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COVID-19 vaccination in RMD patients: Safety data “reassuring”
Two reports support the safety and immunogenicity of SARS-CoV-2 mRNA vaccines in patients with rheumatic and musculoskeletal diseases (RMDs) and represent the first available data on such patients.
In an observational cohort study published in Annals of the Rheumatic Diseases, Caoilfhionn M. Connolly, MD, of Johns Hopkins University, Baltimore, and colleagues reviewed data from 325 adults with RMDs who received the first dose of SARS-CoV-2 mRNA vaccine during the period of Dec. 17, 2020, to Feb. 11, 2021. Of these, 51% received the Pfizer/BioNTech vaccine and 49% received the Moderna vaccine.
The patients, who were invited to participate on social media, were aged 34-54 years, 96% were women, and 89% were White. Inflammatory arthritis was the most common RMD condition (38%), followed by systemic lupus erythematosus (28%) and overlap connective tissue disease (19%). The patients were using a range of immunomodulatory treatment regimens, including nonbiologic disease modifying antirheumatic drugs (DMARDs) in 44%, biologics in 19%, and combination therapy in 37%.
Overall, 89% of patients reported localized symptoms of pain, swelling, and erythema, and 69% reported systemic symptoms. Fatigue was the most common systemic symptom, and 7.4% reported severe fatigue.
None of the patients experienced allergic reactions requiring epinephrine, and 3% reported new infections that required treatment.
“These early, reassuring results may ameliorate concern among patients and provide guidance for rheumatology providers in critical discussions regarding vaccine hesitancy or refusal,” they concluded.
Antibody responses
In another study published in Annals of the Rheumatic Diseases by the same group of researchers, antibody responses against the receptor binding domain of the SARS-CoV-2 spike protein were seen in 74% of 123 adults with an RMD at 18-26 days after receiving a first dose of SARS-CoV-2 mRNA vaccine (52% Pfizer vaccine and 48% Moderna) between Jan. 8, 2021, and Feb. 12, 2021.
The most common diagnoses in these patients were inflammatory arthritis (28%), systemic lupus erythematosus (20%), and Sjögren’s syndrome (13%). A total of 28% of participants reported taking no immunomodulatory agents, 19% reported nonbiologic DMARDs, 14% reported biologic DMARDs, and 19% reported combination therapy.
Although no differences appeared based on disease groups or overall categories of immunomodulatory therapies, patients whose treatment included mycophenolate or rituximab were significantly less likely to develop antibody responses than were patients not taking these medications (P = .001 and P = .04, respectively). Although rituximab and methotrexate have been associated with reduced responses to vaccines such as the flu vaccine, methotrexate was not associated with reduced vaccine response in this study. A total of 94% of patients taking a tumor necrosis factor inhibitor had detectable antibodies.
The studies’ findings were limited by several factors including a lack of longer-term safety data; the small, nonrandomized sample of mainly white women; limited information on immunomodulatory drug dosage and timing; lack of serial antibody measurements; use of an enzyme immunoassay designed to detect antibody response after natural infection; and the inclusion of data only on the first dose of a two-dose vaccine series, the researchers noted. However, the data should provide additional reassurance to RMD patients and their health care teams about vaccination against COVID-19, they said.
Both studies were supported by the Ben-Dov family. In addition, the studies were supported by grants to various study authors from the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Allergy and Infectious Diseases, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, and the Transplantation and Immunology Research Network of the American Society of Transplantation. One author disclosed financial relationships with Sanofi, Novartis, CSL Behring, Jazz Pharmaceuticals, Veloxis, Mallinckrodt, and Thermo Fisher Scientific. The other researchers had no financial conflicts to disclose.
Two reports support the safety and immunogenicity of SARS-CoV-2 mRNA vaccines in patients with rheumatic and musculoskeletal diseases (RMDs) and represent the first available data on such patients.
In an observational cohort study published in Annals of the Rheumatic Diseases, Caoilfhionn M. Connolly, MD, of Johns Hopkins University, Baltimore, and colleagues reviewed data from 325 adults with RMDs who received the first dose of SARS-CoV-2 mRNA vaccine during the period of Dec. 17, 2020, to Feb. 11, 2021. Of these, 51% received the Pfizer/BioNTech vaccine and 49% received the Moderna vaccine.
The patients, who were invited to participate on social media, were aged 34-54 years, 96% were women, and 89% were White. Inflammatory arthritis was the most common RMD condition (38%), followed by systemic lupus erythematosus (28%) and overlap connective tissue disease (19%). The patients were using a range of immunomodulatory treatment regimens, including nonbiologic disease modifying antirheumatic drugs (DMARDs) in 44%, biologics in 19%, and combination therapy in 37%.
Overall, 89% of patients reported localized symptoms of pain, swelling, and erythema, and 69% reported systemic symptoms. Fatigue was the most common systemic symptom, and 7.4% reported severe fatigue.
None of the patients experienced allergic reactions requiring epinephrine, and 3% reported new infections that required treatment.
“These early, reassuring results may ameliorate concern among patients and provide guidance for rheumatology providers in critical discussions regarding vaccine hesitancy or refusal,” they concluded.
Antibody responses
In another study published in Annals of the Rheumatic Diseases by the same group of researchers, antibody responses against the receptor binding domain of the SARS-CoV-2 spike protein were seen in 74% of 123 adults with an RMD at 18-26 days after receiving a first dose of SARS-CoV-2 mRNA vaccine (52% Pfizer vaccine and 48% Moderna) between Jan. 8, 2021, and Feb. 12, 2021.
The most common diagnoses in these patients were inflammatory arthritis (28%), systemic lupus erythematosus (20%), and Sjögren’s syndrome (13%). A total of 28% of participants reported taking no immunomodulatory agents, 19% reported nonbiologic DMARDs, 14% reported biologic DMARDs, and 19% reported combination therapy.
Although no differences appeared based on disease groups or overall categories of immunomodulatory therapies, patients whose treatment included mycophenolate or rituximab were significantly less likely to develop antibody responses than were patients not taking these medications (P = .001 and P = .04, respectively). Although rituximab and methotrexate have been associated with reduced responses to vaccines such as the flu vaccine, methotrexate was not associated with reduced vaccine response in this study. A total of 94% of patients taking a tumor necrosis factor inhibitor had detectable antibodies.
The studies’ findings were limited by several factors including a lack of longer-term safety data; the small, nonrandomized sample of mainly white women; limited information on immunomodulatory drug dosage and timing; lack of serial antibody measurements; use of an enzyme immunoassay designed to detect antibody response after natural infection; and the inclusion of data only on the first dose of a two-dose vaccine series, the researchers noted. However, the data should provide additional reassurance to RMD patients and their health care teams about vaccination against COVID-19, they said.
Both studies were supported by the Ben-Dov family. In addition, the studies were supported by grants to various study authors from the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Allergy and Infectious Diseases, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, and the Transplantation and Immunology Research Network of the American Society of Transplantation. One author disclosed financial relationships with Sanofi, Novartis, CSL Behring, Jazz Pharmaceuticals, Veloxis, Mallinckrodt, and Thermo Fisher Scientific. The other researchers had no financial conflicts to disclose.
Two reports support the safety and immunogenicity of SARS-CoV-2 mRNA vaccines in patients with rheumatic and musculoskeletal diseases (RMDs) and represent the first available data on such patients.
In an observational cohort study published in Annals of the Rheumatic Diseases, Caoilfhionn M. Connolly, MD, of Johns Hopkins University, Baltimore, and colleagues reviewed data from 325 adults with RMDs who received the first dose of SARS-CoV-2 mRNA vaccine during the period of Dec. 17, 2020, to Feb. 11, 2021. Of these, 51% received the Pfizer/BioNTech vaccine and 49% received the Moderna vaccine.
The patients, who were invited to participate on social media, were aged 34-54 years, 96% were women, and 89% were White. Inflammatory arthritis was the most common RMD condition (38%), followed by systemic lupus erythematosus (28%) and overlap connective tissue disease (19%). The patients were using a range of immunomodulatory treatment regimens, including nonbiologic disease modifying antirheumatic drugs (DMARDs) in 44%, biologics in 19%, and combination therapy in 37%.
Overall, 89% of patients reported localized symptoms of pain, swelling, and erythema, and 69% reported systemic symptoms. Fatigue was the most common systemic symptom, and 7.4% reported severe fatigue.
None of the patients experienced allergic reactions requiring epinephrine, and 3% reported new infections that required treatment.
“These early, reassuring results may ameliorate concern among patients and provide guidance for rheumatology providers in critical discussions regarding vaccine hesitancy or refusal,” they concluded.
Antibody responses
In another study published in Annals of the Rheumatic Diseases by the same group of researchers, antibody responses against the receptor binding domain of the SARS-CoV-2 spike protein were seen in 74% of 123 adults with an RMD at 18-26 days after receiving a first dose of SARS-CoV-2 mRNA vaccine (52% Pfizer vaccine and 48% Moderna) between Jan. 8, 2021, and Feb. 12, 2021.
The most common diagnoses in these patients were inflammatory arthritis (28%), systemic lupus erythematosus (20%), and Sjögren’s syndrome (13%). A total of 28% of participants reported taking no immunomodulatory agents, 19% reported nonbiologic DMARDs, 14% reported biologic DMARDs, and 19% reported combination therapy.
Although no differences appeared based on disease groups or overall categories of immunomodulatory therapies, patients whose treatment included mycophenolate or rituximab were significantly less likely to develop antibody responses than were patients not taking these medications (P = .001 and P = .04, respectively). Although rituximab and methotrexate have been associated with reduced responses to vaccines such as the flu vaccine, methotrexate was not associated with reduced vaccine response in this study. A total of 94% of patients taking a tumor necrosis factor inhibitor had detectable antibodies.
The studies’ findings were limited by several factors including a lack of longer-term safety data; the small, nonrandomized sample of mainly white women; limited information on immunomodulatory drug dosage and timing; lack of serial antibody measurements; use of an enzyme immunoassay designed to detect antibody response after natural infection; and the inclusion of data only on the first dose of a two-dose vaccine series, the researchers noted. However, the data should provide additional reassurance to RMD patients and their health care teams about vaccination against COVID-19, they said.
Both studies were supported by the Ben-Dov family. In addition, the studies were supported by grants to various study authors from the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Allergy and Infectious Diseases, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, and the Transplantation and Immunology Research Network of the American Society of Transplantation. One author disclosed financial relationships with Sanofi, Novartis, CSL Behring, Jazz Pharmaceuticals, Veloxis, Mallinckrodt, and Thermo Fisher Scientific. The other researchers had no financial conflicts to disclose.
