Lupus & Connective Tissue Diseases

Targeting cancer screenings based on idiopathic inflammatory myositis (IIM) subtype, autoantibodies, and age may help to maximize cancer detection while limiting false positives.

In a retrospective, single-center study conducted at Johns Hopkins University in Baltimore, researchers found that when screening patients with IIM for cancer via CT imaging, the diagnostic yield (number of cancers detected/tests performed) was highest in patients with dermatomyositis and the autoantibody anti–TIF1-gamma. Screening patients below age 40 years was associated with lower diagnostic yields and higher false positives, regardless of subtype.

Because of the well-known association between IIM and contemporaneous cancer, newly diagnosed patients with IIM often undergo screening. Yet, there is little research on the most efficient assessment approaches, Christopher Mecoli, MD, an assistant professor of medicine at John Hopkins University School of Medicine and lead author of the study, told this news organization. “There has been a lot written about how these patients should be evaluated for cancer. Unfortunately, the majority of literature is based on eminence,” he said. This study is “one of the first pieces of real data to inform that conversation,” he added.

The research was published online in Arthritis Care & Research.

In the study, Dr. Mecoli and colleagues looked at 1,086 patients enrolled in the center’s Myositis Research Registry from 2003 through 2020. The analysis included patients with a diagnosis of dermatomyositis, polymyositis, immune-mediated necrotizing myopathy (IMNM), and antisynthetase syndrome (ASyS). The researchers also looked at myositis-specific autoantibodies, including anti–TIF1-gamma, –Jo1, and –HMGCR. Patients were excluded from the analysis if they had a cancer diagnosis prior to their IIM onset.

Among patients included in the analysis, the average age of IIM onset was 49 years, and median follow-up duration was 5.3 years. Most patients were female (71%), 68% were white, 21% were Black, 3.6% were Asian, and 7.4% had a listed race of other or unknown. About 66% of all patients received a chest CT scan within 3 years of IIM onset, and 51% received an abdomen/pelvis CT in that same time frame. False positives were defined as the percentage of scans that led to a noncancerous biopsy.

During the study period, 62 patients had a cancer diagnosis within the first 3 years of IIM onset, with the most common cancers being breast (19%), melanoma (13%), and cervical/uterine (10%). Of 1,011 chest scans performed, 9 led to a cancer diagnosis (0.9%), compared with 12 of the 657 abdomen/pelvis (a/p) CT scans (1.8%). Patients with the dermatomyositis-specific autoantibody anti–TIF1-gamma had the highest diagnostic yield (2.9% in chest CT and 2.4% in a/p CT). Regardless of autoantibodies, dermatomyositis patients above 40 years of age had a diagnostic yield of 1.4% in chest CT and 2.7% in a/p CT. For patients under the age of 40 with polymyositis, IMNM, and ASyS, the diagnostic yield for all CT scans was 0.0%. The diagnostic yield in patients under 40 with dermatomyositis was also low (0.0% in chest CT, 0.8% in a/p CT).

The false-positive rate for all chest CT scans was 2.8%, with patients with IMNM and ASyS having the highest frequency of false positivity (both 4.4%). “Based on our data, CT chest imaging in ASyS and IMNM patients are associated with the most harm from a cancer screening perspective,” the authors write. In a/p CT, patients with dermatomyositis under 40 and patients with ASyS had the highest false-positive rates (4.9% and 3.8%, respectively).

“Age was a really big deal in terms of predicting diagnostic yield and false-positivity rate,” Dr. Mecoli said, particularly in patients with dermatomyositis. “This subgroup has historically been thought to have the biggest dissociation with cancer,” he said, but in patients under 40, “it doesn’t look like CT scans were that helpful. They were not picking up a lot of cancers, and they were leading to a lot of false-positive results.”

Still, Rohit Aggarwal, MD, of the division of rheumatology and clinical immunology at the University of Pittsburgh, Pennsylvania, noted that the diagnostic yields of 1%-2% and even 2%-4% in higher-risk populations were high. By comparison, lung cancer screening trials had a diagnostic yield of about 1%, and trials examining CT screening for colorectal cancers had diagnostic yields of 0.5%, the authors write.

“The key message for me is that we should definitely perform CT scans of the chest, abdomen, and pelvis within 3 years of diagnosis – typically at presentation – if the patient has any risk factor for increased risk of cancer, which include dermatomyositis and age above 40,” Dr. Aggarwal toldthis news organization. He was not involved with the research. There are also other clinical factors to consider that were not included in the study, he added, such as severe dysphagia, patients with refractory treatment, and male sex.

Both Dr. Aggarwal and Dr. Mecoli agreed that there are limitations to this single-center, retrospective study that make it difficult to generalize the results. Similar studies should be conducted at other institutions to see if these associations hold true, Dr. Mecoli said. A prospective study could also help control for factors such as selection bias, Dr. Aggarwal added. “I don’t think these are definitive data, but I think these data were needed at retrospective levels” to plan future research, he said.

The study was supported in part by grants from the National Institutes of Health, the Jerome L. Greene Foundation, the Donald B. and Dorothy L. Stabler Foundation, the Huayi and Siuling Zhang Discovery Fund, and Dr. Peter Buck. Dr. Mecoli and Dr. Aggarwal have disclosed no relevant financial relationships.

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

Targeting cancer screenings based on idiopathic inflammatory myositis (IIM) subtype, autoantibodies, and age may help to maximize cancer detection while limiting false positives.

In a retrospective, single-center study conducted at Johns Hopkins University in Baltimore, researchers found that when screening patients with IIM for cancer via CT imaging, the diagnostic yield (number of cancers detected/tests performed) was highest in patients with dermatomyositis and the autoantibody anti–TIF1-gamma. Screening patients below age 40 years was associated with lower diagnostic yields and higher false positives, regardless of subtype.

Because of the well-known association between IIM and contemporaneous cancer, newly diagnosed patients with IIM often undergo screening. Yet, there is little research on the most efficient assessment approaches, Christopher Mecoli, MD, an assistant professor of medicine at John Hopkins University School of Medicine and lead author of the study, told this news organization. “There has been a lot written about how these patients should be evaluated for cancer. Unfortunately, the majority of literature is based on eminence,” he said. This study is “one of the first pieces of real data to inform that conversation,” he added.

The research was published online in Arthritis Care & Research.

In the study, Dr. Mecoli and colleagues looked at 1,086 patients enrolled in the center’s Myositis Research Registry from 2003 through 2020. The analysis included patients with a diagnosis of dermatomyositis, polymyositis, immune-mediated necrotizing myopathy (IMNM), and antisynthetase syndrome (ASyS). The researchers also looked at myositis-specific autoantibodies, including anti–TIF1-gamma, –Jo1, and –HMGCR. Patients were excluded from the analysis if they had a cancer diagnosis prior to their IIM onset.

Among patients included in the analysis, the average age of IIM onset was 49 years, and median follow-up duration was 5.3 years. Most patients were female (71%), 68% were white, 21% were Black, 3.6% were Asian, and 7.4% had a listed race of other or unknown. About 66% of all patients received a chest CT scan within 3 years of IIM onset, and 51% received an abdomen/pelvis CT in that same time frame. False positives were defined as the percentage of scans that led to a noncancerous biopsy.

During the study period, 62 patients had a cancer diagnosis within the first 3 years of IIM onset, with the most common cancers being breast (19%), melanoma (13%), and cervical/uterine (10%). Of 1,011 chest scans performed, 9 led to a cancer diagnosis (0.9%), compared with 12 of the 657 abdomen/pelvis (a/p) CT scans (1.8%). Patients with the dermatomyositis-specific autoantibody anti–TIF1-gamma had the highest diagnostic yield (2.9% in chest CT and 2.4% in a/p CT). Regardless of autoantibodies, dermatomyositis patients above 40 years of age had a diagnostic yield of 1.4% in chest CT and 2.7% in a/p CT. For patients under the age of 40 with polymyositis, IMNM, and ASyS, the diagnostic yield for all CT scans was 0.0%. The diagnostic yield in patients under 40 with dermatomyositis was also low (0.0% in chest CT, 0.8% in a/p CT).

The false-positive rate for all chest CT scans was 2.8%, with patients with IMNM and ASyS having the highest frequency of false positivity (both 4.4%). “Based on our data, CT chest imaging in ASyS and IMNM patients are associated with the most harm from a cancer screening perspective,” the authors write. In a/p CT, patients with dermatomyositis under 40 and patients with ASyS had the highest false-positive rates (4.9% and 3.8%, respectively).

“Age was a really big deal in terms of predicting diagnostic yield and false-positivity rate,” Dr. Mecoli said, particularly in patients with dermatomyositis. “This subgroup has historically been thought to have the biggest dissociation with cancer,” he said, but in patients under 40, “it doesn’t look like CT scans were that helpful. They were not picking up a lot of cancers, and they were leading to a lot of false-positive results.”

Still, Rohit Aggarwal, MD, of the division of rheumatology and clinical immunology at the University of Pittsburgh, Pennsylvania, noted that the diagnostic yields of 1%-2% and even 2%-4% in higher-risk populations were high. By comparison, lung cancer screening trials had a diagnostic yield of about 1%, and trials examining CT screening for colorectal cancers had diagnostic yields of 0.5%, the authors write.

“The key message for me is that we should definitely perform CT scans of the chest, abdomen, and pelvis within 3 years of diagnosis – typically at presentation – if the patient has any risk factor for increased risk of cancer, which include dermatomyositis and age above 40,” Dr. Aggarwal toldthis news organization. He was not involved with the research. There are also other clinical factors to consider that were not included in the study, he added, such as severe dysphagia, patients with refractory treatment, and male sex.

Both Dr. Aggarwal and Dr. Mecoli agreed that there are limitations to this single-center, retrospective study that make it difficult to generalize the results. Similar studies should be conducted at other institutions to see if these associations hold true, Dr. Mecoli said. A prospective study could also help control for factors such as selection bias, Dr. Aggarwal added. “I don’t think these are definitive data, but I think these data were needed at retrospective levels” to plan future research, he said.

The study was supported in part by grants from the National Institutes of Health, the Jerome L. Greene Foundation, the Donald B. and Dorothy L. Stabler Foundation, the Huayi and Siuling Zhang Discovery Fund, and Dr. Peter Buck. Dr. Mecoli and Dr. Aggarwal have disclosed no relevant financial relationships.

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

Targeting cancer screenings based on idiopathic inflammatory myositis (IIM) subtype, autoantibodies, and age may help to maximize cancer detection while limiting false positives.

In a retrospective, single-center study conducted at Johns Hopkins University in Baltimore, researchers found that when screening patients with IIM for cancer via CT imaging, the diagnostic yield (number of cancers detected/tests performed) was highest in patients with dermatomyositis and the autoantibody anti–TIF1-gamma. Screening patients below age 40 years was associated with lower diagnostic yields and higher false positives, regardless of subtype.

Because of the well-known association between IIM and contemporaneous cancer, newly diagnosed patients with IIM often undergo screening. Yet, there is little research on the most efficient assessment approaches, Christopher Mecoli, MD, an assistant professor of medicine at John Hopkins University School of Medicine and lead author of the study, told this news organization. “There has been a lot written about how these patients should be evaluated for cancer. Unfortunately, the majority of literature is based on eminence,” he said. This study is “one of the first pieces of real data to inform that conversation,” he added.

The research was published online in Arthritis Care & Research.

In the study, Dr. Mecoli and colleagues looked at 1,086 patients enrolled in the center’s Myositis Research Registry from 2003 through 2020. The analysis included patients with a diagnosis of dermatomyositis, polymyositis, immune-mediated necrotizing myopathy (IMNM), and antisynthetase syndrome (ASyS). The researchers also looked at myositis-specific autoantibodies, including anti–TIF1-gamma, –Jo1, and –HMGCR. Patients were excluded from the analysis if they had a cancer diagnosis prior to their IIM onset.

Among patients included in the analysis, the average age of IIM onset was 49 years, and median follow-up duration was 5.3 years. Most patients were female (71%), 68% were white, 21% were Black, 3.6% were Asian, and 7.4% had a listed race of other or unknown. About 66% of all patients received a chest CT scan within 3 years of IIM onset, and 51% received an abdomen/pelvis CT in that same time frame. False positives were defined as the percentage of scans that led to a noncancerous biopsy.

During the study period, 62 patients had a cancer diagnosis within the first 3 years of IIM onset, with the most common cancers being breast (19%), melanoma (13%), and cervical/uterine (10%). Of 1,011 chest scans performed, 9 led to a cancer diagnosis (0.9%), compared with 12 of the 657 abdomen/pelvis (a/p) CT scans (1.8%). Patients with the dermatomyositis-specific autoantibody anti–TIF1-gamma had the highest diagnostic yield (2.9% in chest CT and 2.4% in a/p CT). Regardless of autoantibodies, dermatomyositis patients above 40 years of age had a diagnostic yield of 1.4% in chest CT and 2.7% in a/p CT. For patients under the age of 40 with polymyositis, IMNM, and ASyS, the diagnostic yield for all CT scans was 0.0%. The diagnostic yield in patients under 40 with dermatomyositis was also low (0.0% in chest CT, 0.8% in a/p CT).

The false-positive rate for all chest CT scans was 2.8%, with patients with IMNM and ASyS having the highest frequency of false positivity (both 4.4%). “Based on our data, CT chest imaging in ASyS and IMNM patients are associated with the most harm from a cancer screening perspective,” the authors write. In a/p CT, patients with dermatomyositis under 40 and patients with ASyS had the highest false-positive rates (4.9% and 3.8%, respectively).

“Age was a really big deal in terms of predicting diagnostic yield and false-positivity rate,” Dr. Mecoli said, particularly in patients with dermatomyositis. “This subgroup has historically been thought to have the biggest dissociation with cancer,” he said, but in patients under 40, “it doesn’t look like CT scans were that helpful. They were not picking up a lot of cancers, and they were leading to a lot of false-positive results.”

Still, Rohit Aggarwal, MD, of the division of rheumatology and clinical immunology at the University of Pittsburgh, Pennsylvania, noted that the diagnostic yields of 1%-2% and even 2%-4% in higher-risk populations were high. By comparison, lung cancer screening trials had a diagnostic yield of about 1%, and trials examining CT screening for colorectal cancers had diagnostic yields of 0.5%, the authors write.

“The key message for me is that we should definitely perform CT scans of the chest, abdomen, and pelvis within 3 years of diagnosis – typically at presentation – if the patient has any risk factor for increased risk of cancer, which include dermatomyositis and age above 40,” Dr. Aggarwal toldthis news organization. He was not involved with the research. There are also other clinical factors to consider that were not included in the study, he added, such as severe dysphagia, patients with refractory treatment, and male sex.

Both Dr. Aggarwal and Dr. Mecoli agreed that there are limitations to this single-center, retrospective study that make it difficult to generalize the results. Similar studies should be conducted at other institutions to see if these associations hold true, Dr. Mecoli said. A prospective study could also help control for factors such as selection bias, Dr. Aggarwal added. “I don’t think these are definitive data, but I think these data were needed at retrospective levels” to plan future research, he said.

The study was supported in part by grants from the National Institutes of Health, the Jerome L. Greene Foundation, the Donald B. and Dorothy L. Stabler Foundation, the Huayi and Siuling Zhang Discovery Fund, and Dr. Peter Buck. Dr. Mecoli and Dr. Aggarwal have disclosed no relevant financial relationships.

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

NEW ORLEANS – A monoclonal antibody targeting interferon-beta (IFN-beta) provided substantial reductions in the skin lesions associated with dermatomyositis in a double-blind, placebo-controlled phase 2 trial, according to results presented as a late-breaker at the annual meeting of the American Academy of Dermatology.

“These findings support the inhibition of IFN-beta as a promising therapeutic strategy in skin-predominant disease,” said principal investigator Aaron Mangold, MD, associate professor of dermatology, Mayo Clinic, Scottsdale, Ariz.

Ted Bosworth/MDedge News

Dermatomyositis, a rare autoimmune inflammatory condition that typically involves both skeletal muscles and skin, is a challenging disease with a diverse set of potential complications.

Immunosuppressive and immunomodulatory agents are used with mixed success for myositis, but skin manifestations, which include papular eruptions, heliotrope rash, photoerythema, burning, and pruritus, are often the most troublesome and the most difficult to control. Treatment options other than immunomodulators that target cutaneous involvement – which include steroids, emollients, and photoprotection – are generally modestly effective, according to Dr. Mangold.
 

Targeting an elevated cytokine

Interest in IFN-beta, which is elevated in the blood of individuals with dermatomyositis, was triggered by evidence that this cytokine plays an important role in driving the skin inflammation, Dr. Mangold explained.

“The blood concentrations of IFN-beta are positively correlated with cutaneous disease activity and severity,” he said.

The study drug, currently known as PF-06823859 (Dazukibart), “is a potent, selective humanized IgG1-neutralizing antibody directed at IFN-beta,” Dr. Mangold said. A dose-ranging phase 1 study published 2 years ago provided evidence of acceptable pharmacokinetics and safety in healthy individuals to support treatment studies for disorders associated with elevated IFN-beta levels. In addition to dermatomyositis, this includes systemic lupus erythematosus.

In this phase 2 trial, patients whose condition was not improved by at least one standard-care therapy for skin manifestations of dermatomyositis were eligible if they had moderate to severe disease as measured with the Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI), according to Dr. Mangold. During the study, patients were allowed to remain on a disease modifying antirheumatic drug and/or prednisone if they had been on stable doses and did not change the dose.

Richard Usatine, MD

After a screening run-in, the trial had two blinded stages. In stage 1, 30 patients were randomly assigned either to 600 mg of PF-06823859 or to placebo, both administered intravenously every 4 weeks. A second cohort of 25 patients was randomly assigned in stage 2 to placebo, 150 mg of PF-06823859, or 600 mg of PF-06823859. The primary endpoint assessed at 12 weeks was a greater than 5-point reduction in CDASI score or greater than 40% CDASI improvement from baseline.

Both endpoints are associated with a clinically meaningful response in regard to an improved quality of life, Dr. Mangold noted.
 

Both doses better than placebo

In results from the stage 1 portion, the mean reduction in CDASI at 12 weeks after three doses of the assigned therapy was 18.8 points in the active-treatment group versus 3.9 points in the placebo group. In pooled data from stage 1 and 2, the reductions were 16.6 points, 19.2 points, and 2.9 points for the 150-mg, 600-mg, and placebo arms, respectively. Both doses achieved a highly significant advantage over placebo.

For both stages and doses, the response curves of the active-treatment groups and the placebo group diverged almost immediately. By 4 weeks, both measures of CDASI reductions on active therapy were significantly improved relative to placebo, and the response curves had a consistent downward slope through the end of the 12-week study, Dr. Mangold reported.

The majority of patients responded by either of the primary endpoint criteria. For a CDASI reduction of greater than 5 points, the response rates were 100% and 96% for the 150-mg and 600-mg doses of PF-06823859, respectively. The placebo response was 35.7%. For the CDASI reduction of greater than 40%, the rates were 80%, 82.1%, and 7.1% for the 150-mg, 600-mg, and placebo arms, respectively.

“There were no major safety concerns. Most of the treatment-emergent adverse events were mild, and adverse events did not have a relationship to dose,” Dr. Mangold said. Notably, there were no cases of herpes zoster, and infections of any kind were low in all study groups.

A phase 3 study is being planned with the 600-mg dose, according to Dr. Mangold, but he acknowledged that regulatory authorities have generally required endpoints for both cutaneous and muscle manifestations in previous trials of therapies for dermatomyositis.

It is not yet certain that “there will be a carve-out for skin,” he said in answer to a question about investigations moving forward. So far, studies have been focused on skin response. However, a meaningful degree of benefit against muscle involvement, which has not yet been well studied, has not been ruled out.

Even though this is a phase 2 trial with small numbers, it was controlled and blinded, and the potential of an inhibitor of IFN-beta to control the skin manifestations of dermatomyositis “is kind of a big deal,” said Paul Nghiem, MD, PhD, professor of dermatology, University of Washington, Seattle.

“There is definitely an unmet need for better therapies to control the skin involvement,” Dr. Nghiem said.

Hensin Tsao, MD, PhD, clinical director of the Melanoma and Pigmented Lesion Center at Massachusetts General Hospital, Boston, agreed. Like Dr. Nghiem, Dr. Tsao was a panelist during the late-breaker session where the study was presented, and he was impressed by the data.

“This is something that is definitely newsworthy,” Dr. Tsao said.

Dr. Mangold reports financial relationships with Actelion, Amgen, Corbus, Eli Lilly, Incyte, miRagen, Novartis, Regeneron, Solagenix, Sun Pharmaceuticals, Teva, and Pfizer, which provided funding for this trial. Both Dr. Nghiem and Dr. Tsao reported no relevant financial relationships.

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

NEW ORLEANS – A monoclonal antibody targeting interferon-beta (IFN-beta) provided substantial reductions in the skin lesions associated with dermatomyositis in a double-blind, placebo-controlled phase 2 trial, according to results presented as a late-breaker at the annual meeting of the American Academy of Dermatology.

“These findings support the inhibition of IFN-beta as a promising therapeutic strategy in skin-predominant disease,” said principal investigator Aaron Mangold, MD, associate professor of dermatology, Mayo Clinic, Scottsdale, Ariz.

