Lupus & Connective Tissue Diseases

An international registry of adult and pediatric rheumatology patients is beginning to identify trends in the types of patients with COVID-19 and who is recovering.

The COVID-19 Global Rheumatology Alliance (GRA) has created pediatric and adult registries for health care providers to enter information on their rheumatology patients with COVID-19. The adult registry is hosted by the University of California, San Francisco, Research Electronic Data Capture system, while the Childhood Arthritis and Rheumatology Research Alliance is supporting the pediatric registry. A separate path for data entry of both adult and pediatric cases has been established through the European League Against Rheumatism for European countries and countries with EULAR member organizations.

Prior to the creation of the registries, there were no data available to guide rheumatologists in clinical decision making for their patients, noted Jinoos Yazdany, MD, MPH, COVID-19 GRA steering committee member and chief of the division of rheumatology at Zuckerberg San Francisco General Hospital. “COVID-19 has potential to severely affect those with rheumatologic diseases or those taking immunosuppressive drugs,” she said in an interview. “The GRA registries were designed to answer critical questions that will inform the medical care of this population.”

The GRA began on Twitter, with conversations between Leonard H. Calabrese, DO, of the Cleveland Clinic; Paul Sufka, MD, of HealthPartners in St. Paul, Minn.; Philip Robinson, MBChB, PhD, of the Royal Brisbane (Australia) Hospital; and herself, Dr. Yazdany said. Dr. Robinson started work on the governance of the GRA, Dr. Yazdany designed the data infrastructure, and Dr. Sufka approached his professional networks and social media followings to promote the effort and ask for support. The COVID-19 GRA steering committee representatives include patients, private practice rheumatologists, and international investigators. Listed among official supporters of the alliance are the American College of Rheumatology and EULAR along with more than 290 medical societies, institutions, journals, and other organizations in rheumatology.

The goal of the registries is to examine the health outcomes of patients with rheumatic diseases and COVID-19 based on sociodemographic factors, comorbidities, and clinical presentations of COVID-19 as well as what role taking immunosuppressive drugs prior to a COVID-19 infection play in helping or hindering outcomes. Hydroxychloroquine, used to treat lupus and arthritis, is a potential treatment candidate for COVID-19. Biologics such as tocilizumab (Actemra) and sarilumab (Kevzara), which target interleukin-6, and anakinra (Kineret), which targets IL-1, are treatment candidates for patients who have experienced COVID-related cytokine storm syndrome, which researchers believe may contribute to worsening or fatal cases.

Dr. Yazdany, who is also vice chair of real-world data infrastructure, registry, and institutional review board/ethics for the GRA, said that there are some important high-level trends in the data thus far. “People with lupus and those taking hydroxychloroquine are becoming infected with SARS-CoV-2, which is counter to misinformation on social media. Most people with rheumatic diseases on immunosuppression are recovering, which is great news for our patients.”

One of the major strengths of the registries is that each case is entered by the rheumatologist treating the patient and contains detailed clinical information, Dr. Yazdany said. However, the registry has no control group, it is not a population surveillance study, and it may contain selection bias through rheumatologists omitting milder, undiagnosed cases.

“The Global Alliance case reporting registry represents the collective effort of hundreds of rheumatologists across the world. I have never been more inspired by the strength and collaboration of the rheumatology community,” Dr. Yazdany said.

According to a paper published in the Lancet Rheumatology, which references data on 110 cases from the combined databases up to April 1, about three-fourths of cases presented with fever (79%) and cough (77%), and about half presented with shortness of breath (50%) and myalgia (45%).
 

Results from the global and UCSF registries

As of April 18, 334 cases were in the global and UCSF registries, with 121 patients (36%) in the database having both COVID-19 and RA, 33 patients (10%) with psoriatic arthritis, 58 patients (17%) with systemic lupus erythematosus, 28 patients (8%) with axial spondyloarthritis, 27 patients (8%) with vasculitis, and 19 patients (6%) with Sjögren’s syndrome. There were less than five cases reported for patients with the following rheumatic diseases: inflammatory myopathy, ocular inflammation, other inflammatory arthritis, polymyalgia rheumatica, sarcoidosis, systemic sclerosis, osteoporosis, psoriasis, isolated pulmonary capillaritis, gout, and autoinflammatory disease. A majority of the patients in the registries are women (74%) aged younger than 65 years (78%) and are white (52%).

The most common comorbid conditions among patients in the registry are hypertension (33%), lung disease (18%), diabetes (11%), cardiovascular disease (10%), chronic renal insufficiency or end-stage renal disease (7%), morbid obesity (7%), and cancer (4%). Before being diagnosed with COVID-19, 219 patients (66%) in the registry were taking conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), which included antimalarials, azathioprine, cyclophosphamide, cyclosporine, leflunomide, methotrexate, mycophenolate mofetil/mycophenolic acid, sulfasalazine, and tacrolimus. A total of 122 patients (37%) were taking biologic DMARDs, 101 patients were taking glucocorticoids (30%), 86 patients (26%) were taking hydroxychloroquine, 41 patients (12%) were taking NSAIDs, and 18 patients (5%) were taking a Janus kinase inhibitor.

The most recent data from the registry show that 128 patients (38%) have been hospitalized for COVID-19, and 19 patients (6%) have died. Although 104 patients (31%) resolved their infections, 177 patients (53%) have a COVID-19 infection status of “unresolved,” and 53 patients (16%) have an unknown infection status.
 

EULAR registry results

As of April 21, 249 cases were in the EULAR registry, including 110 hospitalizations (44%) and 37 deaths (15%). Overall, 64% of these patients were women, and they had a median age of 60 years.

The top five diagnoses of these patients were RA (39%), psoriatic arthritis (15%), spondyloarthritis (9%), systemic lupus erythematosus (9%), and gout (5%). A total of 27% had no reported comorbidities, while lung disease occurred in 26%, hypertension in 34%, diabetes in 11%, and cardiovascular disease on 11%. The registry also reported use of any DMARD in 80%, including 62% on csDMARDs, 31% on biologics, and 2% on targeted synthetic DMARDs.

Ten authors in the Lancet Rheumatology paper reported personal and institutional relationships in the form of grants, corporate sponsorships, advisory board memberships, investigator appointments, speaker’s bureau positions, personal fees, and consultancies for a variety of pharmaceutical companies, agencies, societies, and other organizations. The other authors reported no relevant conflicts of interest.

An international registry of adult and pediatric rheumatology patients is beginning to identify trends in the types of patients with COVID-19 and who is recovering.

The COVID-19 Global Rheumatology Alliance (GRA) has created pediatric and adult registries for health care providers to enter information on their rheumatology patients with COVID-19. The adult registry is hosted by the University of California, San Francisco, Research Electronic Data Capture system, while the Childhood Arthritis and Rheumatology Research Alliance is supporting the pediatric registry. A separate path for data entry of both adult and pediatric cases has been established through the European League Against Rheumatism for European countries and countries with EULAR member organizations.

Prior to the creation of the registries, there were no data available to guide rheumatologists in clinical decision making for their patients, noted Jinoos Yazdany, MD, MPH, COVID-19 GRA steering committee member and chief of the division of rheumatology at Zuckerberg San Francisco General Hospital. “COVID-19 has potential to severely affect those with rheumatologic diseases or those taking immunosuppressive drugs,” she said in an interview. “The GRA registries were designed to answer critical questions that will inform the medical care of this population.”

The GRA began on Twitter, with conversations between Leonard H. Calabrese, DO, of the Cleveland Clinic; Paul Sufka, MD, of HealthPartners in St. Paul, Minn.; Philip Robinson, MBChB, PhD, of the Royal Brisbane (Australia) Hospital; and herself, Dr. Yazdany said. Dr. Robinson started work on the governance of the GRA, Dr. Yazdany designed the data infrastructure, and Dr. Sufka approached his professional networks and social media followings to promote the effort and ask for support. The COVID-19 GRA steering committee representatives include patients, private practice rheumatologists, and international investigators. Listed among official supporters of the alliance are the American College of Rheumatology and EULAR along with more than 290 medical societies, institutions, journals, and other organizations in rheumatology.

The goal of the registries is to examine the health outcomes of patients with rheumatic diseases and COVID-19 based on sociodemographic factors, comorbidities, and clinical presentations of COVID-19 as well as what role taking immunosuppressive drugs prior to a COVID-19 infection play in helping or hindering outcomes. Hydroxychloroquine, used to treat lupus and arthritis, is a potential treatment candidate for COVID-19. Biologics such as tocilizumab (Actemra) and sarilumab (Kevzara), which target interleukin-6, and anakinra (Kineret), which targets IL-1, are treatment candidates for patients who have experienced COVID-related cytokine storm syndrome, which researchers believe may contribute to worsening or fatal cases.

Dr. Yazdany, who is also vice chair of real-world data infrastructure, registry, and institutional review board/ethics for the GRA, said that there are some important high-level trends in the data thus far. “People with lupus and those taking hydroxychloroquine are becoming infected with SARS-CoV-2, which is counter to misinformation on social media. Most people with rheumatic diseases on immunosuppression are recovering, which is great news for our patients.”

One of the major strengths of the registries is that each case is entered by the rheumatologist treating the patient and contains detailed clinical information, Dr. Yazdany said. However, the registry has no control group, it is not a population surveillance study, and it may contain selection bias through rheumatologists omitting milder, undiagnosed cases.

“The Global Alliance case reporting registry represents the collective effort of hundreds of rheumatologists across the world. I have never been more inspired by the strength and collaboration of the rheumatology community,” Dr. Yazdany said.

According to a paper published in the Lancet Rheumatology, which references data on 110 cases from the combined databases up to April 1, about three-fourths of cases presented with fever (79%) and cough (77%), and about half presented with shortness of breath (50%) and myalgia (45%).
 

Results from the global and UCSF registries

As of April 18, 334 cases were in the global and UCSF registries, with 121 patients (36%) in the database having both COVID-19 and RA, 33 patients (10%) with psoriatic arthritis, 58 patients (17%) with systemic lupus erythematosus, 28 patients (8%) with axial spondyloarthritis, 27 patients (8%) with vasculitis, and 19 patients (6%) with Sjögren’s syndrome. There were less than five cases reported for patients with the following rheumatic diseases: inflammatory myopathy, ocular inflammation, other inflammatory arthritis, polymyalgia rheumatica, sarcoidosis, systemic sclerosis, osteoporosis, psoriasis, isolated pulmonary capillaritis, gout, and autoinflammatory disease. A majority of the patients in the registries are women (74%) aged younger than 65 years (78%) and are white (52%).

The most common comorbid conditions among patients in the registry are hypertension (33%), lung disease (18%), diabetes (11%), cardiovascular disease (10%), chronic renal insufficiency or end-stage renal disease (7%), morbid obesity (7%), and cancer (4%). Before being diagnosed with COVID-19, 219 patients (66%) in the registry were taking conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), which included antimalarials, azathioprine, cyclophosphamide, cyclosporine, leflunomide, methotrexate, mycophenolate mofetil/mycophenolic acid, sulfasalazine, and tacrolimus. A total of 122 patients (37%) were taking biologic DMARDs, 101 patients were taking glucocorticoids (30%), 86 patients (26%) were taking hydroxychloroquine, 41 patients (12%) were taking NSAIDs, and 18 patients (5%) were taking a Janus kinase inhibitor.

The most recent data from the registry show that 128 patients (38%) have been hospitalized for COVID-19, and 19 patients (6%) have died. Although 104 patients (31%) resolved their infections, 177 patients (53%) have a COVID-19 infection status of “unresolved,” and 53 patients (16%) have an unknown infection status.
 

EULAR registry results

As of April 21, 249 cases were in the EULAR registry, including 110 hospitalizations (44%) and 37 deaths (15%). Overall, 64% of these patients were women, and they had a median age of 60 years.

The top five diagnoses of these patients were RA (39%), psoriatic arthritis (15%), spondyloarthritis (9%), systemic lupus erythematosus (9%), and gout (5%). A total of 27% had no reported comorbidities, while lung disease occurred in 26%, hypertension in 34%, diabetes in 11%, and cardiovascular disease on 11%. The registry also reported use of any DMARD in 80%, including 62% on csDMARDs, 31% on biologics, and 2% on targeted synthetic DMARDs.

Ten authors in the Lancet Rheumatology paper reported personal and institutional relationships in the form of grants, corporate sponsorships, advisory board memberships, investigator appointments, speaker’s bureau positions, personal fees, and consultancies for a variety of pharmaceutical companies, agencies, societies, and other organizations. The other authors reported no relevant conflicts of interest.

An international registry of adult and pediatric rheumatology patients is beginning to identify trends in the types of patients with COVID-19 and who is recovering.

The COVID-19 Global Rheumatology Alliance (GRA) has created pediatric and adult registries for health care providers to enter information on their rheumatology patients with COVID-19. The adult registry is hosted by the University of California, San Francisco, Research Electronic Data Capture system, while the Childhood Arthritis and Rheumatology Research Alliance is supporting the pediatric registry. A separate path for data entry of both adult and pediatric cases has been established through the European League Against Rheumatism for European countries and countries with EULAR member organizations.

Prior to the creation of the registries, there were no data available to guide rheumatologists in clinical decision making for their patients, noted Jinoos Yazdany, MD, MPH, COVID-19 GRA steering committee member and chief of the division of rheumatology at Zuckerberg San Francisco General Hospital. “COVID-19 has potential to severely affect those with rheumatologic diseases or those taking immunosuppressive drugs,” she said in an interview. “The GRA registries were designed to answer critical questions that will inform the medical care of this population.”

The GRA began on Twitter, with conversations between Leonard H. Calabrese, DO, of the Cleveland Clinic; Paul Sufka, MD, of HealthPartners in St. Paul, Minn.; Philip Robinson, MBChB, PhD, of the Royal Brisbane (Australia) Hospital; and herself, Dr. Yazdany said. Dr. Robinson started work on the governance of the GRA, Dr. Yazdany designed the data infrastructure, and Dr. Sufka approached his professional networks and social media followings to promote the effort and ask for support. The COVID-19 GRA steering committee representatives include patients, private practice rheumatologists, and international investigators. Listed among official supporters of the alliance are the American College of Rheumatology and EULAR along with more than 290 medical societies, institutions, journals, and other organizations in rheumatology.

The goal of the registries is to examine the health outcomes of patients with rheumatic diseases and COVID-19 based on sociodemographic factors, comorbidities, and clinical presentations of COVID-19 as well as what role taking immunosuppressive drugs prior to a COVID-19 infection play in helping or hindering outcomes. Hydroxychloroquine, used to treat lupus and arthritis, is a potential treatment candidate for COVID-19. Biologics such as tocilizumab (Actemra) and sarilumab (Kevzara), which target interleukin-6, and anakinra (Kineret), which targets IL-1, are treatment candidates for patients who have experienced COVID-related cytokine storm syndrome, which researchers believe may contribute to worsening or fatal cases.

Dr. Yazdany, who is also vice chair of real-world data infrastructure, registry, and institutional review board/ethics for the GRA, said that there are some important high-level trends in the data thus far. “People with lupus and those taking hydroxychloroquine are becoming infected with SARS-CoV-2, which is counter to misinformation on social media. Most people with rheumatic diseases on immunosuppression are recovering, which is great news for our patients.”

One of the major strengths of the registries is that each case is entered by the rheumatologist treating the patient and contains detailed clinical information, Dr. Yazdany said. However, the registry has no control group, it is not a population surveillance study, and it may contain selection bias through rheumatologists omitting milder, undiagnosed cases.

“The Global Alliance case reporting registry represents the collective effort of hundreds of rheumatologists across the world. I have never been more inspired by the strength and collaboration of the rheumatology community,” Dr. Yazdany said.

According to a paper published in the Lancet Rheumatology, which references data on 110 cases from the combined databases up to April 1, about three-fourths of cases presented with fever (79%) and cough (77%), and about half presented with shortness of breath (50%) and myalgia (45%).
 

Results from the global and UCSF registries

As of April 18, 334 cases were in the global and UCSF registries, with 121 patients (36%) in the database having both COVID-19 and RA, 33 patients (10%) with psoriatic arthritis, 58 patients (17%) with systemic lupus erythematosus, 28 patients (8%) with axial spondyloarthritis, 27 patients (8%) with vasculitis, and 19 patients (6%) with Sjögren’s syndrome. There were less than five cases reported for patients with the following rheumatic diseases: inflammatory myopathy, ocular inflammation, other inflammatory arthritis, polymyalgia rheumatica, sarcoidosis, systemic sclerosis, osteoporosis, psoriasis, isolated pulmonary capillaritis, gout, and autoinflammatory disease. A majority of the patients in the registries are women (74%) aged younger than 65 years (78%) and are white (52%).