FROM ANNALS OF THE RHEUMATIC DISEASES
FDA warning letters target OTC cannabidiol product claims for pain relief
The Food and Drug Administration has warned two manufacturers about illegal marketing of drugs containing cannabidiol (CBD) for over-the-counter use without an approved new drug application, for using substandard manufacturing processes, and for failure to comply with current good manufacturing practices. These warnings add to 51 previous warning letters issued by the FDA since 2015 to other manufacturers of products containing CBD who were violating the Federal Food, Drug, and Cosmetic Act.
In a news release, the agency explained that its two most recent letters, sent to Honest Globe Inc. on March 15 and BioLyte Laboratories LLC on March 18, were issued because CBD has “known pharmacologic effects on humans, with demonstrated risks, it cannot be legally marketed as an inactive ingredient in OTC drug products that are not reviewed and approved by the FDA.” They also describe the companies’ failures to comply with current good manufacturing practices.
“The FDA continues to alert the public to potential safety and efficacy concerns with unapproved CBD products sold online and in stores across the country,” FDA Principal Deputy Commissioner Amy P. Abernethy, MD, PhD, said in the release. “It’s important that consumers understand that the FDA has only approved one drug containing CBD as an ingredient [Epidiolex]. These other, unapproved, CBD products may have dangerous health impacts and side effects. We remain focused on exploring potential pathways for CBD products to be lawfully marketed while also educating the public about these outstanding questions of CBD’s safety. Meanwhile, we will continue to monitor and take action, as needed, against companies that unlawfully market their products – prioritizing those that pose a risk to public health.”
The specific products from Santa Ana, Calif.–based Honest Globe that the FDA called unapproved new drugs and misbranded under the Federal Food, Drug, and Cosmetic Act included Elixicure Original Pain Relief and Elixicure Lavender Pain Relief, both of which were described as containing CBD. Products from Grand Rapids, Mich.–based BioLyte Laboratories LLC that the FDA similarly cited for violations included Silver Gel, Silver Gel with Aloe, Silver Liquid Supplement, Therapeutic Pain Gel, Pain Relief Cream, and Magnesium Oil Spray.
The agency has asked the two companies to respond to its letters within 15 working days, “stating how they will address these violations or providing their reasoning and supporting information as to why they believe these products are not in violation of the law. Failure to adequately address the violations promptly may result in legal action, including product seizure and/or injunction.”
The Food and Drug Administration has warned two manufacturers about illegal marketing of drugs containing cannabidiol (CBD) for over-the-counter use without an approved new drug application, for using substandard manufacturing processes, and for failure to comply with current good manufacturing practices. These warnings add to 51 previous warning letters issued by the FDA since 2015 to other manufacturers of products containing CBD who were violating the Federal Food, Drug, and Cosmetic Act.
In a news release, the agency explained that its two most recent letters, sent to Honest Globe Inc. on March 15 and BioLyte Laboratories LLC on March 18, were issued because CBD has “known pharmacologic effects on humans, with demonstrated risks, it cannot be legally marketed as an inactive ingredient in OTC drug products that are not reviewed and approved by the FDA.” They also describe the companies’ failures to comply with current good manufacturing practices.
“The FDA continues to alert the public to potential safety and efficacy concerns with unapproved CBD products sold online and in stores across the country,” FDA Principal Deputy Commissioner Amy P. Abernethy, MD, PhD, said in the release. “It’s important that consumers understand that the FDA has only approved one drug containing CBD as an ingredient [Epidiolex]. These other, unapproved, CBD products may have dangerous health impacts and side effects. We remain focused on exploring potential pathways for CBD products to be lawfully marketed while also educating the public about these outstanding questions of CBD’s safety. Meanwhile, we will continue to monitor and take action, as needed, against companies that unlawfully market their products – prioritizing those that pose a risk to public health.”
The specific products from Santa Ana, Calif.–based Honest Globe that the FDA called unapproved new drugs and misbranded under the Federal Food, Drug, and Cosmetic Act included Elixicure Original Pain Relief and Elixicure Lavender Pain Relief, both of which were described as containing CBD. Products from Grand Rapids, Mich.–based BioLyte Laboratories LLC that the FDA similarly cited for violations included Silver Gel, Silver Gel with Aloe, Silver Liquid Supplement, Therapeutic Pain Gel, Pain Relief Cream, and Magnesium Oil Spray.
The agency has asked the two companies to respond to its letters within 15 working days, “stating how they will address these violations or providing their reasoning and supporting information as to why they believe these products are not in violation of the law. Failure to adequately address the violations promptly may result in legal action, including product seizure and/or injunction.”
The Food and Drug Administration has warned two manufacturers about illegal marketing of drugs containing cannabidiol (CBD) for over-the-counter use without an approved new drug application, for using substandard manufacturing processes, and for failure to comply with current good manufacturing practices. These warnings add to 51 previous warning letters issued by the FDA since 2015 to other manufacturers of products containing CBD who were violating the Federal Food, Drug, and Cosmetic Act.
In a news release, the agency explained that its two most recent letters, sent to Honest Globe Inc. on March 15 and BioLyte Laboratories LLC on March 18, were issued because CBD has “known pharmacologic effects on humans, with demonstrated risks, it cannot be legally marketed as an inactive ingredient in OTC drug products that are not reviewed and approved by the FDA.” They also describe the companies’ failures to comply with current good manufacturing practices.
“The FDA continues to alert the public to potential safety and efficacy concerns with unapproved CBD products sold online and in stores across the country,” FDA Principal Deputy Commissioner Amy P. Abernethy, MD, PhD, said in the release. “It’s important that consumers understand that the FDA has only approved one drug containing CBD as an ingredient [Epidiolex]. These other, unapproved, CBD products may have dangerous health impacts and side effects. We remain focused on exploring potential pathways for CBD products to be lawfully marketed while also educating the public about these outstanding questions of CBD’s safety. Meanwhile, we will continue to monitor and take action, as needed, against companies that unlawfully market their products – prioritizing those that pose a risk to public health.”
The specific products from Santa Ana, Calif.–based Honest Globe that the FDA called unapproved new drugs and misbranded under the Federal Food, Drug, and Cosmetic Act included Elixicure Original Pain Relief and Elixicure Lavender Pain Relief, both of which were described as containing CBD. Products from Grand Rapids, Mich.–based BioLyte Laboratories LLC that the FDA similarly cited for violations included Silver Gel, Silver Gel with Aloe, Silver Liquid Supplement, Therapeutic Pain Gel, Pain Relief Cream, and Magnesium Oil Spray.
The agency has asked the two companies to respond to its letters within 15 working days, “stating how they will address these violations or providing their reasoning and supporting information as to why they believe these products are not in violation of the law. Failure to adequately address the violations promptly may result in legal action, including product seizure and/or injunction.”
Checkpoint inhibitor–induced rheumatic complications often arise late
Most checkpoint inhibitor–induced rheumatic complications in cancer patients can be treated successfully with corticosteroids, albeit often at considerably higher doses than rheumatologists typically use in managing rheumatoid arthritis, Eric M. Ruderman, MD, observed at the 2021 Rheumatology Winter Clinical Symposium.
“In RA, we’re all used to the idea that 5 or 10 mg of corticosteroids per day can make a tremendous difference. That’s not always the case here. Patients who develop rheumatic immunotherapy-related adverse events often require 20-30 mg/day to get symptoms under control,” according to Dr. Ruderman, professor of medicine (rheumatology) at Northwestern University, Chicago.
This may be in part because oncologists typically don’t refer affected patients to rheumatologists early on. Guidelines from the National Comprehensive Cancer Network and other oncology groups suggest referral only once a patient develops grade 3 immunotherapy-related rheumatic adverse events, meaning the symptoms significantly impair daily activities, he explained.
Checkpoint inhibitors, which induce T-cell activation to fight the patient’s malignancy, can produce a plethora of off-target effects. These adverse events may involve the skin, heart, lungs, kidneys, eyes, blood, GI tract, and endocrine organs. The drugs also can cause rheumatic or neurologic complications. The most common of these adverse events are colitis and rash. Next most common are arthritis and arthralgia. Rheumatic side effects are most common as a consequence of immunotherapy using a CTLA4 (cytotoxic T-lymphocyte-associated protein 4) inhibitor, but can also occur in association with programmed cell death protein 1 (PD-1) inhibitors and PD-ligand 1 inhibitors. Arthritis and other rheumatic adverse events are more common in patients undergoing combination therapy.
Some form of frank inflammatory arthritis occurs in 5%-10% of cancer patients undergoing checkpoint inhibitor therapy. This can manifest as an RA-like polyarthritis, spondyloarthritis, polymyalgia rheumatica, necrotizing myositis, or vasculitis. Arthralgia occurs in up to 40% of treated patients.
This immunotherapy-related arthritis is typically more inflammatory than RA. It also has a much more abrupt onset. It is usually seronegative and has no gender predisposition, and the limited available evidence to date suggests there is no increased risk of this complication in checkpoint inhibitor–treated patients with a history of prior rheumatic disease, according to Dr. Ruderman.
Delayed onset and resolution of rheumatologic immune-related adverse events
“Onset and resolution of rheumatologic adverse events with immunotherapy may be delayed. This is an important point: While skin rash and colitis often show up pretty early in the course of immunotherapy, some of the arthritic events can happen later. They can actually continue after the immunotherapy is stopped,” the rheumatologist said.
Indeed, a retrospective nationwide Canadian study of 117 patients at nine academic centers who developed 136 rheumatic immune-related adverse events in conjunction with cancer immunotherapy found that the mean time to the first such event was 6.8 months into checkpoint inhibitor therapy. The most common rheumatic complication was symmetric polyarthritis, affecting 45 patients. Other rheumatologic immune-related complications included polymyalgia rheumatica in 17 patients, noninflammatory musculoskeletal symptoms in 18, and myositis in 9.
Seventy-six patients were treated with prednisone for a mean of 8.4 months at a maximum dose of 60 mg/day. Forty-two moved up the treatment ladder to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) to manage their symptoms. Only two patients required escalation to biologic therapy. A reassuring finding in this relatively small study was that treatment of the patients’ rheumatic complications didn’t appear to worsen the tumor response to immunotherapy: Twenty-three patients experienced tumor progression prior to treatment of their rheumatic disorder, and 14 did so following treatment.
Flares of preexisting rheumatic diseases
These tend to occur much earlier in the course of immune checkpoint inhibitor therapy for cancer than de novo immunotherapy-related rheumatic adverse events. In a retrospective Australian study of 12 cancer patients with preexisting rheumatic disease before going on a PD-1 inhibitor and 24 others with no such history, all of whom developed rheumatic adverse events while on the checkpoint inhibitor, the mean time to a flare of preexisting rheumatic disease was 6.2 weeks, compared to 21.5 weeks in patients who experienced a de novo rheumatic adverse event.
