Lupus & Connective Tissue Diseases

Although a phase 3 trial of lenabasum did not meet its primary endpoint for treatment of diffuse cutaneous systemic sclerosis (dcSSc), the drug led to more improvement in participants who were not receiving background immunosuppressant therapy during the trial than that seen in participants who received the placebo. Lenabasum also had a favorable safety profile, according to findings presented at the annual European Congress of Rheumatology.

The double-blind, randomized, placebo-controlled trial involved 363 adults who had had dcSSc for up to 6 years. One third of the participants received 5 mg of oral lenabasum, one third received 20 mg, and one third received a placebo. Patients already receiving immunosuppressant therapy could continue to receive it during the trial if the dose had been stable for at least 8 weeks before screening and corticosteroid therapy did not exceed 10 mg prednisone per day or the equivalent.

“The decision to allow background immunosuppressant therapies was made to reflect real-world clinical practice,” coprincipal investigator Robert Dr. Spiera, MD, director of the Vasculitis and Scleroderma Program at the Hospital for Special Surgery, New York, told attendees.

“It is surprising that we do not see any added efficacy of lenabasum in this trial, given the fact that the previous phase 2 trial in 42 patients did show a clear benefit of lenabasum over placebo in the same population,” Jeska K. de Vries-Bouwstra, MD, PhD, a rheumatologist at Leiden (the Netherlands) University Medical Center told this news organization. “Even more, the clinical response in the phase 2 study was supported by a greater change in gene expression in skin tissue of pathways involved in inflammation and fibrosis with lenabasum as compared to placebo.”

Background immunosuppressants contribute to unprecedented placebo responses

The researchers compared the ACR CRISS (Combined Response Index in Diffuse Cutaneous Systemic Sclerosis) score and several secondary endpoints at 52 weeks between the 123 participants who received the placebo and the 120 participants who received 20 mg of lenabasum. A total of 60% of the lenabasum group and 66% of the placebo group had a disease duration of 3 or fewer years, and the modified Rodnan skin score (mRSS) was 22 in the lenabasum group and 23.3 in the placebo group at baseline.

A large majority of participants in both groups – 89% in the lenabasum group and 84% in the placebo group – were receiving background immunosuppressant therapy during the trial. Specifically, 53% of each group was taking mycophenolate, and 23% of the lenabasum group and 32% of the placebo group were taking corticosteroids. In addition, 22% of the lenabasum group and 12% of the placebo group were on methotrexate, and 27% of the lenabasum group and 22% of the placebo group were on another immunosuppressant therapy.

Half of the placebo group and 58% of the lenabasum group were taking only one immunosuppressive therapy. About one-third of the lenabasum (32%) and placebo (34%) groups were taking two or more immunosuppressive therapies.

The primary endpoint at 52 weeks was not significantly different between the two groups: a CRISS score of 0.888 in the lenabasum group and 0.887 in the placebo group. A CRISS score of 0.6 or higher indicates likelihood that a patient improved on treatment. Patients with significant worsening of renal or cardiopulmonary involvement are classified as not improved (score of 0), regardless of improvements in other core items.

“We had very high CRISS scores in all three groups, and they were comparable in all three groups,” Dr. Spiera reported. Because improvement in placebo group far exceeded expectations, the researchers were unable to discern the treatment effect of lenabasum on top of the placebo effect.

The placebo group had better outcomes than expected because of the background immunosuppressant therapy, particularly the use of mycophenolate. When the researchers looked only at placebo participants, the CRISS score was 0.936 in the 97 patients receiving background immunosuppressant therapy of any kind and 0.935 in the 29 patients taking only mycophenolate with no other immunosuppressant therapy, compared with 0.417 in the 16 patients not receiving any background therapy.

In a prespecified analysis, the researchers investigated background immunosuppressive therapy as a mediator. The CRISS score for the 10 lenabasum participants not receiving background therapy was 0.811, compared with 0.417 seen in the placebo group patients not on background therapy.

Among the 173 participants taking mycophenolate in particular, the mycophenolate “had a statistically significant improvement on CRISS score that increased with each visit,” Dr. Spiera reported. The duration of mycophenolate therapy also affected efficacy results.

Patients who had been taking mycophenolate longer saw less improvement in their CRISS score over time. Those taking it more than 2 years at baseline had a CRISS score of 0.86, compared with 0.96 for those taking it for 1-2 years at baseline and 0.98 for those taking it from 6 months to 1 year at baseline. Those who had only been taking mycophenolate for up to 6 months at baseline had a CRISS score of 0.99. Meanwhile, patients not taking any background immunosuppressant therapies only had a CRISS score of about 0.35.
 

Changes in secondary endpoints followed same pattern as CRISS

The secondary endpoints similarly showed no statistically significant difference when comparing the lenabasum and placebo groups overall. These endpoints included change in mRSS score, change in forced vital capacity (FVC) percentage and volume, and change in the Health Assessment Questionnaire Disability Index (HAQ-DI) score.

However, the researchers again found that duration of background therapy affected FVC.

“You were more likely to have declined [in FVC] if you were on placebo and more likely to have improved or stayed stable if you were on lenabasum if you were a patient on more than 2 years of immunomodulatory therapy at baseline,” Dr. Spiera reported. “There was evidence for an effect of lenabasum on FVC suggested by post-hoc analyses that considered the effect of background immunosuppressive therapies on outcomes, but those results would require confirmation in additional studies to determine the potential of lenabasum for treating patients with diffuse cutaneous systemic sclerosis,” Dr. Spiera noted in his conclusions.

Serious adverse events occurred in 9.2% of the lenabasum group and 5.8% of the placebo group. Rates of severe adverse events were similar between the lenabasum (14.6%) and placebo (13%) groups.

Is there a subgroup for whom lenabasum would be efficacious?

Although De Vries-Bouwstra of Leiden University Medical Center acknowledged the role of mycophenolate in the trial, she does not think background therapy can totally explain the observation and speculated on other possibilities.

“For example, there were fewer males in the placebo group as compared to the phase 2 study. From previous cohort studies we know that males have higher risk of worsening of skin disease,” she said. “In addition, it could be worthwhile to evaluate antibody profiles of the population under study; some subpopulations defined by autoantibody have higher risk for skin progression, while others can show spontaneous improvement.”

Dr. De Vries-Bouwstra said that, although it’s not currently appropriate to advocate for lenabasum to treat dcSSc, it may eventually become an additional treatment in those who still show active skin or lung disease after 2 years of mycophenolate treatment if future research identifies a benefit from that application. She would also like to see an evaluation of lenabasum’s possible benefits in patients with very early and active inflammatory disease. “Ideally, one could stratify patients based on biomarkers reflecting activation in relevant pathways, for example by using gene expression analysis from skin tissue to stratify,” she said.

Jacob M. van Laar, MD, PhD, professor of rheumatology at University Medical Center Utrecht (the Netherlands), also commented on the potential differences in using the drug in early versus later disease.

“Based on ex vivo analyses of skin samples from systemic sclerosis patients, one would expect such a mechanism of action to be particularly relevant in very early disease, so the observation that it might also be effective at a later disease stage is interesting,” Dr. van Laar told this news organization. “We still have a lot to learn about this complex disease.”

Given that safety does not appear to be a major concern and that there may be a benefit in a subgroup of patients, Dr. van Laar also said he hoped “the company is not deterred by the seemingly negative result of the primary endpoint.”

Dr. Spiera expressed optimism about what this trial’s findings have revealed about management of dcSSc.

“Independent of what lenabasum did or didn’t do in this trial, I think there’s going to be a lot that we’re going to learn from this trial and that we’re already learning and analyzing right now about treating scleroderma,” he said in an interview.

He reiterated the value of allowing background therapy in the trial to ensure it better replicated real-world clinical practice.

“You’re not withholding therapies that we think are probably active from patients with active disease that, once you incur organ damage, is probably not going to be reversible,” Dr. Spiera said. “The downside is that it makes it harder to see an effect of a drug on top of the background therapy if that background therapy is effective. So what we saw in terms of this absence of benefit from lenabasum really may have been a ceiling effect.”

Nevertheless, Dr. Spiera said the findings still strongly suggest that lenabasum is an active compound.

“It’s not an enormously powerful effect, but it probably has a role as an adjunctive therapy in people on stable background therapy who have either plateaued or are getting worse,” he said. “The thing we have to keep in mind also is this was an incredibly safe therapy. It’s not immunosuppressive.”

The trial was funded by Corbus. Dr. Spiera has received grant support or consulting fees from Roche-Genentech, GlaxoSmithKline, Boehringer Ingelheim, Chemocentryx, Corbus, Formation Biologics, Inflarx, Kadmon, AstraZeneca, AbbVie, CSL Behring, Sanofi, and Janssen. Dr. De Vries-Bouwstra has received consulting fees from AbbVie and Boehringer Ingelheim and research grants from Galapagos and Janssen. Dr. Van Laar has received grant funding or personal fees from Arthrogen, Arxx Therapeutics, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Gesynta, Leadiant, Merck Sharp & Dohme, Roche, Sanofi, and Thermofisher.

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

Although a phase 3 trial of lenabasum did not meet its primary endpoint for treatment of diffuse cutaneous systemic sclerosis (dcSSc), the drug led to more improvement in participants who were not receiving background immunosuppressant therapy during the trial than that seen in participants who received the placebo. Lenabasum also had a favorable safety profile, according to findings presented at the annual European Congress of Rheumatology.

The double-blind, randomized, placebo-controlled trial involved 363 adults who had had dcSSc for up to 6 years. One third of the participants received 5 mg of oral lenabasum, one third received 20 mg, and one third received a placebo. Patients already receiving immunosuppressant therapy could continue to receive it during the trial if the dose had been stable for at least 8 weeks before screening and corticosteroid therapy did not exceed 10 mg prednisone per day or the equivalent.

“The decision to allow background immunosuppressant therapies was made to reflect real-world clinical practice,” coprincipal investigator Robert Dr. Spiera, MD, director of the Vasculitis and Scleroderma Program at the Hospital for Special Surgery, New York, told attendees.

“It is surprising that we do not see any added efficacy of lenabasum in this trial, given the fact that the previous phase 2 trial in 42 patients did show a clear benefit of lenabasum over placebo in the same population,” Jeska K. de Vries-Bouwstra, MD, PhD, a rheumatologist at Leiden (the Netherlands) University Medical Center told this news organization. “Even more, the clinical response in the phase 2 study was supported by a greater change in gene expression in skin tissue of pathways involved in inflammation and fibrosis with lenabasum as compared to placebo.”

Background immunosuppressants contribute to unprecedented placebo responses

The researchers compared the ACR CRISS (Combined Response Index in Diffuse Cutaneous Systemic Sclerosis) score and several secondary endpoints at 52 weeks between the 123 participants who received the placebo and the 120 participants who received 20 mg of lenabasum. A total of 60% of the lenabasum group and 66% of the placebo group had a disease duration of 3 or fewer years, and the modified Rodnan skin score (mRSS) was 22 in the lenabasum group and 23.3 in the placebo group at baseline.

A large majority of participants in both groups – 89% in the lenabasum group and 84% in the placebo group – were receiving background immunosuppressant therapy during the trial. Specifically, 53% of each group was taking mycophenolate, and 23% of the lenabasum group and 32% of the placebo group were taking corticosteroids. In addition, 22% of the lenabasum group and 12% of the placebo group were on methotrexate, and 27% of the lenabasum group and 22% of the placebo group were on another immunosuppressant therapy.

Half of the placebo group and 58% of the lenabasum group were taking only one immunosuppressive therapy. About one-third of the lenabasum (32%) and placebo (34%) groups were taking two or more immunosuppressive therapies.

The primary endpoint at 52 weeks was not significantly different between the two groups: a CRISS score of 0.888 in the lenabasum group and 0.887 in the placebo group. A CRISS score of 0.6 or higher indicates likelihood that a patient improved on treatment. Patients with significant worsening of renal or cardiopulmonary involvement are classified as not improved (score of 0), regardless of improvements in other core items.

“We had very high CRISS scores in all three groups, and they were comparable in all three groups,” Dr. Spiera reported. Because improvement in placebo group far exceeded expectations, the researchers were unable to discern the treatment effect of lenabasum on top of the placebo effect.

The placebo group had better outcomes than expected because of the background immunosuppressant therapy, particularly the use of mycophenolate. When the researchers looked only at placebo participants, the CRISS score was 0.936 in the 97 patients receiving background immunosuppressant therapy of any kind and 0.935 in the 29 patients taking only mycophenolate with no other immunosuppressant therapy, compared with 0.417 in the 16 patients not receiving any background therapy.

In a prespecified analysis, the researchers investigated background immunosuppressive therapy as a mediator. The CRISS score for the 10 lenabasum participants not receiving background therapy was 0.811, compared with 0.417 seen in the placebo group patients not on background therapy.

Among the 173 participants taking mycophenolate in particular, the mycophenolate “had a statistically significant improvement on CRISS score that increased with each visit,” Dr. Spiera reported. The duration of mycophenolate therapy also affected efficacy results.

Patients who had been taking mycophenolate longer saw less improvement in their CRISS score over time. Those taking it more than 2 years at baseline had a CRISS score of 0.86, compared with 0.96 for those taking it for 1-2 years at baseline and 0.98 for those taking it from 6 months to 1 year at baseline. Those who had only been taking mycophenolate for up to 6 months at baseline had a CRISS score of 0.99. Meanwhile, patients not taking any background immunosuppressant therapies only had a CRISS score of about 0.35.
 

Changes in secondary endpoints followed same pattern as CRISS

The secondary endpoints similarly showed no statistically significant difference when comparing the lenabasum and placebo groups overall. These endpoints included change in mRSS score, change in forced vital capacity (FVC) percentage and volume, and change in the Health Assessment Questionnaire Disability Index (HAQ-DI) score.

However, the researchers again found that duration of background therapy affected FVC.

“You were more likely to have declined [in FVC] if you were on placebo and more likely to have improved or stayed stable if you were on lenabasum if you were a patient on more than 2 years of immunomodulatory therapy at baseline,” Dr. Spiera reported. “There was evidence for an effect of lenabasum on FVC suggested by post-hoc analyses that considered the effect of background immunosuppressive therapies on outcomes, but those results would require confirmation in additional studies to determine the potential of lenabasum for treating patients with diffuse cutaneous systemic sclerosis,” Dr. Spiera noted in his conclusions.

Serious adverse events occurred in 9.2% of the lenabasum group and 5.8% of the placebo group. Rates of severe adverse events were similar between the lenabasum (14.6%) and placebo (13%) groups.

Is there a subgroup for whom lenabasum would be efficacious?

Although De Vries-Bouwstra of Leiden University Medical Center acknowledged the role of mycophenolate in the trial, she does not think background therapy can totally explain the observation and speculated on other possibilities.

“For example, there were fewer males in the placebo group as compared to the phase 2 study. From previous cohort studies we know that males have higher risk of worsening of skin disease,” she said. “In addition, it could be worthwhile to evaluate antibody profiles of the population under study; some subpopulations defined by autoantibody have higher risk for skin progression, while others can show spontaneous improvement.”

Dr. De Vries-Bouwstra said that, although it’s not currently appropriate to advocate for lenabasum to treat dcSSc, it may eventually become an additional treatment in those who still show active skin or lung disease after 2 years of mycophenolate treatment if future research identifies a benefit from that application. She would also like to see an evaluation of lenabasum’s possible benefits in patients with very early and active inflammatory disease. “Ideally, one could stratify patients based on biomarkers reflecting activation in relevant pathways, for example by using gene expression analysis from skin tissue to stratify,” she said.

Jacob M. van Laar, MD, PhD, professor of rheumatology at University Medical Center Utrecht (the Netherlands), also commented on the potential differences in using the drug in early versus later disease.

“Based on ex vivo analyses of skin samples from systemic sclerosis patients, one would expect such a mechanism of action to be particularly relevant in very early disease, so the observation that it might also be effective at a later disease stage is interesting,” Dr. van Laar told this news organization. “We still have a lot to learn about this complex disease.”

Given that safety does not appear to be a major concern and that there may be a benefit in a subgroup of patients, Dr. van Laar also said he hoped “the company is not deterred by the seemingly negative result of the primary endpoint.”

Dr. Spiera expressed optimism about what this trial’s findings have revealed about management of dcSSc.

“Independent of what lenabasum did or didn’t do in this trial, I think there’s going to be a lot that we’re going to learn from this trial and that we’re already learning and analyzing right now about treating scleroderma,” he said in an interview.

He reiterated the value of allowing background therapy in the trial to ensure it better replicated real-world clinical practice.

“You’re not withholding therapies that we think are probably active from patients with active disease that, once you incur organ damage, is probably not going to be reversible,” Dr. Spiera said. “The downside is that it makes it harder to see an effect of a drug on top of the background therapy if that background therapy is effective. So what we saw in terms of this absence of benefit from lenabasum really may have been a ceiling effect.”

Nevertheless, Dr. Spiera said the findings still strongly suggest that lenabasum is an active compound.

“It’s not an enormously powerful effect, but it probably has a role as an adjunctive therapy in people on stable background therapy who have either plateaued or are getting worse,” he said. “The thing we have to keep in mind also is this was an incredibly safe therapy. It’s not immunosuppressive.”

The trial was funded by Corbus. Dr. Spiera has received grant support or consulting fees from Roche-Genentech, GlaxoSmithKline, Boehringer Ingelheim, Chemocentryx, Corbus, Formation Biologics, Inflarx, Kadmon, AstraZeneca, AbbVie, CSL Behring, Sanofi, and Janssen. Dr. De Vries-Bouwstra has received consulting fees from AbbVie and Boehringer Ingelheim and research grants from Galapagos and Janssen. Dr. Van Laar has received grant funding or personal fees from Arthrogen, Arxx Therapeutics, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Gesynta, Leadiant, Merck Sharp & Dohme, Roche, Sanofi, and Thermofisher.

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

Although a phase 3 trial of lenabasum did not meet its primary endpoint for treatment of diffuse cutaneous systemic sclerosis (dcSSc), the drug led to more improvement in participants who were not receiving background immunosuppressant therapy during the trial than that seen in participants who received the placebo. Lenabasum also had a favorable safety profile, according to findings presented at the annual European Congress of Rheumatology.

The double-blind, randomized, placebo-controlled trial involved 363 adults who had had dcSSc for up to 6 years. One third of the participants received 5 mg of oral lenabasum, one third received 20 mg, and one third received a placebo. Patients already receiving immunosuppressant therapy could continue to receive it during the trial if the dose had been stable for at least 8 weeks before screening and corticosteroid therapy did not exceed 10 mg prednisone per day or the equivalent.

“The decision to allow background immunosuppressant therapies was made to reflect real-world clinical practice,” coprincipal investigator Robert Dr. Spiera, MD, director of the Vasculitis and Scleroderma Program at the Hospital for Special Surgery, New York, told attendees.

“It is surprising that we do not see any added efficacy of lenabasum in this trial, given the fact that the previous phase 2 trial in 42 patients did show a clear benefit of lenabasum over placebo in the same population,” Jeska K. de Vries-Bouwstra, MD, PhD, a rheumatologist at Leiden (the Netherlands) University Medical Center told this news organization. “Even more, the clinical response in the phase 2 study was supported by a greater change in gene expression in skin tissue of pathways involved in inflammation and fibrosis with lenabasum as compared to placebo.”

Background immunosuppressants contribute to unprecedented placebo responses

The researchers compared the ACR CRISS (Combined Response Index in Diffuse Cutaneous Systemic Sclerosis) score and several secondary endpoints at 52 weeks between the 123 participants who received the placebo and the 120 participants who received 20 mg of lenabasum. A total of 60% of the lenabasum group and 66% of the placebo group had a disease duration of 3 or fewer years, and the modified Rodnan skin score (mRSS) was 22 in the lenabasum group and 23.3 in the placebo group at baseline.

A large majority of participants in both groups – 89% in the lenabasum group and 84% in the placebo group – were receiving background immunosuppressant therapy during the trial. Specifically, 53% of each group was taking mycophenolate, and 23% of the lenabasum group and 32% of the placebo group were taking corticosteroids. In addition, 22% of the lenabasum group and 12% of the placebo group were on methotrexate, and 27% of the lenabasum group and 22% of the placebo group were on another immunosuppressant therapy.

Half of the placebo group and 58% of the lenabasum group were taking only one immunosuppressive therapy. About one-third of the lenabasum (32%) and placebo (34%) groups were taking two or more immunosuppressive therapies.

The primary endpoint at 52 weeks was not significantly different between the two groups: a CRISS score of 0.888 in the lenabasum group and 0.887 in the placebo group. A CRISS score of 0.6 or higher indicates likelihood that a patient improved on treatment. Patients with significant worsening of renal or cardiopulmonary involvement are classified as not improved (score of 0), regardless of improvements in other core items.

“We had very high CRISS scores in all three groups, and they were comparable in all three groups,” Dr. Spiera reported. Because improvement in placebo group far exceeded expectations, the researchers were unable to discern the treatment effect of lenabasum on top of the placebo effect.

The placebo group had better outcomes than expected because of the background immunosuppressant therapy, particularly the use of mycophenolate. When the researchers looked only at placebo participants, the CRISS score was 0.936 in the 97 patients receiving background immunosuppressant therapy of any kind and 0.935 in the 29 patients taking only mycophenolate with no other immunosuppressant therapy, compared with 0.417 in the 16 patients not receiving any background therapy.

In a prespecified analysis, the researchers investigated background immunosuppressive therapy as a mediator. The CRISS score for the 10 lenabasum participants not receiving background therapy was 0.811, compared with 0.417 seen in the placebo group patients not on background therapy.

Among the 173 participants taking mycophenolate in particular, the mycophenolate “had a statistically significant improvement on CRISS score that increased with each visit,” Dr. Spiera reported. The duration of mycophenolate therapy also affected efficacy results.

Patients who had been taking mycophenolate longer saw less improvement in their CRISS score over time. Those taking it more than 2 years at baseline had a CRISS score of 0.86, compared with 0.96 for those taking it for 1-2 years at baseline and 0.98 for those taking it from 6 months to 1 year at baseline. Those who had only been taking mycophenolate for up to 6 months at baseline had a CRISS score of 0.99. Meanwhile, patients not taking any background immunosuppressant therapies only had a CRISS score of about 0.35.
 

Changes in secondary endpoints followed same pattern as CRISS

The secondary endpoints similarly showed no statistically significant difference when comparing the lenabasum and placebo groups overall. These endpoints included change in mRSS score, change in forced vital capacity (FVC) percentage and volume, and change in the Health Assessment Questionnaire Disability Index (HAQ-DI) score.

However, the researchers again found that duration of background therapy affected FVC.

“You were more likely to have declined [in FVC] if you were on placebo and more likely to have improved or stayed stable if you were on lenabasum if you were a patient on more than 2 years of immunomodulatory therapy at baseline,” Dr. Spiera reported. “There was evidence for an effect of lenabasum on FVC suggested by post-hoc analyses that considered the effect of background immunosuppressive therapies on outcomes, but those results would require confirmation in additional studies to determine the potential of lenabasum for treating patients with diffuse cutaneous systemic sclerosis,” Dr. Spiera noted in his conclusions.

Serious adverse events occurred in 9.2% of the lenabasum group and 5.8% of the placebo group. Rates of severe adverse events were similar between the lenabasum (14.6%) and placebo (13%) groups.

Is there a subgroup for whom lenabasum would be efficacious?

Although De Vries-Bouwstra of Leiden University Medical Center acknowledged the role of mycophenolate in the trial, she does not think background therapy can totally explain the observation and speculated on other possibilities.

“For example, there were fewer males in the placebo group as compared to the phase 2 study. From previous cohort studies we know that males have higher risk of worsening of skin disease,” she said. “In addition, it could be worthwhile to evaluate antibody profiles of the population under study; some subpopulations defined by autoantibody have higher risk for skin progression, while others can show spontaneous improvement.”

Dr. De Vries-Bouwstra said that, although it’s not currently appropriate to advocate for lenabasum to treat dcSSc, it may eventually become an additional treatment in those who still show active skin or lung disease after 2 years of mycophenolate treatment if future research identifies a benefit from that application. She would also like to see an evaluation of lenabasum’s possible benefits in patients with very early and active inflammatory disease. “Ideally, one could stratify patients based on biomarkers reflecting activation in relevant pathways, for example by using gene expression analysis from skin tissue to stratify,” she said.

Jacob M. van Laar, MD, PhD, professor of rheumatology at University Medical Center Utrecht (the Netherlands), also commented on the potential differences in using the drug in early versus later disease.