Ted Bosworth/MDedge News

Dermatomyositis, a rare autoimmune inflammatory condition that typically involves both skeletal muscles and skin, is a challenging disease with a diverse set of potential complications.

Immunosuppressive and immunomodulatory agents are used with mixed success for myositis, but skin manifestations, which include papular eruptions, heliotrope rash, photoerythema, burning, and pruritus, are often the most troublesome and the most difficult to control. Treatment options other than immunomodulators that target cutaneous involvement – which include steroids, emollients, and photoprotection – are generally modestly effective, according to Dr. Mangold.
 

Targeting an elevated cytokine

Interest in IFN-beta, which is elevated in the blood of individuals with dermatomyositis, was triggered by evidence that this cytokine plays an important role in driving the skin inflammation, Dr. Mangold explained.

“The blood concentrations of IFN-beta are positively correlated with cutaneous disease activity and severity,” he said.

The study drug, currently known as PF-06823859 (Dazukibart), “is a potent, selective humanized IgG1-neutralizing antibody directed at IFN-beta,” Dr. Mangold said. A dose-ranging phase 1 study published 2 years ago provided evidence of acceptable pharmacokinetics and safety in healthy individuals to support treatment studies for disorders associated with elevated IFN-beta levels. In addition to dermatomyositis, this includes systemic lupus erythematosus.

In this phase 2 trial, patients whose condition was not improved by at least one standard-care therapy for skin manifestations of dermatomyositis were eligible if they had moderate to severe disease as measured with the Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI), according to Dr. Mangold. During the study, patients were allowed to remain on a disease modifying antirheumatic drug and/or prednisone if they had been on stable doses and did not change the dose.

Richard Usatine, MD

After a screening run-in, the trial had two blinded stages. In stage 1, 30 patients were randomly assigned either to 600 mg of PF-06823859 or to placebo, both administered intravenously every 4 weeks. A second cohort of 25 patients was randomly assigned in stage 2 to placebo, 150 mg of PF-06823859, or 600 mg of PF-06823859. The primary endpoint assessed at 12 weeks was a greater than 5-point reduction in CDASI score or greater than 40% CDASI improvement from baseline.

Both endpoints are associated with a clinically meaningful response in regard to an improved quality of life, Dr. Mangold noted.
 

Both doses better than placebo

In results from the stage 1 portion, the mean reduction in CDASI at 12 weeks after three doses of the assigned therapy was 18.8 points in the active-treatment group versus 3.9 points in the placebo group. In pooled data from stage 1 and 2, the reductions were 16.6 points, 19.2 points, and 2.9 points for the 150-mg, 600-mg, and placebo arms, respectively. Both doses achieved a highly significant advantage over placebo.

For both stages and doses, the response curves of the active-treatment groups and the placebo group diverged almost immediately. By 4 weeks, both measures of CDASI reductions on active therapy were significantly improved relative to placebo, and the response curves had a consistent downward slope through the end of the 12-week study, Dr. Mangold reported.

The majority of patients responded by either of the primary endpoint criteria. For a CDASI reduction of greater than 5 points, the response rates were 100% and 96% for the 150-mg and 600-mg doses of PF-06823859, respectively. The placebo response was 35.7%. For the CDASI reduction of greater than 40%, the rates were 80%, 82.1%, and 7.1% for the 150-mg, 600-mg, and placebo arms, respectively.

“There were no major safety concerns. Most of the treatment-emergent adverse events were mild, and adverse events did not have a relationship to dose,” Dr. Mangold said. Notably, there were no cases of herpes zoster, and infections of any kind were low in all study groups.

A phase 3 study is being planned with the 600-mg dose, according to Dr. Mangold, but he acknowledged that regulatory authorities have generally required endpoints for both cutaneous and muscle manifestations in previous trials of therapies for dermatomyositis.

It is not yet certain that “there will be a carve-out for skin,” he said in answer to a question about investigations moving forward. So far, studies have been focused on skin response. However, a meaningful degree of benefit against muscle involvement, which has not yet been well studied, has not been ruled out.

Even though this is a phase 2 trial with small numbers, it was controlled and blinded, and the potential of an inhibitor of IFN-beta to control the skin manifestations of dermatomyositis “is kind of a big deal,” said Paul Nghiem, MD, PhD, professor of dermatology, University of Washington, Seattle.

“There is definitely an unmet need for better therapies to control the skin involvement,” Dr. Nghiem said.

Hensin Tsao, MD, PhD, clinical director of the Melanoma and Pigmented Lesion Center at Massachusetts General Hospital, Boston, agreed. Like Dr. Nghiem, Dr. Tsao was a panelist during the late-breaker session where the study was presented, and he was impressed by the data.

“This is something that is definitely newsworthy,” Dr. Tsao said.

Dr. Mangold reports financial relationships with Actelion, Amgen, Corbus, Eli Lilly, Incyte, miRagen, Novartis, Regeneron, Solagenix, Sun Pharmaceuticals, Teva, and Pfizer, which provided funding for this trial. Both Dr. Nghiem and Dr. Tsao reported no relevant financial relationships.

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

NEW ORLEANS – A monoclonal antibody targeting interferon-beta (IFN-beta) provided substantial reductions in the skin lesions associated with dermatomyositis in a double-blind, placebo-controlled phase 2 trial, according to results presented as a late-breaker at the annual meeting of the American Academy of Dermatology.

“These findings support the inhibition of IFN-beta as a promising therapeutic strategy in skin-predominant disease,” said principal investigator Aaron Mangold, MD, associate professor of dermatology, Mayo Clinic, Scottsdale, Ariz.

Ted Bosworth/MDedge News

Dermatomyositis, a rare autoimmune inflammatory condition that typically involves both skeletal muscles and skin, is a challenging disease with a diverse set of potential complications.

Immunosuppressive and immunomodulatory agents are used with mixed success for myositis, but skin manifestations, which include papular eruptions, heliotrope rash, photoerythema, burning, and pruritus, are often the most troublesome and the most difficult to control. Treatment options other than immunomodulators that target cutaneous involvement – which include steroids, emollients, and photoprotection – are generally modestly effective, according to Dr. Mangold.
 

Targeting an elevated cytokine

Interest in IFN-beta, which is elevated in the blood of individuals with dermatomyositis, was triggered by evidence that this cytokine plays an important role in driving the skin inflammation, Dr. Mangold explained.

“The blood concentrations of IFN-beta are positively correlated with cutaneous disease activity and severity,” he said.

The study drug, currently known as PF-06823859 (Dazukibart), “is a potent, selective humanized IgG1-neutralizing antibody directed at IFN-beta,” Dr. Mangold said. A dose-ranging phase 1 study published 2 years ago provided evidence of acceptable pharmacokinetics and safety in healthy individuals to support treatment studies for disorders associated with elevated IFN-beta levels. In addition to dermatomyositis, this includes systemic lupus erythematosus.

In this phase 2 trial, patients whose condition was not improved by at least one standard-care therapy for skin manifestations of dermatomyositis were eligible if they had moderate to severe disease as measured with the Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI), according to Dr. Mangold. During the study, patients were allowed to remain on a disease modifying antirheumatic drug and/or prednisone if they had been on stable doses and did not change the dose.

Richard Usatine, MD

After a screening run-in, the trial had two blinded stages. In stage 1, 30 patients were randomly assigned either to 600 mg of PF-06823859 or to placebo, both administered intravenously every 4 weeks. A second cohort of 25 patients was randomly assigned in stage 2 to placebo, 150 mg of PF-06823859, or 600 mg of PF-06823859. The primary endpoint assessed at 12 weeks was a greater than 5-point reduction in CDASI score or greater than 40% CDASI improvement from baseline.

Both endpoints are associated with a clinically meaningful response in regard to an improved quality of life, Dr. Mangold noted.
 

Both doses better than placebo

In results from the stage 1 portion, the mean reduction in CDASI at 12 weeks after three doses of the assigned therapy was 18.8 points in the active-treatment group versus 3.9 points in the placebo group. In pooled data from stage 1 and 2, the reductions were 16.6 points, 19.2 points, and 2.9 points for the 150-mg, 600-mg, and placebo arms, respectively. Both doses achieved a highly significant advantage over placebo.

For both stages and doses, the response curves of the active-treatment groups and the placebo group diverged almost immediately. By 4 weeks, both measures of CDASI reductions on active therapy were significantly improved relative to placebo, and the response curves had a consistent downward slope through the end of the 12-week study, Dr. Mangold reported.

The majority of patients responded by either of the primary endpoint criteria. For a CDASI reduction of greater than 5 points, the response rates were 100% and 96% for the 150-mg and 600-mg doses of PF-06823859, respectively. The placebo response was 35.7%. For the CDASI reduction of greater than 40%, the rates were 80%, 82.1%, and 7.1% for the 150-mg, 600-mg, and placebo arms, respectively.

“There were no major safety concerns. Most of the treatment-emergent adverse events were mild, and adverse events did not have a relationship to dose,” Dr. Mangold said. Notably, there were no cases of herpes zoster, and infections of any kind were low in all study groups.

A phase 3 study is being planned with the 600-mg dose, according to Dr. Mangold, but he acknowledged that regulatory authorities have generally required endpoints for both cutaneous and muscle manifestations in previous trials of therapies for dermatomyositis.

It is not yet certain that “there will be a carve-out for skin,” he said in answer to a question about investigations moving forward. So far, studies have been focused on skin response. However, a meaningful degree of benefit against muscle involvement, which has not yet been well studied, has not been ruled out.

Even though this is a phase 2 trial with small numbers, it was controlled and blinded, and the potential of an inhibitor of IFN-beta to control the skin manifestations of dermatomyositis “is kind of a big deal,” said Paul Nghiem, MD, PhD, professor of dermatology, University of Washington, Seattle.

“There is definitely an unmet need for better therapies to control the skin involvement,” Dr. Nghiem said.

Hensin Tsao, MD, PhD, clinical director of the Melanoma and Pigmented Lesion Center at Massachusetts General Hospital, Boston, agreed. Like Dr. Nghiem, Dr. Tsao was a panelist during the late-breaker session where the study was presented, and he was impressed by the data.

“This is something that is definitely newsworthy,” Dr. Tsao said.

Dr. Mangold reports financial relationships with Actelion, Amgen, Corbus, Eli Lilly, Incyte, miRagen, Novartis, Regeneron, Solagenix, Sun Pharmaceuticals, Teva, and Pfizer, which provided funding for this trial. Both Dr. Nghiem and Dr. Tsao reported no relevant financial relationships.

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

When the Food and Drug Administration approved avacopan (Tavneos) as an adjunctive treatment for severe, active antineutrophil cytoplasmic autoantibody (ANCA)–associated vasculitis (AAV) in October 2021, the oral complement C5a receptor inhibitor was hailed by its developer, ChemoCentryx, as a “new hope” for patients with the disease.

But avacopan’s novelty as a new drug for the rare diseases granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), coupled with its approval as an adjunctive to standard therapy, including glucocorticoids, rather than strictly as a glucocorticoid-sparing agent as it was tested, has so far led to little reported real-world experience with the drug.

M. Alexander Otto

In the phase 3 ADVOCATE trial, the pivotal trial that served as the basis for avacopan’s approval, 331 patients with active newly diagnosed or relapsing GPA or MPA received either avacopan or an oral prednisone taper over 20 weeks on a background of cyclophosphamide followed by azathioprine or rituximab. The results of the trial showed avacopan was noninferior to the group that received prednisone taper for remission at 26 weeks and superior to prednisone taper for sustained remission at 52 weeks, but the FDA was concerned that its complex design made it difficult to define the clinically meaningful benefit of avacopan and its role in the management of AAV.

The FDA noted that, in the avacopan arm of the trial, 86% of patients received glucocorticoids outside of the study protocol. Despite this, avacopan reduced the cumulative glucocorticoid dose over the trial’s 52 weeks by nearly two-thirds, compared with the prednisone group (1,349 mg vs. 3,655 mg).

The data also indicate a higher sustained remission rate at 52 weeks in patients who received induction with rituximab, compared with cyclophosphamide. But trial did not include a maintenance therapy dose of rituximab and is thereby not a good comparison against the standard of care, the FDA said. (ADVOCATE began enrolling patients prior to the FDA's 2018 approval of an expanded indication for patients with GPA or MPA who have achieved disease control after induction treatment.)

At the FDA’s Arthritis Advisory Committee meeting in May 2021, committee members were split on whether to recommend avacopan for approval. The committee voted 9-9 on whether the ADVOCATE trial showed efficacy supporting approval of avacopan, 10-8 in favor of whether the drug’s safety profile supported approval, and 10-8 in favor of the overall benefit-risk profile of avacopan for approval. But rather than give an indication to avacopan to reduce the use of glucocorticoids in adults with GPA or MPA, the agency approved avacopan as an adjunctive treatment for severe, active disease, noting in particular that avacopan “does not eliminate glucocorticoid use.”

The European Union’s marketing authorization for avacopan states its indication for use in combination with a rituximab or cyclophosphamide regimen for the treatment of adult patients with severe, active GPA or MPA and does not mention a role for reducing glucocorticoids. Avacopan will appear in forthcoming guidelines on management of AAV released by the European Alliance of Associations for Rheumatology.

In North America, the Canadian Vasculitis Research Network recently released an addendum to their guidelines on AAV specifically for avacopan, which includes recommendations to consider adding oral avacopan (30 mg twice daily) for induction of remission in patients with new or relapsing GPA or MPA who are also receiving cyclophosphamide or rituximab. The guidelines also recommend clinicians consider a glucocorticoid tapering schedule that aims for discontinuation at 4 weeks, and continuing avacopan for at least 1 year after induction therapy. The American College of Rheumatology guideline for AAV management, updated in 2021, acknowledges avacopan but did not consider its inclusion prior to FDA approval.

There have been few real-world studies of how patients with AAV are responding to avacopan, but recent studies from researchers in the Netherlands and in France have evaluated prednisone tapering and clinical outcomes.

Anisha B. Dua, MD, an associate professor of rheumatology at Northwestern University, Chicago, said those real-world studies “seemed to re-enforce the findings from the ADVOCATE study demonstrating the efficacy of avacopan in severe disease with steroid-sparing effects.”

However, Carol Langford, MD, MHS, director of the Center for Vasculitis Care and Research at the Cleveland Clinic, emphasized caution is needed when drawing conclusions about avacopan use outside formal studies.

“We are all interested in what other settings this might be used. I think those are things that really require formal investigation to really try and understand better as far as through a study process,” she said.
 

Prescribing experience with avacopan

A spokesperson from Amgen, which recently acquired ChemoCentryx, said in an interview that over 800 physicians in the United States have prescribed avacopan to patients with new or relapsing ANCA-associated vasculitis as induction or maintenance treatment, and physicians have reported outcomes consistent with the ADVOCATE trial.

Many rheumatologists are likely familiar with avacopan but are not used to prescribing it, said Lindsay S. Lally, MD, a rheumatologist with Hospital for Special Surgery in New York.

“Rituximab was approved for GPA and MPA a decade ago at this point. It was a drug that we as rheumatologists were used to using. We used it for other indications. Avacopan is a totally new drug, a new mechanism of action, so there’s not a lot of extractable data that we have in terms of comfort with the drug, and so I think that’s one of the biggest hurdles,” she said.

Mehrnaz Hojjati, MD, a rheumatologist with Loma Linda (Calif.) University Health, said that, when the FDA approved avacopan, it was an “exciting time” in her practice. “I have used avacopan now in a handful of my patients with severe ANCA-associated vasculitis, and the results are similar to what [was] reported in the ADVOCATE trial.”

Amgen offers help for clinicians in obtaining avacopan for patients, financial assistance for patients, and support in navigating insurance, which several rheumatologists noted was important for patients. Dr. Langford said the process of working with the manufacturer to get avacopan while insurance information is being processed has been “fairly smooth.”

“Certainly, the ability to get a very rapid 30-day supply with the goal of trying to initiate this as early as possible in the disease process has been helpful,” she said.

In Dr. Dua’s experience, while there were “some glitches or difficulty for providers early on” in how to access and prescribe avacopan, since then “it has been much easier to obtain the medication with the first month being provided to patients free while the authorization process is managed.”

Prescribing avacopan from inpatient pharmacies has been more challenging, she said. “The inpatient side is trickier because each hospital system has their own pharmacy system and regulations that have to be navigated. For outpatients, all the provider needs to do is fill out the start form available on their website, have the patients sign it, and then have it sent in.”
 

Concerns about affordability, insurance approval

Another consideration is cost, with avacopan having an estimated price of $150,000-$200,000 per patient per year.

Dr. Hojjati noted that, while it is easy to prescribe, avacopan is hard to get approved through insurance. “We face the same challenge every time a new medication comes to the market on how to convince the payers to pay for it given higher prices,” she said.

Rheumatologist Michael Putman, MD, MSCI, assistant professor of medicine at the Medical College of Wisconsin, Milwaukee, also acknowledged some difficulties in prescribing the medication. “The insurance companies have no interest in spending $150,000 on a drug that they know nothing about, and patients are a little hesitant to take it because it’s just so new,” he said.

While Dr. Lally said avacopan has not been difficult to get for patients with commercial insurance, reimbursement through Medicare has been problematic. “In many of the Medicare patients it has not really been a feasible option for them to be on the drug for the year of therapy.”
 

Patient response

Dr. Dua said almost all her patients with new or relapsing AAV who require induction are being prescribed avacopan, and that the medication is well tolerated. “The remission and ability to wean prednisone has really paralleled the findings from the clinical trial.”

In her practice, Dr. Hojjati starts patients on avacopan immediately after discharge from the hospital after a major vasculitis flare requiring high-dose glucocorticoids. “Avacopan does not eliminate/replace GC [glucocorticoid] use but has a notable GC-sparing effect and assists in rapid tapering of the GC while treating our severe ANCA-associated vasculitis patients,” she said.

Dr. Lally said her patients are tolerating avacopan well and hasn’t seen any of the safety signals seen in the trial, including liver function abnormalities. She has treated about 20-25 patients with avacopan.

Dr. Putman noted that he has treated about five patients with avacopan but hasn’t seen dramatic efficacy or side effects in his practice, compared with standard therapy.

Unanswered questions about avacopan

A key unanswered question with avacopan is the timeline for tapering glucocorticoids once patients start treatment. “I would like to see much more data on how prednisone is being tapered in clinical practice as well as outcomes in patients who are treated with the standard of care second dose of rituximab at 6 months,” Dr. Dua said.

Dr. Lally noted she has tried to expedite the steroid taper in her patients. “That’s really where I feel this drug is going to have most relevance, is getting it started early in active disease and getting patients off of the reliance on high doses of oral steroids. I have been able to see that in practice, and I do think ultimately that’s going to lead to better outcomes and quality of life for these patients.”

Of the rheumatologists Dr. Lally has spoken to about avacopan, there is “some confusion about what type of patients are appropriate, [and] how sick or not sick the patient needs to be.”

Dr. Putman noted he is unsure which of his patients should be receiving avacopan. “I don’t totally have a sense for where avacopan stands and how often we should be using it” outside of patients with severe disease. He added that the drug is still trying to find a niche because most patients with AAV who take rituximab and steroids get better without additional treatments.

“I think we do a pretty good job treating these diseases even in the preavacopan era. But it’s really a matter of how to really optimize these outcomes, reduce damage, reduce steroid-related and treatment-related toxicity for our patients,” Dr. Lally said.

Dr. Dua reported being a consultant and serving on advisory boards for ChemoCentryx; she was also a site principal investigator for the ADVOCATE trial. Dr. Hojjati reported being on the speaker’s bureau for Amgen. Dr. Langford reported being an investigator in the ADVOCATE trial, and her institution received funding to conduct the trial. Dr. Lally reported being a consultant for Amgen on avacopan. Dr. Putman reported no relevant financial disclosures.

*This story was updated 3/15/2023.

When the Food and Drug Administration approved avacopan (Tavneos) as an adjunctive treatment for severe, active antineutrophil cytoplasmic autoantibody (ANCA)–associated vasculitis (AAV) in October 2021, the oral complement C5a receptor inhibitor was hailed by its developer, ChemoCentryx, as a “new hope” for patients with the disease.

But avacopan’s novelty as a new drug for the rare diseases granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), coupled with its approval as an adjunctive to standard therapy, including glucocorticoids, rather than strictly as a glucocorticoid-sparing agent as it was tested, has so far led to little reported real-world experience with the drug.

M. Alexander Otto

In the phase 3 ADVOCATE trial, the pivotal trial that served as the basis for avacopan’s approval, 331 patients with active newly diagnosed or relapsing GPA or MPA received either avacopan or an oral prednisone taper over 20 weeks on a background of cyclophosphamide followed by azathioprine or rituximab. The results of the trial showed avacopan was noninferior to the group that received prednisone taper for remission at 26 weeks and superior to prednisone taper for sustained remission at 52 weeks, but the FDA was concerned that its complex design made it difficult to define the clinically meaningful benefit of avacopan and its role in the management of AAV.

The FDA noted that, in the avacopan arm of the trial, 86% of patients received glucocorticoids outside of the study protocol. Despite this, avacopan reduced the cumulative glucocorticoid dose over the trial’s 52 weeks by nearly two-thirds, compared with the prednisone group (1,349 mg vs. 3,655 mg).