Dr. Ruderman supports recommendations from the European Alliance of Associations for Rheumatology (EULAR) for the management of rheumatic immune-related adverse events due to cancer immunotherapy, even though the underlying level of evidence is fairly weak. The recommendations call for the use of csDMARDs when corticosteroids don’t adequately control symptoms. And when the response to csDMARDs is insufficient, the next step is a biologic, preferably a tumor necrosis factor inhibitor or interleukin-6 inhibitor.
“At our institution, the oncologists are a little bit nervous about using biologics in cancer patients, but I think more and more they’re going to have to accept it. And so far there isn’t a ton of evidence that suggests the addition of biologics interferes with the efficacy of the immunotherapy,” the rheumatologist said.
He underscored the critical importance of one of the overarching principles of the EULAR guidelines: the need for interdisciplinary coordination between rheumatologists and oncologists regarding the problem of rheumatologic immune-related adverse events.
“Oncologists aren’t good at managing inflammatory arthritis. I think they really need us,” he said.
Dr. Ruderman reported serving as a consultant to and/or receiving a research grant from nine pharmaceutical companies.
Most checkpoint inhibitor–induced rheumatic complications in cancer patients can be treated successfully with corticosteroids, albeit often at considerably higher doses than rheumatologists typically use in managing rheumatoid arthritis, Eric M. Ruderman, MD, observed at the 2021 Rheumatology Winter Clinical Symposium.
“In RA, we’re all used to the idea that 5 or 10 mg of corticosteroids per day can make a tremendous difference. That’s not always the case here. Patients who develop rheumatic immunotherapy-related adverse events often require 20-30 mg/day to get symptoms under control,” according to Dr. Ruderman, professor of medicine (rheumatology) at Northwestern University, Chicago.
This may be in part because oncologists typically don’t refer affected patients to rheumatologists early on. Guidelines from the National Comprehensive Cancer Network and other oncology groups suggest referral only once a patient develops grade 3 immunotherapy-related rheumatic adverse events, meaning the symptoms significantly impair daily activities, he explained.
Checkpoint inhibitors, which induce T-cell activation to fight the patient’s malignancy, can produce a plethora of off-target effects. These adverse events may involve the skin, heart, lungs, kidneys, eyes, blood, GI tract, and endocrine organs. The drugs also can cause rheumatic or neurologic complications. The most common of these adverse events are colitis and rash. Next most common are arthritis and arthralgia. Rheumatic side effects are most common as a consequence of immunotherapy using a CTLA4 (cytotoxic T-lymphocyte-associated protein 4) inhibitor, but can also occur in association with programmed cell death protein 1 (PD-1) inhibitors and PD-ligand 1 inhibitors. Arthritis and other rheumatic adverse events are more common in patients undergoing combination therapy.
Some form of frank inflammatory arthritis occurs in 5%-10% of cancer patients undergoing checkpoint inhibitor therapy. This can manifest as an RA-like polyarthritis, spondyloarthritis, polymyalgia rheumatica, necrotizing myositis, or vasculitis. Arthralgia occurs in up to 40% of treated patients.
This immunotherapy-related arthritis is typically more inflammatory than RA. It also has a much more abrupt onset. It is usually seronegative and has no gender predisposition, and the limited available evidence to date suggests there is no increased risk of this complication in checkpoint inhibitor–treated patients with a history of prior rheumatic disease, according to Dr. Ruderman.
Delayed onset and resolution of rheumatologic immune-related adverse events
“Onset and resolution of rheumatologic adverse events with immunotherapy may be delayed. This is an important point: While skin rash and colitis often show up pretty early in the course of immunotherapy, some of the arthritic events can happen later. They can actually continue after the immunotherapy is stopped,” the rheumatologist said.
Indeed, a retrospective nationwide Canadian study of 117 patients at nine academic centers who developed 136 rheumatic immune-related adverse events in conjunction with cancer immunotherapy found that the mean time to the first such event was 6.8 months into checkpoint inhibitor therapy. The most common rheumatic complication was symmetric polyarthritis, affecting 45 patients. Other rheumatologic immune-related complications included polymyalgia rheumatica in 17 patients, noninflammatory musculoskeletal symptoms in 18, and myositis in 9.
Seventy-six patients were treated with prednisone for a mean of 8.4 months at a maximum dose of 60 mg/day. Forty-two moved up the treatment ladder to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) to manage their symptoms. Only two patients required escalation to biologic therapy. A reassuring finding in this relatively small study was that treatment of the patients’ rheumatic complications didn’t appear to worsen the tumor response to immunotherapy: Twenty-three patients experienced tumor progression prior to treatment of their rheumatic disorder, and 14 did so following treatment.
Flares of preexisting rheumatic diseases
These tend to occur much earlier in the course of immune checkpoint inhibitor therapy for cancer than de novo immunotherapy-related rheumatic adverse events. In a retrospective Australian study of 12 cancer patients with preexisting rheumatic disease before going on a PD-1 inhibitor and 24 others with no such history, all of whom developed rheumatic adverse events while on the checkpoint inhibitor, the mean time to a flare of preexisting rheumatic disease was 6.2 weeks, compared to 21.5 weeks in patients who experienced a de novo rheumatic adverse event.
Dr. Ruderman supports recommendations from the European Alliance of Associations for Rheumatology (EULAR) for the management of rheumatic immune-related adverse events due to cancer immunotherapy, even though the underlying level of evidence is fairly weak. The recommendations call for the use of csDMARDs when corticosteroids don’t adequately control symptoms. And when the response to csDMARDs is insufficient, the next step is a biologic, preferably a tumor necrosis factor inhibitor or interleukin-6 inhibitor.
“At our institution, the oncologists are a little bit nervous about using biologics in cancer patients, but I think more and more they’re going to have to accept it. And so far there isn’t a ton of evidence that suggests the addition of biologics interferes with the efficacy of the immunotherapy,” the rheumatologist said.
He underscored the critical importance of one of the overarching principles of the EULAR guidelines: the need for interdisciplinary coordination between rheumatologists and oncologists regarding the problem of rheumatologic immune-related adverse events.
“Oncologists aren’t good at managing inflammatory arthritis. I think they really need us,” he said.
Dr. Ruderman reported serving as a consultant to and/or receiving a research grant from nine pharmaceutical companies.
Most checkpoint inhibitor–induced rheumatic complications in cancer patients can be treated successfully with corticosteroids, albeit often at considerably higher doses than rheumatologists typically use in managing rheumatoid arthritis, Eric M. Ruderman, MD, observed at the 2021 Rheumatology Winter Clinical Symposium.
“In RA, we’re all used to the idea that 5 or 10 mg of corticosteroids per day can make a tremendous difference. That’s not always the case here. Patients who develop rheumatic immunotherapy-related adverse events often require 20-30 mg/day to get symptoms under control,” according to Dr. Ruderman, professor of medicine (rheumatology) at Northwestern University, Chicago.
This may be in part because oncologists typically don’t refer affected patients to rheumatologists early on. Guidelines from the National Comprehensive Cancer Network and other oncology groups suggest referral only once a patient develops grade 3 immunotherapy-related rheumatic adverse events, meaning the symptoms significantly impair daily activities, he explained.
Checkpoint inhibitors, which induce T-cell activation to fight the patient’s malignancy, can produce a plethora of off-target effects. These adverse events may involve the skin, heart, lungs, kidneys, eyes, blood, GI tract, and endocrine organs. The drugs also can cause rheumatic or neurologic complications. The most common of these adverse events are colitis and rash. Next most common are arthritis and arthralgia. Rheumatic side effects are most common as a consequence of immunotherapy using a CTLA4 (cytotoxic T-lymphocyte-associated protein 4) inhibitor, but can also occur in association with programmed cell death protein 1 (PD-1) inhibitors and PD-ligand 1 inhibitors. Arthritis and other rheumatic adverse events are more common in patients undergoing combination therapy.
Some form of frank inflammatory arthritis occurs in 5%-10% of cancer patients undergoing checkpoint inhibitor therapy. This can manifest as an RA-like polyarthritis, spondyloarthritis, polymyalgia rheumatica, necrotizing myositis, or vasculitis. Arthralgia occurs in up to 40% of treated patients.
This immunotherapy-related arthritis is typically more inflammatory than RA. It also has a much more abrupt onset. It is usually seronegative and has no gender predisposition, and the limited available evidence to date suggests there is no increased risk of this complication in checkpoint inhibitor–treated patients with a history of prior rheumatic disease, according to Dr. Ruderman.
Delayed onset and resolution of rheumatologic immune-related adverse events
“Onset and resolution of rheumatologic adverse events with immunotherapy may be delayed. This is an important point: While skin rash and colitis often show up pretty early in the course of immunotherapy, some of the arthritic events can happen later. They can actually continue after the immunotherapy is stopped,” the rheumatologist said.
Indeed, a retrospective nationwide Canadian study of 117 patients at nine academic centers who developed 136 rheumatic immune-related adverse events in conjunction with cancer immunotherapy found that the mean time to the first such event was 6.8 months into checkpoint inhibitor therapy. The most common rheumatic complication was symmetric polyarthritis, affecting 45 patients. Other rheumatologic immune-related complications included polymyalgia rheumatica in 17 patients, noninflammatory musculoskeletal symptoms in 18, and myositis in 9.
Seventy-six patients were treated with prednisone for a mean of 8.4 months at a maximum dose of 60 mg/day. Forty-two moved up the treatment ladder to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) to manage their symptoms. Only two patients required escalation to biologic therapy. A reassuring finding in this relatively small study was that treatment of the patients’ rheumatic complications didn’t appear to worsen the tumor response to immunotherapy: Twenty-three patients experienced tumor progression prior to treatment of their rheumatic disorder, and 14 did so following treatment.
Flares of preexisting rheumatic diseases
These tend to occur much earlier in the course of immune checkpoint inhibitor therapy for cancer than de novo immunotherapy-related rheumatic adverse events. In a retrospective Australian study of 12 cancer patients with preexisting rheumatic disease before going on a PD-1 inhibitor and 24 others with no such history, all of whom developed rheumatic adverse events while on the checkpoint inhibitor, the mean time to a flare of preexisting rheumatic disease was 6.2 weeks, compared to 21.5 weeks in patients who experienced a de novo rheumatic adverse event.
