high disease activity in the first trimester (aOR, 4.55), a BMI of >30 kg/m² (aOR, 6.14), having high-risk aPL or antiphospholipid syndrome (aOR, 8.02), and a history of preeclampsia (aOR, 9.78).

Only high disease activity in the first trimester and BMI >30 kg/m² remained independent predictors of preeclampsia when the researchers considered only high-risk pregnancies (aOR, 7.74 for high disease activity in first trimester and 10.04 for a high BMI).

The results are “really impressive,” said Angela Tincani, MD, senior consultant at the Rheumatology and Clinical Immunology Unit of ASST–Spedali Civili di Brescia, in Italy.

Dr. Tincani observed that the study had covered a “large number of years” (1995-2020).

“I think that our attitude in looking after lupus patients [changed] during this time,” she said.

“As an example, I think that we probably use less corticosteroids now than in the 90s,” she said.

When asked whether changes in practices have influenced the findings, she acknowledged, “You can see that the prescription of the different medications has changed a lot. We also thought that we have to take into account the years as a confounder, but we haven’t statistically analyzed that, but it’s definitely something that we are going to do next.”

The study received no outside funding. Dr. Haase has received travel fees from AbbVie, Celgene, Chugai, Janssen-Cilag, Eli Lilly, and Medac. Dr. Tincani has disclosed no relevant financial relationships.

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

Women with systemic lupus erythematous (SLE) who are at risk for preeclampsia may benefit from timely treatment with low-dose aspirin and perhaps hydroxychloroquine, according to German researchers.

©American Heart Association

In a prospective, real-world study of 190 pregnancies in 148 women (average age, 30 years), the use of low-dose aspirin starting around the 16th week of gestation was associated with a lower risk for preeclampsia than was no aspirin use (adjusted odds ratio [aOR], 0.21; P < .05).

The use of hydroxychloroquine starting in the first trimester had a “moderating effect,” said Isabell Haase, MD, a senior clinician scientist in the department of rheumatology at Hiller-Research Unit, Düsseldorf, Germany. Although this was not a statistically significant effect (aOR, 0.47; P = .21), the association strengthened if only high-risk pregnancies were considered (aOR, 0.28; P = .075).

“I think this once more shows us that counseling and risk assessment in our lupus patients is very important to find out those with the highest risk and treat them as good as possible,” Dr. Haase said at an international congress on systemic lupus erythematosus.

Preeclampsia and lupus

“Women with SLE face a high risk of preeclampsia because of their autoimmune disease,” Dr. Haase explained. “This [risk] can be further increased if a woman carries additional risk factors, like hypertension or lupus nephritis.”

Low-dose aspirin is known to protect against the development of preeclampsia in women without autoimmune disease if started before the 16th gestational week of pregnancy, Dr. Haase added. That is why it’s recommended by both the American College of Rheumatology and the European Alliance of Associations for Rheumatology.

“For hydroxychloroquine, we only have some small studies and its mechanism of action that lead us to the idea that it could also have a beneficial effect on preeclampsia in lupus patients,” she said.
 

Study design and results

The aim of the study was to see in a real-world cohort whether there was any beneficial effect of either aspirin or hydroxychloroquine regarding the development of preeclampsia.

The researchers used prospectively collected data from pregnancies seen at an outpatient pregnancy clinic during 1995-2019. They used multiple logistic regression to determine whether there was any effect of four treatments on the development of preeclampsia: aspirin (n = 39 patients) or hydroxychloroquine (n = 39) alone, in combination (n = 43), or neither drug (n = 69).

Overall, 56% of the women had significant risk factors for preeclampsia, including a prior history, multifetal gestation, chronic hypertension, lupus nephritis, or antiphospholipid antibodies (aPL). A further 28% had moderate risk factors, including not having had children, a body mass index >30 kg/m², and being older than 35 years.

The overall rate of preeclampsia in the study population was 13.2%, “which is in line with other studies in lupus pregnancies,” Dr. Haase said. Rates in each of the four treatment groups were 15.4% with aspirin alone, 7.7% with hydroxychloroquine alone, 14% with both drugs, and 14.5% with neither.

The odds of developing preeclampsia were lower with both aspirin and hydroxychloroquine. Factors that raised the odds were high disease activity in the first trimester (aOR, 4.55), a BMI of >30 kg/m² (aOR, 6.14), having high-risk aPL or antiphospholipid syndrome (aOR, 8.02), and a history of preeclampsia (aOR, 9.78).

Only high disease activity in the first trimester and BMI >30 kg/m² remained independent predictors of preeclampsia when the researchers considered only high-risk pregnancies (aOR, 7.74 for high disease activity in first trimester and 10.04 for a high BMI).

The results are “really impressive,” said Angela Tincani, MD, senior consultant at the Rheumatology and Clinical Immunology Unit of ASST–Spedali Civili di Brescia, in Italy.

Dr. Tincani observed that the study had covered a “large number of years” (1995-2020).

“I think that our attitude in looking after lupus patients [changed] during this time,” she said.

“As an example, I think that we probably use less corticosteroids now than in the 90s,” she said.

When asked whether changes in practices have influenced the findings, she acknowledged, “You can see that the prescription of the different medications has changed a lot. We also thought that we have to take into account the years as a confounder, but we haven’t statistically analyzed that, but it’s definitely something that we are going to do next.”

The study received no outside funding. Dr. Haase has received travel fees from AbbVie, Celgene, Chugai, Janssen-Cilag, Eli Lilly, and Medac. Dr. Tincani has disclosed no relevant financial relationships.

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