The most common comorbid conditions among patients in the registry are hypertension (33%), lung disease (18%), diabetes (11%), cardiovascular disease (10%), chronic renal insufficiency or end-stage renal disease (7%), morbid obesity (7%), and cancer (4%). Before being diagnosed with COVID-19, 219 patients (66%) in the registry were taking conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), which included antimalarials, azathioprine, cyclophosphamide, cyclosporine, leflunomide, methotrexate, mycophenolate mofetil/mycophenolic acid, sulfasalazine, and tacrolimus. A total of 122 patients (37%) were taking biologic DMARDs, 101 patients were taking glucocorticoids (30%), 86 patients (26%) were taking hydroxychloroquine, 41 patients (12%) were taking NSAIDs, and 18 patients (5%) were taking a Janus kinase inhibitor.

The most recent data from the registry show that 128 patients (38%) have been hospitalized for COVID-19, and 19 patients (6%) have died. Although 104 patients (31%) resolved their infections, 177 patients (53%) have a COVID-19 infection status of “unresolved,” and 53 patients (16%) have an unknown infection status.
 

EULAR registry results

As of April 21, 249 cases were in the EULAR registry, including 110 hospitalizations (44%) and 37 deaths (15%). Overall, 64% of these patients were women, and they had a median age of 60 years.

The top five diagnoses of these patients were RA (39%), psoriatic arthritis (15%), spondyloarthritis (9%), systemic lupus erythematosus (9%), and gout (5%). A total of 27% had no reported comorbidities, while lung disease occurred in 26%, hypertension in 34%, diabetes in 11%, and cardiovascular disease on 11%. The registry also reported use of any DMARD in 80%, including 62% on csDMARDs, 31% on biologics, and 2% on targeted synthetic DMARDs.

Ten authors in the Lancet Rheumatology paper reported personal and institutional relationships in the form of grants, corporate sponsorships, advisory board memberships, investigator appointments, speaker’s bureau positions, personal fees, and consultancies for a variety of pharmaceutical companies, agencies, societies, and other organizations. The other authors reported no relevant conflicts of interest.

MAUI, HAWAII – Desensitization is a powerful and effective tool in patients with certain types of hypersensitivity reactions to therapeutic monoclonal antibodies, but it’s best considered a last resort reserved for individuals with no options left other than the offending biologic, Anna Postolova, MD, said at the 2020 Rheumatology Winter Clinical Symposium.

Bruce Jancin/MDedge News

Why so selective? Desensitization is considered a high-risk intervention. It’s typically done as an inpatient procedure involving an overnight hospital stay followed by an elaborate 12-step protocol involving administration of small quantities of the culprit biologic in ascending concentrations over a 5- to 6-hour period.

Moreover, for an intravenous agent, such as infliximab (Remicade), desensitization has to be repeated prior to giving every dose of the biologic. So it makes sense to skip desensitization and simply switch to an alternative tumor necrosis factor inhibitor or a different class of biologic unless experience has shown that the culprit monoclonal antibody is the only one that works for that patient. It’s known, for example, that infliximab has no crossreactivity with adalimumab (Humira), explained Dr. Postolova, a dual rheumatologist and allergist/immunologist at Stanford (Calif.) University.
 

Defining type and severity of the hypersensitivity reaction

Dr. Postolova favors the hypersensitivity reaction classification system developed by Mariana Castells, MD, PhD, and coworkers at Brigham and Women’s Hospital, Boston.

They divide the field into immediate and delayed hypersensitivity reactions. Immediate hypersensitivity reactions arise rapidly, between minutes and a few hours. They can be categorized as infusion reactions, cytokine-release reactions, and IgE-mediated reactions. Phenotypically, infusion reactions and cytokine-release reactions are typically characterized by various combinations of chills, fever, flushing, hypertension, tachycardia, nausea, vomiting, syncope, and shortness of breath.

IgE-mediated reactions can also involve flushing and shortness of breath, and in addition itch, urticaria, and hypotension. These are anaphylactic reactions. Neither hypertension nor fever is part of the anaphylactic picture; those findings point instead to an infusion reaction or cytokine-release reaction.

Most allergists grade reaction severity on a 1-3 scale. Grade 1 reactions are considered mild and involve symptoms limited to the skin, such as flushing, or a single other organ system.

“That being said, if my patient is having a reaction with bronchospasm, I consider that a moderate, grade 2 reaction, and I stop the infusion. There’s only so much you can do for bronchospasm. It’s a very serious reaction,” Dr. Postolova observed.

Grade 2 reactions ordinarily involve two or more organ systems, but without hypotension or cyanosis. Grade 3 reactions are severe anaphylactic reactions with cardiovascular and/or neurologic compromise.

Delayed hypersensitivity reactions are of two types: serum sickness–like reactions and type IV cell-mediated mucocutaneous reactions.

Type IV reactions can range from a mild maculopapular rash to erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, and DRESS (drug reaction with eosinophilia and systemic symptoms). Onset of type IV reactions can occur after 12 hours up to several weeks after exposure.

Serum sickness–like reactions typically begin 5-7 days after the infusion. These reactions are marked by evidence of immune overactivation: fever, arthralgia, arthritis, malaise, purpura, skin rash, and even renal failure.
 

Management of reactions

A patient with a grade 3 reaction who needs to continue using the culprit monoclonal antibody should be referred to an allergist for skin testing in an effort to identify an IgE-mediated reaction.

The timing of the referral for skin testing is important: The allergist wants to test roughly 4-6 weeks after the hypersensitivity reaction. Test too early and the results will be uninformative because the patient will still be anergic. On the other hand, after 7-8 weeks the patient will have lost the allergy. So there is a sweet spot.

If the patient is skin test positive – with the caveat that skin testing in this setting is not well validated – then the allergist will suggest desensitization, usually as an inpatient.

In contrast, infusion reactions can be handled in the rheumatologist’s infusion center. They are self-limited upon repeat exposure with premedication using antihistamines, NSAIDs, oral or injectable steroids, and perhaps montelukast (Singulair).

If a patient initially thought to have an infusion reaction continues to experience reactions even after the biologic is being delivered more slowly and under the protection of premedication, it’s time to consider the possibility that what’s really going on is a cytokine-release reaction or an IgE-mediated reaction. Diagnostic skin testing is in order.

For a skin test–negative patient with a suspected cytokine-release reaction, the allergist may propose a therapeutic challenge. This is reserved for patients who the allergist believe will not experience an immediate reaction, and unlike desensitization it’s not an intervention intended to induce drug tolerance. The challenge involves giving 10% of a full dose of the biologic, waiting in the allergist’s office for 30-60 minutes, then giving the other 90% of the medication, followed by an hour of in-office observation.

The solution to severe type IV delayed hypersensitivity reactions is strict medication avoidance, not desensitization, according to Dr. Postolova.
 

Top offending monoclonal antibodies

Infliximab and rituximab (Rituxan) are the most common culprits when it comes to immediate hypersensitivity reactions. About 10% of infliximab-treated patients develop these reactions. Although the reaction can occur with the first dose, the peak incidence is with the seventh infusion. Patients with anti-infliximab IgG antibodies are at 140%-300% increased risk; however, concomitant disease-modifying antirheumatic drug therapy lessens that risk.

Infusion reactions or cytokine-release reactions occur upon the first infusion of rituximab in about 25% of treated rheumatology patients and in a higher proportion of cancer patients. Most of these reactions are mild and don’t recur when the biologic is administered more slowly and with premedication. Severe recurrent reactions upon subsequent exposure are much more likely to be an IgE-mediated hypersensitivity reaction.

“Stop the medication, send the patient to your local allergist for skin testing, and they’ll use a desensitization protocol if rituximab is the best drug for your patient,” Dr. Postolova advised.

She reported having no financial conflicts regarding her presentation.

[email protected]

MAUI, HAWAII – Desensitization is a powerful and effective tool in patients with certain types of hypersensitivity reactions to therapeutic monoclonal antibodies, but it’s best considered a last resort reserved for individuals with no options left other than the offending biologic, Anna Postolova, MD, said at the 2020 Rheumatology Winter Clinical Symposium.

Bruce Jancin/MDedge News

Why so selective? Desensitization is considered a high-risk intervention. It’s typically done as an inpatient procedure involving an overnight hospital stay followed by an elaborate 12-step protocol involving administration of small quantities of the culprit biologic in ascending concentrations over a 5- to 6-hour period.

Moreover, for an intravenous agent, such as infliximab (Remicade), desensitization has to be repeated prior to giving every dose of the biologic. So it makes sense to skip desensitization and simply switch to an alternative tumor necrosis factor inhibitor or a different class of biologic unless experience has shown that the culprit monoclonal antibody is the only one that works for that patient. It’s known, for example, that infliximab has no crossreactivity with adalimumab (Humira), explained Dr. Postolova, a dual rheumatologist and allergist/immunologist at Stanford (Calif.) University.
 

Defining type and severity of the hypersensitivity reaction

Dr. Postolova favors the hypersensitivity reaction classification system developed by Mariana Castells, MD, PhD, and coworkers at Brigham and Women’s Hospital, Boston.

They divide the field into immediate and delayed hypersensitivity reactions. Immediate hypersensitivity reactions arise rapidly, between minutes and a few hours. They can be categorized as infusion reactions, cytokine-release reactions, and IgE-mediated reactions. Phenotypically, infusion reactions and cytokine-release reactions are typically characterized by various combinations of chills, fever, flushing, hypertension, tachycardia, nausea, vomiting, syncope, and shortness of breath.

IgE-mediated reactions can also involve flushing and shortness of breath, and in addition itch, urticaria, and hypotension. These are anaphylactic reactions. Neither hypertension nor fever is part of the anaphylactic picture; those findings point instead to an infusion reaction or cytokine-release reaction.

Most allergists grade reaction severity on a 1-3 scale. Grade 1 reactions are considered mild and involve symptoms limited to the skin, such as flushing, or a single other organ system.

“That being said, if my patient is having a reaction with bronchospasm, I consider that a moderate, grade 2 reaction, and I stop the infusion. There’s only so much you can do for bronchospasm. It’s a very serious reaction,” Dr. Postolova observed.

Grade 2 reactions ordinarily involve two or more organ systems, but without hypotension or cyanosis. Grade 3 reactions are severe anaphylactic reactions with cardiovascular and/or neurologic compromise.

Delayed hypersensitivity reactions are of two types: serum sickness–like reactions and type IV cell-mediated mucocutaneous reactions.

Type IV reactions can range from a mild maculopapular rash to erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, and DRESS (drug reaction with eosinophilia and systemic symptoms). Onset of type IV reactions can occur after 12 hours up to several weeks after exposure.

Serum sickness–like reactions typically begin 5-7 days after the infusion. These reactions are marked by evidence of immune overactivation: fever, arthralgia, arthritis, malaise, purpura, skin rash, and even renal failure.
 

Management of reactions

A patient with a grade 3 reaction who needs to continue using the culprit monoclonal antibody should be referred to an allergist for skin testing in an effort to identify an IgE-mediated reaction.

The timing of the referral for skin testing is important: The allergist wants to test roughly 4-6 weeks after the hypersensitivity reaction. Test too early and the results will be uninformative because the patient will still be anergic. On the other hand, after 7-8 weeks the patient will have lost the allergy. So there is a sweet spot.

If the patient is skin test positive – with the caveat that skin testing in this setting is not well validated – then the allergist will suggest desensitization, usually as an inpatient.

In contrast, infusion reactions can be handled in the rheumatologist’s infusion center. They are self-limited upon repeat exposure with premedication using antihistamines, NSAIDs, oral or injectable steroids, and perhaps montelukast (Singulair).

If a patient initially thought to have an infusion reaction continues to experience reactions even after the biologic is being delivered more slowly and under the protection of premedication, it’s time to consider the possibility that what’s really going on is a cytokine-release reaction or an IgE-mediated reaction. Diagnostic skin testing is in order.

For a skin test–negative patient with a suspected cytokine-release reaction, the allergist may propose a therapeutic challenge. This is reserved for patients who the allergist believe will not experience an immediate reaction, and unlike desensitization it’s not an intervention intended to induce drug tolerance. The challenge involves giving 10% of a full dose of the biologic, waiting in the allergist’s office for 30-60 minutes, then giving the other 90% of the medication, followed by an hour of in-office observation.

The solution to severe type IV delayed hypersensitivity reactions is strict medication avoidance, not desensitization, according to Dr. Postolova.
 

Top offending monoclonal antibodies

Infliximab and rituximab (Rituxan) are the most common culprits when it comes to immediate hypersensitivity reactions. About 10% of infliximab-treated patients develop these reactions. Although the reaction can occur with the first dose, the peak incidence is with the seventh infusion. Patients with anti-infliximab IgG antibodies are at 140%-300% increased risk; however, concomitant disease-modifying antirheumatic drug therapy lessens that risk.

Infusion reactions or cytokine-release reactions occur upon the first infusion of rituximab in about 25% of treated rheumatology patients and in a higher proportion of cancer patients. Most of these reactions are mild and don’t recur when the biologic is administered more slowly and with premedication. Severe recurrent reactions upon subsequent exposure are much more likely to be an IgE-mediated hypersensitivity reaction.

“Stop the medication, send the patient to your local allergist for skin testing, and they’ll use a desensitization protocol if rituximab is the best drug for your patient,” Dr. Postolova advised.

She reported having no financial conflicts regarding her presentation.

[email protected]

MAUI, HAWAII – Desensitization is a powerful and effective tool in patients with certain types of hypersensitivity reactions to therapeutic monoclonal antibodies, but it’s best considered a last resort reserved for individuals with no options left other than the offending biologic, Anna Postolova, MD, said at the 2020 Rheumatology Winter Clinical Symposium.

Bruce Jancin/MDedge News

Why so selective? Desensitization is considered a high-risk intervention. It’s typically done as an inpatient procedure involving an overnight hospital stay followed by an elaborate 12-step protocol involving administration of small quantities of the culprit biologic in ascending concentrations over a 5- to 6-hour period.

Moreover, for an intravenous agent, such as infliximab (Remicade), desensitization has to be repeated prior to giving every dose of the biologic. So it makes sense to skip desensitization and simply switch to an alternative tumor necrosis factor inhibitor or a different class of biologic unless experience has shown that the culprit monoclonal antibody is the only one that works for that patient. It’s known, for example, that infliximab has no crossreactivity with adalimumab (Humira), explained Dr. Postolova, a dual rheumatologist and allergist/immunologist at Stanford (Calif.) University.
 

Defining type and severity of the hypersensitivity reaction

Dr. Postolova favors the hypersensitivity reaction classification system developed by Mariana Castells, MD, PhD, and coworkers at Brigham and Women’s Hospital, Boston.

They divide the field into immediate and delayed hypersensitivity reactions. Immediate hypersensitivity reactions arise rapidly, between minutes and a few hours. They can be categorized as infusion reactions, cytokine-release reactions, and IgE-mediated reactions. Phenotypically, infusion reactions and cytokine-release reactions are typically characterized by various combinations of chills, fever, flushing, hypertension, tachycardia, nausea, vomiting, syncope, and shortness of breath.

IgE-mediated reactions can also involve flushing and shortness of breath, and in addition itch, urticaria, and hypotension. These are anaphylactic reactions. Neither hypertension nor fever is part of the anaphylactic picture; those findings point instead to an infusion reaction or cytokine-release reaction.

Most allergists grade reaction severity on a 1-3 scale. Grade 1 reactions are considered mild and involve symptoms limited to the skin, such as flushing, or a single other organ system.

“That being said, if my patient is having a reaction with bronchospasm, I consider that a moderate, grade 2 reaction, and I stop the infusion. There’s only so much you can do for bronchospasm. It’s a very serious reaction,” Dr. Postolova observed.

Grade 2 reactions ordinarily involve two or more organ systems, but without hypotension or cyanosis. Grade 3 reactions are severe anaphylactic reactions with cardiovascular and/or neurologic compromise.

Delayed hypersensitivity reactions are of two types: serum sickness–like reactions and type IV cell-mediated mucocutaneous reactions.

Type IV reactions can range from a mild maculopapular rash to erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, and DRESS (drug reaction with eosinophilia and systemic symptoms). Onset of type IV reactions can occur after 12 hours up to several weeks after exposure.

Serum sickness–like reactions typically begin 5-7 days after the infusion. These reactions are marked by evidence of immune overactivation: fever, arthralgia, arthritis, malaise, purpura, skin rash, and even renal failure.
 