Dr. Ruderman supports recommendations from the European Alliance of Associations for Rheumatology (EULAR) for the management of rheumatic immune-related adverse events due to cancer immunotherapy, even though the underlying level of evidence is fairly weak. The recommendations call for the use of csDMARDs when corticosteroids don’t adequately control symptoms. And when the response to csDMARDs is insufficient, the next step is a biologic, preferably a tumor necrosis factor inhibitor or interleukin-6 inhibitor.
“At our institution, the oncologists are a little bit nervous about using biologics in cancer patients, but I think more and more they’re going to have to accept it. And so far there isn’t a ton of evidence that suggests the addition of biologics interferes with the efficacy of the immunotherapy,” the rheumatologist said.
He underscored the critical importance of one of the overarching principles of the EULAR guidelines: the need for interdisciplinary coordination between rheumatologists and oncologists regarding the problem of rheumatologic immune-related adverse events.
“Oncologists aren’t good at managing inflammatory arthritis. I think they really need us,” he said.
Dr. Ruderman reported serving as a consultant to and/or receiving a research grant from nine pharmaceutical companies.
FROM RWCS 2021
Rise of JAK inhibitors highlights axial spondyloarthritis year in review
Rheumatologists can look forward to the likely regulatory approval of the oral Janus kinase inhibitors tofacitinib and upadacitinib for the treatment of axial spondyloarthritis in the first half of 2021, speakers predicted at the 2021 Rheumatology Winter Clinical Symposium.
This will be a major advance in the treatment of axial spondyloarthritis (axSpA) and promises to be one of the overall highlights of the coming year in rheumatology, according to the speakers. Both medications are now under Food and Drug Administration review for the proposed new indication.
“My sense is within the next 6 months we’re going to have two different oral JAK inhibitors that offer a new option for our ankylosing spondylitis and axial spondyloarthritis patients,” predicted Eric M. Ruderman, MD, professor of medicine (rheumatology) at Northwestern University, Chicago.
Alexis R. Ogdie, MD, MSCE, noted that, at present, only two classes of potent medications are available for treatment of axial spondyloarthritis: tumor necrosis factor (TNF) inhibitors and anti–interleukin-17 biologics.
“I think it would be so exciting to have more treatment options. To have only two classes of drugs you can use for this disease is not enough,” said Dr. Ogdie, a rheumatologist and epidemiologist at the University of Pennsylvania, Philadelphia.
She and her fellow panelists also highlighted other recent key developments in axSpA, including epidemiologic evidence that case numbers are climbing sharply, identification of two previously unrecognized common comorbidities, a successful biologic remission induction and maintenance dose–reduction strategy, data on the best and worst biologics for patients with anterior uveitis, and evidence regarding next-step therapy in axSpA patients who’ve had an inadequate response to a TNF inhibitor.
The JAK inhibitors are coming
Oral tofacitinib (Xeljanz) at 5 mg twice daily was the focus of a pivotal phase 3, double-blind, 16-week, placebo-controlled clinical trial including 269 patients with axSpA. The results were presented at the 2020 annual meeting of the American College of Rheumatology. The primary endpoint was at least a 20% improvement in Assessment of Spondyloarthritis International Society response criteria (ASAS 20). This was accomplished in 56.4% of patients on tofacitinib and 29.4% of placebo-treated controls. The ASAS 40 response rate was even more impressive: 40.6% with the JAK inhibitor, compared with 12.5% with placebo. There was one serious infection in the tofacitinib group, but no cases of venous thromboembolism, interstitial lung disease, opportunistic infection, major adverse cardiovascular events, or malignancy in this brief 4-month study.
Also now under FDA review are data from SELECT-AXIS 1, a phase 2/3, double-blind trial in which 187 biologic-naive patients with ankylosing spondylitis were randomized to 14 weeks of upadacitinib (Rinvoq) at 15 mg once daily or placebo. The primary endpoint, an ASAS 40 response, occurred in 51.6% of patients on the JAK inhibitor and half as many controls.
“They saw improvement in MRI scores with upadacitinib, so there’s biologic plausibility to this,” Dr. Ruderman noted.
He predicted the JAK inhibitors are going to have a big impact in clinical practice, especially in men.
“I have a lot of ankylosing spondylitis and axial spondyloarthritis patients on NSAIDs who I’m not convinced are doing as well as they could, but they push back every time I raise the possibility of going on a biologic,” the rheumatologist said. “I suspect that, given the rapid response with JAK inhibitors here, as in rheumatoid arthritis, it might be a little bit easier to persuade these people to give this a try for 4-6 weeks and then see how much better they are. It’s a pill. You don’t have to give yourself a shot.”
Dr. Ogdie predicted the new oral agents will bring more axSpA patients into rheumatologists’ offices.
“I think it’ll be kind of like the apremilast effect in psoriasis, where the drug got a lot more people into the market,” she said.
U.S. ankylosing spondylitis prevalence rising
The diagnostic prevalence of axSpA in the United States increased by 86% between 2006 and 2014 in a retrospective analysis based on Medicare fee-for-service claims data. A separate analysis using IBM MarketScan data for the same years was confirmatory, showing a 56% increase, Jeffrey R. Curtis, MD, MS, MPH, of the University of Alabama at Birmingham reported at the 2020 annual meeting of the European League Against Rheumatism (EULAR), now known as the European Alliance of Associations for Rheumatology.
“I think the take home is we’re seeing more of this. Some of this is likely due to increased awareness and inclusion of nonradiographic disease,” according to Dr. Ruderman.
Two previously overlooked comorbidities
It’s well recognized that 5%-10% of patients with axSpA have concurrent inflammatory bowel disease. But how about irritable bowel syndrome (IBS)?
A study of 186 Swedish patients with axSpA in the population-based SPARTAKUS registry, none with inflammatory bowel disease, concluded that 30% of them met ROME III diagnostic criteria for IBS, compared with 16% of healthy controls. Of note, the axSpA patients with comorbid IBS had significantly worse axSpA disease outcomes, compared with those without IBS as measured by pain, fatigue, and quality-of-life scores, as well as significantly greater disease activity on the Bath Ankylosing Spondylitis Disease Activity Index.
New-onset inflammatory back pain occurred in a hefty 24% of 513 Saudi patients placed on isotretinoin for acne. About 42% of those with inflammatory back pain displayed evidence of sacroiliitis on MRI. Moreover, 52% of patients with MRI-proven sacroiliitis fulfilled ASAS criteria for axSpA. In this longitudinal study, the MRI abnormalities and back pain symptoms completely resolved after isotretinoin discontinuation, but it took a long time: up to 9 months.
“When you see these people with inflammatory back pain on isotretinoin, I think it’s important that before you saddle them with a diagnosis that they have axSpA – a diagnosis that will go with them forever – give them time off drug, because this can look like the real thing. It’s something to think about as these pretty young kids come in to see you with back pain: Always ask about their medication history because it could be important,” Dr. Ruderman said.
A successful biologic remission induction-and-maintenance strategy
The phase 3b, multicenter C-OPTIMISE study sought to determine the best strategy for avoiding axSpA flares once sustained clinical remission has been achieved with a TNF inhibitor, in this case certolizumab pegol (Cimzia). The first part of the trial involved 736 patients with early axSpA, including 329 with nonradiographic disease. During the 48-week open-label induction period, 43.9% of patients achieved sustained clinical remission at the approved dose of 200 mg every 2 weeks, with similar success rates in radiographic and nonradiographic axSpA.
Those in sustained remission were then randomized double blind to one of three groups: an additional 48 weeks of certolizumab pegol at the full maintenance dose of 200 mg every 2 weeks, reduced maintenance dosing at 200 mg every 4 weeks, or placebo. During this period, 83.7% of the group who continued on full-dose certolizumab remained flare free, as did 79% of those on the reduced maintenance dose. In contrast, only 20.2% of patients in whom the biologic was completely withdrawn remained flare free. The investigators concluded that certolizumab dose reduction is a winning strategy for maintenance of clinical remission, as it reduces costs and limits long-term exposure to immunosuppressive therapy while maintaining clinical benefits.
All biologics aren’t equal when it comes to anterior uveitis risk
An analysis of Swedish Rheumatology Quality Register data presented at the 2020 EULAR meeting concluded that, among 3,568 patients started on one of four biologics for treatment of spondyloarthritis, the incidence of anterior uveitis was 2.9 per 100 patient-years in those on infliximab (Remicade), 4.0 per 100 patient-years with adalimumab (Humira), 6.8 per 100 patient-years with secukinumab (Cosentyx), and 7.5 per 100 patient-years with etanercept (Enbrel).
“This is important information for us in the clinic. The big question has been, do we see a reduced risk of anterior uveitis with secukinumab, an interleukin-17 inhibitor,” observed RWCS director Arthur Kavanaugh, MD, professor of medicine and director of the Center for Innovative Therapy in the division of rheumatology, allergy, and immunology at the University of California, San Diego.
“When I’ve switched people with uveitis to secukinumab or ixekizumab [Taltz], I do see it come back. So I think it’s important to have these data out there,” Dr. Ogdie said.
Certolizumab pegol markedly reduced the incidence of anterior uveitis flares in patients with radiographic and nonradiographic axSpA and a history of recurrent uveitis flares in the ongoing phase 4 C-VIEW study. In the 48 weeks prior to going on certolizumab pegol, the 89 participants included in this analysis had an acute anterior uveitis incidence of 1.5 episodes per patient; during their first 48 weeks on the TNF inhibitor, the rate plunged to 0.2 episodes, representing an 87% reduction.
Secukinumab ‘not the obvious choice’ after inadequate response to a TNF inhibitor
While it might seem logical to turn to an IL-17 inhibitor in patients with an inadequate response to one or more TNF inhibitors, two recently published studies suggest that starting secukinumab is not more effective than trying yet another TNF inhibitor.
A retrospective analysis of Swiss registry data on next-step therapy in 390 axSpA patients who had withdrawn from one or more TNF inhibitors concluded that efficacy at 1 year in the 106 who switched to secukinumab wasn’t significantly different than in the 284 who moved on to another TNF inhibitor.
Similarly, an analysis of 10,583 courses of biologic therapy in 8,050 axSpA patients in five Nordic registries concluded that secukinumab and adalimumab as second-line therapy in patients with inadequate response to an initial TNF inhibitor performed similarly through 1 year of follow-up. However, in patients who’d previously failed to respond to two or three different biologic agents, adalimumab proved superior to the interleukin-17 inhibitor.
“These are two studies that don’t support the intuitive notion of trying a drug with a different mechanism of action when a patient has an inadequate response to a TNF inhibitor. It’s not clear that’s going to make a difference. It doesn’t mean secukinumab can’t work, but it means secukinumab is not the obvious choice,” Dr. Ruderman commented.