“Based on ex vivo analyses of skin samples from systemic sclerosis patients, one would expect such a mechanism of action to be particularly relevant in very early disease, so the observation that it might also be effective at a later disease stage is interesting,” Dr. van Laar told this news organization. “We still have a lot to learn about this complex disease.”

Given that safety does not appear to be a major concern and that there may be a benefit in a subgroup of patients, Dr. van Laar also said he hoped “the company is not deterred by the seemingly negative result of the primary endpoint.”

Dr. Spiera expressed optimism about what this trial’s findings have revealed about management of dcSSc.

“Independent of what lenabasum did or didn’t do in this trial, I think there’s going to be a lot that we’re going to learn from this trial and that we’re already learning and analyzing right now about treating scleroderma,” he said in an interview.

He reiterated the value of allowing background therapy in the trial to ensure it better replicated real-world clinical practice.

“You’re not withholding therapies that we think are probably active from patients with active disease that, once you incur organ damage, is probably not going to be reversible,” Dr. Spiera said. “The downside is that it makes it harder to see an effect of a drug on top of the background therapy if that background therapy is effective. So what we saw in terms of this absence of benefit from lenabasum really may have been a ceiling effect.”

Nevertheless, Dr. Spiera said the findings still strongly suggest that lenabasum is an active compound.

“It’s not an enormously powerful effect, but it probably has a role as an adjunctive therapy in people on stable background therapy who have either plateaued or are getting worse,” he said. “The thing we have to keep in mind also is this was an incredibly safe therapy. It’s not immunosuppressive.”

The trial was funded by Corbus. Dr. Spiera has received grant support or consulting fees from Roche-Genentech, GlaxoSmithKline, Boehringer Ingelheim, Chemocentryx, Corbus, Formation Biologics, Inflarx, Kadmon, AstraZeneca, AbbVie, CSL Behring, Sanofi, and Janssen. Dr. De Vries-Bouwstra has received consulting fees from AbbVie and Boehringer Ingelheim and research grants from Galapagos and Janssen. Dr. Van Laar has received grant funding or personal fees from Arthrogen, Arxx Therapeutics, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Gesynta, Leadiant, Merck Sharp & Dohme, Roche, Sanofi, and Thermofisher.

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

Using belimumab after rituximab to treat patients with systemic lupus erythematosus (SLE) refractory to conventional therapy not only significantly decreased levels of serum IgG anti-dsDNA antibody levels but also prolonged the time before severe flares of disease occurred in the phase 2b BEAT-LUPUS (Belimumab after B cell depletion in SLE) study.

The trial’s primary outcome of serum IgG anti-dsDNA antibody levels showed a decline from a geometric mean of 162 IU/mL at baseline to 69 IU/mL at 24 weeks and 47 IU/mL at 1 year in patients treated with belimumab (Benlysta) after rituximab (Rituxan and biosimilars). These reductions were significantly lower than the values seen in the placebo after rituximab arm (a respective 121 IU/mL, 99 IU/mL, and 103 IU/mL; P < .001).

Just 3 patients who received belimumab versus 10 who received placebo after rituximab experienced a severe BILAG (British Isles Lupus Assessment Group) index A flare by the end of the study at 52 weeks. The hazard ratio (HR) for the flare reduction was 0.27 (P = .03), indicating a 73% reduction.

The use of belimumab rather than a placebo also led to a small reduction in total serum IgG, and significantly suppressed B-cell repopulation (P = .03).

These results need confirming in a larger, phase 3 trial, the trial’s principal investigator, Michael Ehrenstein, PhD, said at the annual European Congress of Rheumatology. They are “clearly encouraging” and “support the hypothesis that BAFF [B-cell–activating factor] can drive flares after rituximab,” he said.

Although B-cell depletion with rituximab is recommended by national and international guidelines to treat some patients with SLE who are refractory to conventional therapy, its use is not licensed.

“Certainly, rituximab is a controversial drug in lupus,” Dr. Ehrenstein, a consultant rheumatologist based at University College London, said in an interview. Although there is real-world evidence from registries and open-label studies suggesting that it is widely used and effective in some patients, the randomized, controlled trials conducted with rituximab about 10 years ago failed to meet their primary endpoints.

“A lot has been written about why that was, but probably the biggest reason was the high dose of steroids in both groups,” Dr. Ehrenstein said. To try to avoid muddying the waters of the BEAT-LUPUS trial findings, the maximum dose of prednisolone allowed to be used as background therapy was 20 mg/day. The trial’s investigators were also encouraged to reduce the baseline steroid dose to at least 50% by the trial’s 6-month halfway point.

“We tried to reflect what was going on in the U.K.,” Dr. Ehrenstein said, noting that the inspiration for the trial was a patient who had received sequential rituximab treatment. Although she got better with each cycle of rituximab, when her disease flared it would be worse than the time before, with increasingly higher anti-dsDNA levels recorded. The reason for this seemed to be because of increasing BAFF levels, and so the hypothesis was that if rituximab was associated with increased BAFF levels, then co-targeting BAFF with belimumab should be able to prevent those flares from happening.

The BEAT-LUPUS trial has been a huge collaborative effort and was conducted across 16 U.K. centers. From initial funding to the data analysis, it has taken 6 years to complete and was made possible by a unique partnership between Versus Arthritis, University College London Hospitals Biomedical Research Center, the National Institute for Health Research UK Musculoskeletal Translational Research Collaboration, and GlaxoSmithKline (GSK). GSK provided belimumab free of charge, as well as additional funding, but had no role in the design of the study and will not have any role going forward.

From an initial 172 patients assessed for eligibility, 52 patients were finally enrolled into the trial and received rituximab as two infusions given 2 weeks apart. Patients were then randomized in a double-blind manner to receive either belimumab (n = 26) or placebo (n = 26) 4-8 weeks after their first dose of rituximab. The intention-to-treat population consisted of 43 patients.

The use of belimumab after rituximab did not increase the risk for infection – serious or otherwise – or adverse effects, Dr. Ehrenstein reported. Serious adverse events were reported in six (23%) patients in each arm, and serious infections were seen in two (8%) of the belimumab- and four (15%) of the placebo-treated patients.

“I think the take-home message is that it seems that belimumab can reduce the number of severe flares that occur after rituximab therapy,” Dr. Ehrenstein said. “It’s promising, but not definitive,” he added. The next step is of course to publish these data and to perform a phase 3 trial.

In the discussion time following the presentation, session moderator Xavier Mariette, MD, PhD, of Bicêtre Hospital, Paris-Saclay University, asked why not give belimumab first before rituximab if using belimumab afterward works?

“Our strategy was driven by the observation that BAFF levels surged after rituximab, and therefore it’s logical to give the belimumab to block that BAFF surge,” he answered.

“Certainly, there are ideas that belimumab releases mature B cells into the circulation and rituximab can target that,” he added. That strategy is under investigation in the BLISS-BELIEVE trial, which should also report by the end of this year. It’s a much larger, phase 3 trial, involving nearly 300 patients and is sponsored by GSK.

“Clearly, this is a combination treatment [but] whether you give one before the other is uncertain,” Dr. Ehrenstein observed.

Another member of the viewing audience asked whether it would have been a fairer comparison if another dose of rituximab had been given to patients at week 24 instead of no treatment. Dr. Ehrenstein noted that it was a “good point” to make, but the investigators mainly wanted to answer whether giving belimumab after rituximab would target BAFF and thereby drop serum anti-dsDNA antibody levels. He said that a full trial of rituximab for patients with SLE, perhaps adding this extra dose, needs to be conducted.

Dr. Ehrenstein disclosed receiving research funding and educational grants from GSK and participating in advisory panels for the company.

Using belimumab after rituximab to treat patients with systemic lupus erythematosus (SLE) refractory to conventional therapy not only significantly decreased levels of serum IgG anti-dsDNA antibody levels but also prolonged the time before severe flares of disease occurred in the phase 2b BEAT-LUPUS (Belimumab after B cell depletion in SLE) study.

The trial’s primary outcome of serum IgG anti-dsDNA antibody levels showed a decline from a geometric mean of 162 IU/mL at baseline to 69 IU/mL at 24 weeks and 47 IU/mL at 1 year in patients treated with belimumab (Benlysta) after rituximab (Rituxan and biosimilars). These reductions were significantly lower than the values seen in the placebo after rituximab arm (a respective 121 IU/mL, 99 IU/mL, and 103 IU/mL; P < .001).

Just 3 patients who received belimumab versus 10 who received placebo after rituximab experienced a severe BILAG (British Isles Lupus Assessment Group) index A flare by the end of the study at 52 weeks. The hazard ratio (HR) for the flare reduction was 0.27 (P = .03), indicating a 73% reduction.

The use of belimumab rather than a placebo also led to a small reduction in total serum IgG, and significantly suppressed B-cell repopulation (P = .03).

These results need confirming in a larger, phase 3 trial, the trial’s principal investigator, Michael Ehrenstein, PhD, said at the annual European Congress of Rheumatology. They are “clearly encouraging” and “support the hypothesis that BAFF [B-cell–activating factor] can drive flares after rituximab,” he said.

Although B-cell depletion with rituximab is recommended by national and international guidelines to treat some patients with SLE who are refractory to conventional therapy, its use is not licensed.

“Certainly, rituximab is a controversial drug in lupus,” Dr. Ehrenstein, a consultant rheumatologist based at University College London, said in an interview. Although there is real-world evidence from registries and open-label studies suggesting that it is widely used and effective in some patients, the randomized, controlled trials conducted with rituximab about 10 years ago failed to meet their primary endpoints.

“A lot has been written about why that was, but probably the biggest reason was the high dose of steroids in both groups,” Dr. Ehrenstein said. To try to avoid muddying the waters of the BEAT-LUPUS trial findings, the maximum dose of prednisolone allowed to be used as background therapy was 20 mg/day. The trial’s investigators were also encouraged to reduce the baseline steroid dose to at least 50% by the trial’s 6-month halfway point.

“We tried to reflect what was going on in the U.K.,” Dr. Ehrenstein said, noting that the inspiration for the trial was a patient who had received sequential rituximab treatment. Although she got better with each cycle of rituximab, when her disease flared it would be worse than the time before, with increasingly higher anti-dsDNA levels recorded. The reason for this seemed to be because of increasing BAFF levels, and so the hypothesis was that if rituximab was associated with increased BAFF levels, then co-targeting BAFF with belimumab should be able to prevent those flares from happening.

The BEAT-LUPUS trial has been a huge collaborative effort and was conducted across 16 U.K. centers. From initial funding to the data analysis, it has taken 6 years to complete and was made possible by a unique partnership between Versus Arthritis, University College London Hospitals Biomedical Research Center, the National Institute for Health Research UK Musculoskeletal Translational Research Collaboration, and GlaxoSmithKline (GSK). GSK provided belimumab free of charge, as well as additional funding, but had no role in the design of the study and will not have any role going forward.

From an initial 172 patients assessed for eligibility, 52 patients were finally enrolled into the trial and received rituximab as two infusions given 2 weeks apart. Patients were then randomized in a double-blind manner to receive either belimumab (n = 26) or placebo (n = 26) 4-8 weeks after their first dose of rituximab. The intention-to-treat population consisted of 43 patients.

The use of belimumab after rituximab did not increase the risk for infection – serious or otherwise – or adverse effects, Dr. Ehrenstein reported. Serious adverse events were reported in six (23%) patients in each arm, and serious infections were seen in two (8%) of the belimumab- and four (15%) of the placebo-treated patients.

“I think the take-home message is that it seems that belimumab can reduce the number of severe flares that occur after rituximab therapy,” Dr. Ehrenstein said. “It’s promising, but not definitive,” he added. The next step is of course to publish these data and to perform a phase 3 trial.

In the discussion time following the presentation, session moderator Xavier Mariette, MD, PhD, of Bicêtre Hospital, Paris-Saclay University, asked why not give belimumab first before rituximab if using belimumab afterward works?

“Our strategy was driven by the observation that BAFF levels surged after rituximab, and therefore it’s logical to give the belimumab to block that BAFF surge,” he answered.

“Certainly, there are ideas that belimumab releases mature B cells into the circulation and rituximab can target that,” he added. That strategy is under investigation in the BLISS-BELIEVE trial, which should also report by the end of this year. It’s a much larger, phase 3 trial, involving nearly 300 patients and is sponsored by GSK.

“Clearly, this is a combination treatment [but] whether you give one before the other is uncertain,” Dr. Ehrenstein observed.

Another member of the viewing audience asked whether it would have been a fairer comparison if another dose of rituximab had been given to patients at week 24 instead of no treatment. Dr. Ehrenstein noted that it was a “good point” to make, but the investigators mainly wanted to answer whether giving belimumab after rituximab would target BAFF and thereby drop serum anti-dsDNA antibody levels. He said that a full trial of rituximab for patients with SLE, perhaps adding this extra dose, needs to be conducted.

Dr. Ehrenstein disclosed receiving research funding and educational grants from GSK and participating in advisory panels for the company.

Using belimumab after rituximab to treat patients with systemic lupus erythematosus (SLE) refractory to conventional therapy not only significantly decreased levels of serum IgG anti-dsDNA antibody levels but also prolonged the time before severe flares of disease occurred in the phase 2b BEAT-LUPUS (Belimumab after B cell depletion in SLE) study.

The trial’s primary outcome of serum IgG anti-dsDNA antibody levels showed a decline from a geometric mean of 162 IU/mL at baseline to 69 IU/mL at 24 weeks and 47 IU/mL at 1 year in patients treated with belimumab (Benlysta) after rituximab (Rituxan and biosimilars). These reductions were significantly lower than the values seen in the placebo after rituximab arm (a respective 121 IU/mL, 99 IU/mL, and 103 IU/mL; P < .001).

Just 3 patients who received belimumab versus 10 who received placebo after rituximab experienced a severe BILAG (British Isles Lupus Assessment Group) index A flare by the end of the study at 52 weeks. The hazard ratio (HR) for the flare reduction was 0.27 (P = .03), indicating a 73% reduction.

The use of belimumab rather than a placebo also led to a small reduction in total serum IgG, and significantly suppressed B-cell repopulation (P = .03).

These results need confirming in a larger, phase 3 trial, the trial’s principal investigator, Michael Ehrenstein, PhD, said at the annual European Congress of Rheumatology. They are “clearly encouraging” and “support the hypothesis that BAFF [B-cell–activating factor] can drive flares after rituximab,” he said.

Although B-cell depletion with rituximab is recommended by national and international guidelines to treat some patients with SLE who are refractory to conventional therapy, its use is not licensed.

“Certainly, rituximab is a controversial drug in lupus,” Dr. Ehrenstein, a consultant rheumatologist based at University College London, said in an interview. Although there is real-world evidence from registries and open-label studies suggesting that it is widely used and effective in some patients, the randomized, controlled trials conducted with rituximab about 10 years ago failed to meet their primary endpoints.

“A lot has been written about why that was, but probably the biggest reason was the high dose of steroids in both groups,” Dr. Ehrenstein said. To try to avoid muddying the waters of the BEAT-LUPUS trial findings, the maximum dose of prednisolone allowed to be used as background therapy was 20 mg/day. The trial’s investigators were also encouraged to reduce the baseline steroid dose to at least 50% by the trial’s 6-month halfway point.

“We tried to reflect what was going on in the U.K.,” Dr. Ehrenstein said, noting that the inspiration for the trial was a patient who had received sequential rituximab treatment. Although she got better with each cycle of rituximab, when her disease flared it would be worse than the time before, with increasingly higher anti-dsDNA levels recorded. The reason for this seemed to be because of increasing BAFF levels, and so the hypothesis was that if rituximab was associated with increased BAFF levels, then co-targeting BAFF with belimumab should be able to prevent those flares from happening.

The BEAT-LUPUS trial has been a huge collaborative effort and was conducted across 16 U.K. centers. From initial funding to the data analysis, it has taken 6 years to complete and was made possible by a unique partnership between Versus Arthritis, University College London Hospitals Biomedical Research Center, the National Institute for Health Research UK Musculoskeletal Translational Research Collaboration, and GlaxoSmithKline (GSK). GSK provided belimumab free of charge, as well as additional funding, but had no role in the design of the study and will not have any role going forward.

From an initial 172 patients assessed for eligibility, 52 patients were finally enrolled into the trial and received rituximab as two infusions given 2 weeks apart. Patients were then randomized in a double-blind manner to receive either belimumab (n = 26) or placebo (n = 26) 4-8 weeks after their first dose of rituximab. The intention-to-treat population consisted of 43 patients.

The use of belimumab after rituximab did not increase the risk for infection – serious or otherwise – or adverse effects, Dr. Ehrenstein reported. Serious adverse events were reported in six (23%) patients in each arm, and serious infections were seen in two (8%) of the belimumab- and four (15%) of the placebo-treated patients.

“I think the take-home message is that it seems that belimumab can reduce the number of severe flares that occur after rituximab therapy,” Dr. Ehrenstein said. “It’s promising, but not definitive,” he added. The next step is of course to publish these data and to perform a phase 3 trial.

In the discussion time following the presentation, session moderator Xavier Mariette, MD, PhD, of Bicêtre Hospital, Paris-Saclay University, asked why not give belimumab first before rituximab if using belimumab afterward works?

“Our strategy was driven by the observation that BAFF levels surged after rituximab, and therefore it’s logical to give the belimumab to block that BAFF surge,” he answered.

“Certainly, there are ideas that belimumab releases mature B cells into the circulation and rituximab can target that,” he added. That strategy is under investigation in the BLISS-BELIEVE trial, which should also report by the end of this year. It’s a much larger, phase 3 trial, involving nearly 300 patients and is sponsored by GSK.

“Clearly, this is a combination treatment [but] whether you give one before the other is uncertain,” Dr. Ehrenstein observed.

Another member of the viewing audience asked whether it would have been a fairer comparison if another dose of rituximab had been given to patients at week 24 instead of no treatment. Dr. Ehrenstein noted that it was a “good point” to make, but the investigators mainly wanted to answer whether giving belimumab after rituximab would target BAFF and thereby drop serum anti-dsDNA antibody levels. He said that a full trial of rituximab for patients with SLE, perhaps adding this extra dose, needs to be conducted.

Dr. Ehrenstein disclosed receiving research funding and educational grants from GSK and participating in advisory panels for the company.

The first multinational, phase 3, placebo-controlled trial conducted with intravenous immunoglobulin therapy (IVIg) for dermatomyositis has confirmed significant efficacy and acceptable safety, according to data presented at the opening plenary abstract session of the annual European Congress of Rheumatology.

At the week 16 evaluation of the trial, called ProDERM, the response rates were 78.7% and 43.8% (P = .0008) for active therapy and placebo, respectively, reported Rohit Aggarwal, MD, medical director of the Arthritis and Autoimmunity Center at the University of Pittsburgh.

ProDERM is a “much-awaited study,” according to session moderator Hendrik Schulze-Koops, MD, PhD, of the division of rheumatology and clinical immunology at Ludwig Maximilian University of Munich (Germany). He was not involved in the study.

“We all have been doing what we have been doing,” Dr. Schulze-Koops said, referring to the use of IVIg for the control of dermatomyositis, “but we had no evidence for support.”

This statement could apply not only to IVIg, which has long been listed among treatment options by the Myositis Association despite the absence of controlled studies, but also to most immunosuppressive therapies and other options used for this challenging disease.

The proprietary IVIg employed in this study, Octagam 10%, has been approved in the United States for the treatment of chronic immune thrombocytopenic purpura. Its manufacturer, Octagam, plans to file a supplemental new drug application with the Food and Drug Administration for the treatment of dermatomyositis. The agent is already approved for dermatomyositis by the European Medicines Agency, according to Dr. Aggarwal.

Multiple response criteria favor IVIg

In the trial, 95 patients with dermatomyositis were randomized to 2 g/kg of IVIg (Octagam 10%) or placebo administered every 4 weeks. In a subsequent open-label extension study in which patients on placebo were switched to active therapy, the same every-4-week treatment schedule was used. The patients’ mean age was 53; 75% were women, and 92% were White.

The primary endpoint was at least minimal improvement on 2016 ACR/EULAR (American College of Rheumatology/European Alliance of Associations for Rheumatology) myositis response criteria, defined as a 20-point or greater gain in the Total Improvement Score (TIS) and no clinical worsening at two consecutive visits. But IVIg also provided a large relative benefit over placebo using more rigorous definitions of improvement. For moderate improvement, defined as at least a 40-point TIS improvement, there was a 45.2% relative advantage for IVIg over placebo (68.1% vs. 22.9%; P < .0001). For major improvement, defined as at least a 60-point TIS improvement, the relative advantage was 23.6% (31.9% vs. 8.3%; P < .0062).

At 16 weeks, the mean TIS score was more than twice as high in those receiving IVIg than in those randomized to placebo (48.4 vs. 21.6). At that point, an open-label extension was initiated. Those in the IVIg group were permitted to remain on therapy for an additional 24 weeks if they had not worsened in the blinded phase.

The mean TIS score in the IVIg group continued to rise during the extension phase. By 12 weeks in this phase, it reached 54.0. Over the same period, mean TIS scores climbed steeply among the placebo-treated patients who had switched to active therapy, reaching 44.4.

At the end of 24 weeks of the extension trial, when patients initiated on IVIg had been on active therapy for 40 weeks, the mean TIS score advantage of starting on IVIg rather than placebo was relatively modest (55.4 vs. 51.1).
 

Benefit is significant for skin and muscle

Changes in the two major components of dermatomyositis were tracked individually. For skin symptoms, patients were evaluated with the Cutaneous Dermatomyositis Disease Areas and Severity Index (CDASI). For muscle involvement, symptoms were evaluated with the 8-item Manual Muscle Testing (MMT-8) tool.

“The effects of IVIg on the muscle and the skin were both highly statistically significant,” Dr. Aggarwal reported. He said the CDASI score was reduced by almost half at the end of 16 weeks among those treated with IVIg relative to those treated with placebo. Improvement in MMT-8 scores were also clinically as well as statistically significant.

The IVIg therapy was well tolerated. The most common adverse effects in this study, like those reported with IVIg when used to treat other diseases, were headache, pyrexia, and nausea, but Dr. Aggarwal reported that these were generally mild.

Serious adverse events, particularly thromboembolism, did occur over the course of the study, but the rate of events was only slightly higher in the group receiving active therapy (5.8% vs. 4.2%).

Patients who entered the study were permitted to remain on most immunosuppressive therapies, such as methotrexate, mycophenolate, tacrolimus, and glucocorticoids. Dr. Aggarwal said that the majority of patients were taking a glucocorticoid and at least one nonglucocorticoid immunosuppressant.

Effect on associated conditions is planned

The data from this trial have not yet been analyzed for the impact of IVIg on conditions that occur frequently in association with dermatomyositis, such as interstitial lung disease (ILD) and dysphagia, but Dr. Aggarwal reported that there are plans to do so. Although severe ILD was a trial exclusion, the presence of mild to moderate ILD and dysphagia were evaluated at baseline, so the impact of treatment can be assessed.

There are also plans to evaluate how the presence or absence of myositis-specific antibodies, which were also evaluated at baseline, affected response to IVIg.

Dr. Aggarwal has financial relationships with more than 15 pharmaceutical companies, including Octapharma, which provided financial support for this trial. Dr. Schulze-Koops reported no relevant potential conflicts of interest.

The first multinational, phase 3, placebo-controlled trial conducted with intravenous immunoglobulin therapy (IVIg) for dermatomyositis has confirmed significant efficacy and acceptable safety, according to data presented at the opening plenary abstract session of the annual European Congress of Rheumatology.

At the week 16 evaluation of the trial, called ProDERM, the response rates were 78.7% and 43.8% (P = .0008) for active therapy and placebo, respectively, reported Rohit Aggarwal, MD, medical director of the Arthritis and Autoimmunity Center at the University of Pittsburgh.

ProDERM is a “much-awaited study,” according to session moderator Hendrik Schulze-Koops, MD, PhD, of the division of rheumatology and clinical immunology at Ludwig Maximilian University of Munich (Germany). He was not involved in the study.

“We all have been doing what we have been doing,” Dr. Schulze-Koops said, referring to the use of IVIg for the control of dermatomyositis, “but we had no evidence for support.”

This statement could apply not only to IVIg, which has long been listed among treatment options by the Myositis Association despite the absence of controlled studies, but also to most immunosuppressive therapies and other options used for this challenging disease.