The data also indicate a higher sustained remission rate at 52 weeks in patients who received induction with rituximab, compared with cyclophosphamide. But trial did not include a maintenance therapy dose of rituximab and is thereby not a good comparison against the standard of care, the FDA said. (ADVOCATE began enrolling patients prior to the FDA's 2018 approval of an expanded indication for patients with GPA or MPA who have achieved disease control after induction treatment.)

At the FDA’s Arthritis Advisory Committee meeting in May 2021, committee members were split on whether to recommend avacopan for approval. The committee voted 9-9 on whether the ADVOCATE trial showed efficacy supporting approval of avacopan, 10-8 in favor of whether the drug’s safety profile supported approval, and 10-8 in favor of the overall benefit-risk profile of avacopan for approval. But rather than give an indication to avacopan to reduce the use of glucocorticoids in adults with GPA or MPA, the agency approved avacopan as an adjunctive treatment for severe, active disease, noting in particular that avacopan “does not eliminate glucocorticoid use.”

The European Union’s marketing authorization for avacopan states its indication for use in combination with a rituximab or cyclophosphamide regimen for the treatment of adult patients with severe, active GPA or MPA and does not mention a role for reducing glucocorticoids. Avacopan will appear in forthcoming guidelines on management of AAV released by the European Alliance of Associations for Rheumatology.

In North America, the Canadian Vasculitis Research Network recently released an addendum to their guidelines on AAV specifically for avacopan, which includes recommendations to consider adding oral avacopan (30 mg twice daily) for induction of remission in patients with new or relapsing GPA or MPA who are also receiving cyclophosphamide or rituximab. The guidelines also recommend clinicians consider a glucocorticoid tapering schedule that aims for discontinuation at 4 weeks, and continuing avacopan for at least 1 year after induction therapy. The American College of Rheumatology guideline for AAV management, updated in 2021, acknowledges avacopan but did not consider its inclusion prior to FDA approval.

There have been few real-world studies of how patients with AAV are responding to avacopan, but recent studies from researchers in the Netherlands and in France have evaluated prednisone tapering and clinical outcomes.

Anisha B. Dua, MD, an associate professor of rheumatology at Northwestern University, Chicago, said those real-world studies “seemed to re-enforce the findings from the ADVOCATE study demonstrating the efficacy of avacopan in severe disease with steroid-sparing effects.”

However, Carol Langford, MD, MHS, director of the Center for Vasculitis Care and Research at the Cleveland Clinic, emphasized caution is needed when drawing conclusions about avacopan use outside formal studies.

“We are all interested in what other settings this might be used. I think those are things that really require formal investigation to really try and understand better as far as through a study process,” she said.
 

Prescribing experience with avacopan

A spokesperson from Amgen, which recently acquired ChemoCentryx, said in an interview that over 800 physicians in the United States have prescribed avacopan to patients with new or relapsing ANCA-associated vasculitis as induction or maintenance treatment, and physicians have reported outcomes consistent with the ADVOCATE trial.

Many rheumatologists are likely familiar with avacopan but are not used to prescribing it, said Lindsay S. Lally, MD, a rheumatologist with Hospital for Special Surgery in New York.

“Rituximab was approved for GPA and MPA a decade ago at this point. It was a drug that we as rheumatologists were used to using. We used it for other indications. Avacopan is a totally new drug, a new mechanism of action, so there’s not a lot of extractable data that we have in terms of comfort with the drug, and so I think that’s one of the biggest hurdles,” she said.

Mehrnaz Hojjati, MD, a rheumatologist with Loma Linda (Calif.) University Health, said that, when the FDA approved avacopan, it was an “exciting time” in her practice. “I have used avacopan now in a handful of my patients with severe ANCA-associated vasculitis, and the results are similar to what [was] reported in the ADVOCATE trial.”

Amgen offers help for clinicians in obtaining avacopan for patients, financial assistance for patients, and support in navigating insurance, which several rheumatologists noted was important for patients. Dr. Langford said the process of working with the manufacturer to get avacopan while insurance information is being processed has been “fairly smooth.”

“Certainly, the ability to get a very rapid 30-day supply with the goal of trying to initiate this as early as possible in the disease process has been helpful,” she said.

In Dr. Dua’s experience, while there were “some glitches or difficulty for providers early on” in how to access and prescribe avacopan, since then “it has been much easier to obtain the medication with the first month being provided to patients free while the authorization process is managed.”

Prescribing avacopan from inpatient pharmacies has been more challenging, she said. “The inpatient side is trickier because each hospital system has their own pharmacy system and regulations that have to be navigated. For outpatients, all the provider needs to do is fill out the start form available on their website, have the patients sign it, and then have it sent in.”
 

Concerns about affordability, insurance approval

Another consideration is cost, with avacopan having an estimated price of $150,000-$200,000 per patient per year.

Dr. Hojjati noted that, while it is easy to prescribe, avacopan is hard to get approved through insurance. “We face the same challenge every time a new medication comes to the market on how to convince the payers to pay for it given higher prices,” she said.

Rheumatologist Michael Putman, MD, MSCI, assistant professor of medicine at the Medical College of Wisconsin, Milwaukee, also acknowledged some difficulties in prescribing the medication. “The insurance companies have no interest in spending $150,000 on a drug that they know nothing about, and patients are a little hesitant to take it because it’s just so new,” he said.

While Dr. Lally said avacopan has not been difficult to get for patients with commercial insurance, reimbursement through Medicare has been problematic. “In many of the Medicare patients it has not really been a feasible option for them to be on the drug for the year of therapy.”
 

Patient response

Dr. Dua said almost all her patients with new or relapsing AAV who require induction are being prescribed avacopan, and that the medication is well tolerated. “The remission and ability to wean prednisone has really paralleled the findings from the clinical trial.”

In her practice, Dr. Hojjati starts patients on avacopan immediately after discharge from the hospital after a major vasculitis flare requiring high-dose glucocorticoids. “Avacopan does not eliminate/replace GC [glucocorticoid] use but has a notable GC-sparing effect and assists in rapid tapering of the GC while treating our severe ANCA-associated vasculitis patients,” she said.

Dr. Lally said her patients are tolerating avacopan well and hasn’t seen any of the safety signals seen in the trial, including liver function abnormalities. She has treated about 20-25 patients with avacopan.

Dr. Putman noted that he has treated about five patients with avacopan but hasn’t seen dramatic efficacy or side effects in his practice, compared with standard therapy.

Unanswered questions about avacopan

A key unanswered question with avacopan is the timeline for tapering glucocorticoids once patients start treatment. “I would like to see much more data on how prednisone is being tapered in clinical practice as well as outcomes in patients who are treated with the standard of care second dose of rituximab at 6 months,” Dr. Dua said.

Dr. Lally noted she has tried to expedite the steroid taper in her patients. “That’s really where I feel this drug is going to have most relevance, is getting it started early in active disease and getting patients off of the reliance on high doses of oral steroids. I have been able to see that in practice, and I do think ultimately that’s going to lead to better outcomes and quality of life for these patients.”

Of the rheumatologists Dr. Lally has spoken to about avacopan, there is “some confusion about what type of patients are appropriate, [and] how sick or not sick the patient needs to be.”

Dr. Putman noted he is unsure which of his patients should be receiving avacopan. “I don’t totally have a sense for where avacopan stands and how often we should be using it” outside of patients with severe disease. He added that the drug is still trying to find a niche because most patients with AAV who take rituximab and steroids get better without additional treatments.

“I think we do a pretty good job treating these diseases even in the preavacopan era. But it’s really a matter of how to really optimize these outcomes, reduce damage, reduce steroid-related and treatment-related toxicity for our patients,” Dr. Lally said.

Dr. Dua reported being a consultant and serving on advisory boards for ChemoCentryx; she was also a site principal investigator for the ADVOCATE trial. Dr. Hojjati reported being on the speaker’s bureau for Amgen. Dr. Langford reported being an investigator in the ADVOCATE trial, and her institution received funding to conduct the trial. Dr. Lally reported being a consultant for Amgen on avacopan. Dr. Putman reported no relevant financial disclosures.

*This story was updated 3/15/2023.

When the Food and Drug Administration approved avacopan (Tavneos) as an adjunctive treatment for severe, active antineutrophil cytoplasmic autoantibody (ANCA)–associated vasculitis (AAV) in October 2021, the oral complement C5a receptor inhibitor was hailed by its developer, ChemoCentryx, as a “new hope” for patients with the disease.

But avacopan’s novelty as a new drug for the rare diseases granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), coupled with its approval as an adjunctive to standard therapy, including glucocorticoids, rather than strictly as a glucocorticoid-sparing agent as it was tested, has so far led to little reported real-world experience with the drug.

M. Alexander Otto

In the phase 3 ADVOCATE trial, the pivotal trial that served as the basis for avacopan’s approval, 331 patients with active newly diagnosed or relapsing GPA or MPA received either avacopan or an oral prednisone taper over 20 weeks on a background of cyclophosphamide followed by azathioprine or rituximab. The results of the trial showed avacopan was noninferior to the group that received prednisone taper for remission at 26 weeks and superior to prednisone taper for sustained remission at 52 weeks, but the FDA was concerned that its complex design made it difficult to define the clinically meaningful benefit of avacopan and its role in the management of AAV.

The FDA noted that, in the avacopan arm of the trial, 86% of patients received glucocorticoids outside of the study protocol. Despite this, avacopan reduced the cumulative glucocorticoid dose over the trial’s 52 weeks by nearly two-thirds, compared with the prednisone group (1,349 mg vs. 3,655 mg).

The data also indicate a higher sustained remission rate at 52 weeks in patients who received induction with rituximab, compared with cyclophosphamide. But trial did not include a maintenance therapy dose of rituximab and is thereby not a good comparison against the standard of care, the FDA said. (ADVOCATE began enrolling patients prior to the FDA's 2018 approval of an expanded indication for patients with GPA or MPA who have achieved disease control after induction treatment.)

At the FDA’s Arthritis Advisory Committee meeting in May 2021, committee members were split on whether to recommend avacopan for approval. The committee voted 9-9 on whether the ADVOCATE trial showed efficacy supporting approval of avacopan, 10-8 in favor of whether the drug’s safety profile supported approval, and 10-8 in favor of the overall benefit-risk profile of avacopan for approval. But rather than give an indication to avacopan to reduce the use of glucocorticoids in adults with GPA or MPA, the agency approved avacopan as an adjunctive treatment for severe, active disease, noting in particular that avacopan “does not eliminate glucocorticoid use.”

The European Union’s marketing authorization for avacopan states its indication for use in combination with a rituximab or cyclophosphamide regimen for the treatment of adult patients with severe, active GPA or MPA and does not mention a role for reducing glucocorticoids. Avacopan will appear in forthcoming guidelines on management of AAV released by the European Alliance of Associations for Rheumatology.

In North America, the Canadian Vasculitis Research Network recently released an addendum to their guidelines on AAV specifically for avacopan, which includes recommendations to consider adding oral avacopan (30 mg twice daily) for induction of remission in patients with new or relapsing GPA or MPA who are also receiving cyclophosphamide or rituximab. The guidelines also recommend clinicians consider a glucocorticoid tapering schedule that aims for discontinuation at 4 weeks, and continuing avacopan for at least 1 year after induction therapy. The American College of Rheumatology guideline for AAV management, updated in 2021, acknowledges avacopan but did not consider its inclusion prior to FDA approval.

There have been few real-world studies of how patients with AAV are responding to avacopan, but recent studies from researchers in the Netherlands and in France have evaluated prednisone tapering and clinical outcomes.

Anisha B. Dua, MD, an associate professor of rheumatology at Northwestern University, Chicago, said those real-world studies “seemed to re-enforce the findings from the ADVOCATE study demonstrating the efficacy of avacopan in severe disease with steroid-sparing effects.”

However, Carol Langford, MD, MHS, director of the Center for Vasculitis Care and Research at the Cleveland Clinic, emphasized caution is needed when drawing conclusions about avacopan use outside formal studies.

“We are all interested in what other settings this might be used. I think those are things that really require formal investigation to really try and understand better as far as through a study process,” she said.
 

Prescribing experience with avacopan

A spokesperson from Amgen, which recently acquired ChemoCentryx, said in an interview that over 800 physicians in the United States have prescribed avacopan to patients with new or relapsing ANCA-associated vasculitis as induction or maintenance treatment, and physicians have reported outcomes consistent with the ADVOCATE trial.

Many rheumatologists are likely familiar with avacopan but are not used to prescribing it, said Lindsay S. Lally, MD, a rheumatologist with Hospital for Special Surgery in New York.

“Rituximab was approved for GPA and MPA a decade ago at this point. It was a drug that we as rheumatologists were used to using. We used it for other indications. Avacopan is a totally new drug, a new mechanism of action, so there’s not a lot of extractable data that we have in terms of comfort with the drug, and so I think that’s one of the biggest hurdles,” she said.

Mehrnaz Hojjati, MD, a rheumatologist with Loma Linda (Calif.) University Health, said that, when the FDA approved avacopan, it was an “exciting time” in her practice. “I have used avacopan now in a handful of my patients with severe ANCA-associated vasculitis, and the results are similar to what [was] reported in the ADVOCATE trial.”

Amgen offers help for clinicians in obtaining avacopan for patients, financial assistance for patients, and support in navigating insurance, which several rheumatologists noted was important for patients. Dr. Langford said the process of working with the manufacturer to get avacopan while insurance information is being processed has been “fairly smooth.”

“Certainly, the ability to get a very rapid 30-day supply with the goal of trying to initiate this as early as possible in the disease process has been helpful,” she said.

In Dr. Dua’s experience, while there were “some glitches or difficulty for providers early on” in how to access and prescribe avacopan, since then “it has been much easier to obtain the medication with the first month being provided to patients free while the authorization process is managed.”

Prescribing avacopan from inpatient pharmacies has been more challenging, she said. “The inpatient side is trickier because each hospital system has their own pharmacy system and regulations that have to be navigated. For outpatients, all the provider needs to do is fill out the start form available on their website, have the patients sign it, and then have it sent in.”
 

Concerns about affordability, insurance approval

Another consideration is cost, with avacopan having an estimated price of $150,000-$200,000 per patient per year.

Dr. Hojjati noted that, while it is easy to prescribe, avacopan is hard to get approved through insurance. “We face the same challenge every time a new medication comes to the market on how to convince the payers to pay for it given higher prices,” she said.

Rheumatologist Michael Putman, MD, MSCI, assistant professor of medicine at the Medical College of Wisconsin, Milwaukee, also acknowledged some difficulties in prescribing the medication. “The insurance companies have no interest in spending $150,000 on a drug that they know nothing about, and patients are a little hesitant to take it because it’s just so new,” he said.

While Dr. Lally said avacopan has not been difficult to get for patients with commercial insurance, reimbursement through Medicare has been problematic. “In many of the Medicare patients it has not really been a feasible option for them to be on the drug for the year of therapy.”
 

Patient response

Dr. Dua said almost all her patients with new or relapsing AAV who require induction are being prescribed avacopan, and that the medication is well tolerated. “The remission and ability to wean prednisone has really paralleled the findings from the clinical trial.”

In her practice, Dr. Hojjati starts patients on avacopan immediately after discharge from the hospital after a major vasculitis flare requiring high-dose glucocorticoids. “Avacopan does not eliminate/replace GC [glucocorticoid] use but has a notable GC-sparing effect and assists in rapid tapering of the GC while treating our severe ANCA-associated vasculitis patients,” she said.

Dr. Lally said her patients are tolerating avacopan well and hasn’t seen any of the safety signals seen in the trial, including liver function abnormalities. She has treated about 20-25 patients with avacopan.

Dr. Putman noted that he has treated about five patients with avacopan but hasn’t seen dramatic efficacy or side effects in his practice, compared with standard therapy.

Unanswered questions about avacopan

A key unanswered question with avacopan is the timeline for tapering glucocorticoids once patients start treatment. “I would like to see much more data on how prednisone is being tapered in clinical practice as well as outcomes in patients who are treated with the standard of care second dose of rituximab at 6 months,” Dr. Dua said.

Dr. Lally noted she has tried to expedite the steroid taper in her patients. “That’s really where I feel this drug is going to have most relevance, is getting it started early in active disease and getting patients off of the reliance on high doses of oral steroids. I have been able to see that in practice, and I do think ultimately that’s going to lead to better outcomes and quality of life for these patients.”

Of the rheumatologists Dr. Lally has spoken to about avacopan, there is “some confusion about what type of patients are appropriate, [and] how sick or not sick the patient needs to be.”

Dr. Putman noted he is unsure which of his patients should be receiving avacopan. “I don’t totally have a sense for where avacopan stands and how often we should be using it” outside of patients with severe disease. He added that the drug is still trying to find a niche because most patients with AAV who take rituximab and steroids get better without additional treatments.

“I think we do a pretty good job treating these diseases even in the preavacopan era. But it’s really a matter of how to really optimize these outcomes, reduce damage, reduce steroid-related and treatment-related toxicity for our patients,” Dr. Lally said.

Dr. Dua reported being a consultant and serving on advisory boards for ChemoCentryx; she was also a site principal investigator for the ADVOCATE trial. Dr. Hojjati reported being on the speaker’s bureau for Amgen. Dr. Langford reported being an investigator in the ADVOCATE trial, and her institution received funding to conduct the trial. Dr. Lally reported being a consultant for Amgen on avacopan. Dr. Putman reported no relevant financial disclosures.

*This story was updated 3/15/2023.

NEW ORLEANS – An investigational, first-in class agent that delivers a completely new type of intervention to patients with pulmonary arterial hypertension (PAH) scored a clear win in the STELLAR trial, the first to complete among three phase 3 trials that are testing this agent.

Sotatercept, administered subcutaneously every 3 weeks for 24 weeks, improved from baseline average 6-minute walk distance (6MWD) by a significant and clinically meaningful 40.8 meters, compared with placebo, for the trial’s primary efficacy endpoint (P < .001). The treatment also “delivered broad clinical benefit across multiple domains including hemodynamics, World Health Organization functional class, disease biomarkers, risk scores and patient-reported outcomes,” Marius M. Hoeper, MD, said at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.

Mitchel L. Zoler/MDedge News

“These results establish the clinical utility of sotatercept, administered in combination with approved PAH therapies, as a new treatment for PAH,” added Dr. Hoeper, professor and deputy director of the department of respiratory medicine at Hannover (Germany) Medical School,

“The most important aspect was the hemodynamic improvement,” with sotatercept treatment, which led to an average 235 dyn/sec per cm⁻⁵ reduction in pulmonary vascular resistance from baseline and an average cut in pulmonary artery pressure of 13.9 mm Hg from baseline, compared with placebo, a result that’s “unheard of,” Dr. Hoeper said in a press conference during the meeting.

“With other tested agents we usually see very little improvement in pulmonary artery pressure. This is a signal that we achieved some reversing of the pathological changes in the pulmonary vessels that lead to” PAH, he added.

Simultaneously with his report the findings also appeared online in the New England Journal of Medicine.
 

‘A new hope’ for patients with PAH

Based on the reported findings, sotatercept is a “very exciting boutique molecule” that will “offer patients with PAH a very exciting new treatment,” commented Rhonda Cooper-DeHoff, PharmD, a designated discussant and a researcher at the University of Florida, Gainesville.

Mitchel L. Zoler/MDedge News

“This study is a new hope for patients with PAH. Until now, they’ve had really bad outcomes, but [in this study] we see significant differences in 6MWD, hemodynamics, and risk factors. Overall, I think the benefit is greater than the risk” it may pose to patients through potential adverse effects, commented Julia Grapsa, MD, PhD, a cardiologist at St. Thomas Hospital in London, and another discussant at the meeting.

“The results are impressive” and “encouraging,” and “suggest that sotatercept may represent a new and clinically consequential addition to current medications for PAH,” wrote three clinicians from Canyons Region Intermountain Medical Center in Murray, Utah, in an editorial that accompanied the published report.

But the authors of the editorial also raised several cautions and concerns. They questioned the generalizability of the findings, noting that the patients with PAH enrolled in the study were all adults who were clinically stable and an average of more than 8 years out from their initial PAH diagnosis, and more than 90% were on stable treatment for PAH with two or three agents specific for treating the disorder. The study cohort also had a disproportionately high enrollment of patients with idiopathic (59%) or heritable (18%) forms of PAH, and the 15% of patients in the trial with connective tissue disease represented a disproportionately low prevalence of this PAH subtype.

The editorialists also called for “ongoing vigilance” for adverse effects from sotatercept treatment, although they acknowledged that the adverse effects reported to date from sotatercept are “largely reassuring.”
 

Death or clinical worsening cut by 84%

STELLAR randomized 323 patients at 91 sites in 21 countries with WHO Group 1 PAH and with WHO functional class II or III disease to receive either sotatercept or placebo for 24 weeks, with an option for treatment to continue beyond that until the last patient in the study reached 24 weeks on treatment, resulting in an overall median treatment duration of nearly 33 weeks.

In addition to the significant result for the primary endpoint, the 163 patients who received sotatercept had significant improvements, compared with 160 placebo-treated patients, for eight of nine secondary endpoints. The only secondary endpoint with a neutral result was for a measure of cognitive and emotional wellbeing, a parameter that was already at a normal level at baseline in most enrolled patients, Dr. Hoeper explained.