All three speakers reported financial relationships with numerous pharmaceutical companies.
Rheumatologists can look forward to the likely regulatory approval of the oral Janus kinase inhibitors tofacitinib and upadacitinib for the treatment of axial spondyloarthritis in the first half of 2021, speakers predicted at the 2021 Rheumatology Winter Clinical Symposium.
This will be a major advance in the treatment of axial spondyloarthritis (axSpA) and promises to be one of the overall highlights of the coming year in rheumatology, according to the speakers. Both medications are now under Food and Drug Administration review for the proposed new indication.
“My sense is within the next 6 months we’re going to have two different oral JAK inhibitors that offer a new option for our ankylosing spondylitis and axial spondyloarthritis patients,” predicted Eric M. Ruderman, MD, professor of medicine (rheumatology) at Northwestern University, Chicago.
Alexis R. Ogdie, MD, MSCE, noted that, at present, only two classes of potent medications are available for treatment of axial spondyloarthritis: tumor necrosis factor (TNF) inhibitors and anti–interleukin-17 biologics.
“I think it would be so exciting to have more treatment options. To have only two classes of drugs you can use for this disease is not enough,” said Dr. Ogdie, a rheumatologist and epidemiologist at the University of Pennsylvania, Philadelphia.
She and her fellow panelists also highlighted other recent key developments in axSpA, including epidemiologic evidence that case numbers are climbing sharply, identification of two previously unrecognized common comorbidities, a successful biologic remission induction and maintenance dose–reduction strategy, data on the best and worst biologics for patients with anterior uveitis, and evidence regarding next-step therapy in axSpA patients who’ve had an inadequate response to a TNF inhibitor.
The JAK inhibitors are coming
Oral tofacitinib (Xeljanz) at 5 mg twice daily was the focus of a pivotal phase 3, double-blind, 16-week, placebo-controlled clinical trial including 269 patients with axSpA. The results were presented at the 2020 annual meeting of the American College of Rheumatology. The primary endpoint was at least a 20% improvement in Assessment of Spondyloarthritis International Society response criteria (ASAS 20). This was accomplished in 56.4% of patients on tofacitinib and 29.4% of placebo-treated controls. The ASAS 40 response rate was even more impressive: 40.6% with the JAK inhibitor, compared with 12.5% with placebo. There was one serious infection in the tofacitinib group, but no cases of venous thromboembolism, interstitial lung disease, opportunistic infection, major adverse cardiovascular events, or malignancy in this brief 4-month study.
Also now under FDA review are data from SELECT-AXIS 1, a phase 2/3, double-blind trial in which 187 biologic-naive patients with ankylosing spondylitis were randomized to 14 weeks of upadacitinib (Rinvoq) at 15 mg once daily or placebo. The primary endpoint, an ASAS 40 response, occurred in 51.6% of patients on the JAK inhibitor and half as many controls.
“They saw improvement in MRI scores with upadacitinib, so there’s biologic plausibility to this,” Dr. Ruderman noted.
He predicted the JAK inhibitors are going to have a big impact in clinical practice, especially in men.
“I have a lot of ankylosing spondylitis and axial spondyloarthritis patients on NSAIDs who I’m not convinced are doing as well as they could, but they push back every time I raise the possibility of going on a biologic,” the rheumatologist said. “I suspect that, given the rapid response with JAK inhibitors here, as in rheumatoid arthritis, it might be a little bit easier to persuade these people to give this a try for 4-6 weeks and then see how much better they are. It’s a pill. You don’t have to give yourself a shot.”
Dr. Ogdie predicted the new oral agents will bring more axSpA patients into rheumatologists’ offices.
“I think it’ll be kind of like the apremilast effect in psoriasis, where the drug got a lot more people into the market,” she said.
U.S. ankylosing spondylitis prevalence rising
The diagnostic prevalence of axSpA in the United States increased by 86% between 2006 and 2014 in a retrospective analysis based on Medicare fee-for-service claims data. A separate analysis using IBM MarketScan data for the same years was confirmatory, showing a 56% increase, Jeffrey R. Curtis, MD, MS, MPH, of the University of Alabama at Birmingham reported at the 2020 annual meeting of the European League Against Rheumatism (EULAR), now known as the European Alliance of Associations for Rheumatology.
“I think the take home is we’re seeing more of this. Some of this is likely due to increased awareness and inclusion of nonradiographic disease,” according to Dr. Ruderman.
Two previously overlooked comorbidities
It’s well recognized that 5%-10% of patients with axSpA have concurrent inflammatory bowel disease. But how about irritable bowel syndrome (IBS)?
A study of 186 Swedish patients with axSpA in the population-based SPARTAKUS registry, none with inflammatory bowel disease, concluded that 30% of them met ROME III diagnostic criteria for IBS, compared with 16% of healthy controls. Of note, the axSpA patients with comorbid IBS had significantly worse axSpA disease outcomes, compared with those without IBS as measured by pain, fatigue, and quality-of-life scores, as well as significantly greater disease activity on the Bath Ankylosing Spondylitis Disease Activity Index.
New-onset inflammatory back pain occurred in a hefty 24% of 513 Saudi patients placed on isotretinoin for acne. About 42% of those with inflammatory back pain displayed evidence of sacroiliitis on MRI. Moreover, 52% of patients with MRI-proven sacroiliitis fulfilled ASAS criteria for axSpA. In this longitudinal study, the MRI abnormalities and back pain symptoms completely resolved after isotretinoin discontinuation, but it took a long time: up to 9 months.
“When you see these people with inflammatory back pain on isotretinoin, I think it’s important that before you saddle them with a diagnosis that they have axSpA – a diagnosis that will go with them forever – give them time off drug, because this can look like the real thing. It’s something to think about as these pretty young kids come in to see you with back pain: Always ask about their medication history because it could be important,” Dr. Ruderman said.
A successful biologic remission induction-and-maintenance strategy
The phase 3b, multicenter C-OPTIMISE study sought to determine the best strategy for avoiding axSpA flares once sustained clinical remission has been achieved with a TNF inhibitor, in this case certolizumab pegol (Cimzia). The first part of the trial involved 736 patients with early axSpA, including 329 with nonradiographic disease. During the 48-week open-label induction period, 43.9% of patients achieved sustained clinical remission at the approved dose of 200 mg every 2 weeks, with similar success rates in radiographic and nonradiographic axSpA.
Those in sustained remission were then randomized double blind to one of three groups: an additional 48 weeks of certolizumab pegol at the full maintenance dose of 200 mg every 2 weeks, reduced maintenance dosing at 200 mg every 4 weeks, or placebo. During this period, 83.7% of the group who continued on full-dose certolizumab remained flare free, as did 79% of those on the reduced maintenance dose. In contrast, only 20.2% of patients in whom the biologic was completely withdrawn remained flare free. The investigators concluded that certolizumab dose reduction is a winning strategy for maintenance of clinical remission, as it reduces costs and limits long-term exposure to immunosuppressive therapy while maintaining clinical benefits.
All biologics aren’t equal when it comes to anterior uveitis risk
An analysis of Swedish Rheumatology Quality Register data presented at the 2020 EULAR meeting concluded that, among 3,568 patients started on one of four biologics for treatment of spondyloarthritis, the incidence of anterior uveitis was 2.9 per 100 patient-years in those on infliximab (Remicade), 4.0 per 100 patient-years with adalimumab (Humira), 6.8 per 100 patient-years with secukinumab (Cosentyx), and 7.5 per 100 patient-years with etanercept (Enbrel).
“This is important information for us in the clinic. The big question has been, do we see a reduced risk of anterior uveitis with secukinumab, an interleukin-17 inhibitor,” observed RWCS director Arthur Kavanaugh, MD, professor of medicine and director of the Center for Innovative Therapy in the division of rheumatology, allergy, and immunology at the University of California, San Diego.
“When I’ve switched people with uveitis to secukinumab or ixekizumab [Taltz], I do see it come back. So I think it’s important to have these data out there,” Dr. Ogdie said.
Certolizumab pegol markedly reduced the incidence of anterior uveitis flares in patients with radiographic and nonradiographic axSpA and a history of recurrent uveitis flares in the ongoing phase 4 C-VIEW study. In the 48 weeks prior to going on certolizumab pegol, the 89 participants included in this analysis had an acute anterior uveitis incidence of 1.5 episodes per patient; during their first 48 weeks on the TNF inhibitor, the rate plunged to 0.2 episodes, representing an 87% reduction.
Secukinumab ‘not the obvious choice’ after inadequate response to a TNF inhibitor
While it might seem logical to turn to an IL-17 inhibitor in patients with an inadequate response to one or more TNF inhibitors, two recently published studies suggest that starting secukinumab is not more effective than trying yet another TNF inhibitor.
A retrospective analysis of Swiss registry data on next-step therapy in 390 axSpA patients who had withdrawn from one or more TNF inhibitors concluded that efficacy at 1 year in the 106 who switched to secukinumab wasn’t significantly different than in the 284 who moved on to another TNF inhibitor.
Similarly, an analysis of 10,583 courses of biologic therapy in 8,050 axSpA patients in five Nordic registries concluded that secukinumab and adalimumab as second-line therapy in patients with inadequate response to an initial TNF inhibitor performed similarly through 1 year of follow-up. However, in patients who’d previously failed to respond to two or three different biologic agents, adalimumab proved superior to the interleukin-17 inhibitor.
“These are two studies that don’t support the intuitive notion of trying a drug with a different mechanism of action when a patient has an inadequate response to a TNF inhibitor. It’s not clear that’s going to make a difference. It doesn’t mean secukinumab can’t work, but it means secukinumab is not the obvious choice,” Dr. Ruderman commented.
All three speakers reported financial relationships with numerous pharmaceutical companies.
Rheumatologists can look forward to the likely regulatory approval of the oral Janus kinase inhibitors tofacitinib and upadacitinib for the treatment of axial spondyloarthritis in the first half of 2021, speakers predicted at the 2021 Rheumatology Winter Clinical Symposium.
This will be a major advance in the treatment of axial spondyloarthritis (axSpA) and promises to be one of the overall highlights of the coming year in rheumatology, according to the speakers. Both medications are now under Food and Drug Administration review for the proposed new indication.
“My sense is within the next 6 months we’re going to have two different oral JAK inhibitors that offer a new option for our ankylosing spondylitis and axial spondyloarthritis patients,” predicted Eric M. Ruderman, MD, professor of medicine (rheumatology) at Northwestern University, Chicago.