Management of reactions

A patient with a grade 3 reaction who needs to continue using the culprit monoclonal antibody should be referred to an allergist for skin testing in an effort to identify an IgE-mediated reaction.

The timing of the referral for skin testing is important: The allergist wants to test roughly 4-6 weeks after the hypersensitivity reaction. Test too early and the results will be uninformative because the patient will still be anergic. On the other hand, after 7-8 weeks the patient will have lost the allergy. So there is a sweet spot.

If the patient is skin test positive – with the caveat that skin testing in this setting is not well validated – then the allergist will suggest desensitization, usually as an inpatient.

In contrast, infusion reactions can be handled in the rheumatologist’s infusion center. They are self-limited upon repeat exposure with premedication using antihistamines, NSAIDs, oral or injectable steroids, and perhaps montelukast (Singulair).

If a patient initially thought to have an infusion reaction continues to experience reactions even after the biologic is being delivered more slowly and under the protection of premedication, it’s time to consider the possibility that what’s really going on is a cytokine-release reaction or an IgE-mediated reaction. Diagnostic skin testing is in order.

For a skin test–negative patient with a suspected cytokine-release reaction, the allergist may propose a therapeutic challenge. This is reserved for patients who the allergist believe will not experience an immediate reaction, and unlike desensitization it’s not an intervention intended to induce drug tolerance. The challenge involves giving 10% of a full dose of the biologic, waiting in the allergist’s office for 30-60 minutes, then giving the other 90% of the medication, followed by an hour of in-office observation.

The solution to severe type IV delayed hypersensitivity reactions is strict medication avoidance, not desensitization, according to Dr. Postolova.
 

Top offending monoclonal antibodies

Infliximab and rituximab (Rituxan) are the most common culprits when it comes to immediate hypersensitivity reactions. About 10% of infliximab-treated patients develop these reactions. Although the reaction can occur with the first dose, the peak incidence is with the seventh infusion. Patients with anti-infliximab IgG antibodies are at 140%-300% increased risk; however, concomitant disease-modifying antirheumatic drug therapy lessens that risk.

Infusion reactions or cytokine-release reactions occur upon the first infusion of rituximab in about 25% of treated rheumatology patients and in a higher proportion of cancer patients. Most of these reactions are mild and don’t recur when the biologic is administered more slowly and with premedication. Severe recurrent reactions upon subsequent exposure are much more likely to be an IgE-mediated hypersensitivity reaction.

“Stop the medication, send the patient to your local allergist for skin testing, and they’ll use a desensitization protocol if rituximab is the best drug for your patient,” Dr. Postolova advised.

She reported having no financial conflicts regarding her presentation.

[email protected]

Between 1988 and 2012, the prevalence of antinuclear antibodies in the United States increased from 11% to 15.9%, especially among adolescents, males, and non-Hispanic whites.

The finding comes from a retrospective, cross-sectional analysis of serum samples from individuals who participated in the U.S. National Health and Nutrition Examination Survey over three time periods: 1988-1991, 1999-2004, and 2011-2012.

“Autoimmune diseases are a diverse group of disorders characterized by damaging immune responses to self-antigens and, for the most part, are of unknown etiology,” authors led by Gregg E. Dinse, ScD, wrote in a study published in Arthritis & Rheumatology. “They are thought to impact 3%-5% of the population, with rising rates noted several decades ago. Recent studies suggest continued increases for certain autoimmune diseases, but it is unclear whether these trends are due to changes in recognition and diagnosis, or are true temporal changes in incidence.”

Dr. Dinse, of the National Institute of Environmental Health Sciences in Research Triangle Park, N.C., and his colleagues evaluated sera samples of 14,211 survey participants aged 12 years and older at 1:80 dilution for antinuclear antibodies (ANA) using a standard indirect immunofluorescence assay (HEp-2 assay). The samples that received a grade of 3 or 4 on a 0-4 scale (compared with standard references, with values of 1-4 indicating positivity) underwent additional assessment by sequential ANA titers up to 1:1,280 dilution. To estimate changes in ANA prevalence over the time periods, they used logistic regression adjusted for age, sex, race/ethnicity, and survey design variables.

The researchers observed an ANA prevalence of 11% in 1988-1991, 11.5% in 1999-2004, and 15.9% in 2011-2012. This corresponds to 22, 27, and 41 million affected individuals, respectively. Females were more likely than males to have ANA (odds ratios of 2.53, 2.97, and 1.94 in 1988-1991, 1999-2004, and 2011-2012, respectively; P less than .0001), as were older adults relative to adolescents (ORs of 3.63, 1.80, and 1.71; P less than .002). Among adolescents, the prevalence of ANA rose steeply, with odds ratios of 2.02 in 1999-2004 and 2.88 in 2011-2012 in the second and third time periods relative to the first (trend P less than .0001). The researchers also found that, compared with non-Hispanic whites, the odds of having ANA were higher for non-Hispanic blacks (OR, 1.75) and Mexican-Americans (OR, 1.87) in 1988-1991, but racial/ethnic differences diminished in 1999-2004 and 2011-2012.

After adjustment for covariates, the researchers found that the estimated odds ratios for the second and third time periods relative to the first were 1.02 and 1.47, respectively, reflecting an overall ANA time trend (P less than .0001). Increases in ANA prevalence among cohorts did not correlate with contemporaneous trends in body mass index, smoking, or alcohol consumption.

Dr. Dinse and his colleagues acknowledged certain limitations of the study, including the fact that associations were based on cross-sectional data rather than repeated measures, and that some variables were self-reported, including the limited questionnaire data on autoimmune diseases.

[email protected]

SOURCE: Dinse G et al. Arthritis Rheumatol. 2020 April 7. doi: 10.1002/ART.41214.

Between 1988 and 2012, the prevalence of antinuclear antibodies in the United States increased from 11% to 15.9%, especially among adolescents, males, and non-Hispanic whites.

The finding comes from a retrospective, cross-sectional analysis of serum samples from individuals who participated in the U.S. National Health and Nutrition Examination Survey over three time periods: 1988-1991, 1999-2004, and 2011-2012.

“Autoimmune diseases are a diverse group of disorders characterized by damaging immune responses to self-antigens and, for the most part, are of unknown etiology,” authors led by Gregg E. Dinse, ScD, wrote in a study published in Arthritis & Rheumatology. “They are thought to impact 3%-5% of the population, with rising rates noted several decades ago. Recent studies suggest continued increases for certain autoimmune diseases, but it is unclear whether these trends are due to changes in recognition and diagnosis, or are true temporal changes in incidence.”

Dr. Dinse, of the National Institute of Environmental Health Sciences in Research Triangle Park, N.C., and his colleagues evaluated sera samples of 14,211 survey participants aged 12 years and older at 1:80 dilution for antinuclear antibodies (ANA) using a standard indirect immunofluorescence assay (HEp-2 assay). The samples that received a grade of 3 or 4 on a 0-4 scale (compared with standard references, with values of 1-4 indicating positivity) underwent additional assessment by sequential ANA titers up to 1:1,280 dilution. To estimate changes in ANA prevalence over the time periods, they used logistic regression adjusted for age, sex, race/ethnicity, and survey design variables.

The researchers observed an ANA prevalence of 11% in 1988-1991, 11.5% in 1999-2004, and 15.9% in 2011-2012. This corresponds to 22, 27, and 41 million affected individuals, respectively. Females were more likely than males to have ANA (odds ratios of 2.53, 2.97, and 1.94 in 1988-1991, 1999-2004, and 2011-2012, respectively; P less than .0001), as were older adults relative to adolescents (ORs of 3.63, 1.80, and 1.71; P less than .002). Among adolescents, the prevalence of ANA rose steeply, with odds ratios of 2.02 in 1999-2004 and 2.88 in 2011-2012 in the second and third time periods relative to the first (trend P less than .0001). The researchers also found that, compared with non-Hispanic whites, the odds of having ANA were higher for non-Hispanic blacks (OR, 1.75) and Mexican-Americans (OR, 1.87) in 1988-1991, but racial/ethnic differences diminished in 1999-2004 and 2011-2012.

After adjustment for covariates, the researchers found that the estimated odds ratios for the second and third time periods relative to the first were 1.02 and 1.47, respectively, reflecting an overall ANA time trend (P less than .0001). Increases in ANA prevalence among cohorts did not correlate with contemporaneous trends in body mass index, smoking, or alcohol consumption.

Dr. Dinse and his colleagues acknowledged certain limitations of the study, including the fact that associations were based on cross-sectional data rather than repeated measures, and that some variables were self-reported, including the limited questionnaire data on autoimmune diseases.

[email protected]

SOURCE: Dinse G et al. Arthritis Rheumatol. 2020 April 7. doi: 10.1002/ART.41214.

Between 1988 and 2012, the prevalence of antinuclear antibodies in the United States increased from 11% to 15.9%, especially among adolescents, males, and non-Hispanic whites.

The finding comes from a retrospective, cross-sectional analysis of serum samples from individuals who participated in the U.S. National Health and Nutrition Examination Survey over three time periods: 1988-1991, 1999-2004, and 2011-2012.

“Autoimmune diseases are a diverse group of disorders characterized by damaging immune responses to self-antigens and, for the most part, are of unknown etiology,” authors led by Gregg E. Dinse, ScD, wrote in a study published in Arthritis & Rheumatology. “They are thought to impact 3%-5% of the population, with rising rates noted several decades ago. Recent studies suggest continued increases for certain autoimmune diseases, but it is unclear whether these trends are due to changes in recognition and diagnosis, or are true temporal changes in incidence.”

Dr. Dinse, of the National Institute of Environmental Health Sciences in Research Triangle Park, N.C., and his colleagues evaluated sera samples of 14,211 survey participants aged 12 years and older at 1:80 dilution for antinuclear antibodies (ANA) using a standard indirect immunofluorescence assay (HEp-2 assay). The samples that received a grade of 3 or 4 on a 0-4 scale (compared with standard references, with values of 1-4 indicating positivity) underwent additional assessment by sequential ANA titers up to 1:1,280 dilution. To estimate changes in ANA prevalence over the time periods, they used logistic regression adjusted for age, sex, race/ethnicity, and survey design variables.

The researchers observed an ANA prevalence of 11% in 1988-1991, 11.5% in 1999-2004, and 15.9% in 2011-2012. This corresponds to 22, 27, and 41 million affected individuals, respectively. Females were more likely than males to have ANA (odds ratios of 2.53, 2.97, and 1.94 in 1988-1991, 1999-2004, and 2011-2012, respectively; P less than .0001), as were older adults relative to adolescents (ORs of 3.63, 1.80, and 1.71; P less than .002). Among adolescents, the prevalence of ANA rose steeply, with odds ratios of 2.02 in 1999-2004 and 2.88 in 2011-2012 in the second and third time periods relative to the first (trend P less than .0001). The researchers also found that, compared with non-Hispanic whites, the odds of having ANA were higher for non-Hispanic blacks (OR, 1.75) and Mexican-Americans (OR, 1.87) in 1988-1991, but racial/ethnic differences diminished in 1999-2004 and 2011-2012.

After adjustment for covariates, the researchers found that the estimated odds ratios for the second and third time periods relative to the first were 1.02 and 1.47, respectively, reflecting an overall ANA time trend (P less than .0001). Increases in ANA prevalence among cohorts did not correlate with contemporaneous trends in body mass index, smoking, or alcohol consumption.

Dr. Dinse and his colleagues acknowledged certain limitations of the study, including the fact that associations were based on cross-sectional data rather than repeated measures, and that some variables were self-reported, including the limited questionnaire data on autoimmune diseases.

[email protected]

SOURCE: Dinse G et al. Arthritis Rheumatol. 2020 April 7. doi: 10.1002/ART.41214.

Adults who smoke or have a past history of smoking are significantly more likely to have antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis, according to data from a large case-control study.

pmphoto/iStockphoto.com

Although smokers have shown an increased risk for ANCA-associated vasculitis (AAV), compared with nonsmokers, previous studies of the association between smoking and AAV risk have been small and the results have been inconsistent, Greg McDermott, MD, and colleagues at Massachusetts General Hospital, Boston, wrote in JAMA Internal Medicine.

The researchers reviewed data from 473 adults diagnosed with AAV between 2002 and 2017 and compared them with 1,419 matched controls without AAV who had completed a smoking history questionnaire.

Overall, the odds of having a diagnosis of AAV were significantly higher among former smokers or current smokers, compared with never smokers (odds ratios, 1.58 and 2.70, respectively). In addition, the researchers found a significant dose-response relationship between pack-years of exposure and risk of AAV. The average age of the cases and controls was 59 years, 59% were women, and 84% were white.

The association between AAV risk and former or current smoking was greater among the 147 former and 29 current smokers with AAV positive for myeloperoxidase (MPO) (OR, 1.73 and 3.54, respectively). “Proteinase 3-ANCA– and MPO-ANCA–positive AAV are increasingly recognized as distinct conditions characterized by differences in genetic risk, pathogenesis, disease manifestations, and response to treatment,” the researchers said. No stronger association was noted in patients with proteinase 3-ANCA–positive AAV, they said. However, the overall associations remained strong after adjustment for demographics and disease manifestations, they noted.

The study findings were limited by several factors including the observational design, homogeneous study population at a single center, and use of self-reports, the researchers wrote. However, the results were strengthened by the large sample size and number of patients who were MPO-ANCA positive, and the data associating smoking with AAV “expand the list of potential risk factors for AAV, including genetics and silica exposure,” they said. “Further studies to confirm these results and investigate a potential pathogenic mechanism are needed,” they concluded.

The study was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases. The researchers had no financial conflicts to disclose.

SOURCE: McDermott G et al. JAMA Intern Med. 2020 Apr 13. doi: 10.1001/jamainternmed.2020.0675.

Adults who smoke or have a past history of smoking are significantly more likely to have antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis, according to data from a large case-control study.

pmphoto/iStockphoto.com

Although smokers have shown an increased risk for ANCA-associated vasculitis (AAV), compared with nonsmokers, previous studies of the association between smoking and AAV risk have been small and the results have been inconsistent, Greg McDermott, MD, and colleagues at Massachusetts General Hospital, Boston, wrote in JAMA Internal Medicine.

The researchers reviewed data from 473 adults diagnosed with AAV between 2002 and 2017 and compared them with 1,419 matched controls without AAV who had completed a smoking history questionnaire.

Overall, the odds of having a diagnosis of AAV were significantly higher among former smokers or current smokers, compared with never smokers (odds ratios, 1.58 and 2.70, respectively). In addition, the researchers found a significant dose-response relationship between pack-years of exposure and risk of AAV. The average age of the cases and controls was 59 years, 59% were women, and 84% were white.

The association between AAV risk and former or current smoking was greater among the 147 former and 29 current smokers with AAV positive for myeloperoxidase (MPO) (OR, 1.73 and 3.54, respectively). “Proteinase 3-ANCA– and MPO-ANCA–positive AAV are increasingly recognized as distinct conditions characterized by differences in genetic risk, pathogenesis, disease manifestations, and response to treatment,” the researchers said. No stronger association was noted in patients with proteinase 3-ANCA–positive AAV, they said. However, the overall associations remained strong after adjustment for demographics and disease manifestations, they noted.

The study findings were limited by several factors including the observational design, homogeneous study population at a single center, and use of self-reports, the researchers wrote. However, the results were strengthened by the large sample size and number of patients who were MPO-ANCA positive, and the data associating smoking with AAV “expand the list of potential risk factors for AAV, including genetics and silica exposure,” they said. “Further studies to confirm these results and investigate a potential pathogenic mechanism are needed,” they concluded.

The study was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases. The researchers had no financial conflicts to disclose.

SOURCE: McDermott G et al. JAMA Intern Med. 2020 Apr 13. doi: 10.1001/jamainternmed.2020.0675.

Adults who smoke or have a past history of smoking are significantly more likely to have antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis, according to data from a large case-control study.

pmphoto/iStockphoto.com

Although smokers have shown an increased risk for ANCA-associated vasculitis (AAV), compared with nonsmokers, previous studies of the association between smoking and AAV risk have been small and the results have been inconsistent, Greg McDermott, MD, and colleagues at Massachusetts General Hospital, Boston, wrote in JAMA Internal Medicine.

The researchers reviewed data from 473 adults diagnosed with AAV between 2002 and 2017 and compared them with 1,419 matched controls without AAV who had completed a smoking history questionnaire.

Overall, the odds of having a diagnosis of AAV were significantly higher among former smokers or current smokers, compared with never smokers (odds ratios, 1.58 and 2.70, respectively). In addition, the researchers found a significant dose-response relationship between pack-years of exposure and risk of AAV. The average age of the cases and controls was 59 years, 59% were women, and 84% were white.