The proprietary IVIg employed in this study, Octagam 10%, has been approved in the United States for the treatment of chronic immune thrombocytopenic purpura. Its manufacturer, Octagam, plans to file a supplemental new drug application with the Food and Drug Administration for the treatment of dermatomyositis. The agent is already approved for dermatomyositis by the European Medicines Agency, according to Dr. Aggarwal.

Multiple response criteria favor IVIg

In the trial, 95 patients with dermatomyositis were randomized to 2 g/kg of IVIg (Octagam 10%) or placebo administered every 4 weeks. In a subsequent open-label extension study in which patients on placebo were switched to active therapy, the same every-4-week treatment schedule was used. The patients’ mean age was 53; 75% were women, and 92% were White.

The primary endpoint was at least minimal improvement on 2016 ACR/EULAR (American College of Rheumatology/European Alliance of Associations for Rheumatology) myositis response criteria, defined as a 20-point or greater gain in the Total Improvement Score (TIS) and no clinical worsening at two consecutive visits. But IVIg also provided a large relative benefit over placebo using more rigorous definitions of improvement. For moderate improvement, defined as at least a 40-point TIS improvement, there was a 45.2% relative advantage for IVIg over placebo (68.1% vs. 22.9%; P < .0001). For major improvement, defined as at least a 60-point TIS improvement, the relative advantage was 23.6% (31.9% vs. 8.3%; P < .0062).

At 16 weeks, the mean TIS score was more than twice as high in those receiving IVIg than in those randomized to placebo (48.4 vs. 21.6). At that point, an open-label extension was initiated. Those in the IVIg group were permitted to remain on therapy for an additional 24 weeks if they had not worsened in the blinded phase.

The mean TIS score in the IVIg group continued to rise during the extension phase. By 12 weeks in this phase, it reached 54.0. Over the same period, mean TIS scores climbed steeply among the placebo-treated patients who had switched to active therapy, reaching 44.4.

At the end of 24 weeks of the extension trial, when patients initiated on IVIg had been on active therapy for 40 weeks, the mean TIS score advantage of starting on IVIg rather than placebo was relatively modest (55.4 vs. 51.1).
 

Benefit is significant for skin and muscle

Changes in the two major components of dermatomyositis were tracked individually. For skin symptoms, patients were evaluated with the Cutaneous Dermatomyositis Disease Areas and Severity Index (CDASI). For muscle involvement, symptoms were evaluated with the 8-item Manual Muscle Testing (MMT-8) tool.

“The effects of IVIg on the muscle and the skin were both highly statistically significant,” Dr. Aggarwal reported. He said the CDASI score was reduced by almost half at the end of 16 weeks among those treated with IVIg relative to those treated with placebo. Improvement in MMT-8 scores were also clinically as well as statistically significant.

The IVIg therapy was well tolerated. The most common adverse effects in this study, like those reported with IVIg when used to treat other diseases, were headache, pyrexia, and nausea, but Dr. Aggarwal reported that these were generally mild.

Serious adverse events, particularly thromboembolism, did occur over the course of the study, but the rate of events was only slightly higher in the group receiving active therapy (5.8% vs. 4.2%).

Patients who entered the study were permitted to remain on most immunosuppressive therapies, such as methotrexate, mycophenolate, tacrolimus, and glucocorticoids. Dr. Aggarwal said that the majority of patients were taking a glucocorticoid and at least one nonglucocorticoid immunosuppressant.

Effect on associated conditions is planned

The data from this trial have not yet been analyzed for the impact of IVIg on conditions that occur frequently in association with dermatomyositis, such as interstitial lung disease (ILD) and dysphagia, but Dr. Aggarwal reported that there are plans to do so. Although severe ILD was a trial exclusion, the presence of mild to moderate ILD and dysphagia were evaluated at baseline, so the impact of treatment can be assessed.

There are also plans to evaluate how the presence or absence of myositis-specific antibodies, which were also evaluated at baseline, affected response to IVIg.

Dr. Aggarwal has financial relationships with more than 15 pharmaceutical companies, including Octapharma, which provided financial support for this trial. Dr. Schulze-Koops reported no relevant potential conflicts of interest.

The first multinational, phase 3, placebo-controlled trial conducted with intravenous immunoglobulin therapy (IVIg) for dermatomyositis has confirmed significant efficacy and acceptable safety, according to data presented at the opening plenary abstract session of the annual European Congress of Rheumatology.

At the week 16 evaluation of the trial, called ProDERM, the response rates were 78.7% and 43.8% (P = .0008) for active therapy and placebo, respectively, reported Rohit Aggarwal, MD, medical director of the Arthritis and Autoimmunity Center at the University of Pittsburgh.

ProDERM is a “much-awaited study,” according to session moderator Hendrik Schulze-Koops, MD, PhD, of the division of rheumatology and clinical immunology at Ludwig Maximilian University of Munich (Germany). He was not involved in the study.

“We all have been doing what we have been doing,” Dr. Schulze-Koops said, referring to the use of IVIg for the control of dermatomyositis, “but we had no evidence for support.”

This statement could apply not only to IVIg, which has long been listed among treatment options by the Myositis Association despite the absence of controlled studies, but also to most immunosuppressive therapies and other options used for this challenging disease.

The proprietary IVIg employed in this study, Octagam 10%, has been approved in the United States for the treatment of chronic immune thrombocytopenic purpura. Its manufacturer, Octagam, plans to file a supplemental new drug application with the Food and Drug Administration for the treatment of dermatomyositis. The agent is already approved for dermatomyositis by the European Medicines Agency, according to Dr. Aggarwal.

Multiple response criteria favor IVIg

In the trial, 95 patients with dermatomyositis were randomized to 2 g/kg of IVIg (Octagam 10%) or placebo administered every 4 weeks. In a subsequent open-label extension study in which patients on placebo were switched to active therapy, the same every-4-week treatment schedule was used. The patients’ mean age was 53; 75% were women, and 92% were White.

The primary endpoint was at least minimal improvement on 2016 ACR/EULAR (American College of Rheumatology/European Alliance of Associations for Rheumatology) myositis response criteria, defined as a 20-point or greater gain in the Total Improvement Score (TIS) and no clinical worsening at two consecutive visits. But IVIg also provided a large relative benefit over placebo using more rigorous definitions of improvement. For moderate improvement, defined as at least a 40-point TIS improvement, there was a 45.2% relative advantage for IVIg over placebo (68.1% vs. 22.9%; P < .0001). For major improvement, defined as at least a 60-point TIS improvement, the relative advantage was 23.6% (31.9% vs. 8.3%; P < .0062).

At 16 weeks, the mean TIS score was more than twice as high in those receiving IVIg than in those randomized to placebo (48.4 vs. 21.6). At that point, an open-label extension was initiated. Those in the IVIg group were permitted to remain on therapy for an additional 24 weeks if they had not worsened in the blinded phase.

The mean TIS score in the IVIg group continued to rise during the extension phase. By 12 weeks in this phase, it reached 54.0. Over the same period, mean TIS scores climbed steeply among the placebo-treated patients who had switched to active therapy, reaching 44.4.

At the end of 24 weeks of the extension trial, when patients initiated on IVIg had been on active therapy for 40 weeks, the mean TIS score advantage of starting on IVIg rather than placebo was relatively modest (55.4 vs. 51.1).
 

Benefit is significant for skin and muscle

Changes in the two major components of dermatomyositis were tracked individually. For skin symptoms, patients were evaluated with the Cutaneous Dermatomyositis Disease Areas and Severity Index (CDASI). For muscle involvement, symptoms were evaluated with the 8-item Manual Muscle Testing (MMT-8) tool.

“The effects of IVIg on the muscle and the skin were both highly statistically significant,” Dr. Aggarwal reported. He said the CDASI score was reduced by almost half at the end of 16 weeks among those treated with IVIg relative to those treated with placebo. Improvement in MMT-8 scores were also clinically as well as statistically significant.

The IVIg therapy was well tolerated. The most common adverse effects in this study, like those reported with IVIg when used to treat other diseases, were headache, pyrexia, and nausea, but Dr. Aggarwal reported that these were generally mild.

Serious adverse events, particularly thromboembolism, did occur over the course of the study, but the rate of events was only slightly higher in the group receiving active therapy (5.8% vs. 4.2%).

Patients who entered the study were permitted to remain on most immunosuppressive therapies, such as methotrexate, mycophenolate, tacrolimus, and glucocorticoids. Dr. Aggarwal said that the majority of patients were taking a glucocorticoid and at least one nonglucocorticoid immunosuppressant.

Effect on associated conditions is planned

The data from this trial have not yet been analyzed for the impact of IVIg on conditions that occur frequently in association with dermatomyositis, such as interstitial lung disease (ILD) and dysphagia, but Dr. Aggarwal reported that there are plans to do so. Although severe ILD was a trial exclusion, the presence of mild to moderate ILD and dysphagia were evaluated at baseline, so the impact of treatment can be assessed.

There are also plans to evaluate how the presence or absence of myositis-specific antibodies, which were also evaluated at baseline, affected response to IVIg.

Dr. Aggarwal has financial relationships with more than 15 pharmaceutical companies, including Octapharma, which provided financial support for this trial. Dr. Schulze-Koops reported no relevant potential conflicts of interest.

A reduced dose of prednisolone plus rituximab was as effective as a conventionally high dose in treating patients with newly diagnosed antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis, according to a new Japanese study, along with significantly fewer adverse events as well.

“To our knowledge, this is the first trial in ANCA-associated vasculitis showing that a lower glucocorticoid dose may reduce serious adverse events,” wrote Shunsuke Furuta, MD, PhD, of the department of allergy and clinical immunology at Chiba (Japan) University Hospital, and colleagues. The study was published June 1, 2021, in JAMA.

To determine the most effective and safe dose of glucocorticoids for treating this specific subset of patients with vasculitis, the researchers launched an open-label noninferiority clinical trial at 21 hospitals in Japan. A group of 140 patients with new-onset ANCA-associated vasculitis (AAV) without severe glomerulonephritis or alveolar hemorrhage were enrolled and split evenly into two treatment subgroups: reduced-dose prednisolone (0.5 mg/kg per day) plus four doses of rituximab (375 mg/m² per week) or high-dose prednisolone (1 mg/kg per day) plus rituximab. The median age for all enrolled patients was 73, and approximately 58% were women.

Of the 140 original patients, 134 (95.7%) completed the trial. After 6 months, 49 participants in the reduced-dose group (71%) and 45 in the high-dose group (69.2%) achieved remission, as assessed via the Birmingham Vasculitis Activity Score. The difference between the two groups – 1.8 percentage points (one-sided 97.5% confidence interval, –13.7 to infinity) – met the prespecified margin of –20 percentage points for noninferiority (P = .003 for noninferiority). Relapse within 6 months occurred in three participants in the reduced-dose group and zero in the high-dose group, frequencies that the researchers identified as not statistically different (difference, 4.3%; 95% CI, –0.5% to 9.3%; P = .24).

Serious adverse events occurred less frequently in the reduced-dose group (21 events in 13 patients, 18.8%), compared with the high-dose group (41 events in 24 patients, 36.9%), as did serious infections in the reduced-dose group (7 events in 5 patients, 7.2%) versus the high-dose group (20 events in 13 patients, 20%). Two patients died in the reduced-dose group and three died in the high-dose group; those frequencies were noted as not statistically different (difference, –1.7%; 95% CI, –4.7% to 8.2%; P = .67). Causes of death included subarachnoid hemorrhage in a 58-year-old in the reduced-dose group, along with a case of sepsis in an 80-year-old and two gastrointestinal bleedings in a 75-year-old and an 85-year-old in the high-dose group.

End-stage kidney disease (ESKD) occurred in one patient in the high-dose group and none in the reduced-dose group. Cumulative survival rates at 6 months were not significantly different between the reduced-dose (97.1%) and the high-dose (95.3%) groups (95% CI, –4.7% to 8.2%; P = .58).

Less glucocorticoids makes sense for subset of patients with milder vasculitis

“We always worry about how much steroids we’re giving our patients,” said Anisha B. Dua, MD, an associate professor of rheumatology at Northwestern University, Chicago. “And it’s not a shock to find out that we can use less. That’s been the theme of many studies across vasculitities that have been coming out: ‘Maybe we are using too much steroids.’ It’s really important to have actual data supporting that, though, so clinicians can feel more confident and figure out what population it applies to.”

M. Alexander Otto

She added that, because the study focused on patients with milder disease, it’s no surprise that remission was achieved with a lesser dose.

“I see a lot of vasculitis patients, and this gives me more confidence in a subset of them – new ANCA vasculitis, MPO positive, not very severe disease – to get away with using less steroids up front,” she said.

To apply these findings more broadly across vasculitis patients, Dr. Dua stressed the need for a follow-up study, preferably a randomized, controlled trial, with an expanded population and a longer duration.

“There were 3 relapses in the low-dose group and zero in the high-dose group in the first 6 months,” she said. “I’d be interested to know when those happened and also, over time, whether the low-dose regiment up front impacts the rate of relapse in the long term.”

The authors acknowledged the study’s limitations, including the necessity of an open-label trial because of the inevitable visible effects of high-dose glucocorticoid on patients. They also addressed the potential subjectivity of the Birmingham Vasculitis Activity Score, though they added that “other endpoints, including death, ESKD, and serious adverse events, were objective.” Finally, they acknowledged that their study was nationwide but not international, with disease phenotypes that were typical of Japanese patients with AAV. That said, “previous studies have shown that treatment responses are similar between Japan and other countries,” they wrote.

The study was funded by an intramural competitive grant from Chiba University Hospital. The authors reported numerous potential conflicts of interest, including receiving grant support, lecture fees, and personal fees from various pharmaceutical companies.

A reduced dose of prednisolone plus rituximab was as effective as a conventionally high dose in treating patients with newly diagnosed antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis, according to a new Japanese study, along with significantly fewer adverse events as well.

“To our knowledge, this is the first trial in ANCA-associated vasculitis showing that a lower glucocorticoid dose may reduce serious adverse events,” wrote Shunsuke Furuta, MD, PhD, of the department of allergy and clinical immunology at Chiba (Japan) University Hospital, and colleagues. The study was published June 1, 2021, in JAMA.

To determine the most effective and safe dose of glucocorticoids for treating this specific subset of patients with vasculitis, the researchers launched an open-label noninferiority clinical trial at 21 hospitals in Japan. A group of 140 patients with new-onset ANCA-associated vasculitis (AAV) without severe glomerulonephritis or alveolar hemorrhage were enrolled and split evenly into two treatment subgroups: reduced-dose prednisolone (0.5 mg/kg per day) plus four doses of rituximab (375 mg/m² per week) or high-dose prednisolone (1 mg/kg per day) plus rituximab. The median age for all enrolled patients was 73, and approximately 58% were women.

Of the 140 original patients, 134 (95.7%) completed the trial. After 6 months, 49 participants in the reduced-dose group (71%) and 45 in the high-dose group (69.2%) achieved remission, as assessed via the Birmingham Vasculitis Activity Score. The difference between the two groups – 1.8 percentage points (one-sided 97.5% confidence interval, –13.7 to infinity) – met the prespecified margin of –20 percentage points for noninferiority (P = .003 for noninferiority). Relapse within 6 months occurred in three participants in the reduced-dose group and zero in the high-dose group, frequencies that the researchers identified as not statistically different (difference, 4.3%; 95% CI, –0.5% to 9.3%; P = .24).

Serious adverse events occurred less frequently in the reduced-dose group (21 events in 13 patients, 18.8%), compared with the high-dose group (41 events in 24 patients, 36.9%), as did serious infections in the reduced-dose group (7 events in 5 patients, 7.2%) versus the high-dose group (20 events in 13 patients, 20%). Two patients died in the reduced-dose group and three died in the high-dose group; those frequencies were noted as not statistically different (difference, –1.7%; 95% CI, –4.7% to 8.2%; P = .67). Causes of death included subarachnoid hemorrhage in a 58-year-old in the reduced-dose group, along with a case of sepsis in an 80-year-old and two gastrointestinal bleedings in a 75-year-old and an 85-year-old in the high-dose group.

End-stage kidney disease (ESKD) occurred in one patient in the high-dose group and none in the reduced-dose group. Cumulative survival rates at 6 months were not significantly different between the reduced-dose (97.1%) and the high-dose (95.3%) groups (95% CI, –4.7% to 8.2%; P = .58).

Less glucocorticoids makes sense for subset of patients with milder vasculitis

“We always worry about how much steroids we’re giving our patients,” said Anisha B. Dua, MD, an associate professor of rheumatology at Northwestern University, Chicago. “And it’s not a shock to find out that we can use less. That’s been the theme of many studies across vasculitities that have been coming out: ‘Maybe we are using too much steroids.’ It’s really important to have actual data supporting that, though, so clinicians can feel more confident and figure out what population it applies to.”

M. Alexander Otto

She added that, because the study focused on patients with milder disease, it’s no surprise that remission was achieved with a lesser dose.

“I see a lot of vasculitis patients, and this gives me more confidence in a subset of them – new ANCA vasculitis, MPO positive, not very severe disease – to get away with using less steroids up front,” she said.

To apply these findings more broadly across vasculitis patients, Dr. Dua stressed the need for a follow-up study, preferably a randomized, controlled trial, with an expanded population and a longer duration.

“There were 3 relapses in the low-dose group and zero in the high-dose group in the first 6 months,” she said. “I’d be interested to know when those happened and also, over time, whether the low-dose regiment up front impacts the rate of relapse in the long term.”

The authors acknowledged the study’s limitations, including the necessity of an open-label trial because of the inevitable visible effects of high-dose glucocorticoid on patients. They also addressed the potential subjectivity of the Birmingham Vasculitis Activity Score, though they added that “other endpoints, including death, ESKD, and serious adverse events, were objective.” Finally, they acknowledged that their study was nationwide but not international, with disease phenotypes that were typical of Japanese patients with AAV. That said, “previous studies have shown that treatment responses are similar between Japan and other countries,” they wrote.

The study was funded by an intramural competitive grant from Chiba University Hospital. The authors reported numerous potential conflicts of interest, including receiving grant support, lecture fees, and personal fees from various pharmaceutical companies.

A reduced dose of prednisolone plus rituximab was as effective as a conventionally high dose in treating patients with newly diagnosed antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis, according to a new Japanese study, along with significantly fewer adverse events as well.

“To our knowledge, this is the first trial in ANCA-associated vasculitis showing that a lower glucocorticoid dose may reduce serious adverse events,” wrote Shunsuke Furuta, MD, PhD, of the department of allergy and clinical immunology at Chiba (Japan) University Hospital, and colleagues. The study was published June 1, 2021, in JAMA.

To determine the most effective and safe dose of glucocorticoids for treating this specific subset of patients with vasculitis, the researchers launched an open-label noninferiority clinical trial at 21 hospitals in Japan. A group of 140 patients with new-onset ANCA-associated vasculitis (AAV) without severe glomerulonephritis or alveolar hemorrhage were enrolled and split evenly into two treatment subgroups: reduced-dose prednisolone (0.5 mg/kg per day) plus four doses of rituximab (375 mg/m² per week) or high-dose prednisolone (1 mg/kg per day) plus rituximab. The median age for all enrolled patients was 73, and approximately 58% were women.

Of the 140 original patients, 134 (95.7%) completed the trial. After 6 months, 49 participants in the reduced-dose group (71%) and 45 in the high-dose group (69.2%) achieved remission, as assessed via the Birmingham Vasculitis Activity Score. The difference between the two groups – 1.8 percentage points (one-sided 97.5% confidence interval, –13.7 to infinity) – met the prespecified margin of –20 percentage points for noninferiority (P = .003 for noninferiority). Relapse within 6 months occurred in three participants in the reduced-dose group and zero in the high-dose group, frequencies that the researchers identified as not statistically different (difference, 4.3%; 95% CI, –0.5% to 9.3%; P = .24).

Serious adverse events occurred less frequently in the reduced-dose group (21 events in 13 patients, 18.8%), compared with the high-dose group (41 events in 24 patients, 36.9%), as did serious infections in the reduced-dose group (7 events in 5 patients, 7.2%) versus the high-dose group (20 events in 13 patients, 20%). Two patients died in the reduced-dose group and three died in the high-dose group; those frequencies were noted as not statistically different (difference, –1.7%; 95% CI, –4.7% to 8.2%; P = .67). Causes of death included subarachnoid hemorrhage in a 58-year-old in the reduced-dose group, along with a case of sepsis in an 80-year-old and two gastrointestinal bleedings in a 75-year-old and an 85-year-old in the high-dose group.

End-stage kidney disease (ESKD) occurred in one patient in the high-dose group and none in the reduced-dose group. Cumulative survival rates at 6 months were not significantly different between the reduced-dose (97.1%) and the high-dose (95.3%) groups (95% CI, –4.7% to 8.2%; P = .58).

Less glucocorticoids makes sense for subset of patients with milder vasculitis

“We always worry about how much steroids we’re giving our patients,” said Anisha B. Dua, MD, an associate professor of rheumatology at Northwestern University, Chicago. “And it’s not a shock to find out that we can use less. That’s been the theme of many studies across vasculitities that have been coming out: ‘Maybe we are using too much steroids.’ It’s really important to have actual data supporting that, though, so clinicians can feel more confident and figure out what population it applies to.”

M. Alexander Otto

She added that, because the study focused on patients with milder disease, it’s no surprise that remission was achieved with a lesser dose.

“I see a lot of vasculitis patients, and this gives me more confidence in a subset of them – new ANCA vasculitis, MPO positive, not very severe disease – to get away with using less steroids up front,” she said.

To apply these findings more broadly across vasculitis patients, Dr. Dua stressed the need for a follow-up study, preferably a randomized, controlled trial, with an expanded population and a longer duration.

“There were 3 relapses in the low-dose group and zero in the high-dose group in the first 6 months,” she said. “I’d be interested to know when those happened and also, over time, whether the low-dose regiment up front impacts the rate of relapse in the long term.”

The authors acknowledged the study’s limitations, including the necessity of an open-label trial because of the inevitable visible effects of high-dose glucocorticoid on patients. They also addressed the potential subjectivity of the Birmingham Vasculitis Activity Score, though they added that “other endpoints, including death, ESKD, and serious adverse events, were objective.” Finally, they acknowledged that their study was nationwide but not international, with disease phenotypes that were typical of Japanese patients with AAV. That said, “previous studies have shown that treatment responses are similar between Japan and other countries,” they wrote.

The study was funded by an intramural competitive grant from Chiba University Hospital. The authors reported numerous potential conflicts of interest, including receiving grant support, lecture fees, and personal fees from various pharmaceutical companies.

Ten percent of patients with immune-mediated inflammatory diseases (IMIDs) fail to respond properly to COVID-19 vaccinations regardless of medication, researchers report, and small new studies suggest those on methotrexate and rituximab may be especially vulnerable to vaccine failure.

Even so, it’s still crucially vital for patients with IMIDs to get vaccinated and for clinicians to follow recommendations to temporarily withhold certain medications around the time of vaccination, rheumatologist Anne R. Bass, MD, of Weill Cornell Medicine and the Hospital for Special Surgery, New York, said in an interview. “We’re not making any significant adjustments,” added Dr. Bass, a coauthor of the American College of Rheumatology’s COVID-19 vaccination guidelines for patients with rheumatic and musculoskeletal diseases.

The findings appear in a trio of studies in Annals of the Rheumatic Diseases. The most recent study, which appeared May 25, 2021, found that more than one-third of patients with IMIDs who took methotrexate didn’t produce adequate antibody levels after vaccination versus 10% of those in other groups. (P < .001) A May 11 study found that 20 of 30 patients with rheumatic diseases on rituximab failed to respond to vaccination. And a May 6 study reported that immune responses against SARS-CoV-2 are “somewhat delayed and reduced” in patients with IMID, with 99.5% of a control group developing neutralizing antibody activity after vaccination versus 90% of those with IMID (P = .0008).


 

Development of neutralizing antibodies somewhat delayed and reduced

Team members were surprised by the high number of vaccine nonresponders in the May 6 IMID study, coauthor Georg Schett, MD, of Germany’s Friedrich-Alexander University Erlangen-Nuremberg and University Hospital Erlangen, said in an interview.

The researchers compared two groups of patients who had no history of COVID-19 and received COVID-19 vaccinations, mostly two shots of the Pfizer-BioNTech vaccine (96%): 84 with IMID (mean age, 53.1 years; 65.5% females) and 182 healthy controls (mean age, 40.8 years; 57.1% females).

The patients with IMID most commonly had spondyloarthritis (32.1%), RA (29.8%), inflammatory bowel disease (9.5%), and psoriasis (9.5%). Nearly 43% of the patients were treated with biologic and targeted synthetic disease-modifying antirheumatic drugs and 23.9% with conventional synthetic DMARDSs. Another 29% were not treated.