Alexis R. Ogdie, MD, MSCE, noted that, at present, only two classes of potent medications are available for treatment of axial spondyloarthritis: tumor necrosis factor (TNF) inhibitors and anti–interleukin-17 biologics.
“I think it would be so exciting to have more treatment options. To have only two classes of drugs you can use for this disease is not enough,” said Dr. Ogdie, a rheumatologist and epidemiologist at the University of Pennsylvania, Philadelphia.
She and her fellow panelists also highlighted other recent key developments in axSpA, including epidemiologic evidence that case numbers are climbing sharply, identification of two previously unrecognized common comorbidities, a successful biologic remission induction and maintenance dose–reduction strategy, data on the best and worst biologics for patients with anterior uveitis, and evidence regarding next-step therapy in axSpA patients who’ve had an inadequate response to a TNF inhibitor.
The JAK inhibitors are coming
Oral tofacitinib (Xeljanz) at 5 mg twice daily was the focus of a pivotal phase 3, double-blind, 16-week, placebo-controlled clinical trial including 269 patients with axSpA. The results were presented at the 2020 annual meeting of the American College of Rheumatology. The primary endpoint was at least a 20% improvement in Assessment of Spondyloarthritis International Society response criteria (ASAS 20). This was accomplished in 56.4% of patients on tofacitinib and 29.4% of placebo-treated controls. The ASAS 40 response rate was even more impressive: 40.6% with the JAK inhibitor, compared with 12.5% with placebo. There was one serious infection in the tofacitinib group, but no cases of venous thromboembolism, interstitial lung disease, opportunistic infection, major adverse cardiovascular events, or malignancy in this brief 4-month study.
Also now under FDA review are data from SELECT-AXIS 1, a phase 2/3, double-blind trial in which 187 biologic-naive patients with ankylosing spondylitis were randomized to 14 weeks of upadacitinib (Rinvoq) at 15 mg once daily or placebo. The primary endpoint, an ASAS 40 response, occurred in 51.6% of patients on the JAK inhibitor and half as many controls.
“They saw improvement in MRI scores with upadacitinib, so there’s biologic plausibility to this,” Dr. Ruderman noted.
He predicted the JAK inhibitors are going to have a big impact in clinical practice, especially in men.
“I have a lot of ankylosing spondylitis and axial spondyloarthritis patients on NSAIDs who I’m not convinced are doing as well as they could, but they push back every time I raise the possibility of going on a biologic,” the rheumatologist said. “I suspect that, given the rapid response with JAK inhibitors here, as in rheumatoid arthritis, it might be a little bit easier to persuade these people to give this a try for 4-6 weeks and then see how much better they are. It’s a pill. You don’t have to give yourself a shot.”
Dr. Ogdie predicted the new oral agents will bring more axSpA patients into rheumatologists’ offices.
“I think it’ll be kind of like the apremilast effect in psoriasis, where the drug got a lot more people into the market,” she said.
U.S. ankylosing spondylitis prevalence rising
The diagnostic prevalence of axSpA in the United States increased by 86% between 2006 and 2014 in a retrospective analysis based on Medicare fee-for-service claims data. A separate analysis using IBM MarketScan data for the same years was confirmatory, showing a 56% increase, Jeffrey R. Curtis, MD, MS, MPH, of the University of Alabama at Birmingham reported at the 2020 annual meeting of the European League Against Rheumatism (EULAR), now known as the European Alliance of Associations for Rheumatology.
“I think the take home is we’re seeing more of this. Some of this is likely due to increased awareness and inclusion of nonradiographic disease,” according to Dr. Ruderman.
Two previously overlooked comorbidities
It’s well recognized that 5%-10% of patients with axSpA have concurrent inflammatory bowel disease. But how about irritable bowel syndrome (IBS)?
A study of 186 Swedish patients with axSpA in the population-based SPARTAKUS registry, none with inflammatory bowel disease, concluded that 30% of them met ROME III diagnostic criteria for IBS, compared with 16% of healthy controls. Of note, the axSpA patients with comorbid IBS had significantly worse axSpA disease outcomes, compared with those without IBS as measured by pain, fatigue, and quality-of-life scores, as well as significantly greater disease activity on the Bath Ankylosing Spondylitis Disease Activity Index.
New-onset inflammatory back pain occurred in a hefty 24% of 513 Saudi patients placed on isotretinoin for acne. About 42% of those with inflammatory back pain displayed evidence of sacroiliitis on MRI. Moreover, 52% of patients with MRI-proven sacroiliitis fulfilled ASAS criteria for axSpA. In this longitudinal study, the MRI abnormalities and back pain symptoms completely resolved after isotretinoin discontinuation, but it took a long time: up to 9 months.
“When you see these people with inflammatory back pain on isotretinoin, I think it’s important that before you saddle them with a diagnosis that they have axSpA – a diagnosis that will go with them forever – give them time off drug, because this can look like the real thing. It’s something to think about as these pretty young kids come in to see you with back pain: Always ask about their medication history because it could be important,” Dr. Ruderman said.
A successful biologic remission induction-and-maintenance strategy
The phase 3b, multicenter C-OPTIMISE study sought to determine the best strategy for avoiding axSpA flares once sustained clinical remission has been achieved with a TNF inhibitor, in this case certolizumab pegol (Cimzia). The first part of the trial involved 736 patients with early axSpA, including 329 with nonradiographic disease. During the 48-week open-label induction period, 43.9% of patients achieved sustained clinical remission at the approved dose of 200 mg every 2 weeks, with similar success rates in radiographic and nonradiographic axSpA.
Those in sustained remission were then randomized double blind to one of three groups: an additional 48 weeks of certolizumab pegol at the full maintenance dose of 200 mg every 2 weeks, reduced maintenance dosing at 200 mg every 4 weeks, or placebo. During this period, 83.7% of the group who continued on full-dose certolizumab remained flare free, as did 79% of those on the reduced maintenance dose. In contrast, only 20.2% of patients in whom the biologic was completely withdrawn remained flare free. The investigators concluded that certolizumab dose reduction is a winning strategy for maintenance of clinical remission, as it reduces costs and limits long-term exposure to immunosuppressive therapy while maintaining clinical benefits.
All biologics aren’t equal when it comes to anterior uveitis risk
An analysis of Swedish Rheumatology Quality Register data presented at the 2020 EULAR meeting concluded that, among 3,568 patients started on one of four biologics for treatment of spondyloarthritis, the incidence of anterior uveitis was 2.9 per 100 patient-years in those on infliximab (Remicade), 4.0 per 100 patient-years with adalimumab (Humira), 6.8 per 100 patient-years with secukinumab (Cosentyx), and 7.5 per 100 patient-years with etanercept (Enbrel).
“This is important information for us in the clinic. The big question has been, do we see a reduced risk of anterior uveitis with secukinumab, an interleukin-17 inhibitor,” observed RWCS director Arthur Kavanaugh, MD, professor of medicine and director of the Center for Innovative Therapy in the division of rheumatology, allergy, and immunology at the University of California, San Diego.
“When I’ve switched people with uveitis to secukinumab or ixekizumab [Taltz], I do see it come back. So I think it’s important to have these data out there,” Dr. Ogdie said.
Certolizumab pegol markedly reduced the incidence of anterior uveitis flares in patients with radiographic and nonradiographic axSpA and a history of recurrent uveitis flares in the ongoing phase 4 C-VIEW study. In the 48 weeks prior to going on certolizumab pegol, the 89 participants included in this analysis had an acute anterior uveitis incidence of 1.5 episodes per patient; during their first 48 weeks on the TNF inhibitor, the rate plunged to 0.2 episodes, representing an 87% reduction.
Secukinumab ‘not the obvious choice’ after inadequate response to a TNF inhibitor
While it might seem logical to turn to an IL-17 inhibitor in patients with an inadequate response to one or more TNF inhibitors, two recently published studies suggest that starting secukinumab is not more effective than trying yet another TNF inhibitor.
A retrospective analysis of Swiss registry data on next-step therapy in 390 axSpA patients who had withdrawn from one or more TNF inhibitors concluded that efficacy at 1 year in the 106 who switched to secukinumab wasn’t significantly different than in the 284 who moved on to another TNF inhibitor.
Similarly, an analysis of 10,583 courses of biologic therapy in 8,050 axSpA patients in five Nordic registries concluded that secukinumab and adalimumab as second-line therapy in patients with inadequate response to an initial TNF inhibitor performed similarly through 1 year of follow-up. However, in patients who’d previously failed to respond to two or three different biologic agents, adalimumab proved superior to the interleukin-17 inhibitor.
“These are two studies that don’t support the intuitive notion of trying a drug with a different mechanism of action when a patient has an inadequate response to a TNF inhibitor. It’s not clear that’s going to make a difference. It doesn’t mean secukinumab can’t work, but it means secukinumab is not the obvious choice,” Dr. Ruderman commented.
All three speakers reported financial relationships with numerous pharmaceutical companies.
FROM RWCS 2021
COVID-19 vaccination recommended for rheumatology patients
People with rheumatic diseases should get vaccinated against SARS-CoV-2 as soon as possible, the American College of Rheumatology (ACR) recommends.
“It may be that people with rheumatic diseases are at increased risk of developing COVID or serious COVID-related complications,” Jonathan Hausmann, MD, assistant professor of medicine at Harvard Medical School, Boston, said in an ACR podcast. “So the need to prevent COVID-19 is incredibly important in this group of patients.”
The guidelines recommend a delay in vaccination only in rare circumstances, such as for patients with very severe illness or who have recently been administered rituximab, Jeffrey R. Curtis, MD, MPH, lead author of the guidelines, said in the podcast.
“Our members have been inundated with questions and concerns from their patients on whether they should receive the vaccine,” ACR President David Karp, MD, PhD, said in a press release.
So the ACR convened a panel of nine rheumatologists, two infectious disease specialists, and two public health experts. Over the course of 8 weeks, the task force reviewed the literature and agreed on recommendations. The organization posted a summary of the guidelines on its website after its board of directors approved it Feb. 8. The paper is pending journal peer review.
Some risks are real
The task force confined its research to the COVID-19 vaccines being offered by Pfizer and Moderna because they are currently the only ones approved by the Food and Drug Administration. It found no reason to distinguish between the two vaccines in its recommendations.
Because little research has directly addressed the question concerning COVID-19 vaccination for patients with rheumatic diseases, the task force extrapolated from data on other vaccinations in people with rheumatic disease and on the COVID-19 vaccinations in other populations.
It analyzed reports that other types of vaccination, such as for influenza, triggered flares of rheumatic conditions. “It is really individual case reports or small cohorts where there may be a somewhat higher incidence of flare, but it’s usually not very large in its magnitude nor duration,” said Dr. Curtis of the University of Alabama at Birmingham.