The association between AAV risk and former or current smoking was greater among the 147 former and 29 current smokers with AAV positive for myeloperoxidase (MPO) (OR, 1.73 and 3.54, respectively). “Proteinase 3-ANCA– and MPO-ANCA–positive AAV are increasingly recognized as distinct conditions characterized by differences in genetic risk, pathogenesis, disease manifestations, and response to treatment,” the researchers said. No stronger association was noted in patients with proteinase 3-ANCA–positive AAV, they said. However, the overall associations remained strong after adjustment for demographics and disease manifestations, they noted.

The study findings were limited by several factors including the observational design, homogeneous study population at a single center, and use of self-reports, the researchers wrote. However, the results were strengthened by the large sample size and number of patients who were MPO-ANCA positive, and the data associating smoking with AAV “expand the list of potential risk factors for AAV, including genetics and silica exposure,” they said. “Further studies to confirm these results and investigate a potential pathogenic mechanism are needed,” they concluded.

The study was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases. The researchers had no financial conflicts to disclose.

SOURCE: McDermott G et al. JAMA Intern Med. 2020 Apr 13. doi: 10.1001/jamainternmed.2020.0675.

Approximately 26% of women with inactive or mild lupus at conception experienced flares at some point during pregnancy, based on data from 384 patients.

zoranm/Getty Images

Active systemic lupus erythematosus (SLE) is a known predictor of poor pregnancy outcomes, including preterm birth, growth restriction, and fetal loss, but predictors of flares during and after pregnancy in women with SLE have not been well studied, wrote Julia Davis-Porada, MD, of the Hospital for Special Surgery, New York, and her colleagues.

In a study published in Arthritis Research & Therapy, the investigators reviewed data from the PROMISSE (Predictors of Pregnancy Outcome: Biomarkers in Antiphospholipid Antibody Syndrome and Systemic Lupus Erythematosus) study, a prospective study of pregnant women aged 18-45 years. The women were enrolled at less than 12 weeks’ gestation, and participants had a baseline hematocrit greater than 26%. Participants met criteria for inactive or mild/stable disease at the time of conception.

Overall, 20.8% of patients experienced at least one mild or moderate flare and 6.25% had one or more severe flares during pregnancy. Mild to moderate flares and severe flares occurred postpartum (2-6 months after the end of pregnancy) in 22.7% and 1.7% of patients, respectively.

Patients who were younger and those who had lower C4 at baseline and higher Physician Global Assessment scores at baseline were significantly more likely to have at least one flare during pregnancy (P = .003, P = .024, P = .0005, respectively).

In the analysis of postpartum flares, the incidence rates for mild to moderate and severe flares were 0.8 and 0.06 per person-year, respectively. “In contrast to the findings observed for flares that occurred during pregnancy, baseline patient characteristics were not correlated with postpartum flares,” the researchers wrote.

No medications were associated with flares during or after pregnancy.

The study findings were limited by several factors, including the exclusion of SLE patients with current nephritis and those who needed high-dose prednisone; the potential for missed flares; and the lack of postpartum data for approximately 10% of patients, the researchers noted. Also, “since many patients presented to this study only after conception, we have no data to review disease activity prior to pregnancy to determine whether pregnancy per se increased the risk for flare,” they said.

However, the results were strengthened by the large, multiethnic population and prospective study design, and support physicians in reassuring patients with SLE that pregnancy and postpartum flares are unlikely if they plan pregnancy during a time of mild or inactive disease, they concluded.

The study was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases. The researchers had no financial conflicts to disclose.

SOURCE: Davis-Porada J et al. Arthritis Res Ther. 2020 Mar 19. doi: 10.1186/s13075-020-2139-9.

Approximately 26% of women with inactive or mild lupus at conception experienced flares at some point during pregnancy, based on data from 384 patients.

zoranm/Getty Images

Active systemic lupus erythematosus (SLE) is a known predictor of poor pregnancy outcomes, including preterm birth, growth restriction, and fetal loss, but predictors of flares during and after pregnancy in women with SLE have not been well studied, wrote Julia Davis-Porada, MD, of the Hospital for Special Surgery, New York, and her colleagues.

In a study published in Arthritis Research & Therapy, the investigators reviewed data from the PROMISSE (Predictors of Pregnancy Outcome: Biomarkers in Antiphospholipid Antibody Syndrome and Systemic Lupus Erythematosus) study, a prospective study of pregnant women aged 18-45 years. The women were enrolled at less than 12 weeks’ gestation, and participants had a baseline hematocrit greater than 26%. Participants met criteria for inactive or mild/stable disease at the time of conception.

Overall, 20.8% of patients experienced at least one mild or moderate flare and 6.25% had one or more severe flares during pregnancy. Mild to moderate flares and severe flares occurred postpartum (2-6 months after the end of pregnancy) in 22.7% and 1.7% of patients, respectively.

Patients who were younger and those who had lower C4 at baseline and higher Physician Global Assessment scores at baseline were significantly more likely to have at least one flare during pregnancy (P = .003, P = .024, P = .0005, respectively).

In the analysis of postpartum flares, the incidence rates for mild to moderate and severe flares were 0.8 and 0.06 per person-year, respectively. “In contrast to the findings observed for flares that occurred during pregnancy, baseline patient characteristics were not correlated with postpartum flares,” the researchers wrote.

No medications were associated with flares during or after pregnancy.

The study findings were limited by several factors, including the exclusion of SLE patients with current nephritis and those who needed high-dose prednisone; the potential for missed flares; and the lack of postpartum data for approximately 10% of patients, the researchers noted. Also, “since many patients presented to this study only after conception, we have no data to review disease activity prior to pregnancy to determine whether pregnancy per se increased the risk for flare,” they said.

However, the results were strengthened by the large, multiethnic population and prospective study design, and support physicians in reassuring patients with SLE that pregnancy and postpartum flares are unlikely if they plan pregnancy during a time of mild or inactive disease, they concluded.

The study was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases. The researchers had no financial conflicts to disclose.

SOURCE: Davis-Porada J et al. Arthritis Res Ther. 2020 Mar 19. doi: 10.1186/s13075-020-2139-9.

Approximately 26% of women with inactive or mild lupus at conception experienced flares at some point during pregnancy, based on data from 384 patients.

zoranm/Getty Images

Active systemic lupus erythematosus (SLE) is a known predictor of poor pregnancy outcomes, including preterm birth, growth restriction, and fetal loss, but predictors of flares during and after pregnancy in women with SLE have not been well studied, wrote Julia Davis-Porada, MD, of the Hospital for Special Surgery, New York, and her colleagues.

In a study published in Arthritis Research & Therapy, the investigators reviewed data from the PROMISSE (Predictors of Pregnancy Outcome: Biomarkers in Antiphospholipid Antibody Syndrome and Systemic Lupus Erythematosus) study, a prospective study of pregnant women aged 18-45 years. The women were enrolled at less than 12 weeks’ gestation, and participants had a baseline hematocrit greater than 26%. Participants met criteria for inactive or mild/stable disease at the time of conception.

Overall, 20.8% of patients experienced at least one mild or moderate flare and 6.25% had one or more severe flares during pregnancy. Mild to moderate flares and severe flares occurred postpartum (2-6 months after the end of pregnancy) in 22.7% and 1.7% of patients, respectively.

Patients who were younger and those who had lower C4 at baseline and higher Physician Global Assessment scores at baseline were significantly more likely to have at least one flare during pregnancy (P = .003, P = .024, P = .0005, respectively).

In the analysis of postpartum flares, the incidence rates for mild to moderate and severe flares were 0.8 and 0.06 per person-year, respectively. “In contrast to the findings observed for flares that occurred during pregnancy, baseline patient characteristics were not correlated with postpartum flares,” the researchers wrote.

No medications were associated with flares during or after pregnancy.

The study findings were limited by several factors, including the exclusion of SLE patients with current nephritis and those who needed high-dose prednisone; the potential for missed flares; and the lack of postpartum data for approximately 10% of patients, the researchers noted. Also, “since many patients presented to this study only after conception, we have no data to review disease activity prior to pregnancy to determine whether pregnancy per se increased the risk for flare,” they said.

However, the results were strengthened by the large, multiethnic population and prospective study design, and support physicians in reassuring patients with SLE that pregnancy and postpartum flares are unlikely if they plan pregnancy during a time of mild or inactive disease, they concluded.

The study was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases. The researchers had no financial conflicts to disclose.

SOURCE: Davis-Porada J et al. Arthritis Res Ther. 2020 Mar 19. doi: 10.1186/s13075-020-2139-9.

MAUI, HAWAII – When a rheumatologist gets a call from an ophthalmologist regarding a patient with an inflamed eye and elevated intraocular pressure unresponsive to the eye specialist’s customary array of topical, systemic, and intraocular implanted corticosteroids, that’s a patient who needs to be seen immediately, Alvin F. Wells, MD, PhD, said at the 2020 Rheumatology Winter Clinical Symposium.

Bruce Jancin/MDedge News

Elevated intraocular pressure due to uveitis or scleritis can result in blindness. Eye specialists call upon rheumatologists here because of their expertise in step-up therapy with methotrexate and other traditional oral disease-modifying antirheumatic drugs as well as biologic agents.

“Here’s my treatment approach to inflammatory eye disease: We’re pulling out all the guns,” declared Dr. Wells, a rheumatologist with a special interest in eye disease. He is director of the Rheumatology and Immunotherapy Center in Franklin, Wisc., with academic appointments to the Karolinska Institute in Stockholm, Duke University, and Marquette University.

Uveitis involves inflammation of the iris, choroid, and ciliary body. A straightforward case of noninfectious anterior uveitis will typically respond to 2 weeks of topical steroid drops, or sometimes even topical NSAID drops.

However, noninfectious posterior, intermediate, or panuveitis is another matter. In those circumstances, he gives the patient 125 mg of methylprednisolone by intramuscular injection and a 20-mg dose of oral methotrexate at that first clinic visit. The patient is sent home with a prescription for oral prednisone, tapering over 2-3 weeks, and another for methotrexate at 15-25 mg/week plus 1-2 mg/day of folic acid. Dr. Wells also gives consideration to add-on azathioprine or mycophenolate mofetil. He views multidrug therapy as having a sound rationale because multiple inflammatory pathways are involved in noninfectious uveitis.

“Ophthalmologists like to push for cyclophosphamide, but there’s no controlled data out there showing it’s effective in inflammatory eye disorders. It’s a pretty toxic regimen, and when you think about all the complications we see in using this drug to treat patients with lupus, I’d rather hold it in reserve for severe cases where we can go to it if we need to,” the rheumatologist explained.

He conducted a literature review to rank rheumatologic medications in terms of their evidence base for treatment of inflammatory ocular disorders. Among oral agents, at the top of the heap is methotrexate, whose efficacy for both noninfectious uveitis and scleritis is supported by multiple randomized, controlled studies. But mycophenolate mofetil is a reasonable alternative first-line corticosteroid-sparing agent, as demonstrated in the 265-patient multicenter FAST (First-line Antimetabolites as Steroid-sparing Treatment) trial sponsored by the National Eye Institute. That trial demonstrated no significant difference in treatment success at 6 months between methotrexate and mycophenolate mofetil.

Oral apremilast (Otezla) is approved for treatment of the oral ulcers of Behçet’s disease, but not for Behçet’s eye disease, where the experience is anecdotal.

Dr. Wells is quick to turn to adalimumab (Humira) when he deems a biologic to be warranted; indeed, it’s the only biologic approved for noninfectious uveitis. Of course, not everyone is a responder.

“Can we extrapolate that high-quality evidence of benefit for adalimumab to other drugs? Probably yes, and if you did that it would be for the IgG monoclonal antibodies that can cross the blood/aqueous barrier,” he said.

Infliximab (Remicade) is the biologic with the second-strongest supporting evidence in noninfectious uveitis. For the uveitis of Behçet’s disease, one of the most common rheumatic causes of inflammatory eye disease, Spanish investigators who conducted a nationwide nonrandomized study reported that both adalimumab and infliximab were effective, although adalimumab had superior outcomes at 1 year.

Uveitis is the most common extra-articular expression of axial spondyloarthritis (axSpA). In the open-label extension of the randomized RAPID-axSpA trial, patients randomized to certolizumab pegol (Cimzia) had a significantly lower incidence of uveitis flares than with placebo through 204 weeks of follow-up.

“The take-home message is we have some post hoc data here to say, ‘Hey, this could work in those patients who have inflammatory eye diseases in the setting of axSpA,’ ” Dr. Wells said.

The interleukin-6 receptor inhibitor tocilizumab (Actemra) “definitely works” for noninfectious uveitis, according to Dr. Wells, pointing to the positive results of the multicenter U.S. STOP-Uveitis study.

“The caveat here is tocilizumab has only been studied in the IV formulation. It’s too bad they didn’t use the [subcutaneous formulation]; you can’t get IV tocilizumab approved by payers in the U.S.,” according to the rheumatologist.

Based upon positive anecdotal case reports, Dr. Wells has a few patients on rituximab (Rituxan) for uveitis, with favorable results. The same for abatacept (Orencia).

It’s imperative that a patient on a biologic for uveitis undergo weekly ophthalmologic examinations. Only after the intraocular pressure is normal and inflammatory cells in the anterior chamber have waned is it appropriate to discontinue the biologic and slowly taper the methotrexate and any other oral disease-modifying antirheumatic drugs. Some experts argue for lifelong therapy in patients who’ve experienced uveitis. Dr. Wells disagrees, preferring to treat acute uveitis flares as they arise, although if underlying disease such as psoriatic arthritis or axSpA is present, some form of background therapy will probably be necessary.
 

Get to know teprotumumab

Rheumatologists who operate an infusion center are likely to increasingly be called upon by endocrinologists and ophthalmologists to administer intravenous teprotumumab-trbw (Tepezza), a human monoclonal antibody directed against the insulin-like growth factor 1 receptor that was approved earlier this year by the Food and Drug Administration as the first-ever drug for thyroid eye disease, a disfiguring and potentially blinding condition.

“This is really exciting,” Dr. Wells said. “The disease has an acute inflammatory stage, and that’s when you’ll be called on to give this drug. It makes a dramatic difference. Once a patient gets to the scarring phase there’s not a whole lot they can do other than surgery.”

In the pivotal phase 3 randomized trial, 83% of the teprotumumab group achieved the primary endpoint, a reduction in proptosis, or eye bulging, of at least 2 mm at week 24, compared with 10% of placebo-treated controls. The number needed to treat was 1.4. The chief side effects were muscle spasms, hair loss, fatigue, and nausea.

“You might say, ‘two millimeters, that’s nothing.’ But the primary drug used before teprotumumab was IV steroids, and there a 0.6-mm reduction in proptosis was considered improvement,” Dr. Wells observed.

Obtaining payer approval

“I’ve found over the last 10 years that when it comes to eye disease, insurance companies have a little more wiggle room,” he said. “They’re not going to let somebody go blind. You can get the references I’ve mentioned and show them the data. After all, we only have one biologic drug that’s been approved, and not everybody responds to it.

“Titrate your therapy based upon the intraocular pressure, the number of inflammatory cells in the anterior chamber, and any visual changes. You’ve got to be very aggressive with therapy, and don’t take no for an answer from the insurance companies,” he advised.

Dr. Wells reported serving as a member of an advisory board and/or speakers bureau for more than a dozen pharmaceutical companies.

[email protected]

MAUI, HAWAII – When a rheumatologist gets a call from an ophthalmologist regarding a patient with an inflamed eye and elevated intraocular pressure unresponsive to the eye specialist’s customary array of topical, systemic, and intraocular implanted corticosteroids, that’s a patient who needs to be seen immediately, Alvin F. Wells, MD, PhD, said at the 2020 Rheumatology Winter Clinical Symposium.

Bruce Jancin/MDedge News

Elevated intraocular pressure due to uveitis or scleritis can result in blindness. Eye specialists call upon rheumatologists here because of their expertise in step-up therapy with methotrexate and other traditional oral disease-modifying antirheumatic drugs as well as biologic agents.

“Here’s my treatment approach to inflammatory eye disease: We’re pulling out all the guns,” declared Dr. Wells, a rheumatologist with a special interest in eye disease. He is director of the Rheumatology and Immunotherapy Center in Franklin, Wisc., with academic appointments to the Karolinska Institute in Stockholm, Duke University, and Marquette University.