The incidence of either death or an event indicative of clinical worsening during the overall median follow-up of almost 33 weeks was 26.3% among the control patients and 5.5% among those who received sotatercept. This translated into a significant reduction for this endpoint of 84% with sotatercept treatment, compared with placebo.

The rates of treatment-emergent adverse events leading to discontinuation were roughly the same in the control and sotatercept arms, and the incidence of severe or serious treatment-emergent adverse events was higher among the control patients.

The most common adverse event on sotatercept was bleeding events, which occurred in 32% of those on sotatercept and in 16% of the control patients, but the events in the sotatercept arm were “mostly mild,” said Dr. Hoeper. The next most frequent adverse event during sotatercept treatment was appearance of telangiectasias, which occurred in 14% of those on sotatercept and in 4% of control patients.

“It’s an uncommon adverse event profile, but not unexpected for a drug with its mechanism of action,” he said.

Drug binds activin, a pathologic driver of PAH

Sotatercept is an engineered molecule that combines a section of a human immunoglobulin G molecule with a portion of the receptor for activin. This structure allows sotatercept to bind free activin molecules in a patient’s blood, thereby removing a key driver of the pulmonary vascular wall remodeling that is at the pathologic root of PAH.

“Hyperproliferation of blood vessel–wall cells” caused by activin signaling “is perhaps the most important driver of PAH,” Dr. Hoeper said. “Sotatercept allows us for the first time to target the underlying mechanism behind PAH.”

Still ongoing are the HYPERION and ZENITH phase 3 trials of sotatercept. HYPERION is enrolling patients with newly diagnosed or high-risk PAH and is expected to complete in 2028. ZENITH is enrolling patients with more advanced PAH and a higher mortality risk, with results expected in 2026.

Sotatercept has received “Breakthrough Therapy” designation and “Orphan Drug” designation by the Food and Drug Administration, and “Priority Medicines” designation and “Orphan Drug” designation by the European Medicines Agency for the treatment of PAH. One recent review estimated a worldwide PAH prevalence of about 3-4 cases/100,000, which for the United States translates into a total prevalence of perhaps 10,000-15,000 affected people.

STELLAR was funded by Acceleron Pharma, a subsidiary of Merck. Dr. Hoeper is a consultant to Acceleron. Dr. Cooper-DeHoff, Dr. Grapsa, and the authors of the editorial on STELLAR have no relevant disclosures.

NEW ORLEANS – An investigational, first-in class agent that delivers a completely new type of intervention to patients with pulmonary arterial hypertension (PAH) scored a clear win in the STELLAR trial, the first to complete among three phase 3 trials that are testing this agent.

Sotatercept, administered subcutaneously every 3 weeks for 24 weeks, improved from baseline average 6-minute walk distance (6MWD) by a significant and clinically meaningful 40.8 meters, compared with placebo, for the trial’s primary efficacy endpoint (P < .001). The treatment also “delivered broad clinical benefit across multiple domains including hemodynamics, World Health Organization functional class, disease biomarkers, risk scores and patient-reported outcomes,” Marius M. Hoeper, MD, said at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.

Mitchel L. Zoler/MDedge News

“These results establish the clinical utility of sotatercept, administered in combination with approved PAH therapies, as a new treatment for PAH,” added Dr. Hoeper, professor and deputy director of the department of respiratory medicine at Hannover (Germany) Medical School,

“The most important aspect was the hemodynamic improvement,” with sotatercept treatment, which led to an average 235 dyn/sec per cm⁻⁵ reduction in pulmonary vascular resistance from baseline and an average cut in pulmonary artery pressure of 13.9 mm Hg from baseline, compared with placebo, a result that’s “unheard of,” Dr. Hoeper said in a press conference during the meeting.

“With other tested agents we usually see very little improvement in pulmonary artery pressure. This is a signal that we achieved some reversing of the pathological changes in the pulmonary vessels that lead to” PAH, he added.

Simultaneously with his report the findings also appeared online in the New England Journal of Medicine.
 

‘A new hope’ for patients with PAH

Based on the reported findings, sotatercept is a “very exciting boutique molecule” that will “offer patients with PAH a very exciting new treatment,” commented Rhonda Cooper-DeHoff, PharmD, a designated discussant and a researcher at the University of Florida, Gainesville.

Mitchel L. Zoler/MDedge News

“This study is a new hope for patients with PAH. Until now, they’ve had really bad outcomes, but [in this study] we see significant differences in 6MWD, hemodynamics, and risk factors. Overall, I think the benefit is greater than the risk” it may pose to patients through potential adverse effects, commented Julia Grapsa, MD, PhD, a cardiologist at St. Thomas Hospital in London, and another discussant at the meeting.

“The results are impressive” and “encouraging,” and “suggest that sotatercept may represent a new and clinically consequential addition to current medications for PAH,” wrote three clinicians from Canyons Region Intermountain Medical Center in Murray, Utah, in an editorial that accompanied the published report.

But the authors of the editorial also raised several cautions and concerns. They questioned the generalizability of the findings, noting that the patients with PAH enrolled in the study were all adults who were clinically stable and an average of more than 8 years out from their initial PAH diagnosis, and more than 90% were on stable treatment for PAH with two or three agents specific for treating the disorder. The study cohort also had a disproportionately high enrollment of patients with idiopathic (59%) or heritable (18%) forms of PAH, and the 15% of patients in the trial with connective tissue disease represented a disproportionately low prevalence of this PAH subtype.

The editorialists also called for “ongoing vigilance” for adverse effects from sotatercept treatment, although they acknowledged that the adverse effects reported to date from sotatercept are “largely reassuring.”
 

Death or clinical worsening cut by 84%

STELLAR randomized 323 patients at 91 sites in 21 countries with WHO Group 1 PAH and with WHO functional class II or III disease to receive either sotatercept or placebo for 24 weeks, with an option for treatment to continue beyond that until the last patient in the study reached 24 weeks on treatment, resulting in an overall median treatment duration of nearly 33 weeks.

In addition to the significant result for the primary endpoint, the 163 patients who received sotatercept had significant improvements, compared with 160 placebo-treated patients, for eight of nine secondary endpoints. The only secondary endpoint with a neutral result was for a measure of cognitive and emotional wellbeing, a parameter that was already at a normal level at baseline in most enrolled patients, Dr. Hoeper explained.

The incidence of either death or an event indicative of clinical worsening during the overall median follow-up of almost 33 weeks was 26.3% among the control patients and 5.5% among those who received sotatercept. This translated into a significant reduction for this endpoint of 84% with sotatercept treatment, compared with placebo.

The rates of treatment-emergent adverse events leading to discontinuation were roughly the same in the control and sotatercept arms, and the incidence of severe or serious treatment-emergent adverse events was higher among the control patients.

The most common adverse event on sotatercept was bleeding events, which occurred in 32% of those on sotatercept and in 16% of the control patients, but the events in the sotatercept arm were “mostly mild,” said Dr. Hoeper. The next most frequent adverse event during sotatercept treatment was appearance of telangiectasias, which occurred in 14% of those on sotatercept and in 4% of control patients.

“It’s an uncommon adverse event profile, but not unexpected for a drug with its mechanism of action,” he said.

Drug binds activin, a pathologic driver of PAH

Sotatercept is an engineered molecule that combines a section of a human immunoglobulin G molecule with a portion of the receptor for activin. This structure allows sotatercept to bind free activin molecules in a patient’s blood, thereby removing a key driver of the pulmonary vascular wall remodeling that is at the pathologic root of PAH.

“Hyperproliferation of blood vessel–wall cells” caused by activin signaling “is perhaps the most important driver of PAH,” Dr. Hoeper said. “Sotatercept allows us for the first time to target the underlying mechanism behind PAH.”

Still ongoing are the HYPERION and ZENITH phase 3 trials of sotatercept. HYPERION is enrolling patients with newly diagnosed or high-risk PAH and is expected to complete in 2028. ZENITH is enrolling patients with more advanced PAH and a higher mortality risk, with results expected in 2026.

Sotatercept has received “Breakthrough Therapy” designation and “Orphan Drug” designation by the Food and Drug Administration, and “Priority Medicines” designation and “Orphan Drug” designation by the European Medicines Agency for the treatment of PAH. One recent review estimated a worldwide PAH prevalence of about 3-4 cases/100,000, which for the United States translates into a total prevalence of perhaps 10,000-15,000 affected people.

STELLAR was funded by Acceleron Pharma, a subsidiary of Merck. Dr. Hoeper is a consultant to Acceleron. Dr. Cooper-DeHoff, Dr. Grapsa, and the authors of the editorial on STELLAR have no relevant disclosures.

NEW ORLEANS – An investigational, first-in class agent that delivers a completely new type of intervention to patients with pulmonary arterial hypertension (PAH) scored a clear win in the STELLAR trial, the first to complete among three phase 3 trials that are testing this agent.

Sotatercept, administered subcutaneously every 3 weeks for 24 weeks, improved from baseline average 6-minute walk distance (6MWD) by a significant and clinically meaningful 40.8 meters, compared with placebo, for the trial’s primary efficacy endpoint (P < .001). The treatment also “delivered broad clinical benefit across multiple domains including hemodynamics, World Health Organization functional class, disease biomarkers, risk scores and patient-reported outcomes,” Marius M. Hoeper, MD, said at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.

Mitchel L. Zoler/MDedge News

“These results establish the clinical utility of sotatercept, administered in combination with approved PAH therapies, as a new treatment for PAH,” added Dr. Hoeper, professor and deputy director of the department of respiratory medicine at Hannover (Germany) Medical School,

“The most important aspect was the hemodynamic improvement,” with sotatercept treatment, which led to an average 235 dyn/sec per cm⁻⁵ reduction in pulmonary vascular resistance from baseline and an average cut in pulmonary artery pressure of 13.9 mm Hg from baseline, compared with placebo, a result that’s “unheard of,” Dr. Hoeper said in a press conference during the meeting.

“With other tested agents we usually see very little improvement in pulmonary artery pressure. This is a signal that we achieved some reversing of the pathological changes in the pulmonary vessels that lead to” PAH, he added.

Simultaneously with his report the findings also appeared online in the New England Journal of Medicine.
 

‘A new hope’ for patients with PAH

Based on the reported findings, sotatercept is a “very exciting boutique molecule” that will “offer patients with PAH a very exciting new treatment,” commented Rhonda Cooper-DeHoff, PharmD, a designated discussant and a researcher at the University of Florida, Gainesville.

Mitchel L. Zoler/MDedge News

“This study is a new hope for patients with PAH. Until now, they’ve had really bad outcomes, but [in this study] we see significant differences in 6MWD, hemodynamics, and risk factors. Overall, I think the benefit is greater than the risk” it may pose to patients through potential adverse effects, commented Julia Grapsa, MD, PhD, a cardiologist at St. Thomas Hospital in London, and another discussant at the meeting.

“The results are impressive” and “encouraging,” and “suggest that sotatercept may represent a new and clinically consequential addition to current medications for PAH,” wrote three clinicians from Canyons Region Intermountain Medical Center in Murray, Utah, in an editorial that accompanied the published report.

But the authors of the editorial also raised several cautions and concerns. They questioned the generalizability of the findings, noting that the patients with PAH enrolled in the study were all adults who were clinically stable and an average of more than 8 years out from their initial PAH diagnosis, and more than 90% were on stable treatment for PAH with two or three agents specific for treating the disorder. The study cohort also had a disproportionately high enrollment of patients with idiopathic (59%) or heritable (18%) forms of PAH, and the 15% of patients in the trial with connective tissue disease represented a disproportionately low prevalence of this PAH subtype.

The editorialists also called for “ongoing vigilance” for adverse effects from sotatercept treatment, although they acknowledged that the adverse effects reported to date from sotatercept are “largely reassuring.”
 

Death or clinical worsening cut by 84%

STELLAR randomized 323 patients at 91 sites in 21 countries with WHO Group 1 PAH and with WHO functional class II or III disease to receive either sotatercept or placebo for 24 weeks, with an option for treatment to continue beyond that until the last patient in the study reached 24 weeks on treatment, resulting in an overall median treatment duration of nearly 33 weeks.

In addition to the significant result for the primary endpoint, the 163 patients who received sotatercept had significant improvements, compared with 160 placebo-treated patients, for eight of nine secondary endpoints. The only secondary endpoint with a neutral result was for a measure of cognitive and emotional wellbeing, a parameter that was already at a normal level at baseline in most enrolled patients, Dr. Hoeper explained.

The incidence of either death or an event indicative of clinical worsening during the overall median follow-up of almost 33 weeks was 26.3% among the control patients and 5.5% among those who received sotatercept. This translated into a significant reduction for this endpoint of 84% with sotatercept treatment, compared with placebo.

The rates of treatment-emergent adverse events leading to discontinuation were roughly the same in the control and sotatercept arms, and the incidence of severe or serious treatment-emergent adverse events was higher among the control patients.

The most common adverse event on sotatercept was bleeding events, which occurred in 32% of those on sotatercept and in 16% of the control patients, but the events in the sotatercept arm were “mostly mild,” said Dr. Hoeper. The next most frequent adverse event during sotatercept treatment was appearance of telangiectasias, which occurred in 14% of those on sotatercept and in 4% of control patients.

“It’s an uncommon adverse event profile, but not unexpected for a drug with its mechanism of action,” he said.

Drug binds activin, a pathologic driver of PAH

Sotatercept is an engineered molecule that combines a section of a human immunoglobulin G molecule with a portion of the receptor for activin. This structure allows sotatercept to bind free activin molecules in a patient’s blood, thereby removing a key driver of the pulmonary vascular wall remodeling that is at the pathologic root of PAH.

“Hyperproliferation of blood vessel–wall cells” caused by activin signaling “is perhaps the most important driver of PAH,” Dr. Hoeper said. “Sotatercept allows us for the first time to target the underlying mechanism behind PAH.”

Still ongoing are the HYPERION and ZENITH phase 3 trials of sotatercept. HYPERION is enrolling patients with newly diagnosed or high-risk PAH and is expected to complete in 2028. ZENITH is enrolling patients with more advanced PAH and a higher mortality risk, with results expected in 2026.

Sotatercept has received “Breakthrough Therapy” designation and “Orphan Drug” designation by the Food and Drug Administration, and “Priority Medicines” designation and “Orphan Drug” designation by the European Medicines Agency for the treatment of PAH. One recent review estimated a worldwide PAH prevalence of about 3-4 cases/100,000, which for the United States translates into a total prevalence of perhaps 10,000-15,000 affected people.

STELLAR was funded by Acceleron Pharma, a subsidiary of Merck. Dr. Hoeper is a consultant to Acceleron. Dr. Cooper-DeHoff, Dr. Grapsa, and the authors of the editorial on STELLAR have no relevant disclosures.

Although patients with lupus nephritis recently gained two new add-on treatment options in voclosporin (Lupkynis) and belimumab (Benlysta), there have been little data published with real-world experience in using these drugs.

Voclosporin, a calcineurin inhibitor, was approved by the Food and Drug Administration in January 2021 to treat lupus nephritis in combination with immunosuppressive medication. Belimumab, a human monoclonal antibody and B-lymphocyte stimulator, was approved in December 2020 in the United States as an add-on treatment for lupus nephritis in adults and later in July 2022 for children who are already receiving standard therapy.

How the two drugs are prescribed for patients with lupus nephritis so far appears to be influenced by presence of extrarenal manifestations of lupus, proteinuria level, clinicians’ prior experience with belimumab, costs of the drugs, and patient preference, experts said.

Voclosporin’s approval was based on data from the phase 3 AURORA 1 trial and phase 2 AURA-LV trial. AURORA 1 evaluated 357 patients with systemic lupus erythematosus (SLE) and lupus nephritis who were randomized to receive voclosporin or placebo with mycophenolate mofetil and tapered low-dose oral steroids. In the voclosporin group, the results showed a significantly higher complete renal response at 52 weeks, compared with the placebo group, while having a similar adverse event profile. The AURA-LV trial, evaluating efficacy and safety of 179 patients with lupus nephritis, showed adding low-dose voclosporin to induction therapy improved renal response, compared with placebo. AURORA 2, a continuation of the AURORA trial, showed patients with lupus nephritis receiving voclosporin have a stable estimated glomerular filtration rate and reductions in proteinuria up to 3 years of follow-up.

Results from the phase 3 BLISS-LN trial of 448 patients with confirmed lupus nephritis were the basis for belimumab’s approval and showed a significantly higher proportion of patients who received belimumab had a primary efficacy renal response, complete renal response, and significantly lower risk of a renal-related adverse event or death, compared with the placebo group.
 

Lack of real-world data

The lack of real-world data on either of these treatments can be attributed to lupus nephritis being a rare disease, and the approvals happening fairly recently, experts said.

“This is really due to the recency of the approvals for both of these medications for lupus nephritis,” Amit Saxena, MD, a rheumatologist and assistant professor of medicine in the division of rheumatology at NYU Langone Health in New York, said in an interview.

“It’s too soon for any appreciable data to be collected.”

Ashira D. Blazer, MD, MSCI, a rheumatologist at Hospital for Special Surgery and assistant professor of medicine at Weill Cornell Medical College, both in New York, said that rheumatologists “are a little bit hesitant” to use newer agents rather than existing therapies, and have existing guidance from the American College of Rheumatology (ACR) on treating the condition.

“I think when someone has something like lupus nephritis that’s so serious, rheumatologists pull for the tried-and-true drugs that we know will affect the inflammation quickly and get that patient to remission,” she said.

Donald E. Thomas Jr., MD, of Arthritis and Pain Associates of P.G. County in Greenbelt, Md., said he was surprised there was a lack of case studies on voclosporin or belimumab for lupus nephritis, but pointed to the time and cost of publishing a case report and the rheumatologist shortage as potential reasons.

Sharon Worcester/MDedge News

Prescribing experience

Despite the lack of published data on real-world use, the drugs are being prescribed, Dr. Thomas said.

“I have quite a few patients on these drugs,” he said, citing one patient with severe membranoproliferative lupus nephritis not in remission who is receiving a combination of voclosporin, belimumab, and hydroxychloroquine.

“I have had absolutely no problems getting either drug. The indications for the medicines are crystal clear,” he said.

Irene Blanco, MD, MS, professor in the department of medicine-rheumatology at Northwestern University, Chicago, said that in her experience, both voclosporin and belimumab have been easy to get for patients.

However, she noted she was seeing mostly patients with government-based insurance in the Bronx, N.Y., prior to moving to Northwestern in September 2022. Belimumab had been available from the New York State Medicaid program for indications other than lupus nephritis for some time, and the program was quick to add voclosporin once it became available. “It wasn’t hard to get at all,” she said.

Dr. Saxena noted the respective pharmaceutical companies have provided help in prescribing voclosporin and belimumab through offering patient assistance programs and navigating insurers’ prior authorization hurdles. As belimumab has been available for many years, its availability hasn’t changed, he noted. “Voclosporin has seen more formulary restrictions, but in my experience, I have been able to get the drug utilizing authorization procedures,” he said.

One issue Dr. Blazer said that she encounters is cost. According to prices obtained from drugs.com in March 2023, belimumab has an estimated annual price of $58.389.96 per patient, and voclosporin has an estimated annual price of $86,506.20 per patient.

“I tend to treat patients who can have some socioeconomic challenges, and so I think very long and hard before prescribing either of them,” she explained. “[C]ertainly in the case of voclosporin, when there are older, cheaper calcineurin inhibitors and I think I need one, I’m more likely to reach for one of the others.”

While GSK offers a patient assistance program for belimumab, which Dr. Blazer said she has used, physicians may not be aware of the program or have the resources in their offices to provide social work support for their patients.

“I have had patients who started it and ... continued to have a flare and needed to go on disability or leave their jobs, and they were just too concerned with the ongoing cost burden, and so I ended up taking them off the medication for that reason at their request,” she said.

The fact that Black patients have lupus nephritis more often than White patients do, as well as greater socioeconomic barriers, points to access to care and cost as major factors in why new drugs are not being used, Dr. Blazer said. “I think that understanding how we can improve access is going to be extremely important in getting more real-world data and getting more patients treated,” she said.

Treatment preference

A chart audit recently released by market research firm Spherix Global Insights highlighted a potential treatment preference for lupus nephritis. Use of voclosporin increased among rheumatologists and nephrologists, but patients with lupus nephritis under the care of rheumatologists were more likely to be treated with belimumab than voclosporin.

Dr. Saxena said he has experience with both and doesn’t have a preference, instead using factors other than experience when deciding the best treatment for patients. “For example, if there are nonrenal manifestations such as arthritis or rashes, I may lean towards belimumab, but if a more rapid reduction in proteinuria is important, I may lean towards voclosporin,” he said.

Dr. Thomas weighs the pros and cons of voclosporin and belimumab with the patient. “With many lupus nephritis scenarios, either drug may be a good choice and it comes down to patient preference. The main scenario where I would choose [voclosporin] over [belimumab] is in patients with [proteinuria of] 3 g protein/day or more,” he said, while belimumab would be the choice for a patient with “nonrenal manifestations of SLE in addition to their nephritis.”

For other rheumatologists, comfort level with belimumab may play a role. “We always had [belimumab] and we were always using [belimumab], and so it would make sense that like we would go for a med, again, that we’re really familiar with and we use,” Dr. Blanco said.