The task force also considered the possibility that vaccinations could lead to a new autoimmune disorder, such as Guillain-Barré syndrome or Bell palsy. The risk is real, the task force decided, but not significant enough to influence their recommendations.
Likewise, in immunocompromised people, vaccinations with live virus, such as those for shingles, might trigger the infection the vaccination is meant to prevent. But this can’t happen with the Pfizer and Moderna COVID-19 vaccines because they contain messenger RNA instead of live viruses, Dr. Curtis said.
Although it might be optimal to administer the vaccines when rheumatic diseases are quiescent, the urgency of getting vaccinated overrides that consideration, Dr. Curtis said. “By and large, there was a general consensus to not want to delay vaccination until somebody was stable and doing great, because you don’t know how long that’s going to be,” he said.
How well does it work?
One unanswered question is whether the COVID-19 vaccines work as well for patients with rheumatic diseases. The task force was reassured by data showing efficacy across a range of subgroups, including some with immunosenescence, Dr. Curtis said. “But until we have data in rheumatology patients, we’re just not going to know,” he said.
The guidelines specify that some drug regimens be modified when patients are vaccinated.
For patients taking rituximab, vaccination should be delayed, but only for those who are able to maintain safe social distancing to reduce the risk for COVID-19 exposure, Dr. Curtis said. “If somebody has just gotten rituximab recently, it might be more ideal to complete the vaccine series about 2-4 weeks before the next rituximab dose,” he said. “So if you are giving that therapy, say, at 6-month intervals, if you could vaccinate them at around month 5 from the most recent rituximab cycle, that might be more ideal.”
The guidance calls for withholding JAK inhibitors for a week after each vaccine dose is administered.
It calls for holding SQ abatacept 1 week prior and 1 week after the first COVID-19 vaccine dose, with no interruption after the second dose.
For abatacept IV, clinicians should “time vaccine administration so that the first vaccination will occur 4 weeks after abatacept infusion (i.e., the entire dosing interval), and postpone the subsequent abatacept infusion by 1 week (i.e., a 5-week gap in total).” It recommends no medication adjustment for the second vaccine dose.
For cyclophosphamide, the guidance recommends timing administration to occur about a week after each vaccine dose, when feasible.
None of this advice should supersede clinical judgment, Dr. Curtis said.
A version of this article first appeared on Medscape.com.
People with rheumatic diseases should get vaccinated against SARS-CoV-2 as soon as possible, the American College of Rheumatology (ACR) recommends.
“It may be that people with rheumatic diseases are at increased risk of developing COVID or serious COVID-related complications,” Jonathan Hausmann, MD, assistant professor of medicine at Harvard Medical School, Boston, said in an ACR podcast. “So the need to prevent COVID-19 is incredibly important in this group of patients.”
The guidelines recommend a delay in vaccination only in rare circumstances, such as for patients with very severe illness or who have recently been administered rituximab, Jeffrey R. Curtis, MD, MPH, lead author of the guidelines, said in the podcast.
“Our members have been inundated with questions and concerns from their patients on whether they should receive the vaccine,” ACR President David Karp, MD, PhD, said in a press release.
So the ACR convened a panel of nine rheumatologists, two infectious disease specialists, and two public health experts. Over the course of 8 weeks, the task force reviewed the literature and agreed on recommendations. The organization posted a summary of the guidelines on its website after its board of directors approved it Feb. 8. The paper is pending journal peer review.
Some risks are real
The task force confined its research to the COVID-19 vaccines being offered by Pfizer and Moderna because they are currently the only ones approved by the Food and Drug Administration. It found no reason to distinguish between the two vaccines in its recommendations.
Because little research has directly addressed the question concerning COVID-19 vaccination for patients with rheumatic diseases, the task force extrapolated from data on other vaccinations in people with rheumatic disease and on the COVID-19 vaccinations in other populations.
It analyzed reports that other types of vaccination, such as for influenza, triggered flares of rheumatic conditions. “It is really individual case reports or small cohorts where there may be a somewhat higher incidence of flare, but it’s usually not very large in its magnitude nor duration,” said Dr. Curtis of the University of Alabama at Birmingham.
The task force also considered the possibility that vaccinations could lead to a new autoimmune disorder, such as Guillain-Barré syndrome or Bell palsy. The risk is real, the task force decided, but not significant enough to influence their recommendations.
Likewise, in immunocompromised people, vaccinations with live virus, such as those for shingles, might trigger the infection the vaccination is meant to prevent. But this can’t happen with the Pfizer and Moderna COVID-19 vaccines because they contain messenger RNA instead of live viruses, Dr. Curtis said.
Although it might be optimal to administer the vaccines when rheumatic diseases are quiescent, the urgency of getting vaccinated overrides that consideration, Dr. Curtis said. “By and large, there was a general consensus to not want to delay vaccination until somebody was stable and doing great, because you don’t know how long that’s going to be,” he said.
How well does it work?
One unanswered question is whether the COVID-19 vaccines work as well for patients with rheumatic diseases. The task force was reassured by data showing efficacy across a range of subgroups, including some with immunosenescence, Dr. Curtis said. “But until we have data in rheumatology patients, we’re just not going to know,” he said.
The guidelines specify that some drug regimens be modified when patients are vaccinated.
For patients taking rituximab, vaccination should be delayed, but only for those who are able to maintain safe social distancing to reduce the risk for COVID-19 exposure, Dr. Curtis said. “If somebody has just gotten rituximab recently, it might be more ideal to complete the vaccine series about 2-4 weeks before the next rituximab dose,” he said. “So if you are giving that therapy, say, at 6-month intervals, if you could vaccinate them at around month 5 from the most recent rituximab cycle, that might be more ideal.”
The guidance calls for withholding JAK inhibitors for a week after each vaccine dose is administered.
It calls for holding SQ abatacept 1 week prior and 1 week after the first COVID-19 vaccine dose, with no interruption after the second dose.
For abatacept IV, clinicians should “time vaccine administration so that the first vaccination will occur 4 weeks after abatacept infusion (i.e., the entire dosing interval), and postpone the subsequent abatacept infusion by 1 week (i.e., a 5-week gap in total).” It recommends no medication adjustment for the second vaccine dose.
For cyclophosphamide, the guidance recommends timing administration to occur about a week after each vaccine dose, when feasible.
None of this advice should supersede clinical judgment, Dr. Curtis said.
A version of this article first appeared on Medscape.com.
People with rheumatic diseases should get vaccinated against SARS-CoV-2 as soon as possible, the American College of Rheumatology (ACR) recommends.
“It may be that people with rheumatic diseases are at increased risk of developing COVID or serious COVID-related complications,” Jonathan Hausmann, MD, assistant professor of medicine at Harvard Medical School, Boston, said in an ACR podcast. “So the need to prevent COVID-19 is incredibly important in this group of patients.”
The guidelines recommend a delay in vaccination only in rare circumstances, such as for patients with very severe illness or who have recently been administered rituximab, Jeffrey R. Curtis, MD, MPH, lead author of the guidelines, said in the podcast.
“Our members have been inundated with questions and concerns from their patients on whether they should receive the vaccine,” ACR President David Karp, MD, PhD, said in a press release.
So the ACR convened a panel of nine rheumatologists, two infectious disease specialists, and two public health experts. Over the course of 8 weeks, the task force reviewed the literature and agreed on recommendations. The organization posted a summary of the guidelines on its website after its board of directors approved it Feb. 8. The paper is pending journal peer review.
Some risks are real
The task force confined its research to the COVID-19 vaccines being offered by Pfizer and Moderna because they are currently the only ones approved by the Food and Drug Administration. It found no reason to distinguish between the two vaccines in its recommendations.
Because little research has directly addressed the question concerning COVID-19 vaccination for patients with rheumatic diseases, the task force extrapolated from data on other vaccinations in people with rheumatic disease and on the COVID-19 vaccinations in other populations.
It analyzed reports that other types of vaccination, such as for influenza, triggered flares of rheumatic conditions. “It is really individual case reports or small cohorts where there may be a somewhat higher incidence of flare, but it’s usually not very large in its magnitude nor duration,” said Dr. Curtis of the University of Alabama at Birmingham.
The task force also considered the possibility that vaccinations could lead to a new autoimmune disorder, such as Guillain-Barré syndrome or Bell palsy. The risk is real, the task force decided, but not significant enough to influence their recommendations.
Likewise, in immunocompromised people, vaccinations with live virus, such as those for shingles, might trigger the infection the vaccination is meant to prevent. But this can’t happen with the Pfizer and Moderna COVID-19 vaccines because they contain messenger RNA instead of live viruses, Dr. Curtis said.
Although it might be optimal to administer the vaccines when rheumatic diseases are quiescent, the urgency of getting vaccinated overrides that consideration, Dr. Curtis said. “By and large, there was a general consensus to not want to delay vaccination until somebody was stable and doing great, because you don’t know how long that’s going to be,” he said.
How well does it work?
One unanswered question is whether the COVID-19 vaccines work as well for patients with rheumatic diseases. The task force was reassured by data showing efficacy across a range of subgroups, including some with immunosenescence, Dr. Curtis said. “But until we have data in rheumatology patients, we’re just not going to know,” he said.
The guidelines specify that some drug regimens be modified when patients are vaccinated.
For patients taking rituximab, vaccination should be delayed, but only for those who are able to maintain safe social distancing to reduce the risk for COVID-19 exposure, Dr. Curtis said. “If somebody has just gotten rituximab recently, it might be more ideal to complete the vaccine series about 2-4 weeks before the next rituximab dose,” he said. “So if you are giving that therapy, say, at 6-month intervals, if you could vaccinate them at around month 5 from the most recent rituximab cycle, that might be more ideal.”
The guidance calls for withholding JAK inhibitors for a week after each vaccine dose is administered.
It calls for holding SQ abatacept 1 week prior and 1 week after the first COVID-19 vaccine dose, with no interruption after the second dose.
For abatacept IV, clinicians should “time vaccine administration so that the first vaccination will occur 4 weeks after abatacept infusion (i.e., the entire dosing interval), and postpone the subsequent abatacept infusion by 1 week (i.e., a 5-week gap in total).” It recommends no medication adjustment for the second vaccine dose.
For cyclophosphamide, the guidance recommends timing administration to occur about a week after each vaccine dose, when feasible.
None of this advice should supersede clinical judgment, Dr. Curtis said.
A version of this article first appeared on Medscape.com.
TNF inhibitors may slow spinal progression in axial spondyloarthritis
Patients with axial spondyloarthritis showed reduced spinal radiographic progression after treatment with tumor necrosis factor (TNF) inhibitors, based on data from 314 adults in a prospective cohort study.