All of the controls developed anti–SARS-CoV-2 IgG, but 6% of the patients with IMID did not (P = .003). The gap in development of neutralizing antibodies was even higher: 99.5% of the controls developed neutralizing antibody activity versus 90% of the IMID group. “Neutralizing antibodies are more relevant because the test shows how much the antibodies interfere with the binding of SARS-CoV-2 proteins to the receptor,” Dr. Schett said.

The study authors concluded that “our study provides evidence that, while vaccination against SARS-CoV-2 is well tolerated and even associated with lower incidence of side effects in patients with IMID, its efficacy is somewhat delayed and reduced. Nonetheless, the data also show that, in principle, patients with IMID respond to SARS-CoV-2 vaccination, supporting an aggressive vaccination strategy.”
 

Lowered antibody response to vaccination for some methotrexate users

In the newer study, led by Rebecca H. Haberman, MD, of New York University Langone Health, researchers examined COVID-19 vaccine response in cohorts in New York City and Erlangen, Germany.

The New York cohort included 25 patients with IMID who were taking methotrexate by itself or with other immunomodulatory medications (mean age, 63.2 years), 26 with IMID who were on anticytokine therapy and/or other oral immunomodulators (mean age, 49.1 years) and 26 healthy controls (mean age, 49.2 years). Most patients with IMID had psoriasis/psoriatic arthritis or RA.

The German validation cohort included 182 healthy subjects (mean age, 45.0 years), 11 subjects with IMID who received TNF inhibitor monotherapy (mean age, 40.8 years), and 20 subjects with IMID on methotrexate monotherapy (mean age, 54.5 years).

In the New York cohort, 96.1% of healthy controls showed “adequate humoral immune response,” along with 92.3% of patients with IMID who weren’t taking methotrexate. However, those on methotrexate had a lower rate of adequate response (72.0%), and the gap persisted even after researchers removed those who showed signs of previous COVID-19 infection (P = .045).

In the German cohort, 98.3% of healthy cohorts and 90.9% of patients with IMID who didn’t receive methotrexate reached an “adequate” humoral response versus just half (50.0%) of those who were taking methotrexate.

When both cohorts are combined, over 90% of the healthy subjects and the patients with IMID on biologic treatments (mainly TNF blockers, n = 37) showed “robust” antibody response. However, only 62% of patients with IMID who took methotrexate (n = 45) reached an “adequate” level of response. The methotrexate gap remained after researchers accounted for differences in age among the cohorts.

What’s going on? “We think that the underlying chronic immune stimulation in autoimmune patients may cause T-cell exhaustion and thus blunts the immune response,” said Dr. Schett, who’s also a coauthor of this study. “In addition, specific drugs such as methotrexate could additionally impair the immune response.”

Still, the findings “reiterate that vaccinations are safe and effective, which is what the recommendations state,” he said, adding that more testing of vaccination immune response is wise.
 

Insights into vaccine response while on rituximab

Two more reports, also published in Annals of the Rheumatic Diseases, offer insight into vaccine response in patients with IMID who take rituximab.

Ridofranz/Getty Images

In one report, published May 11, U.S. researchers retrospectively tracked 89 rheumatic disease patients (76% female; mean age, 61) at a single clinic who’d received at least one dose of a COVID-19 vaccine. Of those, 21 patients showed no sign of vaccine antibody response, and 20 of them were in the group taking rituximab. (The other patient was taking belimumab.) Another 10 patients taking rituximab did show a response.

“Longer duration from most recent rituximab exposure was associated with a greater likelihood of response,” the report’s authors wrote. “The results suggest that time from last rituximab exposure is an important consideration in maximizing the likelihood of a serological response, but this likely is related to the substantial variation in the period of B-cell depletion following rituximab.”

Finally, an Austrian report published May 6 examined COVID-19 vaccine immune response in five patients who were taking rituximab (four with other drugs such as methotrexate and prednisone). Researchers compared them with eight healthy controls, half who’d been vaccinated.

The researchers found evidence that rituximab “may not have to preclude SARS-CoV-2 vaccination, since a cellular immune response will be mounted even in the absence of circulating B cells. Alternatively, in patients with stable disease, delaying [rituximab] treatment until after the second vaccination may be warranted and, therefore, vaccines with a short interval between first and second vaccination or those showing full protection after a single vaccination may be preferable. Importantly, in the presence of circulating B cells also a humoral immune response may be expected despite prior [rituximab] therapy.”

Dr. Bass said the findings reflect growing awareness that “patients with autoimmune disease, especially when they’re on immunosuppressant medications, don’t quite have as optimal responses to the vaccinations.” However, she said, the vaccines are so potent that they’re likely to still have significant efficacy in these patients even if there’s a reduction in response.

What’s next? Dr. Schett said “testing immune response to vaccination is important for patients with autoimmune disease. Some of them may need a third vaccination.”

The American College of Rheumatology’s COVID-19 vaccination guidelines do not recommend third vaccinations or postvaccination immune testing at this time. However, Dr. Bass, one of the coauthors of the recommendations, said it’s likely that postvaccination immune testing and booster shots will become routine.

Dr. Bass reported no relevant disclosures. Dr. Schett reported receiving consulting fees from AbbVie. The May 6 German vaccine study was funded by Deutsche Forschungsgemeinschaft, Bundesministerium für Bildung und Forschung, the ERC Synergy grant 4D Nanoscope, the IMI funded project RTCure, the Emerging Fields Initiative MIRACLE of the Friedrich-Alexander-Universität Erlangen-Nürnberg, the Schreiber Stiftung, and the Else Kröner-Memorial Scholarship. The study authors reported no disclosures. The May 25 study of German and American cohorts was funded by the National Institute of Arthritis and Musculoskletal and Skin Diseases, National Institute of Allergy and Infectious Diseases, Rheumatology Research Foundation, Bloomberg Philanthropies COVID-19 Initiative, Pfizer COVID-19 Competitive Grant Program, Beatrice Snyder Foundation, Riley Family Foundation, National Psoriasis Foundation, and Deutsche Forschungsgemeinschaft. The authors reported a range of financial relationships with pharmaceutical companies. No specific funding was reported for the other two studies mentioned.

Ten percent of patients with immune-mediated inflammatory diseases (IMIDs) fail to respond properly to COVID-19 vaccinations regardless of medication, researchers report, and small new studies suggest those on methotrexate and rituximab may be especially vulnerable to vaccine failure.

Even so, it’s still crucially vital for patients with IMIDs to get vaccinated and for clinicians to follow recommendations to temporarily withhold certain medications around the time of vaccination, rheumatologist Anne R. Bass, MD, of Weill Cornell Medicine and the Hospital for Special Surgery, New York, said in an interview. “We’re not making any significant adjustments,” added Dr. Bass, a coauthor of the American College of Rheumatology’s COVID-19 vaccination guidelines for patients with rheumatic and musculoskeletal diseases.

The findings appear in a trio of studies in Annals of the Rheumatic Diseases. The most recent study, which appeared May 25, 2021, found that more than one-third of patients with IMIDs who took methotrexate didn’t produce adequate antibody levels after vaccination versus 10% of those in other groups. (P < .001) A May 11 study found that 20 of 30 patients with rheumatic diseases on rituximab failed to respond to vaccination. And a May 6 study reported that immune responses against SARS-CoV-2 are “somewhat delayed and reduced” in patients with IMID, with 99.5% of a control group developing neutralizing antibody activity after vaccination versus 90% of those with IMID (P = .0008).


 

Development of neutralizing antibodies somewhat delayed and reduced

Team members were surprised by the high number of vaccine nonresponders in the May 6 IMID study, coauthor Georg Schett, MD, of Germany’s Friedrich-Alexander University Erlangen-Nuremberg and University Hospital Erlangen, said in an interview.

The researchers compared two groups of patients who had no history of COVID-19 and received COVID-19 vaccinations, mostly two shots of the Pfizer-BioNTech vaccine (96%): 84 with IMID (mean age, 53.1 years; 65.5% females) and 182 healthy controls (mean age, 40.8 years; 57.1% females).

The patients with IMID most commonly had spondyloarthritis (32.1%), RA (29.8%), inflammatory bowel disease (9.5%), and psoriasis (9.5%). Nearly 43% of the patients were treated with biologic and targeted synthetic disease-modifying antirheumatic drugs and 23.9% with conventional synthetic DMARDSs. Another 29% were not treated.

All of the controls developed anti–SARS-CoV-2 IgG, but 6% of the patients with IMID did not (P = .003). The gap in development of neutralizing antibodies was even higher: 99.5% of the controls developed neutralizing antibody activity versus 90% of the IMID group. “Neutralizing antibodies are more relevant because the test shows how much the antibodies interfere with the binding of SARS-CoV-2 proteins to the receptor,” Dr. Schett said.

The study authors concluded that “our study provides evidence that, while vaccination against SARS-CoV-2 is well tolerated and even associated with lower incidence of side effects in patients with IMID, its efficacy is somewhat delayed and reduced. Nonetheless, the data also show that, in principle, patients with IMID respond to SARS-CoV-2 vaccination, supporting an aggressive vaccination strategy.”
 

Lowered antibody response to vaccination for some methotrexate users

In the newer study, led by Rebecca H. Haberman, MD, of New York University Langone Health, researchers examined COVID-19 vaccine response in cohorts in New York City and Erlangen, Germany.

The New York cohort included 25 patients with IMID who were taking methotrexate by itself or with other immunomodulatory medications (mean age, 63.2 years), 26 with IMID who were on anticytokine therapy and/or other oral immunomodulators (mean age, 49.1 years) and 26 healthy controls (mean age, 49.2 years). Most patients with IMID had psoriasis/psoriatic arthritis or RA.

The German validation cohort included 182 healthy subjects (mean age, 45.0 years), 11 subjects with IMID who received TNF inhibitor monotherapy (mean age, 40.8 years), and 20 subjects with IMID on methotrexate monotherapy (mean age, 54.5 years).

In the New York cohort, 96.1% of healthy controls showed “adequate humoral immune response,” along with 92.3% of patients with IMID who weren’t taking methotrexate. However, those on methotrexate had a lower rate of adequate response (72.0%), and the gap persisted even after researchers removed those who showed signs of previous COVID-19 infection (P = .045).

In the German cohort, 98.3% of healthy cohorts and 90.9% of patients with IMID who didn’t receive methotrexate reached an “adequate” humoral response versus just half (50.0%) of those who were taking methotrexate.

When both cohorts are combined, over 90% of the healthy subjects and the patients with IMID on biologic treatments (mainly TNF blockers, n = 37) showed “robust” antibody response. However, only 62% of patients with IMID who took methotrexate (n = 45) reached an “adequate” level of response. The methotrexate gap remained after researchers accounted for differences in age among the cohorts.

What’s going on? “We think that the underlying chronic immune stimulation in autoimmune patients may cause T-cell exhaustion and thus blunts the immune response,” said Dr. Schett, who’s also a coauthor of this study. “In addition, specific drugs such as methotrexate could additionally impair the immune response.”

Still, the findings “reiterate that vaccinations are safe and effective, which is what the recommendations state,” he said, adding that more testing of vaccination immune response is wise.
 

Insights into vaccine response while on rituximab

Two more reports, also published in Annals of the Rheumatic Diseases, offer insight into vaccine response in patients with IMID who take rituximab.

Ridofranz/Getty Images

In one report, published May 11, U.S. researchers retrospectively tracked 89 rheumatic disease patients (76% female; mean age, 61) at a single clinic who’d received at least one dose of a COVID-19 vaccine. Of those, 21 patients showed no sign of vaccine antibody response, and 20 of them were in the group taking rituximab. (The other patient was taking belimumab.) Another 10 patients taking rituximab did show a response.

“Longer duration from most recent rituximab exposure was associated with a greater likelihood of response,” the report’s authors wrote. “The results suggest that time from last rituximab exposure is an important consideration in maximizing the likelihood of a serological response, but this likely is related to the substantial variation in the period of B-cell depletion following rituximab.”

Finally, an Austrian report published May 6 examined COVID-19 vaccine immune response in five patients who were taking rituximab (four with other drugs such as methotrexate and prednisone). Researchers compared them with eight healthy controls, half who’d been vaccinated.

The researchers found evidence that rituximab “may not have to preclude SARS-CoV-2 vaccination, since a cellular immune response will be mounted even in the absence of circulating B cells. Alternatively, in patients with stable disease, delaying [rituximab] treatment until after the second vaccination may be warranted and, therefore, vaccines with a short interval between first and second vaccination or those showing full protection after a single vaccination may be preferable. Importantly, in the presence of circulating B cells also a humoral immune response may be expected despite prior [rituximab] therapy.”

Dr. Bass said the findings reflect growing awareness that “patients with autoimmune disease, especially when they’re on immunosuppressant medications, don’t quite have as optimal responses to the vaccinations.” However, she said, the vaccines are so potent that they’re likely to still have significant efficacy in these patients even if there’s a reduction in response.

What’s next? Dr. Schett said “testing immune response to vaccination is important for patients with autoimmune disease. Some of them may need a third vaccination.”

The American College of Rheumatology’s COVID-19 vaccination guidelines do not recommend third vaccinations or postvaccination immune testing at this time. However, Dr. Bass, one of the coauthors of the recommendations, said it’s likely that postvaccination immune testing and booster shots will become routine.

Dr. Bass reported no relevant disclosures. Dr. Schett reported receiving consulting fees from AbbVie. The May 6 German vaccine study was funded by Deutsche Forschungsgemeinschaft, Bundesministerium für Bildung und Forschung, the ERC Synergy grant 4D Nanoscope, the IMI funded project RTCure, the Emerging Fields Initiative MIRACLE of the Friedrich-Alexander-Universität Erlangen-Nürnberg, the Schreiber Stiftung, and the Else Kröner-Memorial Scholarship. The study authors reported no disclosures. The May 25 study of German and American cohorts was funded by the National Institute of Arthritis and Musculoskletal and Skin Diseases, National Institute of Allergy and Infectious Diseases, Rheumatology Research Foundation, Bloomberg Philanthropies COVID-19 Initiative, Pfizer COVID-19 Competitive Grant Program, Beatrice Snyder Foundation, Riley Family Foundation, National Psoriasis Foundation, and Deutsche Forschungsgemeinschaft. The authors reported a range of financial relationships with pharmaceutical companies. No specific funding was reported for the other two studies mentioned.

Ten percent of patients with immune-mediated inflammatory diseases (IMIDs) fail to respond properly to COVID-19 vaccinations regardless of medication, researchers report, and small new studies suggest those on methotrexate and rituximab may be especially vulnerable to vaccine failure.

Even so, it’s still crucially vital for patients with IMIDs to get vaccinated and for clinicians to follow recommendations to temporarily withhold certain medications around the time of vaccination, rheumatologist Anne R. Bass, MD, of Weill Cornell Medicine and the Hospital for Special Surgery, New York, said in an interview. “We’re not making any significant adjustments,” added Dr. Bass, a coauthor of the American College of Rheumatology’s COVID-19 vaccination guidelines for patients with rheumatic and musculoskeletal diseases.

The findings appear in a trio of studies in Annals of the Rheumatic Diseases. The most recent study, which appeared May 25, 2021, found that more than one-third of patients with IMIDs who took methotrexate didn’t produce adequate antibody levels after vaccination versus 10% of those in other groups. (P < .001) A May 11 study found that 20 of 30 patients with rheumatic diseases on rituximab failed to respond to vaccination. And a May 6 study reported that immune responses against SARS-CoV-2 are “somewhat delayed and reduced” in patients with IMID, with 99.5% of a control group developing neutralizing antibody activity after vaccination versus 90% of those with IMID (P = .0008).


 

Development of neutralizing antibodies somewhat delayed and reduced

Team members were surprised by the high number of vaccine nonresponders in the May 6 IMID study, coauthor Georg Schett, MD, of Germany’s Friedrich-Alexander University Erlangen-Nuremberg and University Hospital Erlangen, said in an interview.

The researchers compared two groups of patients who had no history of COVID-19 and received COVID-19 vaccinations, mostly two shots of the Pfizer-BioNTech vaccine (96%): 84 with IMID (mean age, 53.1 years; 65.5% females) and 182 healthy controls (mean age, 40.8 years; 57.1% females).

The patients with IMID most commonly had spondyloarthritis (32.1%), RA (29.8%), inflammatory bowel disease (9.5%), and psoriasis (9.5%). Nearly 43% of the patients were treated with biologic and targeted synthetic disease-modifying antirheumatic drugs and 23.9% with conventional synthetic DMARDSs. Another 29% were not treated.

All of the controls developed anti–SARS-CoV-2 IgG, but 6% of the patients with IMID did not (P = .003). The gap in development of neutralizing antibodies was even higher: 99.5% of the controls developed neutralizing antibody activity versus 90% of the IMID group. “Neutralizing antibodies are more relevant because the test shows how much the antibodies interfere with the binding of SARS-CoV-2 proteins to the receptor,” Dr. Schett said.

The study authors concluded that “our study provides evidence that, while vaccination against SARS-CoV-2 is well tolerated and even associated with lower incidence of side effects in patients with IMID, its efficacy is somewhat delayed and reduced. Nonetheless, the data also show that, in principle, patients with IMID respond to SARS-CoV-2 vaccination, supporting an aggressive vaccination strategy.”
 

Lowered antibody response to vaccination for some methotrexate users

In the newer study, led by Rebecca H. Haberman, MD, of New York University Langone Health, researchers examined COVID-19 vaccine response in cohorts in New York City and Erlangen, Germany.

The New York cohort included 25 patients with IMID who were taking methotrexate by itself or with other immunomodulatory medications (mean age, 63.2 years), 26 with IMID who were on anticytokine therapy and/or other oral immunomodulators (mean age, 49.1 years) and 26 healthy controls (mean age, 49.2 years). Most patients with IMID had psoriasis/psoriatic arthritis or RA.

The German validation cohort included 182 healthy subjects (mean age, 45.0 years), 11 subjects with IMID who received TNF inhibitor monotherapy (mean age, 40.8 years), and 20 subjects with IMID on methotrexate monotherapy (mean age, 54.5 years).

In the New York cohort, 96.1% of healthy controls showed “adequate humoral immune response,” along with 92.3% of patients with IMID who weren’t taking methotrexate. However, those on methotrexate had a lower rate of adequate response (72.0%), and the gap persisted even after researchers removed those who showed signs of previous COVID-19 infection (P = .045).

In the German cohort, 98.3% of healthy cohorts and 90.9% of patients with IMID who didn’t receive methotrexate reached an “adequate” humoral response versus just half (50.0%) of those who were taking methotrexate.

When both cohorts are combined, over 90% of the healthy subjects and the patients with IMID on biologic treatments (mainly TNF blockers, n = 37) showed “robust” antibody response. However, only 62% of patients with IMID who took methotrexate (n = 45) reached an “adequate” level of response. The methotrexate gap remained after researchers accounted for differences in age among the cohorts.

What’s going on? “We think that the underlying chronic immune stimulation in autoimmune patients may cause T-cell exhaustion and thus blunts the immune response,” said Dr. Schett, who’s also a coauthor of this study. “In addition, specific drugs such as methotrexate could additionally impair the immune response.”

Still, the findings “reiterate that vaccinations are safe and effective, which is what the recommendations state,” he said, adding that more testing of vaccination immune response is wise.
 

Insights into vaccine response while on rituximab

Two more reports, also published in Annals of the Rheumatic Diseases, offer insight into vaccine response in patients with IMID who take rituximab.

Ridofranz/Getty Images

In one report, published May 11, U.S. researchers retrospectively tracked 89 rheumatic disease patients (76% female; mean age, 61) at a single clinic who’d received at least one dose of a COVID-19 vaccine. Of those, 21 patients showed no sign of vaccine antibody response, and 20 of them were in the group taking rituximab. (The other patient was taking belimumab.) Another 10 patients taking rituximab did show a response.

“Longer duration from most recent rituximab exposure was associated with a greater likelihood of response,” the report’s authors wrote. “The results suggest that time from last rituximab exposure is an important consideration in maximizing the likelihood of a serological response, but this likely is related to the substantial variation in the period of B-cell depletion following rituximab.”

Finally, an Austrian report published May 6 examined COVID-19 vaccine immune response in five patients who were taking rituximab (four with other drugs such as methotrexate and prednisone). Researchers compared them with eight healthy controls, half who’d been vaccinated.

The researchers found evidence that rituximab “may not have to preclude SARS-CoV-2 vaccination, since a cellular immune response will be mounted even in the absence of circulating B cells. Alternatively, in patients with stable disease, delaying [rituximab] treatment until after the second vaccination may be warranted and, therefore, vaccines with a short interval between first and second vaccination or those showing full protection after a single vaccination may be preferable. Importantly, in the presence of circulating B cells also a humoral immune response may be expected despite prior [rituximab] therapy.”

Dr. Bass said the findings reflect growing awareness that “patients with autoimmune disease, especially when they’re on immunosuppressant medications, don’t quite have as optimal responses to the vaccinations.” However, she said, the vaccines are so potent that they’re likely to still have significant efficacy in these patients even if there’s a reduction in response.

What’s next? Dr. Schett said “testing immune response to vaccination is important for patients with autoimmune disease. Some of them may need a third vaccination.”

The American College of Rheumatology’s COVID-19 vaccination guidelines do not recommend third vaccinations or postvaccination immune testing at this time. However, Dr. Bass, one of the coauthors of the recommendations, said it’s likely that postvaccination immune testing and booster shots will become routine.

Dr. Bass reported no relevant disclosures. Dr. Schett reported receiving consulting fees from AbbVie. The May 6 German vaccine study was funded by Deutsche Forschungsgemeinschaft, Bundesministerium für Bildung und Forschung, the ERC Synergy grant 4D Nanoscope, the IMI funded project RTCure, the Emerging Fields Initiative MIRACLE of the Friedrich-Alexander-Universität Erlangen-Nürnberg, the Schreiber Stiftung, and the Else Kröner-Memorial Scholarship. The study authors reported no disclosures. The May 25 study of German and American cohorts was funded by the National Institute of Arthritis and Musculoskletal and Skin Diseases, National Institute of Allergy and Infectious Diseases, Rheumatology Research Foundation, Bloomberg Philanthropies COVID-19 Initiative, Pfizer COVID-19 Competitive Grant Program, Beatrice Snyder Foundation, Riley Family Foundation, National Psoriasis Foundation, and Deutsche Forschungsgemeinschaft. The authors reported a range of financial relationships with pharmaceutical companies. No specific funding was reported for the other two studies mentioned.

The serious infection risk associated with rituximab treatment for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is high but can be offset by co-prescribing co-trimoxazole, data from a single-center, retrospective study reaffirm.

Over the course of a 3-year study period, 14 (28%) of 50 patients with AAV treated with rituximab experienced at latest one severe infection defined as a grade 3 or higher event. The incidence of severe infections was 15.4 per 100 person-years.

However, a lower rate of infections was seen in patients who had been co-prescribed co-trimoxazole (trimethoprim and sulfamethoxazole), Francesco Dernie, a fifth-year medical student at the University of Oxford (England), reported at the British Society for Rheumatology annual conference.

“In the case of rituximab, the depletion of B cells and associated immune suppression is a double-edged sword, allowing effective disease control, but also leaving the body vulnerable to opportunistic and severe infections,” Mr. Dernie said at the meeting.

Of the patients who developed a severe infection on rituximab, just 7% had been treated with co-trimoxazole. In comparison, 44% of those who did not get a severe infection had received co-trimoxazole. Multivariate analysis confirmed that co-trimoxazole use was an influencing factor, with an odds ratio (OR) of 0.096 (95% confidence interval, 0.009–0.996; P = .05).

Another finding was that patients with low immunoglobulin G levels (less than 6 g/L) were more likely to develop a severe infection than were those with higher IgG levels. Indeed, the OR for hypogammaglobulinemia and the risk for infection was 8.782 (95% CI, 1.19–64.6; P = .033).

“Our results support the monitoring of IgG levels to identify patients who may be more susceptible to infection, as well as the prescription of prophylactic co-trimoxazole to reduce overall severe infection risk,” Mr. Dernie and associates concluded in their abstract.

It’s a “really important message around co-trimoxazole,” observed Neil Basu, MBChB, a clinical senior lecturer and honorary consultant at the Institute of Infection, Immunity & Inflammation, University of Glasgow (Scotland).