Dr. Blanco has prescribed belimumab, but had been using tacrolimus until recently. “I’ve been using tacrolimus since 2016. I’m probably going to lean on the [tacrolimus] rather than going to [belimumab], which works, but maybe it’s not the end-all, be-all in terms of lupus,” she said.

Although she hasn’t yet prescribed voclosporin, Dr. Blazer said she had “much more experience with belimumab.

“I’ve prescribed other calcineurin inhibitors in the past, and usually for a patient who’s very proteinuric and as an adjunct to that standard of care to try to bring down the proteinuria,” she said.

With belimumab, she would consider adding it to a patient with severe disease who has failed treatment with mycophenolate mofetil or cyclophosphamide and has a recurrent lupus nephritis flare. “It’s something I can use as an adjunct, and I think that I can get some extra benefit from it, and it also tends to be well tolerated,” Dr. Blazer said.

How patients are responding

Dr. Thomas’ patients have been responding well on voclosporin and belimumab. “I was an early adopter of [belimumab] and had patients with lupus nephritis do great on it, way before the FDA approval,” he said.

For voclosporin, Dr. Thomas highlighted the “incredibly rapid” proteinuria response. “I had a patient have marked reduction in proteinuria in just 2 weeks. Proteinuria reduction is the number one predictor of long-term better outcomes,” he said.

Many patients receiving mycophenolate and cyclophosphamide do not go into complete remission, while the clinical trials for voclosporin and belimumab had significantly higher rates of complete response and faster response rates, compared with older therapies. “That is what we need,” he said.

“These drugs are game changers in the treatment of lupus nephritis. In my mind, belimumab and voclosporin should be considered the standard of medical care treating lupus nephritis patients,” he added.

Dr. Blanco said her patients appear to like and are tolerating voclosporin and belimumab well, but because there are no pregnancy data on voclosporin, she may choose belimumab or tacrolimus for patients of reproductive age who are considering starting a family.

Patients with extrarenal symptoms tend to do particularly well with belimumab, such as those with arthritis and skin rash, Dr. Blazer said. “In my experience, as an adjunct with those standard of care medications, I have been able to maintain remission in my patients,” she said.

Dr. Saxena said both medications are “important options” for lupus nephritis in patients who don’t respond to standard therapy. “As more doctors utilize each medication and additional data is published, I’d expect an increase uptake in both medications in the future,” he said.

Dr. Blazer reported being a contributor to GSK’s SLE Educators’ Network and has been a consultant for Aurinia. Dr. Saxena reported being a consultant for GSK and Aurinia. Dr. Thomas reported being on the speakers bureau for GSK and Aurinia. Dr. Blanco reported having no relevant financial relationships with pharmaceutical companies.

Although patients with lupus nephritis recently gained two new add-on treatment options in voclosporin (Lupkynis) and belimumab (Benlysta), there have been little data published with real-world experience in using these drugs.

Voclosporin, a calcineurin inhibitor, was approved by the Food and Drug Administration in January 2021 to treat lupus nephritis in combination with immunosuppressive medication. Belimumab, a human monoclonal antibody and B-lymphocyte stimulator, was approved in December 2020 in the United States as an add-on treatment for lupus nephritis in adults and later in July 2022 for children who are already receiving standard therapy.

How the two drugs are prescribed for patients with lupus nephritis so far appears to be influenced by presence of extrarenal manifestations of lupus, proteinuria level, clinicians’ prior experience with belimumab, costs of the drugs, and patient preference, experts said.

Voclosporin’s approval was based on data from the phase 3 AURORA 1 trial and phase 2 AURA-LV trial. AURORA 1 evaluated 357 patients with systemic lupus erythematosus (SLE) and lupus nephritis who were randomized to receive voclosporin or placebo with mycophenolate mofetil and tapered low-dose oral steroids. In the voclosporin group, the results showed a significantly higher complete renal response at 52 weeks, compared with the placebo group, while having a similar adverse event profile. The AURA-LV trial, evaluating efficacy and safety of 179 patients with lupus nephritis, showed adding low-dose voclosporin to induction therapy improved renal response, compared with placebo. AURORA 2, a continuation of the AURORA trial, showed patients with lupus nephritis receiving voclosporin have a stable estimated glomerular filtration rate and reductions in proteinuria up to 3 years of follow-up.

Results from the phase 3 BLISS-LN trial of 448 patients with confirmed lupus nephritis were the basis for belimumab’s approval and showed a significantly higher proportion of patients who received belimumab had a primary efficacy renal response, complete renal response, and significantly lower risk of a renal-related adverse event or death, compared with the placebo group.
 

Lack of real-world data

The lack of real-world data on either of these treatments can be attributed to lupus nephritis being a rare disease, and the approvals happening fairly recently, experts said.

“This is really due to the recency of the approvals for both of these medications for lupus nephritis,” Amit Saxena, MD, a rheumatologist and assistant professor of medicine in the division of rheumatology at NYU Langone Health in New York, said in an interview.

“It’s too soon for any appreciable data to be collected.”

Ashira D. Blazer, MD, MSCI, a rheumatologist at Hospital for Special Surgery and assistant professor of medicine at Weill Cornell Medical College, both in New York, said that rheumatologists “are a little bit hesitant” to use newer agents rather than existing therapies, and have existing guidance from the American College of Rheumatology (ACR) on treating the condition.

“I think when someone has something like lupus nephritis that’s so serious, rheumatologists pull for the tried-and-true drugs that we know will affect the inflammation quickly and get that patient to remission,” she said.

Donald E. Thomas Jr., MD, of Arthritis and Pain Associates of P.G. County in Greenbelt, Md., said he was surprised there was a lack of case studies on voclosporin or belimumab for lupus nephritis, but pointed to the time and cost of publishing a case report and the rheumatologist shortage as potential reasons.

Sharon Worcester/MDedge News

Prescribing experience

Despite the lack of published data on real-world use, the drugs are being prescribed, Dr. Thomas said.

“I have quite a few patients on these drugs,” he said, citing one patient with severe membranoproliferative lupus nephritis not in remission who is receiving a combination of voclosporin, belimumab, and hydroxychloroquine.

“I have had absolutely no problems getting either drug. The indications for the medicines are crystal clear,” he said.

Irene Blanco, MD, MS, professor in the department of medicine-rheumatology at Northwestern University, Chicago, said that in her experience, both voclosporin and belimumab have been easy to get for patients.

However, she noted she was seeing mostly patients with government-based insurance in the Bronx, N.Y., prior to moving to Northwestern in September 2022. Belimumab had been available from the New York State Medicaid program for indications other than lupus nephritis for some time, and the program was quick to add voclosporin once it became available. “It wasn’t hard to get at all,” she said.

Dr. Saxena noted the respective pharmaceutical companies have provided help in prescribing voclosporin and belimumab through offering patient assistance programs and navigating insurers’ prior authorization hurdles. As belimumab has been available for many years, its availability hasn’t changed, he noted. “Voclosporin has seen more formulary restrictions, but in my experience, I have been able to get the drug utilizing authorization procedures,” he said.

One issue Dr. Blazer said that she encounters is cost. According to prices obtained from drugs.com in March 2023, belimumab has an estimated annual price of $58.389.96 per patient, and voclosporin has an estimated annual price of $86,506.20 per patient.

“I tend to treat patients who can have some socioeconomic challenges, and so I think very long and hard before prescribing either of them,” she explained. “[C]ertainly in the case of voclosporin, when there are older, cheaper calcineurin inhibitors and I think I need one, I’m more likely to reach for one of the others.”

While GSK offers a patient assistance program for belimumab, which Dr. Blazer said she has used, physicians may not be aware of the program or have the resources in their offices to provide social work support for their patients.

“I have had patients who started it and ... continued to have a flare and needed to go on disability or leave their jobs, and they were just too concerned with the ongoing cost burden, and so I ended up taking them off the medication for that reason at their request,” she said.

The fact that Black patients have lupus nephritis more often than White patients do, as well as greater socioeconomic barriers, points to access to care and cost as major factors in why new drugs are not being used, Dr. Blazer said. “I think that understanding how we can improve access is going to be extremely important in getting more real-world data and getting more patients treated,” she said.

Treatment preference

A chart audit recently released by market research firm Spherix Global Insights highlighted a potential treatment preference for lupus nephritis. Use of voclosporin increased among rheumatologists and nephrologists, but patients with lupus nephritis under the care of rheumatologists were more likely to be treated with belimumab than voclosporin.

Dr. Saxena said he has experience with both and doesn’t have a preference, instead using factors other than experience when deciding the best treatment for patients. “For example, if there are nonrenal manifestations such as arthritis or rashes, I may lean towards belimumab, but if a more rapid reduction in proteinuria is important, I may lean towards voclosporin,” he said.

Dr. Thomas weighs the pros and cons of voclosporin and belimumab with the patient. “With many lupus nephritis scenarios, either drug may be a good choice and it comes down to patient preference. The main scenario where I would choose [voclosporin] over [belimumab] is in patients with [proteinuria of] 3 g protein/day or more,” he said, while belimumab would be the choice for a patient with “nonrenal manifestations of SLE in addition to their nephritis.”

For other rheumatologists, comfort level with belimumab may play a role. “We always had [belimumab] and we were always using [belimumab], and so it would make sense that like we would go for a med, again, that we’re really familiar with and we use,” Dr. Blanco said.

Dr. Blanco has prescribed belimumab, but had been using tacrolimus until recently. “I’ve been using tacrolimus since 2016. I’m probably going to lean on the [tacrolimus] rather than going to [belimumab], which works, but maybe it’s not the end-all, be-all in terms of lupus,” she said.

Although she hasn’t yet prescribed voclosporin, Dr. Blazer said she had “much more experience with belimumab.

“I’ve prescribed other calcineurin inhibitors in the past, and usually for a patient who’s very proteinuric and as an adjunct to that standard of care to try to bring down the proteinuria,” she said.

With belimumab, she would consider adding it to a patient with severe disease who has failed treatment with mycophenolate mofetil or cyclophosphamide and has a recurrent lupus nephritis flare. “It’s something I can use as an adjunct, and I think that I can get some extra benefit from it, and it also tends to be well tolerated,” Dr. Blazer said.

How patients are responding

Dr. Thomas’ patients have been responding well on voclosporin and belimumab. “I was an early adopter of [belimumab] and had patients with lupus nephritis do great on it, way before the FDA approval,” he said.

For voclosporin, Dr. Thomas highlighted the “incredibly rapid” proteinuria response. “I had a patient have marked reduction in proteinuria in just 2 weeks. Proteinuria reduction is the number one predictor of long-term better outcomes,” he said.

Many patients receiving mycophenolate and cyclophosphamide do not go into complete remission, while the clinical trials for voclosporin and belimumab had significantly higher rates of complete response and faster response rates, compared with older therapies. “That is what we need,” he said.

“These drugs are game changers in the treatment of lupus nephritis. In my mind, belimumab and voclosporin should be considered the standard of medical care treating lupus nephritis patients,” he added.

Dr. Blanco said her patients appear to like and are tolerating voclosporin and belimumab well, but because there are no pregnancy data on voclosporin, she may choose belimumab or tacrolimus for patients of reproductive age who are considering starting a family.

Patients with extrarenal symptoms tend to do particularly well with belimumab, such as those with arthritis and skin rash, Dr. Blazer said. “In my experience, as an adjunct with those standard of care medications, I have been able to maintain remission in my patients,” she said.

Dr. Saxena said both medications are “important options” for lupus nephritis in patients who don’t respond to standard therapy. “As more doctors utilize each medication and additional data is published, I’d expect an increase uptake in both medications in the future,” he said.

Dr. Blazer reported being a contributor to GSK’s SLE Educators’ Network and has been a consultant for Aurinia. Dr. Saxena reported being a consultant for GSK and Aurinia. Dr. Thomas reported being on the speakers bureau for GSK and Aurinia. Dr. Blanco reported having no relevant financial relationships with pharmaceutical companies.

Although patients with lupus nephritis recently gained two new add-on treatment options in voclosporin (Lupkynis) and belimumab (Benlysta), there have been little data published with real-world experience in using these drugs.

Voclosporin, a calcineurin inhibitor, was approved by the Food and Drug Administration in January 2021 to treat lupus nephritis in combination with immunosuppressive medication. Belimumab, a human monoclonal antibody and B-lymphocyte stimulator, was approved in December 2020 in the United States as an add-on treatment for lupus nephritis in adults and later in July 2022 for children who are already receiving standard therapy.

How the two drugs are prescribed for patients with lupus nephritis so far appears to be influenced by presence of extrarenal manifestations of lupus, proteinuria level, clinicians’ prior experience with belimumab, costs of the drugs, and patient preference, experts said.

Voclosporin’s approval was based on data from the phase 3 AURORA 1 trial and phase 2 AURA-LV trial. AURORA 1 evaluated 357 patients with systemic lupus erythematosus (SLE) and lupus nephritis who were randomized to receive voclosporin or placebo with mycophenolate mofetil and tapered low-dose oral steroids. In the voclosporin group, the results showed a significantly higher complete renal response at 52 weeks, compared with the placebo group, while having a similar adverse event profile. The AURA-LV trial, evaluating efficacy and safety of 179 patients with lupus nephritis, showed adding low-dose voclosporin to induction therapy improved renal response, compared with placebo. AURORA 2, a continuation of the AURORA trial, showed patients with lupus nephritis receiving voclosporin have a stable estimated glomerular filtration rate and reductions in proteinuria up to 3 years of follow-up.

Results from the phase 3 BLISS-LN trial of 448 patients with confirmed lupus nephritis were the basis for belimumab’s approval and showed a significantly higher proportion of patients who received belimumab had a primary efficacy renal response, complete renal response, and significantly lower risk of a renal-related adverse event or death, compared with the placebo group.
 

Lack of real-world data

The lack of real-world data on either of these treatments can be attributed to lupus nephritis being a rare disease, and the approvals happening fairly recently, experts said.

“This is really due to the recency of the approvals for both of these medications for lupus nephritis,” Amit Saxena, MD, a rheumatologist and assistant professor of medicine in the division of rheumatology at NYU Langone Health in New York, said in an interview.

“It’s too soon for any appreciable data to be collected.”

Ashira D. Blazer, MD, MSCI, a rheumatologist at Hospital for Special Surgery and assistant professor of medicine at Weill Cornell Medical College, both in New York, said that rheumatologists “are a little bit hesitant” to use newer agents rather than existing therapies, and have existing guidance from the American College of Rheumatology (ACR) on treating the condition.

“I think when someone has something like lupus nephritis that’s so serious, rheumatologists pull for the tried-and-true drugs that we know will affect the inflammation quickly and get that patient to remission,” she said.

Donald E. Thomas Jr., MD, of Arthritis and Pain Associates of P.G. County in Greenbelt, Md., said he was surprised there was a lack of case studies on voclosporin or belimumab for lupus nephritis, but pointed to the time and cost of publishing a case report and the rheumatologist shortage as potential reasons.

Sharon Worcester/MDedge News

Prescribing experience

Despite the lack of published data on real-world use, the drugs are being prescribed, Dr. Thomas said.

“I have quite a few patients on these drugs,” he said, citing one patient with severe membranoproliferative lupus nephritis not in remission who is receiving a combination of voclosporin, belimumab, and hydroxychloroquine.

“I have had absolutely no problems getting either drug. The indications for the medicines are crystal clear,” he said.

Irene Blanco, MD, MS, professor in the department of medicine-rheumatology at Northwestern University, Chicago, said that in her experience, both voclosporin and belimumab have been easy to get for patients.

However, she noted she was seeing mostly patients with government-based insurance in the Bronx, N.Y., prior to moving to Northwestern in September 2022. Belimumab had been available from the New York State Medicaid program for indications other than lupus nephritis for some time, and the program was quick to add voclosporin once it became available. “It wasn’t hard to get at all,” she said.

Dr. Saxena noted the respective pharmaceutical companies have provided help in prescribing voclosporin and belimumab through offering patient assistance programs and navigating insurers’ prior authorization hurdles. As belimumab has been available for many years, its availability hasn’t changed, he noted. “Voclosporin has seen more formulary restrictions, but in my experience, I have been able to get the drug utilizing authorization procedures,” he said.

One issue Dr. Blazer said that she encounters is cost. According to prices obtained from drugs.com in March 2023, belimumab has an estimated annual price of $58.389.96 per patient, and voclosporin has an estimated annual price of $86,506.20 per patient.

“I tend to treat patients who can have some socioeconomic challenges, and so I think very long and hard before prescribing either of them,” she explained. “[C]ertainly in the case of voclosporin, when there are older, cheaper calcineurin inhibitors and I think I need one, I’m more likely to reach for one of the others.”

While GSK offers a patient assistance program for belimumab, which Dr. Blazer said she has used, physicians may not be aware of the program or have the resources in their offices to provide social work support for their patients.

“I have had patients who started it and ... continued to have a flare and needed to go on disability or leave their jobs, and they were just too concerned with the ongoing cost burden, and so I ended up taking them off the medication for that reason at their request,” she said.

The fact that Black patients have lupus nephritis more often than White patients do, as well as greater socioeconomic barriers, points to access to care and cost as major factors in why new drugs are not being used, Dr. Blazer said. “I think that understanding how we can improve access is going to be extremely important in getting more real-world data and getting more patients treated,” she said.

Treatment preference

A chart audit recently released by market research firm Spherix Global Insights highlighted a potential treatment preference for lupus nephritis. Use of voclosporin increased among rheumatologists and nephrologists, but patients with lupus nephritis under the care of rheumatologists were more likely to be treated with belimumab than voclosporin.

Dr. Saxena said he has experience with both and doesn’t have a preference, instead using factors other than experience when deciding the best treatment for patients. “For example, if there are nonrenal manifestations such as arthritis or rashes, I may lean towards belimumab, but if a more rapid reduction in proteinuria is important, I may lean towards voclosporin,” he said.

Dr. Thomas weighs the pros and cons of voclosporin and belimumab with the patient. “With many lupus nephritis scenarios, either drug may be a good choice and it comes down to patient preference. The main scenario where I would choose [voclosporin] over [belimumab] is in patients with [proteinuria of] 3 g protein/day or more,” he said, while belimumab would be the choice for a patient with “nonrenal manifestations of SLE in addition to their nephritis.”

For other rheumatologists, comfort level with belimumab may play a role. “We always had [belimumab] and we were always using [belimumab], and so it would make sense that like we would go for a med, again, that we’re really familiar with and we use,” Dr. Blanco said.

Dr. Blanco has prescribed belimumab, but had been using tacrolimus until recently. “I’ve been using tacrolimus since 2016. I’m probably going to lean on the [tacrolimus] rather than going to [belimumab], which works, but maybe it’s not the end-all, be-all in terms of lupus,” she said.

Although she hasn’t yet prescribed voclosporin, Dr. Blazer said she had “much more experience with belimumab.

“I’ve prescribed other calcineurin inhibitors in the past, and usually for a patient who’s very proteinuric and as an adjunct to that standard of care to try to bring down the proteinuria,” she said.

With belimumab, she would consider adding it to a patient with severe disease who has failed treatment with mycophenolate mofetil or cyclophosphamide and has a recurrent lupus nephritis flare. “It’s something I can use as an adjunct, and I think that I can get some extra benefit from it, and it also tends to be well tolerated,” Dr. Blazer said.

How patients are responding

Dr. Thomas’ patients have been responding well on voclosporin and belimumab. “I was an early adopter of [belimumab] and had patients with lupus nephritis do great on it, way before the FDA approval,” he said.

For voclosporin, Dr. Thomas highlighted the “incredibly rapid” proteinuria response. “I had a patient have marked reduction in proteinuria in just 2 weeks. Proteinuria reduction is the number one predictor of long-term better outcomes,” he said.

Many patients receiving mycophenolate and cyclophosphamide do not go into complete remission, while the clinical trials for voclosporin and belimumab had significantly higher rates of complete response and faster response rates, compared with older therapies. “That is what we need,” he said.

“These drugs are game changers in the treatment of lupus nephritis. In my mind, belimumab and voclosporin should be considered the standard of medical care treating lupus nephritis patients,” he added.

Dr. Blanco said her patients appear to like and are tolerating voclosporin and belimumab well, but because there are no pregnancy data on voclosporin, she may choose belimumab or tacrolimus for patients of reproductive age who are considering starting a family.

Patients with extrarenal symptoms tend to do particularly well with belimumab, such as those with arthritis and skin rash, Dr. Blazer said. “In my experience, as an adjunct with those standard of care medications, I have been able to maintain remission in my patients,” she said.

Dr. Saxena said both medications are “important options” for lupus nephritis in patients who don’t respond to standard therapy. “As more doctors utilize each medication and additional data is published, I’d expect an increase uptake in both medications in the future,” he said.

Dr. Blazer reported being a contributor to GSK’s SLE Educators’ Network and has been a consultant for Aurinia. Dr. Saxena reported being a consultant for GSK and Aurinia. Dr. Thomas reported being on the speakers bureau for GSK and Aurinia. Dr. Blanco reported having no relevant financial relationships with pharmaceutical companies.

The Food and Drug Administration approved sarilumab (Kevzara) on March 1 for the treatment of polymyalgia rheumatica (PMR) in adults who have had an inadequate response to corticosteroids or could not tolerate a corticosteroid taper, joint developers Sanofi and Regeneron announced. The drug is the first and only FDA-approved biologic treatment for this inflammatory rheumatic disease. 