Uveitis involves inflammation of the iris, choroid, and ciliary body. A straightforward case of noninfectious anterior uveitis will typically respond to 2 weeks of topical steroid drops, or sometimes even topical NSAID drops.

However, noninfectious posterior, intermediate, or panuveitis is another matter. In those circumstances, he gives the patient 125 mg of methylprednisolone by intramuscular injection and a 20-mg dose of oral methotrexate at that first clinic visit. The patient is sent home with a prescription for oral prednisone, tapering over 2-3 weeks, and another for methotrexate at 15-25 mg/week plus 1-2 mg/day of folic acid. Dr. Wells also gives consideration to add-on azathioprine or mycophenolate mofetil. He views multidrug therapy as having a sound rationale because multiple inflammatory pathways are involved in noninfectious uveitis.

“Ophthalmologists like to push for cyclophosphamide, but there’s no controlled data out there showing it’s effective in inflammatory eye disorders. It’s a pretty toxic regimen, and when you think about all the complications we see in using this drug to treat patients with lupus, I’d rather hold it in reserve for severe cases where we can go to it if we need to,” the rheumatologist explained.

He conducted a literature review to rank rheumatologic medications in terms of their evidence base for treatment of inflammatory ocular disorders. Among oral agents, at the top of the heap is methotrexate, whose efficacy for both noninfectious uveitis and scleritis is supported by multiple randomized, controlled studies. But mycophenolate mofetil is a reasonable alternative first-line corticosteroid-sparing agent, as demonstrated in the 265-patient multicenter FAST (First-line Antimetabolites as Steroid-sparing Treatment) trial sponsored by the National Eye Institute. That trial demonstrated no significant difference in treatment success at 6 months between methotrexate and mycophenolate mofetil.

Oral apremilast (Otezla) is approved for treatment of the oral ulcers of Behçet’s disease, but not for Behçet’s eye disease, where the experience is anecdotal.

Dr. Wells is quick to turn to adalimumab (Humira) when he deems a biologic to be warranted; indeed, it’s the only biologic approved for noninfectious uveitis. Of course, not everyone is a responder.

“Can we extrapolate that high-quality evidence of benefit for adalimumab to other drugs? Probably yes, and if you did that it would be for the IgG monoclonal antibodies that can cross the blood/aqueous barrier,” he said.

Infliximab (Remicade) is the biologic with the second-strongest supporting evidence in noninfectious uveitis. For the uveitis of Behçet’s disease, one of the most common rheumatic causes of inflammatory eye disease, Spanish investigators who conducted a nationwide nonrandomized study reported that both adalimumab and infliximab were effective, although adalimumab had superior outcomes at 1 year.

Uveitis is the most common extra-articular expression of axial spondyloarthritis (axSpA). In the open-label extension of the randomized RAPID-axSpA trial, patients randomized to certolizumab pegol (Cimzia) had a significantly lower incidence of uveitis flares than with placebo through 204 weeks of follow-up.

“The take-home message is we have some post hoc data here to say, ‘Hey, this could work in those patients who have inflammatory eye diseases in the setting of axSpA,’ ” Dr. Wells said.

The interleukin-6 receptor inhibitor tocilizumab (Actemra) “definitely works” for noninfectious uveitis, according to Dr. Wells, pointing to the positive results of the multicenter U.S. STOP-Uveitis study.

“The caveat here is tocilizumab has only been studied in the IV formulation. It’s too bad they didn’t use the [subcutaneous formulation]; you can’t get IV tocilizumab approved by payers in the U.S.,” according to the rheumatologist.

Based upon positive anecdotal case reports, Dr. Wells has a few patients on rituximab (Rituxan) for uveitis, with favorable results. The same for abatacept (Orencia).

It’s imperative that a patient on a biologic for uveitis undergo weekly ophthalmologic examinations. Only after the intraocular pressure is normal and inflammatory cells in the anterior chamber have waned is it appropriate to discontinue the biologic and slowly taper the methotrexate and any other oral disease-modifying antirheumatic drugs. Some experts argue for lifelong therapy in patients who’ve experienced uveitis. Dr. Wells disagrees, preferring to treat acute uveitis flares as they arise, although if underlying disease such as psoriatic arthritis or axSpA is present, some form of background therapy will probably be necessary.
 

Get to know teprotumumab

Rheumatologists who operate an infusion center are likely to increasingly be called upon by endocrinologists and ophthalmologists to administer intravenous teprotumumab-trbw (Tepezza), a human monoclonal antibody directed against the insulin-like growth factor 1 receptor that was approved earlier this year by the Food and Drug Administration as the first-ever drug for thyroid eye disease, a disfiguring and potentially blinding condition.

“This is really exciting,” Dr. Wells said. “The disease has an acute inflammatory stage, and that’s when you’ll be called on to give this drug. It makes a dramatic difference. Once a patient gets to the scarring phase there’s not a whole lot they can do other than surgery.”

In the pivotal phase 3 randomized trial, 83% of the teprotumumab group achieved the primary endpoint, a reduction in proptosis, or eye bulging, of at least 2 mm at week 24, compared with 10% of placebo-treated controls. The number needed to treat was 1.4. The chief side effects were muscle spasms, hair loss, fatigue, and nausea.

“You might say, ‘two millimeters, that’s nothing.’ But the primary drug used before teprotumumab was IV steroids, and there a 0.6-mm reduction in proptosis was considered improvement,” Dr. Wells observed.

Obtaining payer approval

“I’ve found over the last 10 years that when it comes to eye disease, insurance companies have a little more wiggle room,” he said. “They’re not going to let somebody go blind. You can get the references I’ve mentioned and show them the data. After all, we only have one biologic drug that’s been approved, and not everybody responds to it.

“Titrate your therapy based upon the intraocular pressure, the number of inflammatory cells in the anterior chamber, and any visual changes. You’ve got to be very aggressive with therapy, and don’t take no for an answer from the insurance companies,” he advised.

Dr. Wells reported serving as a member of an advisory board and/or speakers bureau for more than a dozen pharmaceutical companies.

[email protected]

MAUI, HAWAII – When a rheumatologist gets a call from an ophthalmologist regarding a patient with an inflamed eye and elevated intraocular pressure unresponsive to the eye specialist’s customary array of topical, systemic, and intraocular implanted corticosteroids, that’s a patient who needs to be seen immediately, Alvin F. Wells, MD, PhD, said at the 2020 Rheumatology Winter Clinical Symposium.

Bruce Jancin/MDedge News

Elevated intraocular pressure due to uveitis or scleritis can result in blindness. Eye specialists call upon rheumatologists here because of their expertise in step-up therapy with methotrexate and other traditional oral disease-modifying antirheumatic drugs as well as biologic agents.

“Here’s my treatment approach to inflammatory eye disease: We’re pulling out all the guns,” declared Dr. Wells, a rheumatologist with a special interest in eye disease. He is director of the Rheumatology and Immunotherapy Center in Franklin, Wisc., with academic appointments to the Karolinska Institute in Stockholm, Duke University, and Marquette University.

Uveitis involves inflammation of the iris, choroid, and ciliary body. A straightforward case of noninfectious anterior uveitis will typically respond to 2 weeks of topical steroid drops, or sometimes even topical NSAID drops.

However, noninfectious posterior, intermediate, or panuveitis is another matter. In those circumstances, he gives the patient 125 mg of methylprednisolone by intramuscular injection and a 20-mg dose of oral methotrexate at that first clinic visit. The patient is sent home with a prescription for oral prednisone, tapering over 2-3 weeks, and another for methotrexate at 15-25 mg/week plus 1-2 mg/day of folic acid. Dr. Wells also gives consideration to add-on azathioprine or mycophenolate mofetil. He views multidrug therapy as having a sound rationale because multiple inflammatory pathways are involved in noninfectious uveitis.

“Ophthalmologists like to push for cyclophosphamide, but there’s no controlled data out there showing it’s effective in inflammatory eye disorders. It’s a pretty toxic regimen, and when you think about all the complications we see in using this drug to treat patients with lupus, I’d rather hold it in reserve for severe cases where we can go to it if we need to,” the rheumatologist explained.

He conducted a literature review to rank rheumatologic medications in terms of their evidence base for treatment of inflammatory ocular disorders. Among oral agents, at the top of the heap is methotrexate, whose efficacy for both noninfectious uveitis and scleritis is supported by multiple randomized, controlled studies. But mycophenolate mofetil is a reasonable alternative first-line corticosteroid-sparing agent, as demonstrated in the 265-patient multicenter FAST (First-line Antimetabolites as Steroid-sparing Treatment) trial sponsored by the National Eye Institute. That trial demonstrated no significant difference in treatment success at 6 months between methotrexate and mycophenolate mofetil.

Oral apremilast (Otezla) is approved for treatment of the oral ulcers of Behçet’s disease, but not for Behçet’s eye disease, where the experience is anecdotal.

Dr. Wells is quick to turn to adalimumab (Humira) when he deems a biologic to be warranted; indeed, it’s the only biologic approved for noninfectious uveitis. Of course, not everyone is a responder.

“Can we extrapolate that high-quality evidence of benefit for adalimumab to other drugs? Probably yes, and if you did that it would be for the IgG monoclonal antibodies that can cross the blood/aqueous barrier,” he said.

Infliximab (Remicade) is the biologic with the second-strongest supporting evidence in noninfectious uveitis. For the uveitis of Behçet’s disease, one of the most common rheumatic causes of inflammatory eye disease, Spanish investigators who conducted a nationwide nonrandomized study reported that both adalimumab and infliximab were effective, although adalimumab had superior outcomes at 1 year.

Uveitis is the most common extra-articular expression of axial spondyloarthritis (axSpA). In the open-label extension of the randomized RAPID-axSpA trial, patients randomized to certolizumab pegol (Cimzia) had a significantly lower incidence of uveitis flares than with placebo through 204 weeks of follow-up.

“The take-home message is we have some post hoc data here to say, ‘Hey, this could work in those patients who have inflammatory eye diseases in the setting of axSpA,’ ” Dr. Wells said.

The interleukin-6 receptor inhibitor tocilizumab (Actemra) “definitely works” for noninfectious uveitis, according to Dr. Wells, pointing to the positive results of the multicenter U.S. STOP-Uveitis study.

“The caveat here is tocilizumab has only been studied in the IV formulation. It’s too bad they didn’t use the [subcutaneous formulation]; you can’t get IV tocilizumab approved by payers in the U.S.,” according to the rheumatologist.

Based upon positive anecdotal case reports, Dr. Wells has a few patients on rituximab (Rituxan) for uveitis, with favorable results. The same for abatacept (Orencia).

It’s imperative that a patient on a biologic for uveitis undergo weekly ophthalmologic examinations. Only after the intraocular pressure is normal and inflammatory cells in the anterior chamber have waned is it appropriate to discontinue the biologic and slowly taper the methotrexate and any other oral disease-modifying antirheumatic drugs. Some experts argue for lifelong therapy in patients who’ve experienced uveitis. Dr. Wells disagrees, preferring to treat acute uveitis flares as they arise, although if underlying disease such as psoriatic arthritis or axSpA is present, some form of background therapy will probably be necessary.
 

Get to know teprotumumab

Rheumatologists who operate an infusion center are likely to increasingly be called upon by endocrinologists and ophthalmologists to administer intravenous teprotumumab-trbw (Tepezza), a human monoclonal antibody directed against the insulin-like growth factor 1 receptor that was approved earlier this year by the Food and Drug Administration as the first-ever drug for thyroid eye disease, a disfiguring and potentially blinding condition.

“This is really exciting,” Dr. Wells said. “The disease has an acute inflammatory stage, and that’s when you’ll be called on to give this drug. It makes a dramatic difference. Once a patient gets to the scarring phase there’s not a whole lot they can do other than surgery.”

In the pivotal phase 3 randomized trial, 83% of the teprotumumab group achieved the primary endpoint, a reduction in proptosis, or eye bulging, of at least 2 mm at week 24, compared with 10% of placebo-treated controls. The number needed to treat was 1.4. The chief side effects were muscle spasms, hair loss, fatigue, and nausea.

“You might say, ‘two millimeters, that’s nothing.’ But the primary drug used before teprotumumab was IV steroids, and there a 0.6-mm reduction in proptosis was considered improvement,” Dr. Wells observed.

Obtaining payer approval

“I’ve found over the last 10 years that when it comes to eye disease, insurance companies have a little more wiggle room,” he said. “They’re not going to let somebody go blind. You can get the references I’ve mentioned and show them the data. After all, we only have one biologic drug that’s been approved, and not everybody responds to it.

“Titrate your therapy based upon the intraocular pressure, the number of inflammatory cells in the anterior chamber, and any visual changes. You’ve got to be very aggressive with therapy, and don’t take no for an answer from the insurance companies,” he advised.

Dr. Wells reported serving as a member of an advisory board and/or speakers bureau for more than a dozen pharmaceutical companies.

[email protected]

MAUI, HAWAII – Belimumab shows promise as a novel biologic treatment for skin involvement in early diffuse cutaneous systemic sclerosis, Janet E. Pope, MD, said at the 2020 Rheumatology Winter Clinical Symposium.

Bruce Jancin/MDedge News

She highlighted a single-center, double-blind, placebo-controlled, New York pilot study including 20 patients with early diffuse cutaneous systemic sclerosis and moderate skin involvement. Participants had recently started on background mycophenolate mofetil (MMF) at 1,000 mg twice daily and were then randomized to add-on belimumab (Benlysta) at the dosing approved for systemic lupus erythematosus or to infusions of normal saline.

At 52 weeks, the modified Rodnan skin thickness score (mRSS) decreased by a median of 10 points from a baseline of 27 in the belimumab group, compared with just a 3-point reduction in controls on MMF plus placebo.

This small study raises several key points. It definitely warrants confirmation in a large phase 3 trial, according to Dr. Pope, professor of medicine at the University of Western Ontario and head of the division of rheumatology at St. Joseph’s Health Care, both in London.

For one thing, the pilot study makes a good case for multidrug therapy in scleroderma. “In rheumatoid arthritis, if in general one drug is not as good as two, why would we ever think, in our most difficult-to-treat disease, one drug would be okay?” the rheumatologist observed.

The belimumab study also highlights the role of abnormalities in B-cell function in the pathogenesis of skin involvement in early diffuse cutaneous systemic sclerosis. Belimumab is a fully human monoclonal antibody which binds to soluble B-lymphocyte stimulator and inhibits autoantibody production.

Belimumab’s mechanism of benefit was as expected: The improvement in skin scores in the belimumab group was accompanied by decreased expression of profibrotic genes and B-cell signaling, changes that didn’t occur in the controls on MMF alone.

The belimumab study makes another important point: MMF, despite its growing popularity for treatment of skin manifestations of scleroderma, is actually a wimpy drug for that purpose, achieving a mere 3-point reduction in mRSS.

“To be quite honest, mycophenolate mofetil is not all that great on skin,” Dr. Pope said.

Nonetheless, when she and her coworkers recently polled 170 scleroderma experts as to their favored treatments directed at various target organs impaired by the disease, as she had previously done in 2012, a clear trend was evident. “There’s a shift in that mycophenolate mofetil is moving to first-line treatment across the board for skin,” Dr. Pope observed.

Indeed, in the more recent survey, 71% of the experts agreed upon a scleroderma skin involvement treatment algorithm in which the first-line treatment for severe skin disease as defined by an mRSS of 32 was MMF, with methotrexate as second line, intravenous cyclophosphamide third, and autologous stem cell transplantation as fourth line for the small number of patients who qualify for it.

For moderate skin involvement, with an mRSS of 24, methotrexate was endorsed as first line, although by the narrowest of margins, over MMF, with intravenous cyclophosphamide as third line. For mild disease, with an mRSS of 10, methotrexate again narrowly beat out MMF by expert consensus as the preferred first-line therapy.

When asked about concomitant use of corticosteroids for treatment of skin involvement, 35% of experts said they never prescribe them for that indication, 33% do so occasionally, 19% sometimes, and 13% routinely. There was an even split on dosing among those who prescribe steroids: 49% suggested using prednisone at less than 7.5 mg/day, and 51% recommended 7.5-20 mg/day.

The purpose in polling the experts, who were drawn from the Scleroderma Clinical Trials Consortium and the Canadian Scleroderma Research Group, was to provide treatment guidance to general rheumatologists and dermatologists who may not see many patients with scleroderma. In contrast, the great majority of the polled experts see more than 50 scleroderma patients per year. And they had a high level of total agreement for treatment algorithms addressing not only skin disease, but also pulmonary arterial hypertension, interstitial lung disease, Raynaud’s phenomenon, renal crisis, digital ulcers, inflammatory arthritis, cardiac involvement, and gastrointestinal disease, Dr. Pope noted.