“It still frustrates me when I see that patients haven’t received that while receiving rituximab. Of course, co-trimoxazole can have its problems,” said Dr. Basu, who was not involved in the study. “It’s not uncommon for patients to develop reactions or be intolerant to the drug.”

Raashid Luqmani, DM, a senior coauthor of the work and professor of rheumatology at the Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Science, University of Oxford, said: “The tolerance of co-trimoxazole has been remarkably good in this cohort.” If there was a problem with using co-trimoxazole, then “our standard would be to go with trimethoprim alone as the next in line and follow that with inhaled pentamidine. So, it’s kind of following what we would all generally do,” Dr. Luqmani said.

Study details

To look at the characteristics of and risk factors for serious infections associated with rituximab use in AAV, Mr. Dernie and associates retrospectively examined the electronic records of patients who had been treated between August 2016 and August 2019. Follow-up was until August 2020.

Of the 50 patients identified, nearly half (48%) were men. The average age was 60 years, ranging from 25 to 90 years. Most (n = 36; 72%) patients had a diagnosis of granulomatosis with polyangiitis, while another 2 (4%) had microscopic polyangiitis, 1 (2%) had eosinophilic granulomatosis with polyangiitis, and 11 (22%) had an overlapping type of vasculitis or undefined AAV.

Of the 18 severe infection events recorded, most (56%) involved the respiratory tract. Less than one-third (28%) were sepsis or neutropenic sepsis events, and there was one case each (6%) of cellulitis, complicated urinary tract infection, and recurrent wound infection.

There were “small numbers of individual comorbidities that were not sufficient to enter into our regression analysis,” Mr. Dernie noted. “It’s likely that comorbid conditions such as COPD [chronic obstructive pulmonary disease] also contribute to an individual’s risk of developing severe infections, and thus should factor into their individualized management.”

Mr. Dernie acknowledged in discussion: “One of the limitations of the study was we just looked at patients in a time when they were receiving rituximab, so they may have historically been exposed to other treatment options.” However, he added, “they weren’t having any other major DMARDs or immunosuppressive treatments at the time.”

Dr. Luqmani observed: “If you look at Francesco’s data on the hypogammaglobulinemia at the start of rituximab, that probably gives you a good idea of just how immunosuppressed these patients were already before we got to this point.”

Dr. Luqmani added: “I suspect that’s in keeping with a lot of other centers that have started using rituximab an awful lot for patients who previously had episodes of vasculitis treated with other disease-modifying therapies, particularly cyclophosphamide.”

But for how long should co-trimoxazole be given after the last rituximab dose? asked the chair of the session, Richard Watts, DM, of Norwich (England) Medical School. These data are purely observational, so it’s not possible to say, Mr. Dernie noted: “The patients that we included as having co-trimoxazole seem to be on it more or less consistently, permanently,” he said.

What about the best dose? “It’s a tricky one,” Dr. Luqmani said, as “we not only use co-trimoxazole for prophylaxis, but we often also want to use it for treatment of the vasculitis itself.”

It’s very likely that there was a mix of patients in the analysis that had received co-trimoxazole as either a treatment or prophylaxis, which means different doses, he said.

“It might be interesting to know whether there was a difference” between doses used and the prevention of infection, added Dr. Luqmani, “but I suspect the numbers are too small to tell.”

Mr. Dernie, Dr. Luqmani, and the other coauthors had no disclosures.

The serious infection risk associated with rituximab treatment for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is high but can be offset by co-prescribing co-trimoxazole, data from a single-center, retrospective study reaffirm.

Over the course of a 3-year study period, 14 (28%) of 50 patients with AAV treated with rituximab experienced at latest one severe infection defined as a grade 3 or higher event. The incidence of severe infections was 15.4 per 100 person-years.

However, a lower rate of infections was seen in patients who had been co-prescribed co-trimoxazole (trimethoprim and sulfamethoxazole), Francesco Dernie, a fifth-year medical student at the University of Oxford (England), reported at the British Society for Rheumatology annual conference.

“In the case of rituximab, the depletion of B cells and associated immune suppression is a double-edged sword, allowing effective disease control, but also leaving the body vulnerable to opportunistic and severe infections,” Mr. Dernie said at the meeting.

Of the patients who developed a severe infection on rituximab, just 7% had been treated with co-trimoxazole. In comparison, 44% of those who did not get a severe infection had received co-trimoxazole. Multivariate analysis confirmed that co-trimoxazole use was an influencing factor, with an odds ratio (OR) of 0.096 (95% confidence interval, 0.009–0.996; P = .05).

Another finding was that patients with low immunoglobulin G levels (less than 6 g/L) were more likely to develop a severe infection than were those with higher IgG levels. Indeed, the OR for hypogammaglobulinemia and the risk for infection was 8.782 (95% CI, 1.19–64.6; P = .033).

“Our results support the monitoring of IgG levels to identify patients who may be more susceptible to infection, as well as the prescription of prophylactic co-trimoxazole to reduce overall severe infection risk,” Mr. Dernie and associates concluded in their abstract.

It’s a “really important message around co-trimoxazole,” observed Neil Basu, MBChB, a clinical senior lecturer and honorary consultant at the Institute of Infection, Immunity & Inflammation, University of Glasgow (Scotland).

“It still frustrates me when I see that patients haven’t received that while receiving rituximab. Of course, co-trimoxazole can have its problems,” said Dr. Basu, who was not involved in the study. “It’s not uncommon for patients to develop reactions or be intolerant to the drug.”

Raashid Luqmani, DM, a senior coauthor of the work and professor of rheumatology at the Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Science, University of Oxford, said: “The tolerance of co-trimoxazole has been remarkably good in this cohort.” If there was a problem with using co-trimoxazole, then “our standard would be to go with trimethoprim alone as the next in line and follow that with inhaled pentamidine. So, it’s kind of following what we would all generally do,” Dr. Luqmani said.

Study details

To look at the characteristics of and risk factors for serious infections associated with rituximab use in AAV, Mr. Dernie and associates retrospectively examined the electronic records of patients who had been treated between August 2016 and August 2019. Follow-up was until August 2020.

Of the 50 patients identified, nearly half (48%) were men. The average age was 60 years, ranging from 25 to 90 years. Most (n = 36; 72%) patients had a diagnosis of granulomatosis with polyangiitis, while another 2 (4%) had microscopic polyangiitis, 1 (2%) had eosinophilic granulomatosis with polyangiitis, and 11 (22%) had an overlapping type of vasculitis or undefined AAV.

Of the 18 severe infection events recorded, most (56%) involved the respiratory tract. Less than one-third (28%) were sepsis or neutropenic sepsis events, and there was one case each (6%) of cellulitis, complicated urinary tract infection, and recurrent wound infection.

There were “small numbers of individual comorbidities that were not sufficient to enter into our regression analysis,” Mr. Dernie noted. “It’s likely that comorbid conditions such as COPD [chronic obstructive pulmonary disease] also contribute to an individual’s risk of developing severe infections, and thus should factor into their individualized management.”

Mr. Dernie acknowledged in discussion: “One of the limitations of the study was we just looked at patients in a time when they were receiving rituximab, so they may have historically been exposed to other treatment options.” However, he added, “they weren’t having any other major DMARDs or immunosuppressive treatments at the time.”

Dr. Luqmani observed: “If you look at Francesco’s data on the hypogammaglobulinemia at the start of rituximab, that probably gives you a good idea of just how immunosuppressed these patients were already before we got to this point.”

Dr. Luqmani added: “I suspect that’s in keeping with a lot of other centers that have started using rituximab an awful lot for patients who previously had episodes of vasculitis treated with other disease-modifying therapies, particularly cyclophosphamide.”

But for how long should co-trimoxazole be given after the last rituximab dose? asked the chair of the session, Richard Watts, DM, of Norwich (England) Medical School. These data are purely observational, so it’s not possible to say, Mr. Dernie noted: “The patients that we included as having co-trimoxazole seem to be on it more or less consistently, permanently,” he said.

What about the best dose? “It’s a tricky one,” Dr. Luqmani said, as “we not only use co-trimoxazole for prophylaxis, but we often also want to use it for treatment of the vasculitis itself.”

It’s very likely that there was a mix of patients in the analysis that had received co-trimoxazole as either a treatment or prophylaxis, which means different doses, he said.

“It might be interesting to know whether there was a difference” between doses used and the prevention of infection, added Dr. Luqmani, “but I suspect the numbers are too small to tell.”

Mr. Dernie, Dr. Luqmani, and the other coauthors had no disclosures.

The serious infection risk associated with rituximab treatment for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is high but can be offset by co-prescribing co-trimoxazole, data from a single-center, retrospective study reaffirm.

Over the course of a 3-year study period, 14 (28%) of 50 patients with AAV treated with rituximab experienced at latest one severe infection defined as a grade 3 or higher event. The incidence of severe infections was 15.4 per 100 person-years.

However, a lower rate of infections was seen in patients who had been co-prescribed co-trimoxazole (trimethoprim and sulfamethoxazole), Francesco Dernie, a fifth-year medical student at the University of Oxford (England), reported at the British Society for Rheumatology annual conference.

“In the case of rituximab, the depletion of B cells and associated immune suppression is a double-edged sword, allowing effective disease control, but also leaving the body vulnerable to opportunistic and severe infections,” Mr. Dernie said at the meeting.

Of the patients who developed a severe infection on rituximab, just 7% had been treated with co-trimoxazole. In comparison, 44% of those who did not get a severe infection had received co-trimoxazole. Multivariate analysis confirmed that co-trimoxazole use was an influencing factor, with an odds ratio (OR) of 0.096 (95% confidence interval, 0.009–0.996; P = .05).

Another finding was that patients with low immunoglobulin G levels (less than 6 g/L) were more likely to develop a severe infection than were those with higher IgG levels. Indeed, the OR for hypogammaglobulinemia and the risk for infection was 8.782 (95% CI, 1.19–64.6; P = .033).

“Our results support the monitoring of IgG levels to identify patients who may be more susceptible to infection, as well as the prescription of prophylactic co-trimoxazole to reduce overall severe infection risk,” Mr. Dernie and associates concluded in their abstract.

It’s a “really important message around co-trimoxazole,” observed Neil Basu, MBChB, a clinical senior lecturer and honorary consultant at the Institute of Infection, Immunity & Inflammation, University of Glasgow (Scotland).

“It still frustrates me when I see that patients haven’t received that while receiving rituximab. Of course, co-trimoxazole can have its problems,” said Dr. Basu, who was not involved in the study. “It’s not uncommon for patients to develop reactions or be intolerant to the drug.”

Raashid Luqmani, DM, a senior coauthor of the work and professor of rheumatology at the Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Science, University of Oxford, said: “The tolerance of co-trimoxazole has been remarkably good in this cohort.” If there was a problem with using co-trimoxazole, then “our standard would be to go with trimethoprim alone as the next in line and follow that with inhaled pentamidine. So, it’s kind of following what we would all generally do,” Dr. Luqmani said.

Study details

To look at the characteristics of and risk factors for serious infections associated with rituximab use in AAV, Mr. Dernie and associates retrospectively examined the electronic records of patients who had been treated between August 2016 and August 2019. Follow-up was until August 2020.

Of the 50 patients identified, nearly half (48%) were men. The average age was 60 years, ranging from 25 to 90 years. Most (n = 36; 72%) patients had a diagnosis of granulomatosis with polyangiitis, while another 2 (4%) had microscopic polyangiitis, 1 (2%) had eosinophilic granulomatosis with polyangiitis, and 11 (22%) had an overlapping type of vasculitis or undefined AAV.

Of the 18 severe infection events recorded, most (56%) involved the respiratory tract. Less than one-third (28%) were sepsis or neutropenic sepsis events, and there was one case each (6%) of cellulitis, complicated urinary tract infection, and recurrent wound infection.

There were “small numbers of individual comorbidities that were not sufficient to enter into our regression analysis,” Mr. Dernie noted. “It’s likely that comorbid conditions such as COPD [chronic obstructive pulmonary disease] also contribute to an individual’s risk of developing severe infections, and thus should factor into their individualized management.”

Mr. Dernie acknowledged in discussion: “One of the limitations of the study was we just looked at patients in a time when they were receiving rituximab, so they may have historically been exposed to other treatment options.” However, he added, “they weren’t having any other major DMARDs or immunosuppressive treatments at the time.”

Dr. Luqmani observed: “If you look at Francesco’s data on the hypogammaglobulinemia at the start of rituximab, that probably gives you a good idea of just how immunosuppressed these patients were already before we got to this point.”

Dr. Luqmani added: “I suspect that’s in keeping with a lot of other centers that have started using rituximab an awful lot for patients who previously had episodes of vasculitis treated with other disease-modifying therapies, particularly cyclophosphamide.”

But for how long should co-trimoxazole be given after the last rituximab dose? asked the chair of the session, Richard Watts, DM, of Norwich (England) Medical School. These data are purely observational, so it’s not possible to say, Mr. Dernie noted: “The patients that we included as having co-trimoxazole seem to be on it more or less consistently, permanently,” he said.

What about the best dose? “It’s a tricky one,” Dr. Luqmani said, as “we not only use co-trimoxazole for prophylaxis, but we often also want to use it for treatment of the vasculitis itself.”

It’s very likely that there was a mix of patients in the analysis that had received co-trimoxazole as either a treatment or prophylaxis, which means different doses, he said.

“It might be interesting to know whether there was a difference” between doses used and the prevention of infection, added Dr. Luqmani, “but I suspect the numbers are too small to tell.”

Mr. Dernie, Dr. Luqmani, and the other coauthors had no disclosures.

A panel of federal advisers on May 6 lent support to the ChemoCentryx bid for approval of avacopan for a rare and serious autoimmune condition. But they also flagged concerns about both the evidence supporting claims of a benefit for this experimental drug and its safety.

At a meeting of the Food and Drug Administration’s Arthritis Advisory Committee, panelists voted 10-8 on a question of whether the risk-benefit profile of avacopan is adequate to support approval.

ChemoCentryx is seeking approval of avacopan for antineutrophil cytoplasmic autoantibody (ANCA)–associated vasculitis in the subtypes of granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA).

Regardless of their vote on this approval question, the panelists shared an interest in avacopan’s potential to reduce glucocorticoid use among some patients with ANCA-associated vasculitis, also called AAV. Mara L. Becker, MD, MSCE, the chair of the FDA’s panel, was among the panelists who said they reluctantly voted no.

“It pains me because I really want more steroid-sparing” medicines, said Dr. Becker of Duke University, Durham, N.C., who cited a need to gather more data on avacopan.

Margrit Wiesendanger, MD, PhD, of the Icahn School of Medicine at Mount Sinai, New York, who was among the panelists voting yes, spoke of a need for caution if the FDA approves avacopan.

“Judicious use of this new medication will be warranted and perhaps additional guidance could be given to rheumatologists to help them decide for whom this medication is best,” she said.

Panelists had spoken earlier of avacopan as a possible alternative medicine for people with AAV who have conditions that make glucocorticoids riskier for them, such as those who have diabetes.
 

Close votes on safety profile, efficacy

The panel also voted 10-8 on a question about whether the safety profile of avacopan is adequate to support approval of avacopan for the treatment of adult patients with AAV.

In addition, the panel voted 9-9 on a question about whether efficacy data support approval of avacopan for the treatment of adult patients with AAV.

The FDA considers the recommendations of its advisory panels, but is not bound by them.

The FDA staff clearly expressed the view that ChemoCentryx fell short with the evidence presented for avacopan approval. Shares of San Carlos, Calif.–based ChemoCentryx dropped sharply from a May 3 closing price of $48.82 to a May 4 closing price of $26.63 after the FDA released the staff’s review of avacopan.

In a briefing prepared for the meeting, FDA staff detailed concerns about the evidence ChemoCentryx is using to seek approval. While acknowledging a need for new treatments for AAV as a rare condition, FDA staff honed in on what they described flaws in the testing of this experimental medicine, which is a small-molecule antagonist of the receptor of C5a, an end product of the complement cascade that acts as a potent neutrophil chemoattractant and agonist.

The FDA usually requires two phase 3 studies for approval of a new medicine but will do so with a single trial in cases of exceptional need, the agency staff said. But in these cases, the bar rises for the evidence provided from that single trial.
 

Difficulties in interpretation of complex study design

In the case of avacopan, though, the data from the key avacopan trial, Study CL010_168, known as ADVOCATE, there were substantial uncertainties around the phase 3 study design and results, raising questions about the adequacy of this single trial to inform the benefit-risk assessment.

In the briefing document, the FDA staff noted that it had “communicated many of the concerns” about ChemoCentryx’s research earlier to the company.

“Complexities of the study design, as detailed in the briefing document, raise questions about the interpretability of the data to define a clinically meaningful benefit of avacopan and its role in the management of AAV,” the FDA staff wrote.

“We acknowledge that AAV is a rare and serious disease associated with high morbidity and increased mortality. It is also a disease with high unmet need for new therapies. However, FDA wants to ensure that new products have a defined context of use, i.e., how a product would be used, and a favorable benefit-risk assessment for patients,” the staff added.

In addition, there were differences in the assessments performed by investigators and the adjudication committee, most frequently related to the attribution of persistent vasculitis, the FDA staff noted.

Statistical analyses of the primary endpoint using investigators’ estimates “resulted in more conservative estimates of treatment effect, e.g., statistical significance for superiority would no longer be demonstrated,” the FDA staff noted. “While the prespecified analysis used the Adjudicator assessments, the assessment based on the Investigators, experienced in management of vasculitis, may better reflect real-world use.”
 

Imbalances in use of glucocorticoids and maintenance therapy

Also among the complications in assessing the ADVOCATE trial data were the glucocorticoids taken by patients in the study, the FDA staff said.

In the avacopan arm of the trial, 86% of patients received non–study-supplied glucocorticoids. In addition, more avacopan‐treated patients experienced adverse events and serious adverse events within the hepatobiliary system leading to discontinuation.

Subgroups given different treatments represented another challenge in interpreting ADVOCATE results for the FDA staff.

At week 26, the proportion of patients in disease remission in the avacopan group (72.3%) was noninferior to the prednisone group (70.1%), the FDA staff said in the briefing document.

But at week 52, a disparity was observed between subgroups that had received rituximab and cyclophosphamide (intravenous and oral) induction treatment. The estimated risk difference for disease remission at week 52 was 15.0% (95% CI, 2.2%-27.7%) in the subgroup receiving induction with rituximab and 3.3% (95% CI, –14.8% to 21.4%) in the cyclophosphamide plus maintenance azathioprine subgroup, the agency’s staff said.

“Based on the data, there is no evidence of clinically meaningful treatment effect in the cyclophosphamide induction subgroup,” the FDA staff wrote. “Further, the treatment comparison in the complementary rituximab induction subgroup may not be considered meaningful because these patients did not receive maintenance therapy, i.e., due to undertreating of patients, the effect observed in the rituximab subgroup may not represent a clinically meaningful treatment effect, compared to standard of care.”

Bruce Jancin/MDedge News

Rachel L. Glaser, MD, clinical team leader in FDA’s division of rheumatology and transplant medicine, reiterated these concerns to the advisory committee at the May 6 meeting.

“Throughout the development program, FDA advised the applicant that a noninferiority comparison would not be sufficient to show that avacopan can replaced glucocorticoids as it would be difficult to establish whether avacopan is effective or whether an effect was due to the rituximab or cyclophosphamide administered to both treatment arms,” she said.

In its briefing for the meeting, ChemoCentryx noted the limits of treatments now available for AAV. It also emphasized the toll of the condition, ranging from skin manifestations to glomerulonephritis to life-threatening pulmonary hemorrhage. If untreated, 80% of patients with GPA or MPA die within 2 years of disease onset, ChemoCentryx said in its briefing materials for the meeting.

The side effects of glucocorticoids were well known to the FDA panelists and the ChemoCentryx presenters. Witnesses at an open public hearing told their own stories of depression, anxiety, and irritability caused by these medicines.

Bruce Jancin/MDedge News

During the ChemoCentryx presentation, a presenter for the company, Peter Merkel, MD, MPH, of the University of Pennsylvania, Philadelphia, said avacopan would provide patients with AAV with an alternative allowing them “to go on a much lower glucocorticoids regimen.”

A similar view was presented in a February 2021 editorial in the New England Journal of Medicine, titled “Avacopan – Time to Replace Glucocorticoids?” Written by Kenneth J. Warrington, MD, of the Mayo Clinic, Rochester, Minn., the opinion article called the ADVOCATE trial “a milestone in the treatment of ANCA-associated vasculitis; complement inhibition with avacopan has glucocorticoid-sparing effects and results in superior disease control.”

Dr. Warrington reported no conflicts in connection with his editorial nor payments from ChemoCentryx. He did report grants from other firms such as Eli Lilly.

Julia Lewis, MD, of Vanderbilt University, Nashville, Tenn., was among the more skeptical members of the FDA panel. She was among the “nays” in all three voting questions put to the panel. Still, she said there were signs of “clinically meaningful benefit” in the data presented, but noted that the nonstudy use of glucocorticoids made it difficult to interpret the ADVOCATE results.

Dr. Lewis noted that the FDA usually requires two studies for a drug approval, particularly with a compound not yet cleared for any use. While ANCA-associated vasculitis is rare, it would be possible to recruit patients for another trial of avacopan, adding to the results reported already for avacopan from ADVOCATE, she said.

“Were there to be another study, this would certainly be a supportive study and maybe qualify as two studies,” she said.

A panel of federal advisers on May 6 lent support to the ChemoCentryx bid for approval of avacopan for a rare and serious autoimmune condition. But they also flagged concerns about both the evidence supporting claims of a benefit for this experimental drug and its safety.

At a meeting of the Food and Drug Administration’s Arthritis Advisory Committee, panelists voted 10-8 on a question of whether the risk-benefit profile of avacopan is adequate to support approval.

ChemoCentryx is seeking approval of avacopan for antineutrophil cytoplasmic autoantibody (ANCA)–associated vasculitis in the subtypes of granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA).

Regardless of their vote on this approval question, the panelists shared an interest in avacopan’s potential to reduce glucocorticoid use among some patients with ANCA-associated vasculitis, also called AAV. Mara L. Becker, MD, MSCE, the chair of the FDA’s panel, was among the panelists who said they reluctantly voted no.

“It pains me because I really want more steroid-sparing” medicines, said Dr. Becker of Duke University, Durham, N.C., who cited a need to gather more data on avacopan.

Margrit Wiesendanger, MD, PhD, of the Icahn School of Medicine at Mount Sinai, New York, who was among the panelists voting yes, spoke of a need for caution if the FDA approves avacopan.

“Judicious use of this new medication will be warranted and perhaps additional guidance could be given to rheumatologists to help them decide for whom this medication is best,” she said.

Panelists had spoken earlier of avacopan as a possible alternative medicine for people with AAV who have conditions that make glucocorticoids riskier for them, such as those who have diabetes.
 

Close votes on safety profile, efficacy

The panel also voted 10-8 on a question about whether the safety profile of avacopan is adequate to support approval of avacopan for the treatment of adult patients with AAV.

In addition, the panel voted 9-9 on a question about whether efficacy data support approval of avacopan for the treatment of adult patients with AAV.

The FDA considers the recommendations of its advisory panels, but is not bound by them.

The FDA staff clearly expressed the view that ChemoCentryx fell short with the evidence presented for avacopan approval. Shares of San Carlos, Calif.–based ChemoCentryx dropped sharply from a May 3 closing price of $48.82 to a May 4 closing price of $26.63 after the FDA released the staff’s review of avacopan.

In a briefing prepared for the meeting, FDA staff detailed concerns about the evidence ChemoCentryx is using to seek approval. While acknowledging a need for new treatments for AAV as a rare condition, FDA staff honed in on what they described flaws in the testing of this experimental medicine, which is a small-molecule antagonist of the receptor of C5a, an end product of the complement cascade that acts as a potent neutrophil chemoattractant and agonist.

The FDA usually requires two phase 3 studies for approval of a new medicine but will do so with a single trial in cases of exceptional need, the agency staff said. But in these cases, the bar rises for the evidence provided from that single trial.
 

Difficulties in interpretation of complex study design

In the case of avacopan, though, the data from the key avacopan trial, Study CL010_168, known as ADVOCATE, there were substantial uncertainties around the phase 3 study design and results, raising questions about the adequacy of this single trial to inform the benefit-risk assessment.

In the briefing document, the FDA staff noted that it had “communicated many of the concerns” about ChemoCentryx’s research earlier to the company.

“Complexities of the study design, as detailed in the briefing document, raise questions about the interpretability of the data to define a clinically meaningful benefit of avacopan and its role in the management of AAV,” the FDA staff wrote.