The FDA previously approved sarilumab, an interleukin-6 receptor antagonist, in May 2017 for the treatment of moderate to severe active rheumatoid arthritis in adults who do not respond well or have an intolerance to disease-modifying antirheumatic drugs (DMARDs), like methotrexate.

Olivier Le Moal/Getty Images

The FDA approval for this new indication was based on results from the multicenter, phase 3 SAPHYR trial in patients with corticosteroid-resistant, active PMR. In the randomized, double-blind, placebo-controlled study, 59 participants received 200 mg of sarilumab plus a 14-week taper of corticosteroid treatment and 58 participants received placebo every 2 weeks along with a 52-week taper of corticosteroid treatment.

After 1 year, 28% of sarilumab patients achieved sustained remission, compared with 10% of the placebo group (P = .0193). This news organization previously reported these trial results in November when they were presented at the 2022 annual meeting of the American College of Rheumatology.

The most common adverse events in the sarilumab group were neutropenia (15%), leukopenia (7%), constipation (7%), pruritic rash (5%), myalgia (7%), fatigue (5%), and injection-site pruritus (5%). Two patients had serious adverse reactions of neutropenia, which resolved after discontinuing treatment.

“Polymyalgia rheumatica can be an incapacitating disease, causing painful disease flares in multiple parts of the bodies that leave people fatigued and unable to fully perform everyday activities. Corticosteroids have been the primary treatment to date, but many patients do not adequately respond to steroids or cannot be tapered off steroids, which puts such patients at risk of complications from long-term steroid therapy,” George D. Yancopolous, MD, PhD, president and chief scientific officer at Regeneron, said in the announcement. “With the approval of Kevzara for polymyalgia rheumatica, patients now have an FDA-approved treatment to help offer relief from the disabling symptoms of this disease and long-term dependence on steroids.”

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

The Food and Drug Administration approved sarilumab (Kevzara) on March 1 for the treatment of polymyalgia rheumatica (PMR) in adults who have had an inadequate response to corticosteroids or could not tolerate a corticosteroid taper, joint developers Sanofi and Regeneron announced. The drug is the first and only FDA-approved biologic treatment for this inflammatory rheumatic disease. 

The FDA previously approved sarilumab, an interleukin-6 receptor antagonist, in May 2017 for the treatment of moderate to severe active rheumatoid arthritis in adults who do not respond well or have an intolerance to disease-modifying antirheumatic drugs (DMARDs), like methotrexate.

Olivier Le Moal/Getty Images

The FDA approval for this new indication was based on results from the multicenter, phase 3 SAPHYR trial in patients with corticosteroid-resistant, active PMR. In the randomized, double-blind, placebo-controlled study, 59 participants received 200 mg of sarilumab plus a 14-week taper of corticosteroid treatment and 58 participants received placebo every 2 weeks along with a 52-week taper of corticosteroid treatment.

After 1 year, 28% of sarilumab patients achieved sustained remission, compared with 10% of the placebo group (P = .0193). This news organization previously reported these trial results in November when they were presented at the 2022 annual meeting of the American College of Rheumatology.

The most common adverse events in the sarilumab group were neutropenia (15%), leukopenia (7%), constipation (7%), pruritic rash (5%), myalgia (7%), fatigue (5%), and injection-site pruritus (5%). Two patients had serious adverse reactions of neutropenia, which resolved after discontinuing treatment.

“Polymyalgia rheumatica can be an incapacitating disease, causing painful disease flares in multiple parts of the bodies that leave people fatigued and unable to fully perform everyday activities. Corticosteroids have been the primary treatment to date, but many patients do not adequately respond to steroids or cannot be tapered off steroids, which puts such patients at risk of complications from long-term steroid therapy,” George D. Yancopolous, MD, PhD, president and chief scientific officer at Regeneron, said in the announcement. “With the approval of Kevzara for polymyalgia rheumatica, patients now have an FDA-approved treatment to help offer relief from the disabling symptoms of this disease and long-term dependence on steroids.”

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

The Food and Drug Administration approved sarilumab (Kevzara) on March 1 for the treatment of polymyalgia rheumatica (PMR) in adults who have had an inadequate response to corticosteroids or could not tolerate a corticosteroid taper, joint developers Sanofi and Regeneron announced. The drug is the first and only FDA-approved biologic treatment for this inflammatory rheumatic disease. 

The FDA previously approved sarilumab, an interleukin-6 receptor antagonist, in May 2017 for the treatment of moderate to severe active rheumatoid arthritis in adults who do not respond well or have an intolerance to disease-modifying antirheumatic drugs (DMARDs), like methotrexate.

Olivier Le Moal/Getty Images

The FDA approval for this new indication was based on results from the multicenter, phase 3 SAPHYR trial in patients with corticosteroid-resistant, active PMR. In the randomized, double-blind, placebo-controlled study, 59 participants received 200 mg of sarilumab plus a 14-week taper of corticosteroid treatment and 58 participants received placebo every 2 weeks along with a 52-week taper of corticosteroid treatment.

After 1 year, 28% of sarilumab patients achieved sustained remission, compared with 10% of the placebo group (P = .0193). This news organization previously reported these trial results in November when they were presented at the 2022 annual meeting of the American College of Rheumatology.

The most common adverse events in the sarilumab group were neutropenia (15%), leukopenia (7%), constipation (7%), pruritic rash (5%), myalgia (7%), fatigue (5%), and injection-site pruritus (5%). Two patients had serious adverse reactions of neutropenia, which resolved after discontinuing treatment.

“Polymyalgia rheumatica can be an incapacitating disease, causing painful disease flares in multiple parts of the bodies that leave people fatigued and unable to fully perform everyday activities. Corticosteroids have been the primary treatment to date, but many patients do not adequately respond to steroids or cannot be tapered off steroids, which puts such patients at risk of complications from long-term steroid therapy,” George D. Yancopolous, MD, PhD, president and chief scientific officer at Regeneron, said in the announcement. “With the approval of Kevzara for polymyalgia rheumatica, patients now have an FDA-approved treatment to help offer relief from the disabling symptoms of this disease and long-term dependence on steroids.”

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

Adults with the inflammatory autoimmune myopathy dermatomyositis are at increased for concurrent cancers, but new research suggests that certain autoantibodies in patients with a specific dermatomyositis subtype may actually protect against cancer.

A study of cohorts of patients with dermatomyositis, other rheumatic diseases, and those without disease showed that among patients with dermatomyositis positive for antitranscriptional intermediary factor 1 (anti–TIF1-gamma) autoantibodies – a disease subtype associated with increased cancer risk – the presence of autoantibodies directed against cell division cycle and apoptosis regulator 1 (CCAR1) was associated with reduced cancer risk “to a level comparable to that seen in the general population,” Christopher A. Mecoli, MD, MHS, of Johns Hopkins University, Baltimore, and colleagues reported.

“Our prior data suggest that there are autoantigens that, when targeted simultaneously with CCAR1, provide additional cancer protection. Although these autoantigens are less frequently targeted, it is likely that additional, more prevalent ‘autoantigen hubs’ remain undiscovered,” they wrote in Arthritis & Rheumatology.

Identification of other autoantibodies both in the anti–TIF1-gamma–positive and other dermatomyositis subgroups may help with cancer risk stratification in patients with the disease and may ultimately improve cancer screening for adults with dermatomyositis, the investigators said.
 

Toward precision medicine

“I think this is a step toward precision medicine in patients with rheumatic disease, specifically myositis,” Dr. Mecoli said in an interview.

The study supports earlier work showing that dermatomyositis and related myopathies are heterogeneous, he said, noting that, “if you put 10 myositis patients in the same room, you wouldn’t get that they all have the same disease because they can look so different from one another.”

The association of dermatomyositis with concurrent cancers has been known for decades, but in recent years his team and other investigators have noted that the association holds true for only some patients with dermatomyositis, most notably those patients positive for anti–TIF1-gamma autoantibodies.

“And then, of course, once you really start studying just one gamma-positive dermatomyositis patient, you realize that even among that group it is heterogeneous in terms of their cancer risk, and that was the main focus of this study: to reconcile this clinical observation that I had a lot of patients with TIF1-gamma dermatomyositis who never get diagnosed with cancer,” Dr. Mecoli said.

Study details

Dr. Dr. Mecoli and colleagues previously reported that immune responses to CCAR1 and other autoantigens seen in patients with dermatomyositis were associated with lower probability of cancer occurrence.

In the current study, they focused on the disease specificity, clinical phenotype, and cancer risk for patients with dermatomyositis and anti-CCAR1 autoantibodies.

They looked at all patients aged 18 or older with a probable or definite finding of dermatomyositis, according to 2017 American College of Rheumatology/European Alliance of Associations for Rheumatology Idiopathic Inflammatory Myopathy criteria, who were seen at Stanford (Calif.) University Medical Center from August 2004 to April 2020 (101 patients), or the Johns Hopkins Myositis Center (141 patients) from January 2007 to December 2020.

Controls included 44 patients evaluated at the Johns Hopkins Myositis Center with immune-mediated necrotizing myopathy, 186 patients with anti–TIF1-gamma–negative dermatomyositis (defined as an enzyme-linked immunosorbent assay readout of less than seven units) evaluated at either Stanford or Johns Hopkins, 44 patients with inclusion body myositis evaluated at Johns Hopkins, and 46 patients with systemic lupus erythematosus from the Hopkins Lupus Cohort. The investigators also assayed serum from 32 healthy individuals.

They found that patients with anti–TIF1-gamma–positive dermatomyositis were significantly more likely than those with anti–TIF1-gamma–negative dermatomyositis to have anti-CCAR1 autoantibodies (32% vs. 8%; P < .001). Additionally, they noted that the anti-CCAR1 autoantibodies were not seen in serum from healthy controls and were found at only very low frequencies among patients with other rheumatic diseases.

When they looked at the incidence of cancer from the time of dermatomyositis onset (defined as the first patient-reported symptoms of rash, weakness, myalgia, or dyspnea) they found that the standardized incidence ratio in anti–TIF1-gamma–positive patients in both the Stanford and Hopkins cohorts was higher than expected, with SIRs of 3.49 and 4.54, respectively (P < .001 for each comparison).

However, among those patients who were both anti–TIF1-gamma positive and anti-CCAR1 positive, the SIRs were 1.78 in the Stanford cohort and 1.61 in the Hopkins cohort, and neither SIR was significantly higher than that of the general population.
 

Risk prediction

Their findings suggest that autoantibody profiles might be used for cancer risk stratification in patients with anti–TIF1-gamma–positive dermatomyositis, Dr. Mecoli said.

“Are we overscreening? What is the cost in terms of patient anxiety, in terms of radiation, and in terms of false positive results?” he asked. “If I had a patient in front of me with anti–TIF1-gamma dermatomyositis, I would probably manage them differently if I knew that they were CCAR1 positive, because the presence of that additional autoantibody attenuates their cancer risk relative to the general population.”

In an editorial accompanying the study, Manabu Fujimoto, MD, of the department of dermatology at Osaka (Japan) University, commented that it “is of clinical importance in that combination of autoantibodies can predict cancer risk with more accuracy. At the same time, this study will give an insight into the pathomechanisms of how antitumor activity may shape autoimmunity in dermatomyositis.”

It will be “intriguing” to discover whether anti-CCAR1 autoantibodies act only against tumors or might also have an impact on dermatomyositis itself, Dr. Fujimoto said.

The research was supported by grants from the National Institutes of Health; Huayi and Siuling Zhang Discovery Fund; Peter Buck, MD; and the Donald B. and Dorothy L. Stabler Foundation. The authors and Dr. Fujimoto reported no relevant financial relationships.

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

Adults with the inflammatory autoimmune myopathy dermatomyositis are at increased for concurrent cancers, but new research suggests that certain autoantibodies in patients with a specific dermatomyositis subtype may actually protect against cancer.

A study of cohorts of patients with dermatomyositis, other rheumatic diseases, and those without disease showed that among patients with dermatomyositis positive for antitranscriptional intermediary factor 1 (anti–TIF1-gamma) autoantibodies – a disease subtype associated with increased cancer risk – the presence of autoantibodies directed against cell division cycle and apoptosis regulator 1 (CCAR1) was associated with reduced cancer risk “to a level comparable to that seen in the general population,” Christopher A. Mecoli, MD, MHS, of Johns Hopkins University, Baltimore, and colleagues reported.

“Our prior data suggest that there are autoantigens that, when targeted simultaneously with CCAR1, provide additional cancer protection. Although these autoantigens are less frequently targeted, it is likely that additional, more prevalent ‘autoantigen hubs’ remain undiscovered,” they wrote in Arthritis & Rheumatology.

Identification of other autoantibodies both in the anti–TIF1-gamma–positive and other dermatomyositis subgroups may help with cancer risk stratification in patients with the disease and may ultimately improve cancer screening for adults with dermatomyositis, the investigators said.
 

Toward precision medicine

“I think this is a step toward precision medicine in patients with rheumatic disease, specifically myositis,” Dr. Mecoli said in an interview.

The study supports earlier work showing that dermatomyositis and related myopathies are heterogeneous, he said, noting that, “if you put 10 myositis patients in the same room, you wouldn’t get that they all have the same disease because they can look so different from one another.”

The association of dermatomyositis with concurrent cancers has been known for decades, but in recent years his team and other investigators have noted that the association holds true for only some patients with dermatomyositis, most notably those patients positive for anti–TIF1-gamma autoantibodies.

“And then, of course, once you really start studying just one gamma-positive dermatomyositis patient, you realize that even among that group it is heterogeneous in terms of their cancer risk, and that was the main focus of this study: to reconcile this clinical observation that I had a lot of patients with TIF1-gamma dermatomyositis who never get diagnosed with cancer,” Dr. Mecoli said.

Study details

Dr. Dr. Mecoli and colleagues previously reported that immune responses to CCAR1 and other autoantigens seen in patients with dermatomyositis were associated with lower probability of cancer occurrence.

In the current study, they focused on the disease specificity, clinical phenotype, and cancer risk for patients with dermatomyositis and anti-CCAR1 autoantibodies.

They looked at all patients aged 18 or older with a probable or definite finding of dermatomyositis, according to 2017 American College of Rheumatology/European Alliance of Associations for Rheumatology Idiopathic Inflammatory Myopathy criteria, who were seen at Stanford (Calif.) University Medical Center from August 2004 to April 2020 (101 patients), or the Johns Hopkins Myositis Center (141 patients) from January 2007 to December 2020.

Controls included 44 patients evaluated at the Johns Hopkins Myositis Center with immune-mediated necrotizing myopathy, 186 patients with anti–TIF1-gamma–negative dermatomyositis (defined as an enzyme-linked immunosorbent assay readout of less than seven units) evaluated at either Stanford or Johns Hopkins, 44 patients with inclusion body myositis evaluated at Johns Hopkins, and 46 patients with systemic lupus erythematosus from the Hopkins Lupus Cohort. The investigators also assayed serum from 32 healthy individuals.

They found that patients with anti–TIF1-gamma–positive dermatomyositis were significantly more likely than those with anti–TIF1-gamma–negative dermatomyositis to have anti-CCAR1 autoantibodies (32% vs. 8%; P < .001). Additionally, they noted that the anti-CCAR1 autoantibodies were not seen in serum from healthy controls and were found at only very low frequencies among patients with other rheumatic diseases.

When they looked at the incidence of cancer from the time of dermatomyositis onset (defined as the first patient-reported symptoms of rash, weakness, myalgia, or dyspnea) they found that the standardized incidence ratio in anti–TIF1-gamma–positive patients in both the Stanford and Hopkins cohorts was higher than expected, with SIRs of 3.49 and 4.54, respectively (P < .001 for each comparison).

However, among those patients who were both anti–TIF1-gamma positive and anti-CCAR1 positive, the SIRs were 1.78 in the Stanford cohort and 1.61 in the Hopkins cohort, and neither SIR was significantly higher than that of the general population.
 

Risk prediction

Their findings suggest that autoantibody profiles might be used for cancer risk stratification in patients with anti–TIF1-gamma–positive dermatomyositis, Dr. Mecoli said.

“Are we overscreening? What is the cost in terms of patient anxiety, in terms of radiation, and in terms of false positive results?” he asked. “If I had a patient in front of me with anti–TIF1-gamma dermatomyositis, I would probably manage them differently if I knew that they were CCAR1 positive, because the presence of that additional autoantibody attenuates their cancer risk relative to the general population.”

In an editorial accompanying the study, Manabu Fujimoto, MD, of the department of dermatology at Osaka (Japan) University, commented that it “is of clinical importance in that combination of autoantibodies can predict cancer risk with more accuracy. At the same time, this study will give an insight into the pathomechanisms of how antitumor activity may shape autoimmunity in dermatomyositis.”

It will be “intriguing” to discover whether anti-CCAR1 autoantibodies act only against tumors or might also have an impact on dermatomyositis itself, Dr. Fujimoto said.

The research was supported by grants from the National Institutes of Health; Huayi and Siuling Zhang Discovery Fund; Peter Buck, MD; and the Donald B. and Dorothy L. Stabler Foundation. The authors and Dr. Fujimoto reported no relevant financial relationships.

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

Adults with the inflammatory autoimmune myopathy dermatomyositis are at increased for concurrent cancers, but new research suggests that certain autoantibodies in patients with a specific dermatomyositis subtype may actually protect against cancer.

A study of cohorts of patients with dermatomyositis, other rheumatic diseases, and those without disease showed that among patients with dermatomyositis positive for antitranscriptional intermediary factor 1 (anti–TIF1-gamma) autoantibodies – a disease subtype associated with increased cancer risk – the presence of autoantibodies directed against cell division cycle and apoptosis regulator 1 (CCAR1) was associated with reduced cancer risk “to a level comparable to that seen in the general population,” Christopher A. Mecoli, MD, MHS, of Johns Hopkins University, Baltimore, and colleagues reported.

“Our prior data suggest that there are autoantigens that, when targeted simultaneously with CCAR1, provide additional cancer protection. Although these autoantigens are less frequently targeted, it is likely that additional, more prevalent ‘autoantigen hubs’ remain undiscovered,” they wrote in Arthritis & Rheumatology.

Identification of other autoantibodies both in the anti–TIF1-gamma–positive and other dermatomyositis subgroups may help with cancer risk stratification in patients with the disease and may ultimately improve cancer screening for adults with dermatomyositis, the investigators said.
 

Toward precision medicine

“I think this is a step toward precision medicine in patients with rheumatic disease, specifically myositis,” Dr. Mecoli said in an interview.

The study supports earlier work showing that dermatomyositis and related myopathies are heterogeneous, he said, noting that, “if you put 10 myositis patients in the same room, you wouldn’t get that they all have the same disease because they can look so different from one another.”

The association of dermatomyositis with concurrent cancers has been known for decades, but in recent years his team and other investigators have noted that the association holds true for only some patients with dermatomyositis, most notably those patients positive for anti–TIF1-gamma autoantibodies.

“And then, of course, once you really start studying just one gamma-positive dermatomyositis patient, you realize that even among that group it is heterogeneous in terms of their cancer risk, and that was the main focus of this study: to reconcile this clinical observation that I had a lot of patients with TIF1-gamma dermatomyositis who never get diagnosed with cancer,” Dr. Mecoli said.

Study details

Dr. Dr. Mecoli and colleagues previously reported that immune responses to CCAR1 and other autoantigens seen in patients with dermatomyositis were associated with lower probability of cancer occurrence.

In the current study, they focused on the disease specificity, clinical phenotype, and cancer risk for patients with dermatomyositis and anti-CCAR1 autoantibodies.

They looked at all patients aged 18 or older with a probable or definite finding of dermatomyositis, according to 2017 American College of Rheumatology/European Alliance of Associations for Rheumatology Idiopathic Inflammatory Myopathy criteria, who were seen at Stanford (Calif.) University Medical Center from August 2004 to April 2020 (101 patients), or the Johns Hopkins Myositis Center (141 patients) from January 2007 to December 2020.

Controls included 44 patients evaluated at the Johns Hopkins Myositis Center with immune-mediated necrotizing myopathy, 186 patients with anti–TIF1-gamma–negative dermatomyositis (defined as an enzyme-linked immunosorbent assay readout of less than seven units) evaluated at either Stanford or Johns Hopkins, 44 patients with inclusion body myositis evaluated at Johns Hopkins, and 46 patients with systemic lupus erythematosus from the Hopkins Lupus Cohort. The investigators also assayed serum from 32 healthy individuals.

They found that patients with anti–TIF1-gamma–positive dermatomyositis were significantly more likely than those with anti–TIF1-gamma–negative dermatomyositis to have anti-CCAR1 autoantibodies (32% vs. 8%; P < .001). Additionally, they noted that the anti-CCAR1 autoantibodies were not seen in serum from healthy controls and were found at only very low frequencies among patients with other rheumatic diseases.

When they looked at the incidence of cancer from the time of dermatomyositis onset (defined as the first patient-reported symptoms of rash, weakness, myalgia, or dyspnea) they found that the standardized incidence ratio in anti–TIF1-gamma–positive patients in both the Stanford and Hopkins cohorts was higher than expected, with SIRs of 3.49 and 4.54, respectively (P < .001 for each comparison).

However, among those patients who were both anti–TIF1-gamma positive and anti-CCAR1 positive, the SIRs were 1.78 in the Stanford cohort and 1.61 in the Hopkins cohort, and neither SIR was significantly higher than that of the general population.
 