She attributed the experts’ rising enthusiasm for MMF for scleroderma skin involvement to the results of the Scleroderma Lung Study II, the first randomized, controlled trial to compare MMF and cyclophosphamide for the treatment of symptomatic scleroderma interstitial lung disease. Two years of MMF improved forced vital capacity as much as 1 year of oral cyclophosphamide. At 2 years of follow-up, the mRSS dropped modestly from baseline by an average of 6.1 points in the cyclophosphamide group and 2.9 points with MMF, a nonsignificant difference. But the incidence of serious adverse events was roughly three times higher and deaths were twice as frequent in the cyclophosphamide group.

“I think mycophenolate mofetil is surging for treatment of skin because of the lung protection and it was safer, but it’s hard for me to know if the deaths were more common in the cyclophosphamide group because of the cyclophosphamide or because of no treatment in year 2,” Dr. Pope commented.

She reported receiving research grants from Bristol-Myers Squibb, Merck, Roche, Seattle Genetics, and UCB, and serving as a consultant to more than a dozen pharmaceutical companies.

[email protected]

MAUI, HAWAII – Belimumab shows promise as a novel biologic treatment for skin involvement in early diffuse cutaneous systemic sclerosis, Janet E. Pope, MD, said at the 2020 Rheumatology Winter Clinical Symposium.

Bruce Jancin/MDedge News

She highlighted a single-center, double-blind, placebo-controlled, New York pilot study including 20 patients with early diffuse cutaneous systemic sclerosis and moderate skin involvement. Participants had recently started on background mycophenolate mofetil (MMF) at 1,000 mg twice daily and were then randomized to add-on belimumab (Benlysta) at the dosing approved for systemic lupus erythematosus or to infusions of normal saline.

At 52 weeks, the modified Rodnan skin thickness score (mRSS) decreased by a median of 10 points from a baseline of 27 in the belimumab group, compared with just a 3-point reduction in controls on MMF plus placebo.

This small study raises several key points. It definitely warrants confirmation in a large phase 3 trial, according to Dr. Pope, professor of medicine at the University of Western Ontario and head of the division of rheumatology at St. Joseph’s Health Care, both in London.

For one thing, the pilot study makes a good case for multidrug therapy in scleroderma. “In rheumatoid arthritis, if in general one drug is not as good as two, why would we ever think, in our most difficult-to-treat disease, one drug would be okay?” the rheumatologist observed.

The belimumab study also highlights the role of abnormalities in B-cell function in the pathogenesis of skin involvement in early diffuse cutaneous systemic sclerosis. Belimumab is a fully human monoclonal antibody which binds to soluble B-lymphocyte stimulator and inhibits autoantibody production.

Belimumab’s mechanism of benefit was as expected: The improvement in skin scores in the belimumab group was accompanied by decreased expression of profibrotic genes and B-cell signaling, changes that didn’t occur in the controls on MMF alone.

The belimumab study makes another important point: MMF, despite its growing popularity for treatment of skin manifestations of scleroderma, is actually a wimpy drug for that purpose, achieving a mere 3-point reduction in mRSS.

“To be quite honest, mycophenolate mofetil is not all that great on skin,” Dr. Pope said.

Nonetheless, when she and her coworkers recently polled 170 scleroderma experts as to their favored treatments directed at various target organs impaired by the disease, as she had previously done in 2012, a clear trend was evident. “There’s a shift in that mycophenolate mofetil is moving to first-line treatment across the board for skin,” Dr. Pope observed.

Indeed, in the more recent survey, 71% of the experts agreed upon a scleroderma skin involvement treatment algorithm in which the first-line treatment for severe skin disease as defined by an mRSS of 32 was MMF, with methotrexate as second line, intravenous cyclophosphamide third, and autologous stem cell transplantation as fourth line for the small number of patients who qualify for it.

For moderate skin involvement, with an mRSS of 24, methotrexate was endorsed as first line, although by the narrowest of margins, over MMF, with intravenous cyclophosphamide as third line. For mild disease, with an mRSS of 10, methotrexate again narrowly beat out MMF by expert consensus as the preferred first-line therapy.

When asked about concomitant use of corticosteroids for treatment of skin involvement, 35% of experts said they never prescribe them for that indication, 33% do so occasionally, 19% sometimes, and 13% routinely. There was an even split on dosing among those who prescribe steroids: 49% suggested using prednisone at less than 7.5 mg/day, and 51% recommended 7.5-20 mg/day.

The purpose in polling the experts, who were drawn from the Scleroderma Clinical Trials Consortium and the Canadian Scleroderma Research Group, was to provide treatment guidance to general rheumatologists and dermatologists who may not see many patients with scleroderma. In contrast, the great majority of the polled experts see more than 50 scleroderma patients per year. And they had a high level of total agreement for treatment algorithms addressing not only skin disease, but also pulmonary arterial hypertension, interstitial lung disease, Raynaud’s phenomenon, renal crisis, digital ulcers, inflammatory arthritis, cardiac involvement, and gastrointestinal disease, Dr. Pope noted.

She attributed the experts’ rising enthusiasm for MMF for scleroderma skin involvement to the results of the Scleroderma Lung Study II, the first randomized, controlled trial to compare MMF and cyclophosphamide for the treatment of symptomatic scleroderma interstitial lung disease. Two years of MMF improved forced vital capacity as much as 1 year of oral cyclophosphamide. At 2 years of follow-up, the mRSS dropped modestly from baseline by an average of 6.1 points in the cyclophosphamide group and 2.9 points with MMF, a nonsignificant difference. But the incidence of serious adverse events was roughly three times higher and deaths were twice as frequent in the cyclophosphamide group.

“I think mycophenolate mofetil is surging for treatment of skin because of the lung protection and it was safer, but it’s hard for me to know if the deaths were more common in the cyclophosphamide group because of the cyclophosphamide or because of no treatment in year 2,” Dr. Pope commented.

She reported receiving research grants from Bristol-Myers Squibb, Merck, Roche, Seattle Genetics, and UCB, and serving as a consultant to more than a dozen pharmaceutical companies.

[email protected]

MAUI, HAWAII – Belimumab shows promise as a novel biologic treatment for skin involvement in early diffuse cutaneous systemic sclerosis, Janet E. Pope, MD, said at the 2020 Rheumatology Winter Clinical Symposium.

Bruce Jancin/MDedge News

She highlighted a single-center, double-blind, placebo-controlled, New York pilot study including 20 patients with early diffuse cutaneous systemic sclerosis and moderate skin involvement. Participants had recently started on background mycophenolate mofetil (MMF) at 1,000 mg twice daily and were then randomized to add-on belimumab (Benlysta) at the dosing approved for systemic lupus erythematosus or to infusions of normal saline.

At 52 weeks, the modified Rodnan skin thickness score (mRSS) decreased by a median of 10 points from a baseline of 27 in the belimumab group, compared with just a 3-point reduction in controls on MMF plus placebo.

This small study raises several key points. It definitely warrants confirmation in a large phase 3 trial, according to Dr. Pope, professor of medicine at the University of Western Ontario and head of the division of rheumatology at St. Joseph’s Health Care, both in London.

For one thing, the pilot study makes a good case for multidrug therapy in scleroderma. “In rheumatoid arthritis, if in general one drug is not as good as two, why would we ever think, in our most difficult-to-treat disease, one drug would be okay?” the rheumatologist observed.

The belimumab study also highlights the role of abnormalities in B-cell function in the pathogenesis of skin involvement in early diffuse cutaneous systemic sclerosis. Belimumab is a fully human monoclonal antibody which binds to soluble B-lymphocyte stimulator and inhibits autoantibody production.

Belimumab’s mechanism of benefit was as expected: The improvement in skin scores in the belimumab group was accompanied by decreased expression of profibrotic genes and B-cell signaling, changes that didn’t occur in the controls on MMF alone.

The belimumab study makes another important point: MMF, despite its growing popularity for treatment of skin manifestations of scleroderma, is actually a wimpy drug for that purpose, achieving a mere 3-point reduction in mRSS.

“To be quite honest, mycophenolate mofetil is not all that great on skin,” Dr. Pope said.

Nonetheless, when she and her coworkers recently polled 170 scleroderma experts as to their favored treatments directed at various target organs impaired by the disease, as she had previously done in 2012, a clear trend was evident. “There’s a shift in that mycophenolate mofetil is moving to first-line treatment across the board for skin,” Dr. Pope observed.

Indeed, in the more recent survey, 71% of the experts agreed upon a scleroderma skin involvement treatment algorithm in which the first-line treatment for severe skin disease as defined by an mRSS of 32 was MMF, with methotrexate as second line, intravenous cyclophosphamide third, and autologous stem cell transplantation as fourth line for the small number of patients who qualify for it.

For moderate skin involvement, with an mRSS of 24, methotrexate was endorsed as first line, although by the narrowest of margins, over MMF, with intravenous cyclophosphamide as third line. For mild disease, with an mRSS of 10, methotrexate again narrowly beat out MMF by expert consensus as the preferred first-line therapy.

When asked about concomitant use of corticosteroids for treatment of skin involvement, 35% of experts said they never prescribe them for that indication, 33% do so occasionally, 19% sometimes, and 13% routinely. There was an even split on dosing among those who prescribe steroids: 49% suggested using prednisone at less than 7.5 mg/day, and 51% recommended 7.5-20 mg/day.

The purpose in polling the experts, who were drawn from the Scleroderma Clinical Trials Consortium and the Canadian Scleroderma Research Group, was to provide treatment guidance to general rheumatologists and dermatologists who may not see many patients with scleroderma. In contrast, the great majority of the polled experts see more than 50 scleroderma patients per year. And they had a high level of total agreement for treatment algorithms addressing not only skin disease, but also pulmonary arterial hypertension, interstitial lung disease, Raynaud’s phenomenon, renal crisis, digital ulcers, inflammatory arthritis, cardiac involvement, and gastrointestinal disease, Dr. Pope noted.

She attributed the experts’ rising enthusiasm for MMF for scleroderma skin involvement to the results of the Scleroderma Lung Study II, the first randomized, controlled trial to compare MMF and cyclophosphamide for the treatment of symptomatic scleroderma interstitial lung disease. Two years of MMF improved forced vital capacity as much as 1 year of oral cyclophosphamide. At 2 years of follow-up, the mRSS dropped modestly from baseline by an average of 6.1 points in the cyclophosphamide group and 2.9 points with MMF, a nonsignificant difference. But the incidence of serious adverse events was roughly three times higher and deaths were twice as frequent in the cyclophosphamide group.

“I think mycophenolate mofetil is surging for treatment of skin because of the lung protection and it was safer, but it’s hard for me to know if the deaths were more common in the cyclophosphamide group because of the cyclophosphamide or because of no treatment in year 2,” Dr. Pope commented.

She reported receiving research grants from Bristol-Myers Squibb, Merck, Roche, Seattle Genetics, and UCB, and serving as a consultant to more than a dozen pharmaceutical companies.

[email protected]

Levels of three vascular biomarkers – hepatocyte growth factor, soluble Flt-1, and platelet-derived growth factor – were elevated a mean of 3 years before systemic sclerosis (SSc) patients developed pulmonary hypertension (PH) in a prospective cohort of 300 subjects.

However, the associations with PH were not very robust. For instance, above an optimal cut point of 9.89 pg/mL for platelet-derived growth factor (PlGF), the sensitivity for future PH was 82%, specificity 56%, and area under the curve (AUC) 0.69. An elevation above the optimal cut point for soluble Flt-1 (sFlt1) – 93.8 pg/mL – was 71% specific and 51% sensitive, with an AUC of 0.61.

Adding PlGF and sFlt1 elevations to carbon monoxide diffusing capacity, N-terminal of the prohormone brain natriuretic peptide (NT-proBNP) level, and percent forced vital capacity to predict PH increased the AUC modestly, from 0.72 to 0.77.

The data suggest, perhaps, an early warning system for PH. “Once vascular biomarkers are observed to be elevated, the frequency of other screening tests (e.g., NT-proBNP, DLCO) may be increased in a more cost-effective approach,” wrote investigators led by rheumatologist Christopher Mecoli, MD, an assistant professor at Johns Hopkins University, Baltimore, in Arthritis & Rheumatology.

“In the end, the authors did not overstate the case and cautiously recommended that using biomarkers might be useful in the future. The finding that when there are increased numbers of abnormalities of vascular markers, there would be an increased probability of pulmonary hypertension, makes sense.” However, “this was a major fishing expedition, and the data are certainly not sufficient to suggest anything clinical but are of some interest with respect to the general hypothesis,” said rheumatologist Daniel Furst, MD, professor of medicine (emeritus) at the University of California, Los Angeles, when asked for comment.

The subjects were followed for at least 5 years and had no evidence of PH at study entry. Levels of P1GF, sFlt-1, hepatocyte growth factor (HGF), soluble endoglin, and endostatin were assessed at baseline and at regular intervals thereafter. A total of 46 patients (15%) developed PH after a mean of 3 years.

Risk of PH was associated with baseline elevations of HGF (hazard ratio, 1.99; 95% CI, 1.24-3.17; P = .004); sFlt1 (HR, 3.04; 95% CI, 1.29-7.14; P = .011); and PlGF (HR, 2.74; 95% CI, 1.32-5.69; P = .007).

Just 2 of 25 patients (8%) with no biomarkers elevated at baseline developed PH versus 12 of 29 (42%) with all five elevated. That translated to a dose-response relationship, with each additional elevated biomarker increasing the risk of PH by 78% (95% CI, 1.2-2.6; P = .004).

“There [was] no consistent trend of increasing biomarker levels over time as patients approach[ed] a diagnosis of [PH]. ... Serial testing may have value in patients with early disease to first detect elevations in biomarkers,” but “once elevated, the utility of serially monitoring appears low,” the investigators wrote.

It’s not surprising that “a higher number of elevated biomarkers relating to vascular dysfunction would correspond to a higher risk of PH,” the team wrote. However, “while these biomarkers hold promise in the risk stratification of SSc patients, many more vascular molecules exist which may have similar or greater value.”

There was no substantial correlation between any biomarker and disease duration, age at enrollment, or age at diagnosis, and no significant difference in biomarker level based on patient comorbidities. No biomarker was significantly associated with medication use at cohort entry, and none were significantly associated with the risk of ischemic digital lesions.

The majority of patients were white women. At enrollment, the average age was 52 years, and subjects had SSc for a mean of 10 years.

The work was funded by the National Institutes of Health, among others. Investigator disclosures were not reported.

[email protected]

SOURCE: Mecoli C et al. Arthritis Rheumatol. 2020 Mar 21. doi: 10.1002/art.41265.

Levels of three vascular biomarkers – hepatocyte growth factor, soluble Flt-1, and platelet-derived growth factor – were elevated a mean of 3 years before systemic sclerosis (SSc) patients developed pulmonary hypertension (PH) in a prospective cohort of 300 subjects.

However, the associations with PH were not very robust. For instance, above an optimal cut point of 9.89 pg/mL for platelet-derived growth factor (PlGF), the sensitivity for future PH was 82%, specificity 56%, and area under the curve (AUC) 0.69. An elevation above the optimal cut point for soluble Flt-1 (sFlt1) – 93.8 pg/mL – was 71% specific and 51% sensitive, with an AUC of 0.61.

Adding PlGF and sFlt1 elevations to carbon monoxide diffusing capacity, N-terminal of the prohormone brain natriuretic peptide (NT-proBNP) level, and percent forced vital capacity to predict PH increased the AUC modestly, from 0.72 to 0.77.

The data suggest, perhaps, an early warning system for PH. “Once vascular biomarkers are observed to be elevated, the frequency of other screening tests (e.g., NT-proBNP, DLCO) may be increased in a more cost-effective approach,” wrote investigators led by rheumatologist Christopher Mecoli, MD, an assistant professor at Johns Hopkins University, Baltimore, in Arthritis & Rheumatology.

“In the end, the authors did not overstate the case and cautiously recommended that using biomarkers might be useful in the future. The finding that when there are increased numbers of abnormalities of vascular markers, there would be an increased probability of pulmonary hypertension, makes sense.” However, “this was a major fishing expedition, and the data are certainly not sufficient to suggest anything clinical but are of some interest with respect to the general hypothesis,” said rheumatologist Daniel Furst, MD, professor of medicine (emeritus) at the University of California, Los Angeles, when asked for comment.