“We acknowledge that AAV is a rare and serious disease associated with high morbidity and increased mortality. It is also a disease with high unmet need for new therapies. However, FDA wants to ensure that new products have a defined context of use, i.e., how a product would be used, and a favorable benefit-risk assessment for patients,” the staff added.

In addition, there were differences in the assessments performed by investigators and the adjudication committee, most frequently related to the attribution of persistent vasculitis, the FDA staff noted.

Statistical analyses of the primary endpoint using investigators’ estimates “resulted in more conservative estimates of treatment effect, e.g., statistical significance for superiority would no longer be demonstrated,” the FDA staff noted. “While the prespecified analysis used the Adjudicator assessments, the assessment based on the Investigators, experienced in management of vasculitis, may better reflect real-world use.”
 

Imbalances in use of glucocorticoids and maintenance therapy

Also among the complications in assessing the ADVOCATE trial data were the glucocorticoids taken by patients in the study, the FDA staff said.

In the avacopan arm of the trial, 86% of patients received non–study-supplied glucocorticoids. In addition, more avacopan‐treated patients experienced adverse events and serious adverse events within the hepatobiliary system leading to discontinuation.

Subgroups given different treatments represented another challenge in interpreting ADVOCATE results for the FDA staff.

At week 26, the proportion of patients in disease remission in the avacopan group (72.3%) was noninferior to the prednisone group (70.1%), the FDA staff said in the briefing document.

But at week 52, a disparity was observed between subgroups that had received rituximab and cyclophosphamide (intravenous and oral) induction treatment. The estimated risk difference for disease remission at week 52 was 15.0% (95% CI, 2.2%-27.7%) in the subgroup receiving induction with rituximab and 3.3% (95% CI, –14.8% to 21.4%) in the cyclophosphamide plus maintenance azathioprine subgroup, the agency’s staff said.

“Based on the data, there is no evidence of clinically meaningful treatment effect in the cyclophosphamide induction subgroup,” the FDA staff wrote. “Further, the treatment comparison in the complementary rituximab induction subgroup may not be considered meaningful because these patients did not receive maintenance therapy, i.e., due to undertreating of patients, the effect observed in the rituximab subgroup may not represent a clinically meaningful treatment effect, compared to standard of care.”

Bruce Jancin/MDedge News

Rachel L. Glaser, MD, clinical team leader in FDA’s division of rheumatology and transplant medicine, reiterated these concerns to the advisory committee at the May 6 meeting.

“Throughout the development program, FDA advised the applicant that a noninferiority comparison would not be sufficient to show that avacopan can replaced glucocorticoids as it would be difficult to establish whether avacopan is effective or whether an effect was due to the rituximab or cyclophosphamide administered to both treatment arms,” she said.

In its briefing for the meeting, ChemoCentryx noted the limits of treatments now available for AAV. It also emphasized the toll of the condition, ranging from skin manifestations to glomerulonephritis to life-threatening pulmonary hemorrhage. If untreated, 80% of patients with GPA or MPA die within 2 years of disease onset, ChemoCentryx said in its briefing materials for the meeting.

The side effects of glucocorticoids were well known to the FDA panelists and the ChemoCentryx presenters. Witnesses at an open public hearing told their own stories of depression, anxiety, and irritability caused by these medicines.

Bruce Jancin/MDedge News

During the ChemoCentryx presentation, a presenter for the company, Peter Merkel, MD, MPH, of the University of Pennsylvania, Philadelphia, said avacopan would provide patients with AAV with an alternative allowing them “to go on a much lower glucocorticoids regimen.”

A similar view was presented in a February 2021 editorial in the New England Journal of Medicine, titled “Avacopan – Time to Replace Glucocorticoids?” Written by Kenneth J. Warrington, MD, of the Mayo Clinic, Rochester, Minn., the opinion article called the ADVOCATE trial “a milestone in the treatment of ANCA-associated vasculitis; complement inhibition with avacopan has glucocorticoid-sparing effects and results in superior disease control.”

Dr. Warrington reported no conflicts in connection with his editorial nor payments from ChemoCentryx. He did report grants from other firms such as Eli Lilly.

Julia Lewis, MD, of Vanderbilt University, Nashville, Tenn., was among the more skeptical members of the FDA panel. She was among the “nays” in all three voting questions put to the panel. Still, she said there were signs of “clinically meaningful benefit” in the data presented, but noted that the nonstudy use of glucocorticoids made it difficult to interpret the ADVOCATE results.

Dr. Lewis noted that the FDA usually requires two studies for a drug approval, particularly with a compound not yet cleared for any use. While ANCA-associated vasculitis is rare, it would be possible to recruit patients for another trial of avacopan, adding to the results reported already for avacopan from ADVOCATE, she said.

“Were there to be another study, this would certainly be a supportive study and maybe qualify as two studies,” she said.

A panel of federal advisers on May 6 lent support to the ChemoCentryx bid for approval of avacopan for a rare and serious autoimmune condition. But they also flagged concerns about both the evidence supporting claims of a benefit for this experimental drug and its safety.

At a meeting of the Food and Drug Administration’s Arthritis Advisory Committee, panelists voted 10-8 on a question of whether the risk-benefit profile of avacopan is adequate to support approval.

ChemoCentryx is seeking approval of avacopan for antineutrophil cytoplasmic autoantibody (ANCA)–associated vasculitis in the subtypes of granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA).

Regardless of their vote on this approval question, the panelists shared an interest in avacopan’s potential to reduce glucocorticoid use among some patients with ANCA-associated vasculitis, also called AAV. Mara L. Becker, MD, MSCE, the chair of the FDA’s panel, was among the panelists who said they reluctantly voted no.

“It pains me because I really want more steroid-sparing” medicines, said Dr. Becker of Duke University, Durham, N.C., who cited a need to gather more data on avacopan.

Margrit Wiesendanger, MD, PhD, of the Icahn School of Medicine at Mount Sinai, New York, who was among the panelists voting yes, spoke of a need for caution if the FDA approves avacopan.

“Judicious use of this new medication will be warranted and perhaps additional guidance could be given to rheumatologists to help them decide for whom this medication is best,” she said.

Panelists had spoken earlier of avacopan as a possible alternative medicine for people with AAV who have conditions that make glucocorticoids riskier for them, such as those who have diabetes.
 

Close votes on safety profile, efficacy

The panel also voted 10-8 on a question about whether the safety profile of avacopan is adequate to support approval of avacopan for the treatment of adult patients with AAV.

In addition, the panel voted 9-9 on a question about whether efficacy data support approval of avacopan for the treatment of adult patients with AAV.

The FDA considers the recommendations of its advisory panels, but is not bound by them.

The FDA staff clearly expressed the view that ChemoCentryx fell short with the evidence presented for avacopan approval. Shares of San Carlos, Calif.–based ChemoCentryx dropped sharply from a May 3 closing price of $48.82 to a May 4 closing price of $26.63 after the FDA released the staff’s review of avacopan.

In a briefing prepared for the meeting, FDA staff detailed concerns about the evidence ChemoCentryx is using to seek approval. While acknowledging a need for new treatments for AAV as a rare condition, FDA staff honed in on what they described flaws in the testing of this experimental medicine, which is a small-molecule antagonist of the receptor of C5a, an end product of the complement cascade that acts as a potent neutrophil chemoattractant and agonist.

The FDA usually requires two phase 3 studies for approval of a new medicine but will do so with a single trial in cases of exceptional need, the agency staff said. But in these cases, the bar rises for the evidence provided from that single trial.
 

Difficulties in interpretation of complex study design

In the case of avacopan, though, the data from the key avacopan trial, Study CL010_168, known as ADVOCATE, there were substantial uncertainties around the phase 3 study design and results, raising questions about the adequacy of this single trial to inform the benefit-risk assessment.

In the briefing document, the FDA staff noted that it had “communicated many of the concerns” about ChemoCentryx’s research earlier to the company.

“Complexities of the study design, as detailed in the briefing document, raise questions about the interpretability of the data to define a clinically meaningful benefit of avacopan and its role in the management of AAV,” the FDA staff wrote.

“We acknowledge that AAV is a rare and serious disease associated with high morbidity and increased mortality. It is also a disease with high unmet need for new therapies. However, FDA wants to ensure that new products have a defined context of use, i.e., how a product would be used, and a favorable benefit-risk assessment for patients,” the staff added.

In addition, there were differences in the assessments performed by investigators and the adjudication committee, most frequently related to the attribution of persistent vasculitis, the FDA staff noted.

Statistical analyses of the primary endpoint using investigators’ estimates “resulted in more conservative estimates of treatment effect, e.g., statistical significance for superiority would no longer be demonstrated,” the FDA staff noted. “While the prespecified analysis used the Adjudicator assessments, the assessment based on the Investigators, experienced in management of vasculitis, may better reflect real-world use.”
 

Imbalances in use of glucocorticoids and maintenance therapy

Also among the complications in assessing the ADVOCATE trial data were the glucocorticoids taken by patients in the study, the FDA staff said.

In the avacopan arm of the trial, 86% of patients received non–study-supplied glucocorticoids. In addition, more avacopan‐treated patients experienced adverse events and serious adverse events within the hepatobiliary system leading to discontinuation.

Subgroups given different treatments represented another challenge in interpreting ADVOCATE results for the FDA staff.

At week 26, the proportion of patients in disease remission in the avacopan group (72.3%) was noninferior to the prednisone group (70.1%), the FDA staff said in the briefing document.

But at week 52, a disparity was observed between subgroups that had received rituximab and cyclophosphamide (intravenous and oral) induction treatment. The estimated risk difference for disease remission at week 52 was 15.0% (95% CI, 2.2%-27.7%) in the subgroup receiving induction with rituximab and 3.3% (95% CI, –14.8% to 21.4%) in the cyclophosphamide plus maintenance azathioprine subgroup, the agency’s staff said.

“Based on the data, there is no evidence of clinically meaningful treatment effect in the cyclophosphamide induction subgroup,” the FDA staff wrote. “Further, the treatment comparison in the complementary rituximab induction subgroup may not be considered meaningful because these patients did not receive maintenance therapy, i.e., due to undertreating of patients, the effect observed in the rituximab subgroup may not represent a clinically meaningful treatment effect, compared to standard of care.”

Bruce Jancin/MDedge News

Rachel L. Glaser, MD, clinical team leader in FDA’s division of rheumatology and transplant medicine, reiterated these concerns to the advisory committee at the May 6 meeting.

“Throughout the development program, FDA advised the applicant that a noninferiority comparison would not be sufficient to show that avacopan can replaced glucocorticoids as it would be difficult to establish whether avacopan is effective or whether an effect was due to the rituximab or cyclophosphamide administered to both treatment arms,” she said.

In its briefing for the meeting, ChemoCentryx noted the limits of treatments now available for AAV. It also emphasized the toll of the condition, ranging from skin manifestations to glomerulonephritis to life-threatening pulmonary hemorrhage. If untreated, 80% of patients with GPA or MPA die within 2 years of disease onset, ChemoCentryx said in its briefing materials for the meeting.

The side effects of glucocorticoids were well known to the FDA panelists and the ChemoCentryx presenters. Witnesses at an open public hearing told their own stories of depression, anxiety, and irritability caused by these medicines.

Bruce Jancin/MDedge News

During the ChemoCentryx presentation, a presenter for the company, Peter Merkel, MD, MPH, of the University of Pennsylvania, Philadelphia, said avacopan would provide patients with AAV with an alternative allowing them “to go on a much lower glucocorticoids regimen.”

A similar view was presented in a February 2021 editorial in the New England Journal of Medicine, titled “Avacopan – Time to Replace Glucocorticoids?” Written by Kenneth J. Warrington, MD, of the Mayo Clinic, Rochester, Minn., the opinion article called the ADVOCATE trial “a milestone in the treatment of ANCA-associated vasculitis; complement inhibition with avacopan has glucocorticoid-sparing effects and results in superior disease control.”

Dr. Warrington reported no conflicts in connection with his editorial nor payments from ChemoCentryx. He did report grants from other firms such as Eli Lilly.

Julia Lewis, MD, of Vanderbilt University, Nashville, Tenn., was among the more skeptical members of the FDA panel. She was among the “nays” in all three voting questions put to the panel. Still, she said there were signs of “clinically meaningful benefit” in the data presented, but noted that the nonstudy use of glucocorticoids made it difficult to interpret the ADVOCATE results.

Dr. Lewis noted that the FDA usually requires two studies for a drug approval, particularly with a compound not yet cleared for any use. While ANCA-associated vasculitis is rare, it would be possible to recruit patients for another trial of avacopan, adding to the results reported already for avacopan from ADVOCATE, she said.

“Were there to be another study, this would certainly be a supportive study and maybe qualify as two studies,” she said.

Reduced access to medical care, increased mental health issues, poor lifestyle habits, and concern over future care are just some of the patient-reported problems associated with the early phases of the COVID-19 pandemic, according to the results of multiple studies.

Data from the Europe-based REUMAVID study, which surveyed more 1,800 patients between April and July last year, have revealed that 58% of patients with rheumatic and musculoskeletal diseases (RMDs) had their appointments with their rheumatologists canceled, 42% could not get in touch with their primary care physicians, and 52% experienced interrupted visits to mental health specialists.

Not surprisingly, this took a toll on patients’ self-perceived health, with nearly two-thirds stating that they had fair to very poor health, and 47% reporting that their health had worsened. Furthermore, 57% of respondents reported high levels of anxiety, almost 46% were at risk for depression, and 49% reported having poor well-being overall.

“The COVID-19 pandemic has had tremendous impact,” Marco Garrido-Cumbrera, PhD, of the University of Seville, Spain, said at the British Society for Rheumatology annual conference.

Dr. Garrido-Cumbrera, who is key player in the REUMAVID initiative, explained that the project was conceived to respond to concerns raised by the president of the Spanish Federation of Spondyloarthritis Associations (CEADE) about providing the right information to their members.

“First in Italy and then in Spain, it was really difficult to deal with the pandemic and there was a lot of uncertainty from a patient perspective,” Dr. Garrido-Cumbrera said.

Victoria Navarro-Compán, MD, PhD, of La Paz University Hospital, Madrid, who was not involved in the study, observed: “I think this reflects how important collaboration between patient organizations is in order to gather relevant data, and to do it in record time.”

The REUMAVID project was the result of initial collaboration between the Health and Territory Research Group at the University of Seville and CEADE but also involved patient organizations from six other European countries: the National Axial Spondyloarthritis Society, National Rheumatoid Arthritis Society, and Arthritis Action in the United Kingdom; the French Association for the Fight against Rheumatism (AFLAR; L’Association Française de Lutte Anti-Rhumatismale); the National Association of People with Rheumatological and Rare Diseases (APMARR; Associazione Nazionale Persone con Malattie Reumatologiche e Rare) in Italy; Portuguese League Against Rheumatic Diseases (LPCDR; Liga Portuguesa contra as Doenças Reumáticas) in Portugal; the Hellenic League Against Rheumatism (ELEANA) in Greece; and the Cyprus League Against Rheumatism.
 

Pandemic presented ‘perfect storm’

“We’ve never been so well-communicated as we are now,” said Helena Marzo-Ortega, MD, PhD, a consultant rheumatologist at Leeds Teaching Hospitals NHS Trust in England who participated the REUMAVID project. The beginning of the pandemic was “the perfect storm” in that everybody jumped in to try to do something. This resulted in a myriad of research publications, surveys, and attempts to try to understand and make sense of what was happening.

“Research is being conducted in a more structured manner, and it’s given us a lot of very insightful information,” Dr. Marzo-Ortega added. Obviously, patients are important stakeholders to consult when conducting research into how the pandemic has affected them, she added, as they are the ones who had their lives turned upside down.

“A pandemic knows no boundaries, has no limits, everybody can be affected equally. But patients with rheumatic conditions were at particular risk because of the treatments,” she said. “You can remember how worried we all were initially, and thinking about the potential impact of immunosuppressants and many other aspects of these conditions.”

One of the many positives to come out of the pandemic is the “possibility of doing collaborative research at a worldwide level, not just European,” Dr. Marzo-Ortega said, referring to how the EULAR COVID-19 registries are part of the COVID-19 Global Rheumatology Alliance.

Furthermore, Dr. Marzo-Ortega believes the rheumatology community is now better prepared for any upsurges in COVID-19 or any new potentially pandemic-causing viruses.

“What we know now is that we have to be alert, and we know how to respond. We also know how to communicate effectively in order to be able to improve outcomes, not only for the health of the whole population, but also to protect patients such as ours,” she said.
 

Rheumatology practice changed practically overnight

The REUMAVID study is not alone in looking at the impact that the COVID-19 pandemic has had on RMD patients’ health and well-being, particularly during periods of lockdown or where patients were advised to “shield.”

There were “near overnight changes to rheumatology practice,” said Chris Wincup, MBBS, a clinical research fellow at University College London (UCL), who presented the findings of another large-scale survey that looked at the early effects of the pandemic nationally in the United Kingdom.

“The recovery of those services has taken time and, speaking with patients, this varies between different locations,” Dr. Wincup noted. “Unfortunately, access to care does remain a major area of unmet need [and] is something that we’re going to need to think about when planning services in the future,” he added.

Between September and October last year, Dr. Wincup and fellow UCL researchers conducted an online survey among 2,054 patients attending U.K. rheumatology clinics. As in the REUMAVID study, accessing care was difficult or very difficult for a substantial proportion of patients. However, getting medication and monitoring “were generally well maintained” despite lockdown measures.

Many patients (57%) had “extremely high levels of worry about their future care being negatively impacted as a result of the pandemic,” Dr. Wincup said, with 44% saying that their current care was worse than before the pandemic and 41% being dissatisfied with the services they were able to access.

While 48% of patients welcomed a more hybrid approach to their care, 69% thought face-to-face appointments with their rheumatologists were important and 49% wanted only face-to-face appointments. “A possible more hybrid approach, compared with pure face-to-face, is going to be something that may be required,” he said.
 

Different approach taken in CONTAIN Study

A different approach to assessing the impact of the COVID pandemic was taken by researchers at the University of Aberdeen in Scotland, observed Gary Macfarlane, MBChB, PhD.

In the COVID-19 and Musculoskeletal Heath During Lockdown (CONTAIN) study, three well-defined populations of patients from existing cohort studies were looked at prospectively. This included patients with ankylosing spondylitis (AS) and psoriatic arthritis (PsA) participating in two separate British Society for Rheumatology registries, and patients at high risk for developing chronic widespread pain who had been part of the MAmMOTH (Maintaining Musculoskeletal Health) study.

“Our aim was to quantify the changes from the previous prepandemic assessment, focusing on quality of life, changes in lifestyle, and recording what has happened to their musculoskeletal health, including symptoms and disease-specific measures,” Dr. Macfarlane said.

Patients had been invited to participate in June 2020 and were reminded in October 2020 and could respond online or via a postal questionnaire. Some patients were invited to participate in in-depth interviews.

Although the participation rate was low, at 29%, this was typical of studies being conducted at this time due to “survey fatigue,” Dr. Macfarlane said. The CONTAIN study population still included a good number of patients, however, with 596 having AS, 162 PsA, and 296 at risk for chronic widespread pain.

According to Dr. Macfarlane, the CONTAIN study results were “generally reassuring.” Although there was a significant decrease in quality of life as measured by the five-level EQ-5D instrument overall, and in every subgroup population studied, “the magnitude of the decrease was small.” There was no change in disease-specific quality of life in patients with AS, for example.

Levels of pain, anxiety, or depression did increase somewhat, he reported, but the factors that influenced quality of life remained the same before and during the pandemic, such as high levels of deprivation, living in an urban location, low levels of physical activity, and sleep problems.

“Rather surprisingly, sleep problems significantly decreased overall,” Dr. Macfarlane reported. Again, it was only a small change, but “the benefit in terms of the improvement in sleep strengthened with later periods in the follow-up.”

There was also some evidence of increased low-level and high-level physical activity in patients with psoriatic arthritis.

“Mental health is a key issue not just in maintaining musculoskeletal health but also, in terms of the likelihood responding to therapy,” Dr. Macfarlane acknowledged. “Focusing on addressing anxiety is important,” he added.

“Providing enhanced support for self-management, including in relation to pain, is likely to be a priority in the absence of normal health care being available,” he suggested. Importantly, regardless of circumstances, “all patients can be affected.”

The REUMAVID study is conducted by the Health & Territory Research of the University of Seville, with the support of Novartis Pharma AG. The CONTAIN study is supported by the British Society for Rheumatology and Versus Arthritis.

No other relevant conflicts of interested were declared.
 

Reduced access to medical care, increased mental health issues, poor lifestyle habits, and concern over future care are just some of the patient-reported problems associated with the early phases of the COVID-19 pandemic, according to the results of multiple studies.

Data from the Europe-based REUMAVID study, which surveyed more 1,800 patients between April and July last year, have revealed that 58% of patients with rheumatic and musculoskeletal diseases (RMDs) had their appointments with their rheumatologists canceled, 42% could not get in touch with their primary care physicians, and 52% experienced interrupted visits to mental health specialists.

Not surprisingly, this took a toll on patients’ self-perceived health, with nearly two-thirds stating that they had fair to very poor health, and 47% reporting that their health had worsened. Furthermore, 57% of respondents reported high levels of anxiety, almost 46% were at risk for depression, and 49% reported having poor well-being overall.

“The COVID-19 pandemic has had tremendous impact,” Marco Garrido-Cumbrera, PhD, of the University of Seville, Spain, said at the British Society for Rheumatology annual conference.

Dr. Garrido-Cumbrera, who is key player in the REUMAVID initiative, explained that the project was conceived to respond to concerns raised by the president of the Spanish Federation of Spondyloarthritis Associations (CEADE) about providing the right information to their members.

“First in Italy and then in Spain, it was really difficult to deal with the pandemic and there was a lot of uncertainty from a patient perspective,” Dr. Garrido-Cumbrera said.

Victoria Navarro-Compán, MD, PhD, of La Paz University Hospital, Madrid, who was not involved in the study, observed: “I think this reflects how important collaboration between patient organizations is in order to gather relevant data, and to do it in record time.”

The REUMAVID project was the result of initial collaboration between the Health and Territory Research Group at the University of Seville and CEADE but also involved patient organizations from six other European countries: the National Axial Spondyloarthritis Society, National Rheumatoid Arthritis Society, and Arthritis Action in the United Kingdom; the French Association for the Fight against Rheumatism (AFLAR; L’Association Française de Lutte Anti-Rhumatismale); the National Association of People with Rheumatological and Rare Diseases (APMARR; Associazione Nazionale Persone con Malattie Reumatologiche e Rare) in Italy; Portuguese League Against Rheumatic Diseases (LPCDR; Liga Portuguesa contra as Doenças Reumáticas) in Portugal; the Hellenic League Against Rheumatism (ELEANA) in Greece; and the Cyprus League Against Rheumatism.
 

Pandemic presented ‘perfect storm’

“We’ve never been so well-communicated as we are now,” said Helena Marzo-Ortega, MD, PhD, a consultant rheumatologist at Leeds Teaching Hospitals NHS Trust in England who participated the REUMAVID project. The beginning of the pandemic was “the perfect storm” in that everybody jumped in to try to do something. This resulted in a myriad of research publications, surveys, and attempts to try to understand and make sense of what was happening.

“Research is being conducted in a more structured manner, and it’s given us a lot of very insightful information,” Dr. Marzo-Ortega added. Obviously, patients are important stakeholders to consult when conducting research into how the pandemic has affected them, she added, as they are the ones who had their lives turned upside down.

“A pandemic knows no boundaries, has no limits, everybody can be affected equally. But patients with rheumatic conditions were at particular risk because of the treatments,” she said. “You can remember how worried we all were initially, and thinking about the potential impact of immunosuppressants and many other aspects of these conditions.”

One of the many positives to come out of the pandemic is the “possibility of doing collaborative research at a worldwide level, not just European,” Dr. Marzo-Ortega said, referring to how the EULAR COVID-19 registries are part of the COVID-19 Global Rheumatology Alliance.

Furthermore, Dr. Marzo-Ortega believes the rheumatology community is now better prepared for any upsurges in COVID-19 or any new potentially pandemic-causing viruses.

“What we know now is that we have to be alert, and we know how to respond. We also know how to communicate effectively in order to be able to improve outcomes, not only for the health of the whole population, but also to protect patients such as ours,” she said.
 

Rheumatology practice changed practically overnight

The REUMAVID study is not alone in looking at the impact that the COVID-19 pandemic has had on RMD patients’ health and well-being, particularly during periods of lockdown or where patients were advised to “shield.”