Risk prediction

Their findings suggest that autoantibody profiles might be used for cancer risk stratification in patients with anti–TIF1-gamma–positive dermatomyositis, Dr. Mecoli said.

“Are we overscreening? What is the cost in terms of patient anxiety, in terms of radiation, and in terms of false positive results?” he asked. “If I had a patient in front of me with anti–TIF1-gamma dermatomyositis, I would probably manage them differently if I knew that they were CCAR1 positive, because the presence of that additional autoantibody attenuates their cancer risk relative to the general population.”

In an editorial accompanying the study, Manabu Fujimoto, MD, of the department of dermatology at Osaka (Japan) University, commented that it “is of clinical importance in that combination of autoantibodies can predict cancer risk with more accuracy. At the same time, this study will give an insight into the pathomechanisms of how antitumor activity may shape autoimmunity in dermatomyositis.”

It will be “intriguing” to discover whether anti-CCAR1 autoantibodies act only against tumors or might also have an impact on dermatomyositis itself, Dr. Fujimoto said.

The research was supported by grants from the National Institutes of Health; Huayi and Siuling Zhang Discovery Fund; Peter Buck, MD; and the Donald B. and Dorothy L. Stabler Foundation. The authors and Dr. Fujimoto reported no relevant financial relationships.

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

IgG4 fights viruses and bacteria. However, sometimes it targets the body itself. “This then leads to inflammation, the healing of which the body is unable to keep under control,” explained Ulf Müller-Ladner, MD, PhD, chairperson of the German Society of Internal Medicine.

At the DGIM annual press conference, Dr. Müller-Ladner, who is also director of the department of rheumatology and clinical immunology at the Kerckhoff Clinic in Bad Nauheim, Germany, explained how IgG4 inflammation is triggered throughout the body and what therapeutic options are available.
 

Many manifestations

IgG4-associated inflammation can affect one or more organs or the surrounding connective tissue and cause fibrosis. As a result of fibrosis, the organ gradually loses function and is eventually transformed completely into scarred connective tissue.

“In the case of IgG4-associated inflammation, these fibroses have a histological structure, but extracting a sample is not possible from every affected organ,” said Dr. Müller-Ladner. Liver, bile ducts, blood vessels, skin, eyes, or even the central nervous system – practically every organ system can be affected by these inflammatory reactions.

IgG4-associated diseases have likely been around for some time, but it is only in the past 10 years that awareness has grown that, despite various manifestations, “they are all one and the same disease,” said Dr. Müller-Ladner.

IgG4-associated chronic, inflammatory, fibrosing diseases were only classified together as a single entity in the past few years. In terms of pathophysiology, B lymphocytes, IgG4-positive plasma cells, follicular T-helper cells, cytotoxic CD4-positive T cells, and macrophages work together and trigger an inflammatory reaction, which then encourages fibroblasts to overproduce connective tissue.
 

Beware inexplicable inflammation

It is estimated that 1 in 100,000 people suffer from the disease, but the number of incorrectly categorized patients may be significantly higher.

The diagnostic challenge lies in the fact that IgG4-associated inflammation occurs in almost every organ. It can cause different symptoms, depending on the organ affected.

Dr. Müller-Ladner provided the following take-home message: “Every inexplicable inflammation event and every organ dysfunction, especially if associated with an increase in connective tissue, could be an IgG4-associated disease. Keeping this in mind is the key to recovery.”

With most people, the inflammation persists for many years before any symptoms of the disease develop. Highly acute courses of progression are also possible.

Classic symptoms, such as fever, are not so characteristic of the latent inflammatory reaction, and according to classification criteria published by specialist rheumatology societies, they are an exclusion criterion. This is true with respect to the differential diagnosis for vasculitis, which also occurs throughout the body.
 

Histology is key

Blood levels of IgG4 and imaging are not always enough to confirm the diagnosis. In such cases, the histology is often a crucial factor in making a definitive diagnosis. Dominant organs in IgG4-associated diseases are the pancreas, the liver, the gallbladder, the intestines, the retroperitoneum, large blood vessels, the kidneys, the heart, the brain, saliva, tear ducts, as well all of the body’s connective tissue.

The kidneys play host to inflammation in the connective tissue and space-occupying masses in particular. “If the pancreas is affected, the signs can vary from diffuse swelling to the onset of diabetes mellitus. In contrast, if the aorta is affected, then the inflammation is characterized through a thickening of the vessel walls, aneurysms, and the corresponding circulation disorders,” said Dr. Müller-Ladner.

Because of the long period before the diagnosis is made, more than 50% of patients exhibit irreversible organ damage at the time of diagnosis, he added.
 

Glucocorticoids and immunosuppressants

Despite therapeutic intervention, the disease can have a fatal outcome, even if the patient is young, said Dr. Müller-Ladner. Glucocorticoids are the current therapy of choice. The dose is more than 0.5 mg of prednisolone equivalent per kg of body weight. “This usually leads to a rapid improvement in the inflammation. Subsequently, every organ is thoroughly diagnosed to assess the severity of the disease and to plan further treatment steps.”

In the long term, proven immunosuppressants, such as azathioprine, mycophenolate, leflunomide, and methotrexate, can be used, just as for many other chronic inflammatory diseases. Cyclophosphamide or cyclosporine is used more rarely, owing to their side effect profiles.

Because of the B-cell dominance, B-cell–depleting therapy with rituximab is currently a highly effective therapeutic option but one that must be applied for, because such use is off label. “If the body responds well to the medication, organ function often recovers,” said Dr. Müller-Ladner.

This article was translated from the Medscape German edition. A version appeared on Medscape.com.

IgG4 fights viruses and bacteria. However, sometimes it targets the body itself. “This then leads to inflammation, the healing of which the body is unable to keep under control,” explained Ulf Müller-Ladner, MD, PhD, chairperson of the German Society of Internal Medicine.

At the DGIM annual press conference, Dr. Müller-Ladner, who is also director of the department of rheumatology and clinical immunology at the Kerckhoff Clinic in Bad Nauheim, Germany, explained how IgG4 inflammation is triggered throughout the body and what therapeutic options are available.
 

Many manifestations

IgG4-associated inflammation can affect one or more organs or the surrounding connective tissue and cause fibrosis. As a result of fibrosis, the organ gradually loses function and is eventually transformed completely into scarred connective tissue.

“In the case of IgG4-associated inflammation, these fibroses have a histological structure, but extracting a sample is not possible from every affected organ,” said Dr. Müller-Ladner. Liver, bile ducts, blood vessels, skin, eyes, or even the central nervous system – practically every organ system can be affected by these inflammatory reactions.

IgG4-associated diseases have likely been around for some time, but it is only in the past 10 years that awareness has grown that, despite various manifestations, “they are all one and the same disease,” said Dr. Müller-Ladner.

IgG4-associated chronic, inflammatory, fibrosing diseases were only classified together as a single entity in the past few years. In terms of pathophysiology, B lymphocytes, IgG4-positive plasma cells, follicular T-helper cells, cytotoxic CD4-positive T cells, and macrophages work together and trigger an inflammatory reaction, which then encourages fibroblasts to overproduce connective tissue.
 

Beware inexplicable inflammation

It is estimated that 1 in 100,000 people suffer from the disease, but the number of incorrectly categorized patients may be significantly higher.

The diagnostic challenge lies in the fact that IgG4-associated inflammation occurs in almost every organ. It can cause different symptoms, depending on the organ affected.

Dr. Müller-Ladner provided the following take-home message: “Every inexplicable inflammation event and every organ dysfunction, especially if associated with an increase in connective tissue, could be an IgG4-associated disease. Keeping this in mind is the key to recovery.”

With most people, the inflammation persists for many years before any symptoms of the disease develop. Highly acute courses of progression are also possible.

Classic symptoms, such as fever, are not so characteristic of the latent inflammatory reaction, and according to classification criteria published by specialist rheumatology societies, they are an exclusion criterion. This is true with respect to the differential diagnosis for vasculitis, which also occurs throughout the body.
 

Histology is key

Blood levels of IgG4 and imaging are not always enough to confirm the diagnosis. In such cases, the histology is often a crucial factor in making a definitive diagnosis. Dominant organs in IgG4-associated diseases are the pancreas, the liver, the gallbladder, the intestines, the retroperitoneum, large blood vessels, the kidneys, the heart, the brain, saliva, tear ducts, as well all of the body’s connective tissue.

The kidneys play host to inflammation in the connective tissue and space-occupying masses in particular. “If the pancreas is affected, the signs can vary from diffuse swelling to the onset of diabetes mellitus. In contrast, if the aorta is affected, then the inflammation is characterized through a thickening of the vessel walls, aneurysms, and the corresponding circulation disorders,” said Dr. Müller-Ladner.

Because of the long period before the diagnosis is made, more than 50% of patients exhibit irreversible organ damage at the time of diagnosis, he added.
 

Glucocorticoids and immunosuppressants

Despite therapeutic intervention, the disease can have a fatal outcome, even if the patient is young, said Dr. Müller-Ladner. Glucocorticoids are the current therapy of choice. The dose is more than 0.5 mg of prednisolone equivalent per kg of body weight. “This usually leads to a rapid improvement in the inflammation. Subsequently, every organ is thoroughly diagnosed to assess the severity of the disease and to plan further treatment steps.”

In the long term, proven immunosuppressants, such as azathioprine, mycophenolate, leflunomide, and methotrexate, can be used, just as for many other chronic inflammatory diseases. Cyclophosphamide or cyclosporine is used more rarely, owing to their side effect profiles.

Because of the B-cell dominance, B-cell–depleting therapy with rituximab is currently a highly effective therapeutic option but one that must be applied for, because such use is off label. “If the body responds well to the medication, organ function often recovers,” said Dr. Müller-Ladner.

This article was translated from the Medscape German edition. A version appeared on Medscape.com.

IgG4 fights viruses and bacteria. However, sometimes it targets the body itself. “This then leads to inflammation, the healing of which the body is unable to keep under control,” explained Ulf Müller-Ladner, MD, PhD, chairperson of the German Society of Internal Medicine.

At the DGIM annual press conference, Dr. Müller-Ladner, who is also director of the department of rheumatology and clinical immunology at the Kerckhoff Clinic in Bad Nauheim, Germany, explained how IgG4 inflammation is triggered throughout the body and what therapeutic options are available.
 

Many manifestations

IgG4-associated inflammation can affect one or more organs or the surrounding connective tissue and cause fibrosis. As a result of fibrosis, the organ gradually loses function and is eventually transformed completely into scarred connective tissue.

“In the case of IgG4-associated inflammation, these fibroses have a histological structure, but extracting a sample is not possible from every affected organ,” said Dr. Müller-Ladner. Liver, bile ducts, blood vessels, skin, eyes, or even the central nervous system – practically every organ system can be affected by these inflammatory reactions.

IgG4-associated diseases have likely been around for some time, but it is only in the past 10 years that awareness has grown that, despite various manifestations, “they are all one and the same disease,” said Dr. Müller-Ladner.

IgG4-associated chronic, inflammatory, fibrosing diseases were only classified together as a single entity in the past few years. In terms of pathophysiology, B lymphocytes, IgG4-positive plasma cells, follicular T-helper cells, cytotoxic CD4-positive T cells, and macrophages work together and trigger an inflammatory reaction, which then encourages fibroblasts to overproduce connective tissue.
 

Beware inexplicable inflammation

It is estimated that 1 in 100,000 people suffer from the disease, but the number of incorrectly categorized patients may be significantly higher.

The diagnostic challenge lies in the fact that IgG4-associated inflammation occurs in almost every organ. It can cause different symptoms, depending on the organ affected.

Dr. Müller-Ladner provided the following take-home message: “Every inexplicable inflammation event and every organ dysfunction, especially if associated with an increase in connective tissue, could be an IgG4-associated disease. Keeping this in mind is the key to recovery.”

With most people, the inflammation persists for many years before any symptoms of the disease develop. Highly acute courses of progression are also possible.

Classic symptoms, such as fever, are not so characteristic of the latent inflammatory reaction, and according to classification criteria published by specialist rheumatology societies, they are an exclusion criterion. This is true with respect to the differential diagnosis for vasculitis, which also occurs throughout the body.
 

Histology is key

Blood levels of IgG4 and imaging are not always enough to confirm the diagnosis. In such cases, the histology is often a crucial factor in making a definitive diagnosis. Dominant organs in IgG4-associated diseases are the pancreas, the liver, the gallbladder, the intestines, the retroperitoneum, large blood vessels, the kidneys, the heart, the brain, saliva, tear ducts, as well all of the body’s connective tissue.

The kidneys play host to inflammation in the connective tissue and space-occupying masses in particular. “If the pancreas is affected, the signs can vary from diffuse swelling to the onset of diabetes mellitus. In contrast, if the aorta is affected, then the inflammation is characterized through a thickening of the vessel walls, aneurysms, and the corresponding circulation disorders,” said Dr. Müller-Ladner.

Because of the long period before the diagnosis is made, more than 50% of patients exhibit irreversible organ damage at the time of diagnosis, he added.
 

Glucocorticoids and immunosuppressants

Despite therapeutic intervention, the disease can have a fatal outcome, even if the patient is young, said Dr. Müller-Ladner. Glucocorticoids are the current therapy of choice. The dose is more than 0.5 mg of prednisolone equivalent per kg of body weight. “This usually leads to a rapid improvement in the inflammation. Subsequently, every organ is thoroughly diagnosed to assess the severity of the disease and to plan further treatment steps.”

In the long term, proven immunosuppressants, such as azathioprine, mycophenolate, leflunomide, and methotrexate, can be used, just as for many other chronic inflammatory diseases. Cyclophosphamide or cyclosporine is used more rarely, owing to their side effect profiles.

Because of the B-cell dominance, B-cell–depleting therapy with rituximab is currently a highly effective therapeutic option but one that must be applied for, because such use is off label. “If the body responds well to the medication, organ function often recovers,” said Dr. Müller-Ladner.

This article was translated from the Medscape German edition. A version appeared on Medscape.com.

A tool that incorporates lupus-related variables with traditional risk factors provides a much more accurate assessment of cardiovascular (CV) risk in patients with systemic lupus erythematosus (SLE), according to data presented at the annual meeting of the Canadian Rheumatology Association.

In the initial clinical assessment of this tool, called the SLECRISK, “it identified high-risk lupus patients who would otherwise be missed by traditional methods of CV risk assessment,” reported May Y. Choi, MD, associate director of translational research at the University of Calgary’s (Alta.) Lupus Centre of Excellence.

bowdenimages/iStock/Getty Images

It is well known that patients with SLE face an increased risk of CV events starting at an age long before risk begins climbing in the general population, according to Dr. Choi. She cited one study that showed women aged 35-44 years have a 50-fold greater risk of myocardial infarction than healthy individuals.

All major guidelines recognize this increased risk and recommend CV risk assessment in patients with SLE, even though Dr. Choi pointed out that traditional tools, such as the American College of Cardiology atherosclerotic cardiovascular disease (ASCVD) risk calculator or the Framingham Risk Score (FRS) have a limited ability to detect the patients with SLE who are most likely to have an event.
 

In SLE, current tools are inadequate

“These risk assessment tools perform poorly in SLE patients because they do not capture SLE-related inflammation,” Dr. Choi said. Of several examples, Dr. Choi cited a study showing “seven times more MIs and strokes observed than expected in SLE patients on the basis of the FRS.”

The disparity between expected and observed MIs and strokes is worse with increasing severity of SLE. In a study she presented 3 years ago, rates of CV events were 12 times higher in those with inactive or mild SLE, rising to a 16-fold increase among those with moderate disease and jumping to a 32-fold increase in those with severe SLE.

The SLECRISK tool was developed from the Brigham and Women’s Hospital SLE Registry, which was initiated in 1992. Patients without a history of CV disease were evaluated for traditional CV risk factors and for SLE-specific characteristics such as disease activity, levels of the complement proteins C3 and C4, kidney function, the presence of nephritis, and SLE duration. The value of these characteristics as predictors of CV events were then assessed over a 10-year follow-up period before being assembled into the SLECRISK tool.

In an example of the risk equation, Dr. Choi described a 50-year-old patient with SLE and a 5% 10-year ASCVD risk score, which is low. After adjustment for SLE risks, which included 10 years disease duration, high disease activity, elevated creatinine, and positive anti–double stranded DNA status, the 10-year CV risk score climbed to 16.2%, which is moderate.

The performance of the SLECRISK was evaluated in 1,243 patients providing 8,946.51 person-years of follow-up. During this period, there were 90 major adverse cardiac events (MACE), of which 82% were adjudicated by cardiologists, and 211 secondary events.

Relative to the ASCVD risk score, the SLECRISK identified about twice as many patients with SLE as having moderate risk and 3.5-fold more patients as having high risk. Among patients who experienced CV events, traditional CV risk factors were more common but so were SLE-specific risk factors, including greater disease severity, a greater likelihood of lupus nephritis, increased complement levels, and greater exposure to glucocorticoids, according to Dr. Choi.

Specificities for CV events higher on SLECRISK

In predicting CV events, the differences in specificities were in the same general range, although somewhat higher for the ASCVD risk score in regard to predicting MACE (83% vs. 72%) and MACE plus secondary events (90% vs. 79%). However, the sensitivities were much higher for SLECRISK relative to the ASCVD risk score for MACE alone (64% vs. 41%) and for MACE plus secondary events (58% vs. 35%).

When comparing those who had an MI or stroke, the ASCVD risk score identified 8 (7%) patients missed by SLECRISK, whereas SLECRISK identified 89 (73%) missed by the ASCVD risk score. The remaining 25 patients (20%) were identified by both. The advantage of SLECRISK was similar for MACE plus secondary outcomes.

Dr. Choi noted that all of the SLE-specific variables in SLECRISK are readily obtained and often already available in patient charts. She said that there is a plan to validate the tool in larger groups, but with a goal of creating a tool available online for clinicians and their patients to use. There is also an even more ambitious plan for the future.

“We have funding to look at machine learning to evaluate predictive variables in SLE patients,” Dr. Choi said. Rather than adding SLE-specific variables to traditional risks, the plan is to “start from scratch,” letting artificial intelligence assemble predictors without prejudice to what might or might not be relevant.

A SLE-specific tool for evaluating CV risk is an important “unmet need,” according to Karen H. Costenbader, MD, professor in the division of rheumatology, inflammation, and immunity at Brigham and Women’s Hospital and Harvard Medical School, both in Boston. In an interview, she reiterated that measuring CV risk in SLE is already guideline recommended, but conventional tools have been shown to be inaccurate.

“I can envision it being used in clinical encounters to help guide shared decision-making with patients,” explained Dr. Costenbader, who was not involved in the presentation at the CRA meeting but worked with Dr. Choi in developing SLECRISK. “It would give us more precise estimates, allowing us to risk stratify our patients and informing us as to which modifiable SLE-specific and nonspecific factors are contributing most to CV risk.’

The problem of using conventional risk assessments in SLE has been well recognized. Of those who have written on this subject, Maureen McMahon, MD, site director of the Lupus Clinical Trials Network at the University of California, Los Angeles, said: “There is a critical need for the development of SLE-specific risk assessment tools like SLECRISK.”

Author of several studies looking at alternatives for CV risk assessment in SLE, including a study looking at a panel of biomarkers that was published in ACR Open Rheumatology, Dr. McMahon said in an interview that CV risk in SLE is high but conventional risk assessments are flawed.

“Multiple previous studies have demonstrated that these currently available calculators are not adequate for identifying risk in the lupus patient population,” she said. According to Dr. McMahon, the fact that rheumatologists remain “dependent upon [these conventional] cardiovascular risk calculators” is a well-recognized problem that needs resolution.

Dr. Choi has financial relationships with AstraZeneca, GlaxoSmithKline, Mallinckrodt. MitogenDx, Organon, and Werfen International. Dr. Costenbader reports no potential conflicts of interest. Dr. McMahon has financial relationships with AstraZeneca, Aurinia Pharmaceuticals, Eli Lilly, and GlaxoSmithKline.

A tool that incorporates lupus-related variables with traditional risk factors provides a much more accurate assessment of cardiovascular (CV) risk in patients with systemic lupus erythematosus (SLE), according to data presented at the annual meeting of the Canadian Rheumatology Association.

In the initial clinical assessment of this tool, called the SLECRISK, “it identified high-risk lupus patients who would otherwise be missed by traditional methods of CV risk assessment,” reported May Y. Choi, MD, associate director of translational research at the University of Calgary’s (Alta.) Lupus Centre of Excellence.

bowdenimages/iStock/Getty Images

It is well known that patients with SLE face an increased risk of CV events starting at an age long before risk begins climbing in the general population, according to Dr. Choi. She cited one study that showed women aged 35-44 years have a 50-fold greater risk of myocardial infarction than healthy individuals.

All major guidelines recognize this increased risk and recommend CV risk assessment in patients with SLE, even though Dr. Choi pointed out that traditional tools, such as the American College of Cardiology atherosclerotic cardiovascular disease (ASCVD) risk calculator or the Framingham Risk Score (FRS) have a limited ability to detect the patients with SLE who are most likely to have an event.
 