The subjects were followed for at least 5 years and had no evidence of PH at study entry. Levels of P1GF, sFlt-1, hepatocyte growth factor (HGF), soluble endoglin, and endostatin were assessed at baseline and at regular intervals thereafter. A total of 46 patients (15%) developed PH after a mean of 3 years.

Risk of PH was associated with baseline elevations of HGF (hazard ratio, 1.99; 95% CI, 1.24-3.17; P = .004); sFlt1 (HR, 3.04; 95% CI, 1.29-7.14; P = .011); and PlGF (HR, 2.74; 95% CI, 1.32-5.69; P = .007).

Just 2 of 25 patients (8%) with no biomarkers elevated at baseline developed PH versus 12 of 29 (42%) with all five elevated. That translated to a dose-response relationship, with each additional elevated biomarker increasing the risk of PH by 78% (95% CI, 1.2-2.6; P = .004).

“There [was] no consistent trend of increasing biomarker levels over time as patients approach[ed] a diagnosis of [PH]. ... Serial testing may have value in patients with early disease to first detect elevations in biomarkers,” but “once elevated, the utility of serially monitoring appears low,” the investigators wrote.

It’s not surprising that “a higher number of elevated biomarkers relating to vascular dysfunction would correspond to a higher risk of PH,” the team wrote. However, “while these biomarkers hold promise in the risk stratification of SSc patients, many more vascular molecules exist which may have similar or greater value.”

There was no substantial correlation between any biomarker and disease duration, age at enrollment, or age at diagnosis, and no significant difference in biomarker level based on patient comorbidities. No biomarker was significantly associated with medication use at cohort entry, and none were significantly associated with the risk of ischemic digital lesions.

The majority of patients were white women. At enrollment, the average age was 52 years, and subjects had SSc for a mean of 10 years.

The work was funded by the National Institutes of Health, among others. Investigator disclosures were not reported.

[email protected]

SOURCE: Mecoli C et al. Arthritis Rheumatol. 2020 Mar 21. doi: 10.1002/art.41265.

Levels of three vascular biomarkers – hepatocyte growth factor, soluble Flt-1, and platelet-derived growth factor – were elevated a mean of 3 years before systemic sclerosis (SSc) patients developed pulmonary hypertension (PH) in a prospective cohort of 300 subjects.

However, the associations with PH were not very robust. For instance, above an optimal cut point of 9.89 pg/mL for platelet-derived growth factor (PlGF), the sensitivity for future PH was 82%, specificity 56%, and area under the curve (AUC) 0.69. An elevation above the optimal cut point for soluble Flt-1 (sFlt1) – 93.8 pg/mL – was 71% specific and 51% sensitive, with an AUC of 0.61.

Adding PlGF and sFlt1 elevations to carbon monoxide diffusing capacity, N-terminal of the prohormone brain natriuretic peptide (NT-proBNP) level, and percent forced vital capacity to predict PH increased the AUC modestly, from 0.72 to 0.77.

The data suggest, perhaps, an early warning system for PH. “Once vascular biomarkers are observed to be elevated, the frequency of other screening tests (e.g., NT-proBNP, DLCO) may be increased in a more cost-effective approach,” wrote investigators led by rheumatologist Christopher Mecoli, MD, an assistant professor at Johns Hopkins University, Baltimore, in Arthritis & Rheumatology.

“In the end, the authors did not overstate the case and cautiously recommended that using biomarkers might be useful in the future. The finding that when there are increased numbers of abnormalities of vascular markers, there would be an increased probability of pulmonary hypertension, makes sense.” However, “this was a major fishing expedition, and the data are certainly not sufficient to suggest anything clinical but are of some interest with respect to the general hypothesis,” said rheumatologist Daniel Furst, MD, professor of medicine (emeritus) at the University of California, Los Angeles, when asked for comment.

The subjects were followed for at least 5 years and had no evidence of PH at study entry. Levels of P1GF, sFlt-1, hepatocyte growth factor (HGF), soluble endoglin, and endostatin were assessed at baseline and at regular intervals thereafter. A total of 46 patients (15%) developed PH after a mean of 3 years.

Risk of PH was associated with baseline elevations of HGF (hazard ratio, 1.99; 95% CI, 1.24-3.17; P = .004); sFlt1 (HR, 3.04; 95% CI, 1.29-7.14; P = .011); and PlGF (HR, 2.74; 95% CI, 1.32-5.69; P = .007).

Just 2 of 25 patients (8%) with no biomarkers elevated at baseline developed PH versus 12 of 29 (42%) with all five elevated. That translated to a dose-response relationship, with each additional elevated biomarker increasing the risk of PH by 78% (95% CI, 1.2-2.6; P = .004).

“There [was] no consistent trend of increasing biomarker levels over time as patients approach[ed] a diagnosis of [PH]. ... Serial testing may have value in patients with early disease to first detect elevations in biomarkers,” but “once elevated, the utility of serially monitoring appears low,” the investigators wrote.

It’s not surprising that “a higher number of elevated biomarkers relating to vascular dysfunction would correspond to a higher risk of PH,” the team wrote. However, “while these biomarkers hold promise in the risk stratification of SSc patients, many more vascular molecules exist which may have similar or greater value.”

There was no substantial correlation between any biomarker and disease duration, age at enrollment, or age at diagnosis, and no significant difference in biomarker level based on patient comorbidities. No biomarker was significantly associated with medication use at cohort entry, and none were significantly associated with the risk of ischemic digital lesions.

The majority of patients were white women. At enrollment, the average age was 52 years, and subjects had SSc for a mean of 10 years.

The work was funded by the National Institutes of Health, among others. Investigator disclosures were not reported.

[email protected]

SOURCE: Mecoli C et al. Arthritis Rheumatol. 2020 Mar 21. doi: 10.1002/art.41265.

Combination therapy with leflunomide and hydroxychloroquine is safe in patients with primary Sjögren’s syndrome and may elicit clinical improvement, according to results from a phase 2a, randomized clinical trial published in Lancet Rheumatology.

The combination’s statistically significant effect on the European League Against Rheumatism (EULAR) Sjögren’s syndrome disease activity index (ESSDAI) score at 24 weeks, the primary endpoint of the small, double-blind, placebo-controlled trial, suggests that the combination should be studied further in larger trials, according to first author Eefje Hanna Martine van der Heijden, MD, a rheumatologist at University Medical Center Utrecht (the Netherlands), and colleagues.

The investigators decided to study leflunomide and hydroxychloroquine, which target overlapping and distinct immunopathologic pathways, because data support the safety of each drug individually, and a previous in vitro study by the authors indicated that they have complementary effects when administered together.

“To our knowledge, this is the first randomized, placebo-controlled clinical trial in patients with primary Sjögren’s syndrome that shows significant clinical efficacy, as measured by ESSDAI, and is associated with significant improvements in other clinical parameters, including dryness and fatigue,” the investigators wrote.

Dr. van der Heijden and colleagues screened 37 patients from the outpatient clinic of their medical center and enrolled 29 (28 women) who met American-European Consensus Criteria into their study. They had moderate to active disease, defined as an ESSDAI score of 5 or higher, and a lymphocytic focus score of 1 or higher in labial salivary gland biopsy specimens that were obtained before inclusion. The population’s average age was approximately 54 years. They had an average disease duration of about 8 years, a mean ESSDAI score of about 9, and mean EULAR Sjögren’s syndrome patient reported index (ESSPRI) score of 6.7. A total of 21 patients were randomized to leflunomide 20 mg and hydroxychloroquine 400 mg daily, and 8 patients were randomized to placebos. Baseline characteristics were similar between groups, but mean serum IgG level was 19.4 g/L in the treatment group and 13.8 g/L in the placebo group. One patient in the placebo group developed polymyalgia rheumatica and required high-dose prednisone treatment. The investigators excluded this patient from the primary analysis.

At 24 weeks, the mean difference in ESSDAI score in the leflunomide-hydroxychloroquine group, compared with the placebo group, was –4.35 points after adjustment for baseline values. This difference was statistically significant.

Secondary endpoints in the study showed inconsistent statistically significant differences between the treatment groups at 8, 16, and 24 weeks. The total ESSPRI score at 16 weeks was 1.66 points lower in the treatment group than in the placebo group. Stimulated whole saliva production was increased in the leflunomide-hydroxychloroquine group at 16 weeks, compared with the placebo group. Unstimulated whole saliva production at 24 weeks was higher in the leflunomide-hydroxychloroquine group than in controls. The investigators found no differences between groups in visual analog scores for ocular or oral dryness.

No patient in the leflunomide-hydroxychloroquine group had a serious adverse event. Two serious adverse events (hospital admission for pancreatitis and hospital admission for nephrolithiasis) occurred in the placebo group. The most common adverse events in the leflunomide-hydroxychloroquine group were GI discomfort (52% vs. 25% in the placebo group), modest transient increases in ALT (48% vs. 13%), and short episodes of general malaise and shivering (43% vs. 13%).

In an accompanying editorial, Astrid Rasmussen, MD, PhD, of the Oklahoma Sjögren’s Syndrome Center of Research Translation at the Oklahoma Medical Research Foundation in Oklahoma City, wrote that the trial by Dr. van der Heijden and colleagues was limited by a small sample size and short duration. In addition, some of the findings were unexplained, such as modest changes in secondary endpoints and a concomitant decrease in ESSDAI scores at 8 weeks for both study groups.

Nevertheless, the study provides reason to think in new ways about old drugs, wrote Dr. Rasmussen. “Combination or sequential use of existing agents that target different aspects of immune dysregulation, while having acceptable safety profiles and cost-benefit ratios, should represent an avenue of further exploration. Just as importantly, subphenotyping patients on the basis of their underlying pathogenic processes and identifying sensitive outcome measures could transform the current enthusiasm for identifying effective treatments for Sjögren’s syndrome into a reality for the patients that need them the most.”

The study was funded by ZonMw. The authors of the study reported no conflicts of interest. Dr. Rasmussen reported having no conflicts of interest.

[email protected]

SOURCE: van der Heijden EHM et al. Lancet Rheumatol. 2020 Mar 26. doi: 10.1016/S2665-9913(20)30057-6.

Combination therapy with leflunomide and hydroxychloroquine is safe in patients with primary Sjögren’s syndrome and may elicit clinical improvement, according to results from a phase 2a, randomized clinical trial published in Lancet Rheumatology.

The combination’s statistically significant effect on the European League Against Rheumatism (EULAR) Sjögren’s syndrome disease activity index (ESSDAI) score at 24 weeks, the primary endpoint of the small, double-blind, placebo-controlled trial, suggests that the combination should be studied further in larger trials, according to first author Eefje Hanna Martine van der Heijden, MD, a rheumatologist at University Medical Center Utrecht (the Netherlands), and colleagues.

The investigators decided to study leflunomide and hydroxychloroquine, which target overlapping and distinct immunopathologic pathways, because data support the safety of each drug individually, and a previous in vitro study by the authors indicated that they have complementary effects when administered together.

“To our knowledge, this is the first randomized, placebo-controlled clinical trial in patients with primary Sjögren’s syndrome that shows significant clinical efficacy, as measured by ESSDAI, and is associated with significant improvements in other clinical parameters, including dryness and fatigue,” the investigators wrote.

Dr. van der Heijden and colleagues screened 37 patients from the outpatient clinic of their medical center and enrolled 29 (28 women) who met American-European Consensus Criteria into their study. They had moderate to active disease, defined as an ESSDAI score of 5 or higher, and a lymphocytic focus score of 1 or higher in labial salivary gland biopsy specimens that were obtained before inclusion. The population’s average age was approximately 54 years. They had an average disease duration of about 8 years, a mean ESSDAI score of about 9, and mean EULAR Sjögren’s syndrome patient reported index (ESSPRI) score of 6.7. A total of 21 patients were randomized to leflunomide 20 mg and hydroxychloroquine 400 mg daily, and 8 patients were randomized to placebos. Baseline characteristics were similar between groups, but mean serum IgG level was 19.4 g/L in the treatment group and 13.8 g/L in the placebo group. One patient in the placebo group developed polymyalgia rheumatica and required high-dose prednisone treatment. The investigators excluded this patient from the primary analysis.

At 24 weeks, the mean difference in ESSDAI score in the leflunomide-hydroxychloroquine group, compared with the placebo group, was –4.35 points after adjustment for baseline values. This difference was statistically significant.

Secondary endpoints in the study showed inconsistent statistically significant differences between the treatment groups at 8, 16, and 24 weeks. The total ESSPRI score at 16 weeks was 1.66 points lower in the treatment group than in the placebo group. Stimulated whole saliva production was increased in the leflunomide-hydroxychloroquine group at 16 weeks, compared with the placebo group. Unstimulated whole saliva production at 24 weeks was higher in the leflunomide-hydroxychloroquine group than in controls. The investigators found no differences between groups in visual analog scores for ocular or oral dryness.

No patient in the leflunomide-hydroxychloroquine group had a serious adverse event. Two serious adverse events (hospital admission for pancreatitis and hospital admission for nephrolithiasis) occurred in the placebo group. The most common adverse events in the leflunomide-hydroxychloroquine group were GI discomfort (52% vs. 25% in the placebo group), modest transient increases in ALT (48% vs. 13%), and short episodes of general malaise and shivering (43% vs. 13%).

In an accompanying editorial, Astrid Rasmussen, MD, PhD, of the Oklahoma Sjögren’s Syndrome Center of Research Translation at the Oklahoma Medical Research Foundation in Oklahoma City, wrote that the trial by Dr. van der Heijden and colleagues was limited by a small sample size and short duration. In addition, some of the findings were unexplained, such as modest changes in secondary endpoints and a concomitant decrease in ESSDAI scores at 8 weeks for both study groups.

Nevertheless, the study provides reason to think in new ways about old drugs, wrote Dr. Rasmussen. “Combination or sequential use of existing agents that target different aspects of immune dysregulation, while having acceptable safety profiles and cost-benefit ratios, should represent an avenue of further exploration. Just as importantly, subphenotyping patients on the basis of their underlying pathogenic processes and identifying sensitive outcome measures could transform the current enthusiasm for identifying effective treatments for Sjögren’s syndrome into a reality for the patients that need them the most.”

The study was funded by ZonMw. The authors of the study reported no conflicts of interest. Dr. Rasmussen reported having no conflicts of interest.

[email protected]

SOURCE: van der Heijden EHM et al. Lancet Rheumatol. 2020 Mar 26. doi: 10.1016/S2665-9913(20)30057-6.

Combination therapy with leflunomide and hydroxychloroquine is safe in patients with primary Sjögren’s syndrome and may elicit clinical improvement, according to results from a phase 2a, randomized clinical trial published in Lancet Rheumatology.

The combination’s statistically significant effect on the European League Against Rheumatism (EULAR) Sjögren’s syndrome disease activity index (ESSDAI) score at 24 weeks, the primary endpoint of the small, double-blind, placebo-controlled trial, suggests that the combination should be studied further in larger trials, according to first author Eefje Hanna Martine van der Heijden, MD, a rheumatologist at University Medical Center Utrecht (the Netherlands), and colleagues.

The investigators decided to study leflunomide and hydroxychloroquine, which target overlapping and distinct immunopathologic pathways, because data support the safety of each drug individually, and a previous in vitro study by the authors indicated that they have complementary effects when administered together.

“To our knowledge, this is the first randomized, placebo-controlled clinical trial in patients with primary Sjögren’s syndrome that shows significant clinical efficacy, as measured by ESSDAI, and is associated with significant improvements in other clinical parameters, including dryness and fatigue,” the investigators wrote.

Dr. van der Heijden and colleagues screened 37 patients from the outpatient clinic of their medical center and enrolled 29 (28 women) who met American-European Consensus Criteria into their study. They had moderate to active disease, defined as an ESSDAI score of 5 or higher, and a lymphocytic focus score of 1 or higher in labial salivary gland biopsy specimens that were obtained before inclusion. The population’s average age was approximately 54 years. They had an average disease duration of about 8 years, a mean ESSDAI score of about 9, and mean EULAR Sjögren’s syndrome patient reported index (ESSPRI) score of 6.7. A total of 21 patients were randomized to leflunomide 20 mg and hydroxychloroquine 400 mg daily, and 8 patients were randomized to placebos. Baseline characteristics were similar between groups, but mean serum IgG level was 19.4 g/L in the treatment group and 13.8 g/L in the placebo group. One patient in the placebo group developed polymyalgia rheumatica and required high-dose prednisone treatment. The investigators excluded this patient from the primary analysis.

At 24 weeks, the mean difference in ESSDAI score in the leflunomide-hydroxychloroquine group, compared with the placebo group, was –4.35 points after adjustment for baseline values. This difference was statistically significant.