There were “near overnight changes to rheumatology practice,” said Chris Wincup, MBBS, a clinical research fellow at University College London (UCL), who presented the findings of another large-scale survey that looked at the early effects of the pandemic nationally in the United Kingdom.

“The recovery of those services has taken time and, speaking with patients, this varies between different locations,” Dr. Wincup noted. “Unfortunately, access to care does remain a major area of unmet need [and] is something that we’re going to need to think about when planning services in the future,” he added.

Between September and October last year, Dr. Wincup and fellow UCL researchers conducted an online survey among 2,054 patients attending U.K. rheumatology clinics. As in the REUMAVID study, accessing care was difficult or very difficult for a substantial proportion of patients. However, getting medication and monitoring “were generally well maintained” despite lockdown measures.

Many patients (57%) had “extremely high levels of worry about their future care being negatively impacted as a result of the pandemic,” Dr. Wincup said, with 44% saying that their current care was worse than before the pandemic and 41% being dissatisfied with the services they were able to access.

While 48% of patients welcomed a more hybrid approach to their care, 69% thought face-to-face appointments with their rheumatologists were important and 49% wanted only face-to-face appointments. “A possible more hybrid approach, compared with pure face-to-face, is going to be something that may be required,” he said.
 

Different approach taken in CONTAIN Study

A different approach to assessing the impact of the COVID pandemic was taken by researchers at the University of Aberdeen in Scotland, observed Gary Macfarlane, MBChB, PhD.

In the COVID-19 and Musculoskeletal Heath During Lockdown (CONTAIN) study, three well-defined populations of patients from existing cohort studies were looked at prospectively. This included patients with ankylosing spondylitis (AS) and psoriatic arthritis (PsA) participating in two separate British Society for Rheumatology registries, and patients at high risk for developing chronic widespread pain who had been part of the MAmMOTH (Maintaining Musculoskeletal Health) study.

“Our aim was to quantify the changes from the previous prepandemic assessment, focusing on quality of life, changes in lifestyle, and recording what has happened to their musculoskeletal health, including symptoms and disease-specific measures,” Dr. Macfarlane said.

Patients had been invited to participate in June 2020 and were reminded in October 2020 and could respond online or via a postal questionnaire. Some patients were invited to participate in in-depth interviews.

Although the participation rate was low, at 29%, this was typical of studies being conducted at this time due to “survey fatigue,” Dr. Macfarlane said. The CONTAIN study population still included a good number of patients, however, with 596 having AS, 162 PsA, and 296 at risk for chronic widespread pain.

According to Dr. Macfarlane, the CONTAIN study results were “generally reassuring.” Although there was a significant decrease in quality of life as measured by the five-level EQ-5D instrument overall, and in every subgroup population studied, “the magnitude of the decrease was small.” There was no change in disease-specific quality of life in patients with AS, for example.

Levels of pain, anxiety, or depression did increase somewhat, he reported, but the factors that influenced quality of life remained the same before and during the pandemic, such as high levels of deprivation, living in an urban location, low levels of physical activity, and sleep problems.

“Rather surprisingly, sleep problems significantly decreased overall,” Dr. Macfarlane reported. Again, it was only a small change, but “the benefit in terms of the improvement in sleep strengthened with later periods in the follow-up.”

There was also some evidence of increased low-level and high-level physical activity in patients with psoriatic arthritis.

“Mental health is a key issue not just in maintaining musculoskeletal health but also, in terms of the likelihood responding to therapy,” Dr. Macfarlane acknowledged. “Focusing on addressing anxiety is important,” he added.

“Providing enhanced support for self-management, including in relation to pain, is likely to be a priority in the absence of normal health care being available,” he suggested. Importantly, regardless of circumstances, “all patients can be affected.”

The REUMAVID study is conducted by the Health & Territory Research of the University of Seville, with the support of Novartis Pharma AG. The CONTAIN study is supported by the British Society for Rheumatology and Versus Arthritis.

No other relevant conflicts of interested were declared.
 

Reduced access to medical care, increased mental health issues, poor lifestyle habits, and concern over future care are just some of the patient-reported problems associated with the early phases of the COVID-19 pandemic, according to the results of multiple studies.

Data from the Europe-based REUMAVID study, which surveyed more 1,800 patients between April and July last year, have revealed that 58% of patients with rheumatic and musculoskeletal diseases (RMDs) had their appointments with their rheumatologists canceled, 42% could not get in touch with their primary care physicians, and 52% experienced interrupted visits to mental health specialists.

Not surprisingly, this took a toll on patients’ self-perceived health, with nearly two-thirds stating that they had fair to very poor health, and 47% reporting that their health had worsened. Furthermore, 57% of respondents reported high levels of anxiety, almost 46% were at risk for depression, and 49% reported having poor well-being overall.

“The COVID-19 pandemic has had tremendous impact,” Marco Garrido-Cumbrera, PhD, of the University of Seville, Spain, said at the British Society for Rheumatology annual conference.

Dr. Garrido-Cumbrera, who is key player in the REUMAVID initiative, explained that the project was conceived to respond to concerns raised by the president of the Spanish Federation of Spondyloarthritis Associations (CEADE) about providing the right information to their members.

“First in Italy and then in Spain, it was really difficult to deal with the pandemic and there was a lot of uncertainty from a patient perspective,” Dr. Garrido-Cumbrera said.

Victoria Navarro-Compán, MD, PhD, of La Paz University Hospital, Madrid, who was not involved in the study, observed: “I think this reflects how important collaboration between patient organizations is in order to gather relevant data, and to do it in record time.”

The REUMAVID project was the result of initial collaboration between the Health and Territory Research Group at the University of Seville and CEADE but also involved patient organizations from six other European countries: the National Axial Spondyloarthritis Society, National Rheumatoid Arthritis Society, and Arthritis Action in the United Kingdom; the French Association for the Fight against Rheumatism (AFLAR; L’Association Française de Lutte Anti-Rhumatismale); the National Association of People with Rheumatological and Rare Diseases (APMARR; Associazione Nazionale Persone con Malattie Reumatologiche e Rare) in Italy; Portuguese League Against Rheumatic Diseases (LPCDR; Liga Portuguesa contra as Doenças Reumáticas) in Portugal; the Hellenic League Against Rheumatism (ELEANA) in Greece; and the Cyprus League Against Rheumatism.
 

Pandemic presented ‘perfect storm’

“We’ve never been so well-communicated as we are now,” said Helena Marzo-Ortega, MD, PhD, a consultant rheumatologist at Leeds Teaching Hospitals NHS Trust in England who participated the REUMAVID project. The beginning of the pandemic was “the perfect storm” in that everybody jumped in to try to do something. This resulted in a myriad of research publications, surveys, and attempts to try to understand and make sense of what was happening.

“Research is being conducted in a more structured manner, and it’s given us a lot of very insightful information,” Dr. Marzo-Ortega added. Obviously, patients are important stakeholders to consult when conducting research into how the pandemic has affected them, she added, as they are the ones who had their lives turned upside down.

“A pandemic knows no boundaries, has no limits, everybody can be affected equally. But patients with rheumatic conditions were at particular risk because of the treatments,” she said. “You can remember how worried we all were initially, and thinking about the potential impact of immunosuppressants and many other aspects of these conditions.”

One of the many positives to come out of the pandemic is the “possibility of doing collaborative research at a worldwide level, not just European,” Dr. Marzo-Ortega said, referring to how the EULAR COVID-19 registries are part of the COVID-19 Global Rheumatology Alliance.

Furthermore, Dr. Marzo-Ortega believes the rheumatology community is now better prepared for any upsurges in COVID-19 or any new potentially pandemic-causing viruses.

“What we know now is that we have to be alert, and we know how to respond. We also know how to communicate effectively in order to be able to improve outcomes, not only for the health of the whole population, but also to protect patients such as ours,” she said.
 

Rheumatology practice changed practically overnight

The REUMAVID study is not alone in looking at the impact that the COVID-19 pandemic has had on RMD patients’ health and well-being, particularly during periods of lockdown or where patients were advised to “shield.”

There were “near overnight changes to rheumatology practice,” said Chris Wincup, MBBS, a clinical research fellow at University College London (UCL), who presented the findings of another large-scale survey that looked at the early effects of the pandemic nationally in the United Kingdom.

“The recovery of those services has taken time and, speaking with patients, this varies between different locations,” Dr. Wincup noted. “Unfortunately, access to care does remain a major area of unmet need [and] is something that we’re going to need to think about when planning services in the future,” he added.

Between September and October last year, Dr. Wincup and fellow UCL researchers conducted an online survey among 2,054 patients attending U.K. rheumatology clinics. As in the REUMAVID study, accessing care was difficult or very difficult for a substantial proportion of patients. However, getting medication and monitoring “were generally well maintained” despite lockdown measures.

Many patients (57%) had “extremely high levels of worry about their future care being negatively impacted as a result of the pandemic,” Dr. Wincup said, with 44% saying that their current care was worse than before the pandemic and 41% being dissatisfied with the services they were able to access.

While 48% of patients welcomed a more hybrid approach to their care, 69% thought face-to-face appointments with their rheumatologists were important and 49% wanted only face-to-face appointments. “A possible more hybrid approach, compared with pure face-to-face, is going to be something that may be required,” he said.
 

Different approach taken in CONTAIN Study

A different approach to assessing the impact of the COVID pandemic was taken by researchers at the University of Aberdeen in Scotland, observed Gary Macfarlane, MBChB, PhD.

In the COVID-19 and Musculoskeletal Heath During Lockdown (CONTAIN) study, three well-defined populations of patients from existing cohort studies were looked at prospectively. This included patients with ankylosing spondylitis (AS) and psoriatic arthritis (PsA) participating in two separate British Society for Rheumatology registries, and patients at high risk for developing chronic widespread pain who had been part of the MAmMOTH (Maintaining Musculoskeletal Health) study.

“Our aim was to quantify the changes from the previous prepandemic assessment, focusing on quality of life, changes in lifestyle, and recording what has happened to their musculoskeletal health, including symptoms and disease-specific measures,” Dr. Macfarlane said.

Patients had been invited to participate in June 2020 and were reminded in October 2020 and could respond online or via a postal questionnaire. Some patients were invited to participate in in-depth interviews.

Although the participation rate was low, at 29%, this was typical of studies being conducted at this time due to “survey fatigue,” Dr. Macfarlane said. The CONTAIN study population still included a good number of patients, however, with 596 having AS, 162 PsA, and 296 at risk for chronic widespread pain.

According to Dr. Macfarlane, the CONTAIN study results were “generally reassuring.” Although there was a significant decrease in quality of life as measured by the five-level EQ-5D instrument overall, and in every subgroup population studied, “the magnitude of the decrease was small.” There was no change in disease-specific quality of life in patients with AS, for example.

Levels of pain, anxiety, or depression did increase somewhat, he reported, but the factors that influenced quality of life remained the same before and during the pandemic, such as high levels of deprivation, living in an urban location, low levels of physical activity, and sleep problems.

“Rather surprisingly, sleep problems significantly decreased overall,” Dr. Macfarlane reported. Again, it was only a small change, but “the benefit in terms of the improvement in sleep strengthened with later periods in the follow-up.”

There was also some evidence of increased low-level and high-level physical activity in patients with psoriatic arthritis.

“Mental health is a key issue not just in maintaining musculoskeletal health but also, in terms of the likelihood responding to therapy,” Dr. Macfarlane acknowledged. “Focusing on addressing anxiety is important,” he added.

“Providing enhanced support for self-management, including in relation to pain, is likely to be a priority in the absence of normal health care being available,” he suggested. Importantly, regardless of circumstances, “all patients can be affected.”

The REUMAVID study is conducted by the Health & Territory Research of the University of Seville, with the support of Novartis Pharma AG. The CONTAIN study is supported by the British Society for Rheumatology and Versus Arthritis.

No other relevant conflicts of interested were declared.
 

Patients with neuropsychiatric manifestations of systemic lupus erythematosus (NPSLE) seem to benefit from rituximab (Rituxan) therapy, according to data from the British Isles Lupus Assessment Group Biologics Register (BILAG-BR).

Indeed, the percentage of patients with active disease, as scored by the BILAG-2004 index or SLEDAI-2K (SLE Disease Activity Index 2000), fell significantly (P < .0001) when comparing pre- and postrituximab treatment scores. There was also a reduction in the dose of oral steroids used.

Interestingly, the use of concomitant cyclophosphamide might enhance the level of improvement seen in some patients, Trixy David, MBBS, reported during an abstract session at the British Society for Rheumatology annual conference.

“Larger-scale studies are warranted to establish the effectiveness of rituximab alone, or in combination with cyclophosphamide, in the treatment neuropsychiatric lupus,” said Dr. David, a clinical research fellow at the University of Manchester (England) and specialist registrar in rheumatology at the Manchester University National Health Service Foundation Trust.

Neil Basu, MBChB, PhD, who chaired the virtual session, called the findings “enlightening” and “descriptive.”

The study “provides some interesting data, which should be tested in a robust, randomized clinical trial,” he agreed, and not that clinicians should now start using rituximab for their NPSLE cases.

Dr. Basu, who is a clinical senior lecturer in rheumatology and honorary consultant rheumatologist at the Institute of Infection, Immunity and Inflammation at the University of Glasgow, added: “It is really important that we do these studies to help support a rationale for such a trial, which are obviously very expensive and require strong evidence before we go down that track. I think these data have really been quite enlightening in that respect.”

Rationale for rituximab in neuropsychiatric lupus

Managing patients with NPSLE remains an area of substantial unmet need. According to a recent review in Rheumatology, “there is a dearth of controlled clinical trials to guide management” and “therapeutic options include symptomatic, antithrombotic, and immunosuppressive agents that are supported by observational cohort studies.”

Despite being seen in at least half of all patients with SLE, neuropsychiatric disease “is not very well studied in patients with lupus, as a lot of large-scale trials tend to exclude patients with active neurological disease,” Dr. David said.

Although it is unclear why neuropsychiatric disease occurs in SLE, it could be “as a result of vascular injury or disruption of the blood brain barrier, thereby allowing the passive diffusion of autoantibodies and cytokines across through the cerebral spinal fluid, thereby generating a proinflammatory response,” Dr. David suggested.

“We know B cells are involved in the pathogenesis of lupus, and rituximab is a chimeric monoclonal antibody that selectively targets CD20-positive B cells and mediates transient B-cell depletion,” she said. Notably, there have been some small studies suggesting that rituximab may be effective in neuropsychiatric lupus, and it is currently widely used to treat refractory lupus in the United Kingdom.
 

About the BILAG-BR and results

“Our aim was to describe the baseline characteristics and short-term effectiveness of rituximab in patients treated for neuropsychiatric lupus within the BILAG-BR,” Dr. David explained.

Started in 2009, the BILAG-BR now contains information on more than 1,400 individuals with SLE who have been recruited at 62 centers in the United Kingdom. Its purpose is to evaluate the long-term safety and effectiveness of biologic drugs versus standard immunosuppressive therapy such as azathioprine, mycophenolate mofetil, cyclophosphamide, and cyclosporine. To date, 1,229 patients have been treated with biologics, of whom 1,056 have received rituximab.

A total of 74 rituximab-treated patients were identified as having active neuropsychiatric disease, making this “the largest prospective observational cohort to date, to our knowledge,” Dr. David said.

The median age of patients was 45.5 years, the majority was female (82%) and White (74%). The median disease duration was 11.5 years.

A total of 96% had multiple organ involvement and not just neuropsychiatric disease, and 91% were positive for antineutrophil antibodies.

The top six neuropsychiatric manifestations were cognitive dysfunction and lupus headache (both affecting 27.5% of patients); acute confessional state or mononeuropathy (each seen in 10% of patients); and seizure disorder and polyneuropathy, seen in a respective 8.6% and 8.7% of patients. These findings are in line with a 2011 meta-analysis, Dr. David pointed out.

BILAG-2004 scores before and after rituximab treatment were available for 50 patients. The number of patients with a BILAG A score dropped from 24 (48%) at baseline to 7 (14%) after treatment with rituximab, and the number with a BILAG B score declined from 26 (52%) at baseline to 4 (8%) after rituximab (both P < .0001).

There was also a reduction following rituximab treatment in the percentage of patients categorized as having mainly central nervous system disease (70% vs. 11%), peripheral nervous system disease (19% vs. 6%), or both (11% vs. 8%).

Total SLEDAI-2K scores were also reduced following rituximab treatment, from a median of 12 at baseline to 2 (P < .0001).

Pre- and postrituximab oral prednisolone doses were a median of 15 mg and 10 mg (P = .009).

Limitations

“Our data are from a real-world setting of patients who had active neuropsychiatric disease and were treated with rituximab,” Dr. David said. There are of course many limitations that go hand in hand with observational studies.

“There was the issue of missing data,” Dr. David said. It was difficult or not possible to determine what doses of steroids patients were taking after rituximab therapy, particularly in terms of intravenous steroids, and what doses of any other concomitant disease-modifying therapy might have been around the time that patients initiated or stopped rituximab treatment.

“These could have acted as potential confounders,” she acknowledged.

Dr. Basu noted: “My major haziness from it is the uncertainty of knowing why these patients improved. Yes, they had rituximab, but I’m sure also that they probably received high doses of steroids if they had quite severe CNS lupus which was categorized as a BILAG-A or a B.”

Patients may also be given methylprednisolone when clinicians are really concerned, he continued, and “as was quite clearly pointed out,” there was quite a lot of missing data from a steroid perspective.

Dr. David and coinvestigators reported having no conflicts of interest. The BILAG-BR is supported by funding from Lupus UK, GlaxoSmithKline, and Roche. Dr. Basu did not state having any disclosures.

Patients with neuropsychiatric manifestations of systemic lupus erythematosus (NPSLE) seem to benefit from rituximab (Rituxan) therapy, according to data from the British Isles Lupus Assessment Group Biologics Register (BILAG-BR).

Indeed, the percentage of patients with active disease, as scored by the BILAG-2004 index or SLEDAI-2K (SLE Disease Activity Index 2000), fell significantly (P < .0001) when comparing pre- and postrituximab treatment scores. There was also a reduction in the dose of oral steroids used.

Interestingly, the use of concomitant cyclophosphamide might enhance the level of improvement seen in some patients, Trixy David, MBBS, reported during an abstract session at the British Society for Rheumatology annual conference.

“Larger-scale studies are warranted to establish the effectiveness of rituximab alone, or in combination with cyclophosphamide, in the treatment neuropsychiatric lupus,” said Dr. David, a clinical research fellow at the University of Manchester (England) and specialist registrar in rheumatology at the Manchester University National Health Service Foundation Trust.

Neil Basu, MBChB, PhD, who chaired the virtual session, called the findings “enlightening” and “descriptive.”

The study “provides some interesting data, which should be tested in a robust, randomized clinical trial,” he agreed, and not that clinicians should now start using rituximab for their NPSLE cases.

Dr. Basu, who is a clinical senior lecturer in rheumatology and honorary consultant rheumatologist at the Institute of Infection, Immunity and Inflammation at the University of Glasgow, added: “It is really important that we do these studies to help support a rationale for such a trial, which are obviously very expensive and require strong evidence before we go down that track. I think these data have really been quite enlightening in that respect.”

Rationale for rituximab in neuropsychiatric lupus

Managing patients with NPSLE remains an area of substantial unmet need. According to a recent review in Rheumatology, “there is a dearth of controlled clinical trials to guide management” and “therapeutic options include symptomatic, antithrombotic, and immunosuppressive agents that are supported by observational cohort studies.”

Despite being seen in at least half of all patients with SLE, neuropsychiatric disease “is not very well studied in patients with lupus, as a lot of large-scale trials tend to exclude patients with active neurological disease,” Dr. David said.

Although it is unclear why neuropsychiatric disease occurs in SLE, it could be “as a result of vascular injury or disruption of the blood brain barrier, thereby allowing the passive diffusion of autoantibodies and cytokines across through the cerebral spinal fluid, thereby generating a proinflammatory response,” Dr. David suggested.

“We know B cells are involved in the pathogenesis of lupus, and rituximab is a chimeric monoclonal antibody that selectively targets CD20-positive B cells and mediates transient B-cell depletion,” she said. Notably, there have been some small studies suggesting that rituximab may be effective in neuropsychiatric lupus, and it is currently widely used to treat refractory lupus in the United Kingdom.
 

About the BILAG-BR and results

“Our aim was to describe the baseline characteristics and short-term effectiveness of rituximab in patients treated for neuropsychiatric lupus within the BILAG-BR,” Dr. David explained.

Started in 2009, the BILAG-BR now contains information on more than 1,400 individuals with SLE who have been recruited at 62 centers in the United Kingdom. Its purpose is to evaluate the long-term safety and effectiveness of biologic drugs versus standard immunosuppressive therapy such as azathioprine, mycophenolate mofetil, cyclophosphamide, and cyclosporine. To date, 1,229 patients have been treated with biologics, of whom 1,056 have received rituximab.

A total of 74 rituximab-treated patients were identified as having active neuropsychiatric disease, making this “the largest prospective observational cohort to date, to our knowledge,” Dr. David said.

The median age of patients was 45.5 years, the majority was female (82%) and White (74%). The median disease duration was 11.5 years.

A total of 96% had multiple organ involvement and not just neuropsychiatric disease, and 91% were positive for antineutrophil antibodies.

The top six neuropsychiatric manifestations were cognitive dysfunction and lupus headache (both affecting 27.5% of patients); acute confessional state or mononeuropathy (each seen in 10% of patients); and seizure disorder and polyneuropathy, seen in a respective 8.6% and 8.7% of patients. These findings are in line with a 2011 meta-analysis, Dr. David pointed out.

BILAG-2004 scores before and after rituximab treatment were available for 50 patients. The number of patients with a BILAG A score dropped from 24 (48%) at baseline to 7 (14%) after treatment with rituximab, and the number with a BILAG B score declined from 26 (52%) at baseline to 4 (8%) after rituximab (both P < .0001).

There was also a reduction following rituximab treatment in the percentage of patients categorized as having mainly central nervous system disease (70% vs. 11%), peripheral nervous system disease (19% vs. 6%), or both (11% vs. 8%).

Total SLEDAI-2K scores were also reduced following rituximab treatment, from a median of 12 at baseline to 2 (P < .0001).

Pre- and postrituximab oral prednisolone doses were a median of 15 mg and 10 mg (P = .009).

Limitations

“Our data are from a real-world setting of patients who had active neuropsychiatric disease and were treated with rituximab,” Dr. David said. There are of course many limitations that go hand in hand with observational studies.

“There was the issue of missing data,” Dr. David said. It was difficult or not possible to determine what doses of steroids patients were taking after rituximab therapy, particularly in terms of intravenous steroids, and what doses of any other concomitant disease-modifying therapy might have been around the time that patients initiated or stopped rituximab treatment.

“These could have acted as potential confounders,” she acknowledged.

Dr. Basu noted: “My major haziness from it is the uncertainty of knowing why these patients improved. Yes, they had rituximab, but I’m sure also that they probably received high doses of steroids if they had quite severe CNS lupus which was categorized as a BILAG-A or a B.”

Patients may also be given methylprednisolone when clinicians are really concerned, he continued, and “as was quite clearly pointed out,” there was quite a lot of missing data from a steroid perspective.

Dr. David and coinvestigators reported having no conflicts of interest. The BILAG-BR is supported by funding from Lupus UK, GlaxoSmithKline, and Roche. Dr. Basu did not state having any disclosures.

Patients with neuropsychiatric manifestations of systemic lupus erythematosus (NPSLE) seem to benefit from rituximab (Rituxan) therapy, according to data from the British Isles Lupus Assessment Group Biologics Register (BILAG-BR).

Indeed, the percentage of patients with active disease, as scored by the BILAG-2004 index or SLEDAI-2K (SLE Disease Activity Index 2000), fell significantly (P < .0001) when comparing pre- and postrituximab treatment scores. There was also a reduction in the dose of oral steroids used.

Interestingly, the use of concomitant cyclophosphamide might enhance the level of improvement seen in some patients, Trixy David, MBBS, reported during an abstract session at the British Society for Rheumatology annual conference.

“Larger-scale studies are warranted to establish the effectiveness of rituximab alone, or in combination with cyclophosphamide, in the treatment neuropsychiatric lupus,” said Dr. David, a clinical research fellow at the University of Manchester (England) and specialist registrar in rheumatology at the Manchester University National Health Service Foundation Trust.

Neil Basu, MBChB, PhD, who chaired the virtual session, called the findings “enlightening” and “descriptive.”