In SLE, current tools are inadequate

“These risk assessment tools perform poorly in SLE patients because they do not capture SLE-related inflammation,” Dr. Choi said. Of several examples, Dr. Choi cited a study showing “seven times more MIs and strokes observed than expected in SLE patients on the basis of the FRS.”

The disparity between expected and observed MIs and strokes is worse with increasing severity of SLE. In a study she presented 3 years ago, rates of CV events were 12 times higher in those with inactive or mild SLE, rising to a 16-fold increase among those with moderate disease and jumping to a 32-fold increase in those with severe SLE.

The SLECRISK tool was developed from the Brigham and Women’s Hospital SLE Registry, which was initiated in 1992. Patients without a history of CV disease were evaluated for traditional CV risk factors and for SLE-specific characteristics such as disease activity, levels of the complement proteins C3 and C4, kidney function, the presence of nephritis, and SLE duration. The value of these characteristics as predictors of CV events were then assessed over a 10-year follow-up period before being assembled into the SLECRISK tool.

In an example of the risk equation, Dr. Choi described a 50-year-old patient with SLE and a 5% 10-year ASCVD risk score, which is low. After adjustment for SLE risks, which included 10 years disease duration, high disease activity, elevated creatinine, and positive anti–double stranded DNA status, the 10-year CV risk score climbed to 16.2%, which is moderate.

The performance of the SLECRISK was evaluated in 1,243 patients providing 8,946.51 person-years of follow-up. During this period, there were 90 major adverse cardiac events (MACE), of which 82% were adjudicated by cardiologists, and 211 secondary events.

Relative to the ASCVD risk score, the SLECRISK identified about twice as many patients with SLE as having moderate risk and 3.5-fold more patients as having high risk. Among patients who experienced CV events, traditional CV risk factors were more common but so were SLE-specific risk factors, including greater disease severity, a greater likelihood of lupus nephritis, increased complement levels, and greater exposure to glucocorticoids, according to Dr. Choi.

Specificities for CV events higher on SLECRISK

In predicting CV events, the differences in specificities were in the same general range, although somewhat higher for the ASCVD risk score in regard to predicting MACE (83% vs. 72%) and MACE plus secondary events (90% vs. 79%). However, the sensitivities were much higher for SLECRISK relative to the ASCVD risk score for MACE alone (64% vs. 41%) and for MACE plus secondary events (58% vs. 35%).

When comparing those who had an MI or stroke, the ASCVD risk score identified 8 (7%) patients missed by SLECRISK, whereas SLECRISK identified 89 (73%) missed by the ASCVD risk score. The remaining 25 patients (20%) were identified by both. The advantage of SLECRISK was similar for MACE plus secondary outcomes.

Dr. Choi noted that all of the SLE-specific variables in SLECRISK are readily obtained and often already available in patient charts. She said that there is a plan to validate the tool in larger groups, but with a goal of creating a tool available online for clinicians and their patients to use. There is also an even more ambitious plan for the future.

“We have funding to look at machine learning to evaluate predictive variables in SLE patients,” Dr. Choi said. Rather than adding SLE-specific variables to traditional risks, the plan is to “start from scratch,” letting artificial intelligence assemble predictors without prejudice to what might or might not be relevant.

A SLE-specific tool for evaluating CV risk is an important “unmet need,” according to Karen H. Costenbader, MD, professor in the division of rheumatology, inflammation, and immunity at Brigham and Women’s Hospital and Harvard Medical School, both in Boston. In an interview, she reiterated that measuring CV risk in SLE is already guideline recommended, but conventional tools have been shown to be inaccurate.

“I can envision it being used in clinical encounters to help guide shared decision-making with patients,” explained Dr. Costenbader, who was not involved in the presentation at the CRA meeting but worked with Dr. Choi in developing SLECRISK. “It would give us more precise estimates, allowing us to risk stratify our patients and informing us as to which modifiable SLE-specific and nonspecific factors are contributing most to CV risk.’

The problem of using conventional risk assessments in SLE has been well recognized. Of those who have written on this subject, Maureen McMahon, MD, site director of the Lupus Clinical Trials Network at the University of California, Los Angeles, said: “There is a critical need for the development of SLE-specific risk assessment tools like SLECRISK.”

Author of several studies looking at alternatives for CV risk assessment in SLE, including a study looking at a panel of biomarkers that was published in ACR Open Rheumatology, Dr. McMahon said in an interview that CV risk in SLE is high but conventional risk assessments are flawed.

“Multiple previous studies have demonstrated that these currently available calculators are not adequate for identifying risk in the lupus patient population,” she said. According to Dr. McMahon, the fact that rheumatologists remain “dependent upon [these conventional] cardiovascular risk calculators” is a well-recognized problem that needs resolution.

Dr. Choi has financial relationships with AstraZeneca, GlaxoSmithKline, Mallinckrodt. MitogenDx, Organon, and Werfen International. Dr. Costenbader reports no potential conflicts of interest. Dr. McMahon has financial relationships with AstraZeneca, Aurinia Pharmaceuticals, Eli Lilly, and GlaxoSmithKline.

A tool that incorporates lupus-related variables with traditional risk factors provides a much more accurate assessment of cardiovascular (CV) risk in patients with systemic lupus erythematosus (SLE), according to data presented at the annual meeting of the Canadian Rheumatology Association.

In the initial clinical assessment of this tool, called the SLECRISK, “it identified high-risk lupus patients who would otherwise be missed by traditional methods of CV risk assessment,” reported May Y. Choi, MD, associate director of translational research at the University of Calgary’s (Alta.) Lupus Centre of Excellence.

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It is well known that patients with SLE face an increased risk of CV events starting at an age long before risk begins climbing in the general population, according to Dr. Choi. She cited one study that showed women aged 35-44 years have a 50-fold greater risk of myocardial infarction than healthy individuals.

All major guidelines recognize this increased risk and recommend CV risk assessment in patients with SLE, even though Dr. Choi pointed out that traditional tools, such as the American College of Cardiology atherosclerotic cardiovascular disease (ASCVD) risk calculator or the Framingham Risk Score (FRS) have a limited ability to detect the patients with SLE who are most likely to have an event.
 

In SLE, current tools are inadequate

“These risk assessment tools perform poorly in SLE patients because they do not capture SLE-related inflammation,” Dr. Choi said. Of several examples, Dr. Choi cited a study showing “seven times more MIs and strokes observed than expected in SLE patients on the basis of the FRS.”

The disparity between expected and observed MIs and strokes is worse with increasing severity of SLE. In a study she presented 3 years ago, rates of CV events were 12 times higher in those with inactive or mild SLE, rising to a 16-fold increase among those with moderate disease and jumping to a 32-fold increase in those with severe SLE.

The SLECRISK tool was developed from the Brigham and Women’s Hospital SLE Registry, which was initiated in 1992. Patients without a history of CV disease were evaluated for traditional CV risk factors and for SLE-specific characteristics such as disease activity, levels of the complement proteins C3 and C4, kidney function, the presence of nephritis, and SLE duration. The value of these characteristics as predictors of CV events were then assessed over a 10-year follow-up period before being assembled into the SLECRISK tool.

In an example of the risk equation, Dr. Choi described a 50-year-old patient with SLE and a 5% 10-year ASCVD risk score, which is low. After adjustment for SLE risks, which included 10 years disease duration, high disease activity, elevated creatinine, and positive anti–double stranded DNA status, the 10-year CV risk score climbed to 16.2%, which is moderate.

The performance of the SLECRISK was evaluated in 1,243 patients providing 8,946.51 person-years of follow-up. During this period, there were 90 major adverse cardiac events (MACE), of which 82% were adjudicated by cardiologists, and 211 secondary events.

Relative to the ASCVD risk score, the SLECRISK identified about twice as many patients with SLE as having moderate risk and 3.5-fold more patients as having high risk. Among patients who experienced CV events, traditional CV risk factors were more common but so were SLE-specific risk factors, including greater disease severity, a greater likelihood of lupus nephritis, increased complement levels, and greater exposure to glucocorticoids, according to Dr. Choi.

Specificities for CV events higher on SLECRISK

In predicting CV events, the differences in specificities were in the same general range, although somewhat higher for the ASCVD risk score in regard to predicting MACE (83% vs. 72%) and MACE plus secondary events (90% vs. 79%). However, the sensitivities were much higher for SLECRISK relative to the ASCVD risk score for MACE alone (64% vs. 41%) and for MACE plus secondary events (58% vs. 35%).

When comparing those who had an MI or stroke, the ASCVD risk score identified 8 (7%) patients missed by SLECRISK, whereas SLECRISK identified 89 (73%) missed by the ASCVD risk score. The remaining 25 patients (20%) were identified by both. The advantage of SLECRISK was similar for MACE plus secondary outcomes.

Dr. Choi noted that all of the SLE-specific variables in SLECRISK are readily obtained and often already available in patient charts. She said that there is a plan to validate the tool in larger groups, but with a goal of creating a tool available online for clinicians and their patients to use. There is also an even more ambitious plan for the future.

“We have funding to look at machine learning to evaluate predictive variables in SLE patients,” Dr. Choi said. Rather than adding SLE-specific variables to traditional risks, the plan is to “start from scratch,” letting artificial intelligence assemble predictors without prejudice to what might or might not be relevant.

A SLE-specific tool for evaluating CV risk is an important “unmet need,” according to Karen H. Costenbader, MD, professor in the division of rheumatology, inflammation, and immunity at Brigham and Women’s Hospital and Harvard Medical School, both in Boston. In an interview, she reiterated that measuring CV risk in SLE is already guideline recommended, but conventional tools have been shown to be inaccurate.

“I can envision it being used in clinical encounters to help guide shared decision-making with patients,” explained Dr. Costenbader, who was not involved in the presentation at the CRA meeting but worked with Dr. Choi in developing SLECRISK. “It would give us more precise estimates, allowing us to risk stratify our patients and informing us as to which modifiable SLE-specific and nonspecific factors are contributing most to CV risk.’

The problem of using conventional risk assessments in SLE has been well recognized. Of those who have written on this subject, Maureen McMahon, MD, site director of the Lupus Clinical Trials Network at the University of California, Los Angeles, said: “There is a critical need for the development of SLE-specific risk assessment tools like SLECRISK.”

Author of several studies looking at alternatives for CV risk assessment in SLE, including a study looking at a panel of biomarkers that was published in ACR Open Rheumatology, Dr. McMahon said in an interview that CV risk in SLE is high but conventional risk assessments are flawed.

“Multiple previous studies have demonstrated that these currently available calculators are not adequate for identifying risk in the lupus patient population,” she said. According to Dr. McMahon, the fact that rheumatologists remain “dependent upon [these conventional] cardiovascular risk calculators” is a well-recognized problem that needs resolution.

Dr. Choi has financial relationships with AstraZeneca, GlaxoSmithKline, Mallinckrodt. MitogenDx, Organon, and Werfen International. Dr. Costenbader reports no potential conflicts of interest. Dr. McMahon has financial relationships with AstraZeneca, Aurinia Pharmaceuticals, Eli Lilly, and GlaxoSmithKline.

Both public and private health plans score poorly when it comes to providing access to autoimmune medication, according to a report commissioned by the Autoimmune Association and Let My Doctors Decide, a national partnership of health care professionals. The analysis, published Jan. 26, found that 75% of insurers in the United States have policies that can limit coverage for Food and Drug Administration–approved medications for Crohn’s disease, lupus nephritis, multiple sclerosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, and ulcerative colitis.

“Choice among health plans is a hallmark of the American health insurance system, yet this analysis shows that people living with autoimmune conditions have few, if any, coverage choices that do not involve significant to severe access restrictions,” the authors wrote.

The study looked at three common utilization management policies by health plans that can limit coverage of certain medications: step therapy, formulary/tier placement, and prior authorization. To compare health plans, researchers weighted these policies using a point system. Each medication indicated for each condition was given a score of 0-4 based on access restrictions in a health plan. If a plan used step therapy, it received one point, and requiring prior authorization added an additional point. They also added points based on where a drug appeared on a plan’s formulary. A lower total score meant fewer access barriers. The numbers were then added, and each health plan received a grade of A, B, C, or F based on their average score. The datasets and analysis were provided and performed by the data analytics firm MMIT.

Nearly 9 in 10 Medicare plans received a C or worse for coverage of medication received via mail order or the pharmacy. In commercial plans, the majority of plans scored Cs or Fs for six of the seven conditions, excluding lupus nephritis, where 67% of all commercial health plans scored a B for access to these medications.

Physician-administered medications tended to receive poorer coverage than drugs received via pharmacy. Across all conditions, 65% of Medicare Advantage plans scored an F for physician-administered medication access. For both psoriasis and multiple sclerosis, at least 80% of Medicare plans earned failing scores because of these restrictions. Coverage was poorer on both commercial and health exchange plans, where across all conditions, 83% achieved failing scores. Two exceptions were the Southern and Northern California PPO plans by the Kaiser Foundation Health Plan. Out of the largest 25 health plans in the United States, these two plans earned As in coverage for physician-administered medications across all seven autoimmune conditions.

The report shows “a growing disconnect between science and health insurance benefit designs that were developed in the 1960s and 1970s,” Kenneth Thorpe, PhD, of Emory University, Atlanta, said in an interview. Insurers originally designed these benefits to prevent excessive utilization in a population of mostly acutely ill patients, he said, whereas now, 90% of healthcare spending is linked to chronic conditions. For these patients, research shows that incentivizing patients to adhere to medications results in fewer hospitalizations and, therefore, more cost savings, Thorpe noted. These plans also do not consider that there is no average patient, he said, and healthcare providers should be able to match each patient to the best treatment option for them rather than trying out other less expensive medications first. “To the extent that physicians can have the flexibility to provide medications and treatments to patients that are going to have the best clinical response, that’s better outcomes at lower cost,” Dr. Thorpe said. While research shows heterogeneity in patient outcomes with different medication, “benefit designs from the past just don’t recognize that.”

Neither America’s Health Insurance Plans nor Pharmaceutical Care Management Association responded to a request for comment.

Quardricos Driskell, executive director of Let My Doctors Decide and vice president of government relations and public policy at the Autoimmune Association, hopes the study will spur action by policy makers and health plans to improve access to medications for the people who need them. Another larger point of the report is to “uphold the sanctity of protecting the doctor and patient relationship,” he said in an interview, adding “that decisions fundamentally need to be made not by insurance plans or middleman pharmacy benefit managers, but by the provider and patient.”

Mr. Driskell and Dr. Thorpe reported no relevant financial relationships. 

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

Both public and private health plans score poorly when it comes to providing access to autoimmune medication, according to a report commissioned by the Autoimmune Association and Let My Doctors Decide, a national partnership of health care professionals. The analysis, published Jan. 26, found that 75% of insurers in the United States have policies that can limit coverage for Food and Drug Administration–approved medications for Crohn’s disease, lupus nephritis, multiple sclerosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, and ulcerative colitis.

“Choice among health plans is a hallmark of the American health insurance system, yet this analysis shows that people living with autoimmune conditions have few, if any, coverage choices that do not involve significant to severe access restrictions,” the authors wrote.

The study looked at three common utilization management policies by health plans that can limit coverage of certain medications: step therapy, formulary/tier placement, and prior authorization. To compare health plans, researchers weighted these policies using a point system. Each medication indicated for each condition was given a score of 0-4 based on access restrictions in a health plan. If a plan used step therapy, it received one point, and requiring prior authorization added an additional point. They also added points based on where a drug appeared on a plan’s formulary. A lower total score meant fewer access barriers. The numbers were then added, and each health plan received a grade of A, B, C, or F based on their average score. The datasets and analysis were provided and performed by the data analytics firm MMIT.

Nearly 9 in 10 Medicare plans received a C or worse for coverage of medication received via mail order or the pharmacy. In commercial plans, the majority of plans scored Cs or Fs for six of the seven conditions, excluding lupus nephritis, where 67% of all commercial health plans scored a B for access to these medications.

Physician-administered medications tended to receive poorer coverage than drugs received via pharmacy. Across all conditions, 65% of Medicare Advantage plans scored an F for physician-administered medication access. For both psoriasis and multiple sclerosis, at least 80% of Medicare plans earned failing scores because of these restrictions. Coverage was poorer on both commercial and health exchange plans, where across all conditions, 83% achieved failing scores. Two exceptions were the Southern and Northern California PPO plans by the Kaiser Foundation Health Plan. Out of the largest 25 health plans in the United States, these two plans earned As in coverage for physician-administered medications across all seven autoimmune conditions.

The report shows “a growing disconnect between science and health insurance benefit designs that were developed in the 1960s and 1970s,” Kenneth Thorpe, PhD, of Emory University, Atlanta, said in an interview. Insurers originally designed these benefits to prevent excessive utilization in a population of mostly acutely ill patients, he said, whereas now, 90% of healthcare spending is linked to chronic conditions. For these patients, research shows that incentivizing patients to adhere to medications results in fewer hospitalizations and, therefore, more cost savings, Thorpe noted. These plans also do not consider that there is no average patient, he said, and healthcare providers should be able to match each patient to the best treatment option for them rather than trying out other less expensive medications first. “To the extent that physicians can have the flexibility to provide medications and treatments to patients that are going to have the best clinical response, that’s better outcomes at lower cost,” Dr. Thorpe said. While research shows heterogeneity in patient outcomes with different medication, “benefit designs from the past just don’t recognize that.”

Neither America’s Health Insurance Plans nor Pharmaceutical Care Management Association responded to a request for comment.

Quardricos Driskell, executive director of Let My Doctors Decide and vice president of government relations and public policy at the Autoimmune Association, hopes the study will spur action by policy makers and health plans to improve access to medications for the people who need them. Another larger point of the report is to “uphold the sanctity of protecting the doctor and patient relationship,” he said in an interview, adding “that decisions fundamentally need to be made not by insurance plans or middleman pharmacy benefit managers, but by the provider and patient.”

Mr. Driskell and Dr. Thorpe reported no relevant financial relationships. 

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

Both public and private health plans score poorly when it comes to providing access to autoimmune medication, according to a report commissioned by the Autoimmune Association and Let My Doctors Decide, a national partnership of health care professionals. The analysis, published Jan. 26, found that 75% of insurers in the United States have policies that can limit coverage for Food and Drug Administration–approved medications for Crohn’s disease, lupus nephritis, multiple sclerosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, and ulcerative colitis.

“Choice among health plans is a hallmark of the American health insurance system, yet this analysis shows that people living with autoimmune conditions have few, if any, coverage choices that do not involve significant to severe access restrictions,” the authors wrote.

The study looked at three common utilization management policies by health plans that can limit coverage of certain medications: step therapy, formulary/tier placement, and prior authorization. To compare health plans, researchers weighted these policies using a point system. Each medication indicated for each condition was given a score of 0-4 based on access restrictions in a health plan. If a plan used step therapy, it received one point, and requiring prior authorization added an additional point. They also added points based on where a drug appeared on a plan’s formulary. A lower total score meant fewer access barriers. The numbers were then added, and each health plan received a grade of A, B, C, or F based on their average score. The datasets and analysis were provided and performed by the data analytics firm MMIT.

Nearly 9 in 10 Medicare plans received a C or worse for coverage of medication received via mail order or the pharmacy. In commercial plans, the majority of plans scored Cs or Fs for six of the seven conditions, excluding lupus nephritis, where 67% of all commercial health plans scored a B for access to these medications.

Physician-administered medications tended to receive poorer coverage than drugs received via pharmacy. Across all conditions, 65% of Medicare Advantage plans scored an F for physician-administered medication access. For both psoriasis and multiple sclerosis, at least 80% of Medicare plans earned failing scores because of these restrictions. Coverage was poorer on both commercial and health exchange plans, where across all conditions, 83% achieved failing scores. Two exceptions were the Southern and Northern California PPO plans by the Kaiser Foundation Health Plan. Out of the largest 25 health plans in the United States, these two plans earned As in coverage for physician-administered medications across all seven autoimmune conditions.

The report shows “a growing disconnect between science and health insurance benefit designs that were developed in the 1960s and 1970s,” Kenneth Thorpe, PhD, of Emory University, Atlanta, said in an interview. Insurers originally designed these benefits to prevent excessive utilization in a population of mostly acutely ill patients, he said, whereas now, 90% of healthcare spending is linked to chronic conditions. For these patients, research shows that incentivizing patients to adhere to medications results in fewer hospitalizations and, therefore, more cost savings, Thorpe noted. These plans also do not consider that there is no average patient, he said, and healthcare providers should be able to match each patient to the best treatment option for them rather than trying out other less expensive medications first. “To the extent that physicians can have the flexibility to provide medications and treatments to patients that are going to have the best clinical response, that’s better outcomes at lower cost,” Dr. Thorpe said. While research shows heterogeneity in patient outcomes with different medication, “benefit designs from the past just don’t recognize that.”

Neither America’s Health Insurance Plans nor Pharmaceutical Care Management Association responded to a request for comment.

Quardricos Driskell, executive director of Let My Doctors Decide and vice president of government relations and public policy at the Autoimmune Association, hopes the study will spur action by policy makers and health plans to improve access to medications for the people who need them. Another larger point of the report is to “uphold the sanctity of protecting the doctor and patient relationship,” he said in an interview, adding “that decisions fundamentally need to be made not by insurance plans or middleman pharmacy benefit managers, but by the provider and patient.”

Mr. Driskell and Dr. Thorpe reported no relevant financial relationships. 

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