Secondary endpoints in the study showed inconsistent statistically significant differences between the treatment groups at 8, 16, and 24 weeks. The total ESSPRI score at 16 weeks was 1.66 points lower in the treatment group than in the placebo group. Stimulated whole saliva production was increased in the leflunomide-hydroxychloroquine group at 16 weeks, compared with the placebo group. Unstimulated whole saliva production at 24 weeks was higher in the leflunomide-hydroxychloroquine group than in controls. The investigators found no differences between groups in visual analog scores for ocular or oral dryness.

No patient in the leflunomide-hydroxychloroquine group had a serious adverse event. Two serious adverse events (hospital admission for pancreatitis and hospital admission for nephrolithiasis) occurred in the placebo group. The most common adverse events in the leflunomide-hydroxychloroquine group were GI discomfort (52% vs. 25% in the placebo group), modest transient increases in ALT (48% vs. 13%), and short episodes of general malaise and shivering (43% vs. 13%).

In an accompanying editorial, Astrid Rasmussen, MD, PhD, of the Oklahoma Sjögren’s Syndrome Center of Research Translation at the Oklahoma Medical Research Foundation in Oklahoma City, wrote that the trial by Dr. van der Heijden and colleagues was limited by a small sample size and short duration. In addition, some of the findings were unexplained, such as modest changes in secondary endpoints and a concomitant decrease in ESSDAI scores at 8 weeks for both study groups.

Nevertheless, the study provides reason to think in new ways about old drugs, wrote Dr. Rasmussen. “Combination or sequential use of existing agents that target different aspects of immune dysregulation, while having acceptable safety profiles and cost-benefit ratios, should represent an avenue of further exploration. Just as importantly, subphenotyping patients on the basis of their underlying pathogenic processes and identifying sensitive outcome measures could transform the current enthusiasm for identifying effective treatments for Sjögren’s syndrome into a reality for the patients that need them the most.”

The study was funded by ZonMw. The authors of the study reported no conflicts of interest. Dr. Rasmussen reported having no conflicts of interest.

[email protected]

SOURCE: van der Heijden EHM et al. Lancet Rheumatol. 2020 Mar 26. doi: 10.1016/S2665-9913(20)30057-6.

For patients with lupus nephritis, kidney response improves when voclosporin (Aurinia Pharmaceuticals) is added to mycophenolate and low-dose corticosteroids, results from the phase 3 AURORA trial show.
 

The calcineurin inhibitor is the first novel agent to demonstrate effectiveness in the treatment of people with lupus nephritis, a disease that can lead to irreversible kidney damage, kidney failure, and even death.

“We believe that voclosporin – as an add-on therapy – will help more patients achieve remission,” said Keisha Gibson, MD, MPH, chief of pediatric nephrology at the UNC Kidney Center in Chapel Hill, North Carolina, who led the study and presented the findings during a virtual session at the National Kidney Foundation 2020 Spring Clinical Meetings.

The burden that lupus places on patients and the health system is high, she reported. Patients with lupus and uncontrolled kidney disease frequently have complications that require hospitalization, can suffer complete or partial loss of income, and can become temporarily disabled. And up to 50% of lupus patients will develop lupus nephritis.

“When we are lucky and see early treatment responses in our patients, we know that their long-term outcomes, measured by proteinuria reduction, are quite good,” said Gibson. “Unfortunately, in 10% to 30% of patients, despite standard-of-care therapies, we see progression to end-stage kidney disease within 15 years of diagnosis. This confers a huge cost to overall health and quality of life, and is an excess burden to the healthcare system.

“It is clear that one of the biggest risk factors for these patients who have kidney disease that is progressing to kidney failure is an inability to control the inflammation and chronic damage from uncontrolled disease,” she told Medscape Medical News.

“While there have certainly been a few advances in the care of patients with lupus disease, I believe that this therapy may help move the needle, specifically for patients with kidney involvement from their lupus disease,” she added.

Renal Response Much Higher With Voclosporin

The typical standard of care for patients with active lupus and kidney disease is either a combination of cyclophosphamide plus steroids or a combination of mycophenolate mofetil plus steroids.

The global, double-blind, randomized, placebo-controlled trial compared the effectiveness and safety of twice-daily oral voclosporin 23.7 mg with placebo. All 357 study participants also received mycophenolate 2 g daily and rapidly tapered low-dose oral corticosteroids.

At 1 year, the renal response rate was higher in the voclosporin group than in the placebo group (40.8% vs 22.5%; odds ratio, 2.65; P < .001).

“AURORA patients achieved low levels of protein twice as quickly as patients on standard of care,” the researchers write in their abstract. Median time to the achievement of a urine protein to creatinine ratio below 0.5 mg/mg was significantly and clinically better with voclosporin than with placebo (169 vs 372 days; log rank P < .001).

And voclosporin was well tolerated. The percentage of serious adverse events was similar in the voclosporin and placebo groups (20.8% vs 21.3%), with infection being the most common serious event (10.1% vs 11.2%).

In the voclosporin group, there were no significant differences between baseline and 1 year estimated glomerular filtration rates (eGFR), blood pressure, lipid levels, or sugar levels.

And there were fewer deaths in the voclosporin group than in the placebo group (1 vs 5).

Benefits were seen in all subgroups, including age, sex, race, biopsy class, geographic region of origin, and mycophenolate exposure at screening, Gibson reported.

Promise of a New Treatment

The promise of a new treatment is exciting for the field, said Joseph Vassalotti, MD, chief medical officer of the National Kidney Foundation.

However, it’s important to note that “this study is applicable only to patients with lupus nephritis with preserved kidney function,” he added.

An “eGFR less than 45 mL/min per 1.73 m² was implied as an exclusion criteria, so I would say it certainly doesn’t apply to patients with impaired kidney function,” he said, pointing out that this will be clearer when the final data are published.

The study cohort was heterogeneous; 86% of participants had class 3 or 4 biopsy findings and 14% had class 5, so the superiority of voclosporin is convincing, he said.

“We look forward to full publication and more details,” he told Medscape Medical News. “They do have an extension study, and it will be interesting to see how that plays out.”

Voclosporin was granted Fast Track designation by the US Food and Drug Administration in 2016, and these positive phase 3 results mean that a New Drug Application will likely be filed in the next few months. If approved, the drug could be on the market by 2021, according to a press release from Aurinia.

Nephrologists are familiar with calcineurin inhibitors, so it will be interesting to see, given the success of this trial, if voclosporin has a potential role in other kidney diseases, “such as minimal change disease,” said Vassalotti.

He added that there are concerns, unrelated to the AURORA trial, about the supply of hydroxychloroquine, which is also used for the treatment of lupus nephritis. “An overarching concern is that the supply will be limited now that the drug is being studied and used as prophylaxis after exposure to SARS-CoV-2 and as a treatment for COVID-19, creating challenges for patients with lupus nephritis trying to obtain their needed medication,” he said.

Gibson reports no relevant financial relationships. Two coauthors work for the drugmaker, Aurinia. Vassalotti reports no relevant financial relationships.
 

This article first appeared on Medscape.com.

For patients with lupus nephritis, kidney response improves when voclosporin (Aurinia Pharmaceuticals) is added to mycophenolate and low-dose corticosteroids, results from the phase 3 AURORA trial show.
 

The calcineurin inhibitor is the first novel agent to demonstrate effectiveness in the treatment of people with lupus nephritis, a disease that can lead to irreversible kidney damage, kidney failure, and even death.

“We believe that voclosporin – as an add-on therapy – will help more patients achieve remission,” said Keisha Gibson, MD, MPH, chief of pediatric nephrology at the UNC Kidney Center in Chapel Hill, North Carolina, who led the study and presented the findings during a virtual session at the National Kidney Foundation 2020 Spring Clinical Meetings.

The burden that lupus places on patients and the health system is high, she reported. Patients with lupus and uncontrolled kidney disease frequently have complications that require hospitalization, can suffer complete or partial loss of income, and can become temporarily disabled. And up to 50% of lupus patients will develop lupus nephritis.

“When we are lucky and see early treatment responses in our patients, we know that their long-term outcomes, measured by proteinuria reduction, are quite good,” said Gibson. “Unfortunately, in 10% to 30% of patients, despite standard-of-care therapies, we see progression to end-stage kidney disease within 15 years of diagnosis. This confers a huge cost to overall health and quality of life, and is an excess burden to the healthcare system.

“It is clear that one of the biggest risk factors for these patients who have kidney disease that is progressing to kidney failure is an inability to control the inflammation and chronic damage from uncontrolled disease,” she told Medscape Medical News.

“While there have certainly been a few advances in the care of patients with lupus disease, I believe that this therapy may help move the needle, specifically for patients with kidney involvement from their lupus disease,” she added.

Renal Response Much Higher With Voclosporin

The typical standard of care for patients with active lupus and kidney disease is either a combination of cyclophosphamide plus steroids or a combination of mycophenolate mofetil plus steroids.

The global, double-blind, randomized, placebo-controlled trial compared the effectiveness and safety of twice-daily oral voclosporin 23.7 mg with placebo. All 357 study participants also received mycophenolate 2 g daily and rapidly tapered low-dose oral corticosteroids.

At 1 year, the renal response rate was higher in the voclosporin group than in the placebo group (40.8% vs 22.5%; odds ratio, 2.65; P < .001).

“AURORA patients achieved low levels of protein twice as quickly as patients on standard of care,” the researchers write in their abstract. Median time to the achievement of a urine protein to creatinine ratio below 0.5 mg/mg was significantly and clinically better with voclosporin than with placebo (169 vs 372 days; log rank P < .001).

And voclosporin was well tolerated. The percentage of serious adverse events was similar in the voclosporin and placebo groups (20.8% vs 21.3%), with infection being the most common serious event (10.1% vs 11.2%).

In the voclosporin group, there were no significant differences between baseline and 1 year estimated glomerular filtration rates (eGFR), blood pressure, lipid levels, or sugar levels.

And there were fewer deaths in the voclosporin group than in the placebo group (1 vs 5).

Benefits were seen in all subgroups, including age, sex, race, biopsy class, geographic region of origin, and mycophenolate exposure at screening, Gibson reported.

Promise of a New Treatment

The promise of a new treatment is exciting for the field, said Joseph Vassalotti, MD, chief medical officer of the National Kidney Foundation.

However, it’s important to note that “this study is applicable only to patients with lupus nephritis with preserved kidney function,” he added.

An “eGFR less than 45 mL/min per 1.73 m² was implied as an exclusion criteria, so I would say it certainly doesn’t apply to patients with impaired kidney function,” he said, pointing out that this will be clearer when the final data are published.

The study cohort was heterogeneous; 86% of participants had class 3 or 4 biopsy findings and 14% had class 5, so the superiority of voclosporin is convincing, he said.

“We look forward to full publication and more details,” he told Medscape Medical News. “They do have an extension study, and it will be interesting to see how that plays out.”

Voclosporin was granted Fast Track designation by the US Food and Drug Administration in 2016, and these positive phase 3 results mean that a New Drug Application will likely be filed in the next few months. If approved, the drug could be on the market by 2021, according to a press release from Aurinia.

Nephrologists are familiar with calcineurin inhibitors, so it will be interesting to see, given the success of this trial, if voclosporin has a potential role in other kidney diseases, “such as minimal change disease,” said Vassalotti.

He added that there are concerns, unrelated to the AURORA trial, about the supply of hydroxychloroquine, which is also used for the treatment of lupus nephritis. “An overarching concern is that the supply will be limited now that the drug is being studied and used as prophylaxis after exposure to SARS-CoV-2 and as a treatment for COVID-19, creating challenges for patients with lupus nephritis trying to obtain their needed medication,” he said.

Gibson reports no relevant financial relationships. Two coauthors work for the drugmaker, Aurinia. Vassalotti reports no relevant financial relationships.
 

This article first appeared on Medscape.com.

For patients with lupus nephritis, kidney response improves when voclosporin (Aurinia Pharmaceuticals) is added to mycophenolate and low-dose corticosteroids, results from the phase 3 AURORA trial show.
 

The calcineurin inhibitor is the first novel agent to demonstrate effectiveness in the treatment of people with lupus nephritis, a disease that can lead to irreversible kidney damage, kidney failure, and even death.

“We believe that voclosporin – as an add-on therapy – will help more patients achieve remission,” said Keisha Gibson, MD, MPH, chief of pediatric nephrology at the UNC Kidney Center in Chapel Hill, North Carolina, who led the study and presented the findings during a virtual session at the National Kidney Foundation 2020 Spring Clinical Meetings.

The burden that lupus places on patients and the health system is high, she reported. Patients with lupus and uncontrolled kidney disease frequently have complications that require hospitalization, can suffer complete or partial loss of income, and can become temporarily disabled. And up to 50% of lupus patients will develop lupus nephritis.

“When we are lucky and see early treatment responses in our patients, we know that their long-term outcomes, measured by proteinuria reduction, are quite good,” said Gibson. “Unfortunately, in 10% to 30% of patients, despite standard-of-care therapies, we see progression to end-stage kidney disease within 15 years of diagnosis. This confers a huge cost to overall health and quality of life, and is an excess burden to the healthcare system.

“It is clear that one of the biggest risk factors for these patients who have kidney disease that is progressing to kidney failure is an inability to control the inflammation and chronic damage from uncontrolled disease,” she told Medscape Medical News.

“While there have certainly been a few advances in the care of patients with lupus disease, I believe that this therapy may help move the needle, specifically for patients with kidney involvement from their lupus disease,” she added.

Renal Response Much Higher With Voclosporin

The typical standard of care for patients with active lupus and kidney disease is either a combination of cyclophosphamide plus steroids or a combination of mycophenolate mofetil plus steroids.

The global, double-blind, randomized, placebo-controlled trial compared the effectiveness and safety of twice-daily oral voclosporin 23.7 mg with placebo. All 357 study participants also received mycophenolate 2 g daily and rapidly tapered low-dose oral corticosteroids.

At 1 year, the renal response rate was higher in the voclosporin group than in the placebo group (40.8% vs 22.5%; odds ratio, 2.65; P < .001).

“AURORA patients achieved low levels of protein twice as quickly as patients on standard of care,” the researchers write in their abstract. Median time to the achievement of a urine protein to creatinine ratio below 0.5 mg/mg was significantly and clinically better with voclosporin than with placebo (169 vs 372 days; log rank P < .001).

And voclosporin was well tolerated. The percentage of serious adverse events was similar in the voclosporin and placebo groups (20.8% vs 21.3%), with infection being the most common serious event (10.1% vs 11.2%).

In the voclosporin group, there were no significant differences between baseline and 1 year estimated glomerular filtration rates (eGFR), blood pressure, lipid levels, or sugar levels.

And there were fewer deaths in the voclosporin group than in the placebo group (1 vs 5).

Benefits were seen in all subgroups, including age, sex, race, biopsy class, geographic region of origin, and mycophenolate exposure at screening, Gibson reported.

Promise of a New Treatment

The promise of a new treatment is exciting for the field, said Joseph Vassalotti, MD, chief medical officer of the National Kidney Foundation.

However, it’s important to note that “this study is applicable only to patients with lupus nephritis with preserved kidney function,” he added.

An “eGFR less than 45 mL/min per 1.73 m² was implied as an exclusion criteria, so I would say it certainly doesn’t apply to patients with impaired kidney function,” he said, pointing out that this will be clearer when the final data are published.

The study cohort was heterogeneous; 86% of participants had class 3 or 4 biopsy findings and 14% had class 5, so the superiority of voclosporin is convincing, he said.

“We look forward to full publication and more details,” he told Medscape Medical News. “They do have an extension study, and it will be interesting to see how that plays out.”

Voclosporin was granted Fast Track designation by the US Food and Drug Administration in 2016, and these positive phase 3 results mean that a New Drug Application will likely be filed in the next few months. If approved, the drug could be on the market by 2021, according to a press release from Aurinia.

Nephrologists are familiar with calcineurin inhibitors, so it will be interesting to see, given the success of this trial, if voclosporin has a potential role in other kidney diseases, “such as minimal change disease,” said Vassalotti.

He added that there are concerns, unrelated to the AURORA trial, about the supply of hydroxychloroquine, which is also used for the treatment of lupus nephritis. “An overarching concern is that the supply will be limited now that the drug is being studied and used as prophylaxis after exposure to SARS-CoV-2 and as a treatment for COVID-19, creating challenges for patients with lupus nephritis trying to obtain their needed medication,” he said.

Gibson reports no relevant financial relationships. Two coauthors work for the drugmaker, Aurinia. Vassalotti reports no relevant financial relationships.
 

This article first appeared on Medscape.com.