The study “provides some interesting data, which should be tested in a robust, randomized clinical trial,” he agreed, and not that clinicians should now start using rituximab for their NPSLE cases.

Dr. Basu, who is a clinical senior lecturer in rheumatology and honorary consultant rheumatologist at the Institute of Infection, Immunity and Inflammation at the University of Glasgow, added: “It is really important that we do these studies to help support a rationale for such a trial, which are obviously very expensive and require strong evidence before we go down that track. I think these data have really been quite enlightening in that respect.”

Rationale for rituximab in neuropsychiatric lupus

Managing patients with NPSLE remains an area of substantial unmet need. According to a recent review in Rheumatology, “there is a dearth of controlled clinical trials to guide management” and “therapeutic options include symptomatic, antithrombotic, and immunosuppressive agents that are supported by observational cohort studies.”

Despite being seen in at least half of all patients with SLE, neuropsychiatric disease “is not very well studied in patients with lupus, as a lot of large-scale trials tend to exclude patients with active neurological disease,” Dr. David said.

Although it is unclear why neuropsychiatric disease occurs in SLE, it could be “as a result of vascular injury or disruption of the blood brain barrier, thereby allowing the passive diffusion of autoantibodies and cytokines across through the cerebral spinal fluid, thereby generating a proinflammatory response,” Dr. David suggested.

“We know B cells are involved in the pathogenesis of lupus, and rituximab is a chimeric monoclonal antibody that selectively targets CD20-positive B cells and mediates transient B-cell depletion,” she said. Notably, there have been some small studies suggesting that rituximab may be effective in neuropsychiatric lupus, and it is currently widely used to treat refractory lupus in the United Kingdom.
 

About the BILAG-BR and results

“Our aim was to describe the baseline characteristics and short-term effectiveness of rituximab in patients treated for neuropsychiatric lupus within the BILAG-BR,” Dr. David explained.

Started in 2009, the BILAG-BR now contains information on more than 1,400 individuals with SLE who have been recruited at 62 centers in the United Kingdom. Its purpose is to evaluate the long-term safety and effectiveness of biologic drugs versus standard immunosuppressive therapy such as azathioprine, mycophenolate mofetil, cyclophosphamide, and cyclosporine. To date, 1,229 patients have been treated with biologics, of whom 1,056 have received rituximab.

A total of 74 rituximab-treated patients were identified as having active neuropsychiatric disease, making this “the largest prospective observational cohort to date, to our knowledge,” Dr. David said.

The median age of patients was 45.5 years, the majority was female (82%) and White (74%). The median disease duration was 11.5 years.

A total of 96% had multiple organ involvement and not just neuropsychiatric disease, and 91% were positive for antineutrophil antibodies.

The top six neuropsychiatric manifestations were cognitive dysfunction and lupus headache (both affecting 27.5% of patients); acute confessional state or mononeuropathy (each seen in 10% of patients); and seizure disorder and polyneuropathy, seen in a respective 8.6% and 8.7% of patients. These findings are in line with a 2011 meta-analysis, Dr. David pointed out.

BILAG-2004 scores before and after rituximab treatment were available for 50 patients. The number of patients with a BILAG A score dropped from 24 (48%) at baseline to 7 (14%) after treatment with rituximab, and the number with a BILAG B score declined from 26 (52%) at baseline to 4 (8%) after rituximab (both P < .0001).

There was also a reduction following rituximab treatment in the percentage of patients categorized as having mainly central nervous system disease (70% vs. 11%), peripheral nervous system disease (19% vs. 6%), or both (11% vs. 8%).

Total SLEDAI-2K scores were also reduced following rituximab treatment, from a median of 12 at baseline to 2 (P < .0001).

Pre- and postrituximab oral prednisolone doses were a median of 15 mg and 10 mg (P = .009).

Limitations

“Our data are from a real-world setting of patients who had active neuropsychiatric disease and were treated with rituximab,” Dr. David said. There are of course many limitations that go hand in hand with observational studies.

“There was the issue of missing data,” Dr. David said. It was difficult or not possible to determine what doses of steroids patients were taking after rituximab therapy, particularly in terms of intravenous steroids, and what doses of any other concomitant disease-modifying therapy might have been around the time that patients initiated or stopped rituximab treatment.

“These could have acted as potential confounders,” she acknowledged.

Dr. Basu noted: “My major haziness from it is the uncertainty of knowing why these patients improved. Yes, they had rituximab, but I’m sure also that they probably received high doses of steroids if they had quite severe CNS lupus which was categorized as a BILAG-A or a B.”

Patients may also be given methylprednisolone when clinicians are really concerned, he continued, and “as was quite clearly pointed out,” there was quite a lot of missing data from a steroid perspective.

Dr. David and coinvestigators reported having no conflicts of interest. The BILAG-BR is supported by funding from Lupus UK, GlaxoSmithKline, and Roche. Dr. Basu did not state having any disclosures.

The prices of two new drugs that have been approved by the Food and Drug Administration for the treatment of lupus nephritis are in “reasonable alignment” with the drugs’ estimated benefits for patients with the disease, the Institute for Clinical and Economic Review has determined.

“Both belimumab [Benlysta] and voclosporin [Lupkynis] are important new treatment options,” Steven Pearson, MD, president of ICER, observed in a summary of the report’s findings.

“Despite remaining uncertainty about both treatments’ longer-term outcomes, their estimated net prices appear to be aligned with their anticipated clinical benefits. ... For patients and clinicians to have responsibly priced options specifically indicated for lupus nephritis is a win for patients and the entire health system,” Dr. Pearson added.

The estimated annual price of belimumab is approximately $43,000 per patient; the estimated annual price for voclosporin is approximately $92,000 per patient.

The incremental cost-effectiveness ratio for belimumab is approximately $90,0000 per quality-adjusted life-year; the corresponding value for voclosporin is higher, at approximately $149,000 per QALY, the ICER authors noted.

The report was published by ICER in April 2021.

Large unmet need for treatment of lupus nephritis

In their report, the ICER reviewed belimumab, a parenteral B-lymphocyte inhibitor, as well as voclosporin, an oral calcineurin inhibitor, as initial treatment of patients with lupus nephritis. Lupus nephritis is a serious complication of systemic lupus erythematosus (SLE).

Belimumab was first approved for the treatment of lupus in adults in the United States in March 2011. In April 2019, it was approved for use for the same indication for children aged 5 years and older. The FDA expanded the indication in December 2020 to include adults with active lupus nephritis who are receiving standard therapy.

Voclosporin was approved for the treatment of lupus nephritis in January 2021.

In the pivotal trials for the two agents, each drug was added to standard induction therapy for lupus nephritis, which consisted of high-dose corticosteroids combined with either mycophenolate mofetil (MMF) or cyclophosphamide.

Compared with standard therapy alone, belimumab increased the complete renal response and the primary efficacy renal response at 2 years. With voclosporin, complete response was nearly doubled, and there was marked increased in partial response at 1 year, compared with standard therapy alone.

Neither drug appeared to increase the adverse-event rate or the rate of discontinuations, compared with standard therapy, although the FDA did add a black box warning regarding the possible risk for serious infections and malignancies with voclosporin use.

“There is a very large unmet need for the treatment of lupus nephritis,” Chris Phillips, MD, of Paducah (Ky.) Rheumatology said in an interview.

“A very large percentage of patients who do not achieve complete remission on traditional treatments have side effects or contraindications to these treatments, so we’ve needed new ones for sure,” he stressed.

The ICER authors made it clear that there is considerable uncertainty as to how short-term assessment of each of the two drugs’ performance might translate into meaningful long-term outcomes for patients, especially given that SLE is a lifelong illness.

On the other hand, “there are a lot of attributes for both of these new drugs that suggest there is potential for kidney benefit over time,” Brad Rovin, MD, professor of medicine and pathology at the Ohio State University Wexner Medical Center, Columbus, said in an interview.

For example, data from the BLISS-LN study, reported by Dr. Rovin during a meeting last year, suggest that belimumab reduces the flare rate and appears to stabilize kidney function over time, compared with standard therapy alone.

“BLISS-LN was 2 years long, so it gave us an opportunity to look at kidney function over a longer period of time than most of our prior trials in lupus nephritis,” he explained.

“The stabilization of kidney function is important, because it suggests that belimumab has a kidney protective effect, while a decrease in lupus nephritis flares is also important, because each time the disease flares, you can accumulate chronic tissue damage, which can eventually cause end-stage renal disease [ESRD],” he said.

Dr. Rovin also pointed out that the BLISS-LN trial results indicate that patients who achieve a urine protein level less than 700 mg/d after the first year of treatment do very well on long-term follow-up – another hint that belimumab may have long-term benefits for kidney function.

Voclosporin is a calcineurin inhibitor, which are protective of podocytes. “When you start to lose too many podocytes, the kidney can again progress onto ESRD, so this is again an extra benefit of the calcineurin inhibitors in the context of kidney disease that affects the glomeruli,” he noted.

“So both of these drugs have these interesting attributes that go beyond, or at least are maybe tied to, their immunosuppressive actions, but they do offer some kidney protective effects,” he reaffirmed.
 

Black patients underrepresented in trials

The ICER authors voiced concern over the fact that individuals most at risk for SLE – mostly Black patients, but also patients of other racial groups – were underrepresented in clinical trials that evaluated both agents.

“We cannot stress enough that the results are highly uncertain due to the small numbers of Black patients in the available clinical trials and the lack of data on differences among subgroups in long-term outcomes,” they stated.

This is not an academic issue, Dr. Phillips pointed out. Responses to both MMF and cyclophosphamide differ among persons of different races, “so it’s not unreasonable to consider that there could be racial differences in treatment responses to both drugs, and these definitely need to be investigated.”

This is not an academic issue, Dr. Phillips said, because there are racial disparities in how patients respond to both MMF and cyclophosphamide – “so it’s not unreasonable to consider that there could be racial differences in treatment responses to both drugs, and these definitely need to be investigated.”

The ICER authors appear to agree. They urged the manufacturers of the two new agents to expand their research to include adequate representation of lupus nephritis patients from Black and other non-White communities.

However, it is somewhat reassuring that the pivotal voclosporin trial enrolled about 30% of Hispanic patients and that about 17% of participants in the BLISS-LN trial were also Hispanic, Dr. Rovin pointed out.

This is important because Hispanic patients can have very aggressive disease, as can Black patients, he noted. There is some evidence to suggest both drugs are effective in aggressive disease.

The ICER also pointed out that the length of time that both drugs can be used prior to tapering of treatment, after which patients receive standard maintenance therapy alone, has yet to be established.

This is important, Dr. Rovin and Dr. Phillips agreed, because calcineurin inhibitors are known to be nephrotoxic, and both drugs are immunosuppressive. At least with respect to voclosporin, there is some cause of concern regarding prolonged use of the drug for patients with kidney disease.

“We don’t want patients to be on an immunosuppressive drug forever if they don’t need to be,” Dr. Rovin emphasized.

“But we are seeing really long-term remission in the setting of other inflammatory diseases, like vasculitis with rituximab. So there is hope that we can achieve the same thing in lupus. If we use drugs that target T cells in the immune system, like voclosporin, or B cells, like belimumab, maybe we can ‘reset’ the immune system and get rid of potentially autoreactive cells that could allow long-lasting disease remission, which is an unanswered question but an intriguing possibility,” he concluded.

Dr. Rovin has served as a consultant for GlaxoSmithKline. Dr. Phillips disclosed no relevant financial relationships.

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

The prices of two new drugs that have been approved by the Food and Drug Administration for the treatment of lupus nephritis are in “reasonable alignment” with the drugs’ estimated benefits for patients with the disease, the Institute for Clinical and Economic Review has determined.

“Both belimumab [Benlysta] and voclosporin [Lupkynis] are important new treatment options,” Steven Pearson, MD, president of ICER, observed in a summary of the report’s findings.

“Despite remaining uncertainty about both treatments’ longer-term outcomes, their estimated net prices appear to be aligned with their anticipated clinical benefits. ... For patients and clinicians to have responsibly priced options specifically indicated for lupus nephritis is a win for patients and the entire health system,” Dr. Pearson added.

The estimated annual price of belimumab is approximately $43,000 per patient; the estimated annual price for voclosporin is approximately $92,000 per patient.

The incremental cost-effectiveness ratio for belimumab is approximately $90,0000 per quality-adjusted life-year; the corresponding value for voclosporin is higher, at approximately $149,000 per QALY, the ICER authors noted.

The report was published by ICER in April 2021.

Large unmet need for treatment of lupus nephritis

In their report, the ICER reviewed belimumab, a parenteral B-lymphocyte inhibitor, as well as voclosporin, an oral calcineurin inhibitor, as initial treatment of patients with lupus nephritis. Lupus nephritis is a serious complication of systemic lupus erythematosus (SLE).

Belimumab was first approved for the treatment of lupus in adults in the United States in March 2011. In April 2019, it was approved for use for the same indication for children aged 5 years and older. The FDA expanded the indication in December 2020 to include adults with active lupus nephritis who are receiving standard therapy.

Voclosporin was approved for the treatment of lupus nephritis in January 2021.

In the pivotal trials for the two agents, each drug was added to standard induction therapy for lupus nephritis, which consisted of high-dose corticosteroids combined with either mycophenolate mofetil (MMF) or cyclophosphamide.

Compared with standard therapy alone, belimumab increased the complete renal response and the primary efficacy renal response at 2 years. With voclosporin, complete response was nearly doubled, and there was marked increased in partial response at 1 year, compared with standard therapy alone.

Neither drug appeared to increase the adverse-event rate or the rate of discontinuations, compared with standard therapy, although the FDA did add a black box warning regarding the possible risk for serious infections and malignancies with voclosporin use.

“There is a very large unmet need for the treatment of lupus nephritis,” Chris Phillips, MD, of Paducah (Ky.) Rheumatology said in an interview.

“A very large percentage of patients who do not achieve complete remission on traditional treatments have side effects or contraindications to these treatments, so we’ve needed new ones for sure,” he stressed.

The ICER authors made it clear that there is considerable uncertainty as to how short-term assessment of each of the two drugs’ performance might translate into meaningful long-term outcomes for patients, especially given that SLE is a lifelong illness.

On the other hand, “there are a lot of attributes for both of these new drugs that suggest there is potential for kidney benefit over time,” Brad Rovin, MD, professor of medicine and pathology at the Ohio State University Wexner Medical Center, Columbus, said in an interview.

For example, data from the BLISS-LN study, reported by Dr. Rovin during a meeting last year, suggest that belimumab reduces the flare rate and appears to stabilize kidney function over time, compared with standard therapy alone.

“BLISS-LN was 2 years long, so it gave us an opportunity to look at kidney function over a longer period of time than most of our prior trials in lupus nephritis,” he explained.

“The stabilization of kidney function is important, because it suggests that belimumab has a kidney protective effect, while a decrease in lupus nephritis flares is also important, because each time the disease flares, you can accumulate chronic tissue damage, which can eventually cause end-stage renal disease [ESRD],” he said.

Dr. Rovin also pointed out that the BLISS-LN trial results indicate that patients who achieve a urine protein level less than 700 mg/d after the first year of treatment do very well on long-term follow-up – another hint that belimumab may have long-term benefits for kidney function.

Voclosporin is a calcineurin inhibitor, which are protective of podocytes. “When you start to lose too many podocytes, the kidney can again progress onto ESRD, so this is again an extra benefit of the calcineurin inhibitors in the context of kidney disease that affects the glomeruli,” he noted.

“So both of these drugs have these interesting attributes that go beyond, or at least are maybe tied to, their immunosuppressive actions, but they do offer some kidney protective effects,” he reaffirmed.
 

Black patients underrepresented in trials

The ICER authors voiced concern over the fact that individuals most at risk for SLE – mostly Black patients, but also patients of other racial groups – were underrepresented in clinical trials that evaluated both agents.

“We cannot stress enough that the results are highly uncertain due to the small numbers of Black patients in the available clinical trials and the lack of data on differences among subgroups in long-term outcomes,” they stated.

This is not an academic issue, Dr. Phillips pointed out. Responses to both MMF and cyclophosphamide differ among persons of different races, “so it’s not unreasonable to consider that there could be racial differences in treatment responses to both drugs, and these definitely need to be investigated.”

This is not an academic issue, Dr. Phillips said, because there are racial disparities in how patients respond to both MMF and cyclophosphamide – “so it’s not unreasonable to consider that there could be racial differences in treatment responses to both drugs, and these definitely need to be investigated.”

The ICER authors appear to agree. They urged the manufacturers of the two new agents to expand their research to include adequate representation of lupus nephritis patients from Black and other non-White communities.

However, it is somewhat reassuring that the pivotal voclosporin trial enrolled about 30% of Hispanic patients and that about 17% of participants in the BLISS-LN trial were also Hispanic, Dr. Rovin pointed out.

This is important because Hispanic patients can have very aggressive disease, as can Black patients, he noted. There is some evidence to suggest both drugs are effective in aggressive disease.

The ICER also pointed out that the length of time that both drugs can be used prior to tapering of treatment, after which patients receive standard maintenance therapy alone, has yet to be established.

This is important, Dr. Rovin and Dr. Phillips agreed, because calcineurin inhibitors are known to be nephrotoxic, and both drugs are immunosuppressive. At least with respect to voclosporin, there is some cause of concern regarding prolonged use of the drug for patients with kidney disease.

“We don’t want patients to be on an immunosuppressive drug forever if they don’t need to be,” Dr. Rovin emphasized.

“But we are seeing really long-term remission in the setting of other inflammatory diseases, like vasculitis with rituximab. So there is hope that we can achieve the same thing in lupus. If we use drugs that target T cells in the immune system, like voclosporin, or B cells, like belimumab, maybe we can ‘reset’ the immune system and get rid of potentially autoreactive cells that could allow long-lasting disease remission, which is an unanswered question but an intriguing possibility,” he concluded.

Dr. Rovin has served as a consultant for GlaxoSmithKline. Dr. Phillips disclosed no relevant financial relationships.

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

The prices of two new drugs that have been approved by the Food and Drug Administration for the treatment of lupus nephritis are in “reasonable alignment” with the drugs’ estimated benefits for patients with the disease, the Institute for Clinical and Economic Review has determined.

“Both belimumab [Benlysta] and voclosporin [Lupkynis] are important new treatment options,” Steven Pearson, MD, president of ICER, observed in a summary of the report’s findings.

“Despite remaining uncertainty about both treatments’ longer-term outcomes, their estimated net prices appear to be aligned with their anticipated clinical benefits. ... For patients and clinicians to have responsibly priced options specifically indicated for lupus nephritis is a win for patients and the entire health system,” Dr. Pearson added.

The estimated annual price of belimumab is approximately $43,000 per patient; the estimated annual price for voclosporin is approximately $92,000 per patient.

The incremental cost-effectiveness ratio for belimumab is approximately $90,0000 per quality-adjusted life-year; the corresponding value for voclosporin is higher, at approximately $149,000 per QALY, the ICER authors noted.

The report was published by ICER in April 2021.

Large unmet need for treatment of lupus nephritis

In their report, the ICER reviewed belimumab, a parenteral B-lymphocyte inhibitor, as well as voclosporin, an oral calcineurin inhibitor, as initial treatment of patients with lupus nephritis. Lupus nephritis is a serious complication of systemic lupus erythematosus (SLE).

Belimumab was first approved for the treatment of lupus in adults in the United States in March 2011. In April 2019, it was approved for use for the same indication for children aged 5 years and older. The FDA expanded the indication in December 2020 to include adults with active lupus nephritis who are receiving standard therapy.

Voclosporin was approved for the treatment of lupus nephritis in January 2021.

In the pivotal trials for the two agents, each drug was added to standard induction therapy for lupus nephritis, which consisted of high-dose corticosteroids combined with either mycophenolate mofetil (MMF) or cyclophosphamide.

Compared with standard therapy alone, belimumab increased the complete renal response and the primary efficacy renal response at 2 years. With voclosporin, complete response was nearly doubled, and there was marked increased in partial response at 1 year, compared with standard therapy alone.

Neither drug appeared to increase the adverse-event rate or the rate of discontinuations, compared with standard therapy, although the FDA did add a black box warning regarding the possible risk for serious infections and malignancies with voclosporin use.

“There is a very large unmet need for the treatment of lupus nephritis,” Chris Phillips, MD, of Paducah (Ky.) Rheumatology said in an interview.

“A very large percentage of patients who do not achieve complete remission on traditional treatments have side effects or contraindications to these treatments, so we’ve needed new ones for sure,” he stressed.

The ICER authors made it clear that there is considerable uncertainty as to how short-term assessment of each of the two drugs’ performance might translate into meaningful long-term outcomes for patients, especially given that SLE is a lifelong illness.

On the other hand, “there are a lot of attributes for both of these new drugs that suggest there is potential for kidney benefit over time,” Brad Rovin, MD, professor of medicine and pathology at the Ohio State University Wexner Medical Center, Columbus, said in an interview.

For example, data from the BLISS-LN study, reported by Dr. Rovin during a meeting last year, suggest that belimumab reduces the flare rate and appears to stabilize kidney function over time, compared with standard therapy alone.

“BLISS-LN was 2 years long, so it gave us an opportunity to look at kidney function over a longer period of time than most of our prior trials in lupus nephritis,” he explained.

“The stabilization of kidney function is important, because it suggests that belimumab has a kidney protective effect, while a decrease in lupus nephritis flares is also important, because each time the disease flares, you can accumulate chronic tissue damage, which can eventually cause end-stage renal disease [ESRD],” he said.

Dr. Rovin also pointed out that the BLISS-LN trial results indicate that patients who achieve a urine protein level less than 700 mg/d after the first year of treatment do very well on long-term follow-up – another hint that belimumab may have long-term benefits for kidney function.

Voclosporin is a calcineurin inhibitor, which are protective of podocytes. “When you start to lose too many podocytes, the kidney can again progress onto ESRD, so this is again an extra benefit of the calcineurin inhibitors in the context of kidney disease that affects the glomeruli,” he noted.

“So both of these drugs have these interesting attributes that go beyond, or at least are maybe tied to, their immunosuppressive actions, but they do offer some kidney protective effects,” he reaffirmed.
 

Black patients underrepresented in trials

The ICER authors voiced concern over the fact that individuals most at risk for SLE – mostly Black patients, but also patients of other racial groups – were underrepresented in clinical trials that evaluated both agents.

“We cannot stress enough that the results are highly uncertain due to the small numbers of Black patients in the available clinical trials and the lack of data on differences among subgroups in long-term outcomes,” they stated.

This is not an academic issue, Dr. Phillips pointed out. Responses to both MMF and cyclophosphamide differ among persons of different races, “so it’s not unreasonable to consider that there could be racial differences in treatment responses to both drugs, and these definitely need to be investigated.”

This is not an academic issue, Dr. Phillips said, because there are racial disparities in how patients respond to both MMF and cyclophosphamide – “so it’s not unreasonable to consider that there could be racial differences in treatment responses to both drugs, and these definitely need to be investigated.”

The ICER authors appear to agree. They urged the manufacturers of the two new agents to expand their research to include adequate representation of lupus nephritis patients from Black and other non-White communities.

However, it is somewhat reassuring that the pivotal voclosporin trial enrolled about 30% of Hispanic patients and that about 17% of participants in the BLISS-LN trial were also Hispanic, Dr. Rovin pointed out.

This is important because Hispanic patients can have very aggressive disease, as can Black patients, he noted. There is some evidence to suggest both drugs are effective in aggressive disease.

The ICER also pointed out that the length of time that both drugs can be used prior to tapering of treatment, after which patients receive standard maintenance therapy alone, has yet to be established.

This is important, Dr. Rovin and Dr. Phillips agreed, because calcineurin inhibitors are known to be nephrotoxic, and both drugs are immunosuppressive. At least with respect to voclosporin, there is some cause of concern regarding prolonged use of the drug for patients with kidney disease.

“We don’t want patients to be on an immunosuppressive drug forever if they don’t need to be,” Dr. Rovin emphasized.

“But we are seeing really long-term remission in the setting of other inflammatory diseases, like vasculitis with rituximab. So there is hope that we can achieve the same thing in lupus. If we use drugs that target T cells in the immune system, like voclosporin, or B cells, like belimumab, maybe we can ‘reset’ the immune system and get rid of potentially autoreactive cells that could allow long-lasting disease remission, which is an unanswered question but an intriguing possibility,” he concluded.

Dr. Rovin has served as a consultant for GlaxoSmithKline. Dr. Phillips disclosed no relevant financial relationships.

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