Evidence of a link between inflammation and axial damage in patients with axial spondyloarthritis (axSpA) has been reported, and these patients are routinely treated with NSAIDs and TNF inhibitors (TNFi), wrote Alexandre Sepriano, MD, PhD, of Leiden (the Netherlands) University Medical Center, and colleagues.
“However, and despite significant efforts, it remains to be clarified whether there is also an effect of these drugs on axial damage accrual,” they noted.
In a study published in Arthritis & Rheumatology, the researchers recruited consecutive patients from rheumatology practices in Northern Alberta to enroll in the Follow Up Research Cohort in Ankylosing Spondylitis Treatment (ALBERTA FORCAST) observational cohort study. The average age of the patients was 41 years, 74% were men, 83% were HLA-B27 positive, and the average duration of symptoms was 18 years.
Progression was measured via spine radiographs every 2 years for up to 10 years; the radiographs were scored using the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). In addition, the researchers assessed the interaction between TNFi exposure and clinical disease activity using the Ankylosing Spondylitis Disease Activity Score (ASDAS) and the impact on mSASSS every 2 years. The analysis included 442 2-year intervals.
Overall, the researchers found a significant interaction between ASDAS and TNFi at the start of the interval, followed by gradient effect of ASDAS at the start of the interval on mSASSS 2 years later, which was more than twice as high in patients never treated with TNFi (beta = 0.41), compared with patients who were continuously treated with a TNFi (beta = 0.16).
“Similarly, patients treated with TNFi were 30% less likely to develop a new syndesmophyte 2 years later compared to those not treated,” the researchers said.
TNFi also directly slowed progression, as treated patients averaged 0.85 mSASSS units less 2 years later, compared with untreated patients.
Of note, “treatment with NSAIDs during follow-up was neither associated with the outcome nor did it modify or confound the association between TNFi and mSASSS,” the researchers said. In addition, “the direct effect of TNFi on mSASSS was still present after adjusting for a propensity score,” they wrote.
The study results were limited by several factors including the observational design, lack of data on long-term treatment effects, and inability to assess individual TNFi drugs separately, the researchers noted.
However, “the present study informs the rheumatology community by addressing the question as to whether or not TNFi inhibit radiographic progression in axSpA and if this effect is mediated solely by their effects on inflammation, as measured by the ASDAS, or whether additional mechanisms may be relevant,” they emphasized.
“A better understanding of these mechanisms might open avenues to further treatment strategies that might finally lead to effective disease modification in axial SpA,” they concluded.
The ALBERTA FORCAST study was supported by AbbVie. Several authors disclosed financial relationships with AbbVie and other manufacturers of TNFi.
Patients with axial spondyloarthritis showed reduced spinal radiographic progression after treatment with tumor necrosis factor (TNF) inhibitors, based on data from 314 adults in a prospective cohort study.
Evidence of a link between inflammation and axial damage in patients with axial spondyloarthritis (axSpA) has been reported, and these patients are routinely treated with NSAIDs and TNF inhibitors (TNFi), wrote Alexandre Sepriano, MD, PhD, of Leiden (the Netherlands) University Medical Center, and colleagues.
“However, and despite significant efforts, it remains to be clarified whether there is also an effect of these drugs on axial damage accrual,” they noted.
In a study published in Arthritis & Rheumatology, the researchers recruited consecutive patients from rheumatology practices in Northern Alberta to enroll in the Follow Up Research Cohort in Ankylosing Spondylitis Treatment (ALBERTA FORCAST) observational cohort study. The average age of the patients was 41 years, 74% were men, 83% were HLA-B27 positive, and the average duration of symptoms was 18 years.
Progression was measured via spine radiographs every 2 years for up to 10 years; the radiographs were scored using the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). In addition, the researchers assessed the interaction between TNFi exposure and clinical disease activity using the Ankylosing Spondylitis Disease Activity Score (ASDAS) and the impact on mSASSS every 2 years. The analysis included 442 2-year intervals.
Overall, the researchers found a significant interaction between ASDAS and TNFi at the start of the interval, followed by gradient effect of ASDAS at the start of the interval on mSASSS 2 years later, which was more than twice as high in patients never treated with TNFi (beta = 0.41), compared with patients who were continuously treated with a TNFi (beta = 0.16).
“Similarly, patients treated with TNFi were 30% less likely to develop a new syndesmophyte 2 years later compared to those not treated,” the researchers said.
TNFi also directly slowed progression, as treated patients averaged 0.85 mSASSS units less 2 years later, compared with untreated patients.
Of note, “treatment with NSAIDs during follow-up was neither associated with the outcome nor did it modify or confound the association between TNFi and mSASSS,” the researchers said. In addition, “the direct effect of TNFi on mSASSS was still present after adjusting for a propensity score,” they wrote.
The study results were limited by several factors including the observational design, lack of data on long-term treatment effects, and inability to assess individual TNFi drugs separately, the researchers noted.
However, “the present study informs the rheumatology community by addressing the question as to whether or not TNFi inhibit radiographic progression in axSpA and if this effect is mediated solely by their effects on inflammation, as measured by the ASDAS, or whether additional mechanisms may be relevant,” they emphasized.
“A better understanding of these mechanisms might open avenues to further treatment strategies that might finally lead to effective disease modification in axial SpA,” they concluded.
The ALBERTA FORCAST study was supported by AbbVie. Several authors disclosed financial relationships with AbbVie and other manufacturers of TNFi.
Patients with axial spondyloarthritis showed reduced spinal radiographic progression after treatment with tumor necrosis factor (TNF) inhibitors, based on data from 314 adults in a prospective cohort study.
Evidence of a link between inflammation and axial damage in patients with axial spondyloarthritis (axSpA) has been reported, and these patients are routinely treated with NSAIDs and TNF inhibitors (TNFi), wrote Alexandre Sepriano, MD, PhD, of Leiden (the Netherlands) University Medical Center, and colleagues.
“However, and despite significant efforts, it remains to be clarified whether there is also an effect of these drugs on axial damage accrual,” they noted.
In a study published in Arthritis & Rheumatology, the researchers recruited consecutive patients from rheumatology practices in Northern Alberta to enroll in the Follow Up Research Cohort in Ankylosing Spondylitis Treatment (ALBERTA FORCAST) observational cohort study. The average age of the patients was 41 years, 74% were men, 83% were HLA-B27 positive, and the average duration of symptoms was 18 years.
Progression was measured via spine radiographs every 2 years for up to 10 years; the radiographs were scored using the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). In addition, the researchers assessed the interaction between TNFi exposure and clinical disease activity using the Ankylosing Spondylitis Disease Activity Score (ASDAS) and the impact on mSASSS every 2 years. The analysis included 442 2-year intervals.
Overall, the researchers found a significant interaction between ASDAS and TNFi at the start of the interval, followed by gradient effect of ASDAS at the start of the interval on mSASSS 2 years later, which was more than twice as high in patients never treated with TNFi (beta = 0.41), compared with patients who were continuously treated with a TNFi (beta = 0.16).
“Similarly, patients treated with TNFi were 30% less likely to develop a new syndesmophyte 2 years later compared to those not treated,” the researchers said.
TNFi also directly slowed progression, as treated patients averaged 0.85 mSASSS units less 2 years later, compared with untreated patients.
Of note, “treatment with NSAIDs during follow-up was neither associated with the outcome nor did it modify or confound the association between TNFi and mSASSS,” the researchers said. In addition, “the direct effect of TNFi on mSASSS was still present after adjusting for a propensity score,” they wrote.
The study results were limited by several factors including the observational design, lack of data on long-term treatment effects, and inability to assess individual TNFi drugs separately, the researchers noted.
However, “the present study informs the rheumatology community by addressing the question as to whether or not TNFi inhibit radiographic progression in axSpA and if this effect is mediated solely by their effects on inflammation, as measured by the ASDAS, or whether additional mechanisms may be relevant,” they emphasized.
“A better understanding of these mechanisms might open avenues to further treatment strategies that might finally lead to effective disease modification in axial SpA,” they concluded.
The ALBERTA FORCAST study was supported by AbbVie. Several authors disclosed financial relationships with AbbVie and other manufacturers of TNFi.
FROM ARTHRITIS & RHEUMATOLOGY
Rheumatologic disease activity an important influencer of COVID-19 death risk
People with rheumatic and musculoskeletal diseases (RMDs) who contract the SARS-CoV-2 virus appear more likely to die from COVID-19 if their rheumatologic condition is not being well controlled at the time of their infection.
New data from the COVID-19 Global Rheumatology Alliance (GRA) physician registry reported in Annals of the Rheumatic Diseases have found that the odds of dying from COVID-19 were 87% higher in individuals recorded as having moderate to high disease activity versus those reported to be in remission or having low disease activity.
“I think this really highlights the importance of continuing to appropriately, and actively, treat our patients, and the importance of controlling their disease,” Pedro Machado, MD, PhD, said in an interview. Dr. Machado, an associate professor in rheumatology and muscle diseases at University College London and a consultant rheumatologist at several U.K. hospitals, has been involved in the GRA physician registry from the start, and sits on the GRA steering committee.
Alongside higher disease activity, several other important factors were found to be associated with increased odds of dying from COVID-19 – older age, male gender, and the presence of one or more comorbidities, such as hypertension combined with cardiovascular disease or chronic lung disease.
These demographic and disease-based factors have been linked to an increased risk for COVID-19–related hospitalization before, both in people with RMDs and in the general population, but the latest GRA physician registry data now take that a step further, and link them also to an increased risk for death, together with several other factors more specific to RMDs.
Logging COVID-19 rheumatologic cases
Since the start of the global pandemic, the potential effects that SARS-CoV-2 infection might have on people with RMDs in particular has concerned the rheumatology community. The main worries being that, either because of the underlying RMD itself or to its treatment, there may be immunoregulatory deficits or other risk factors that would make individuals more susceptible to not only infection but also to developing more severe COVID-19 than the general population.
These concerns led to the rapid formation of the GRA and the COVID-19 GRA physician registry in March 2020 to collect and analyze data on adults with rheumatic disease and confirmed or presumptive COVID-19. Entries into the registry are made by or under the direction of rheumatologists, and this is a voluntary process.
“This population cannot ever be entirely representative of the population of patients with rheumatic diseases,” Dr. Machado acknowledged. There will be selection and other biases that affect the reported data. That said, it’s the largest database of reported COVID-19 cases in adult rheumatology patients across the world, with more than 9,000 cases so far included from multiple registries, including those based in Europe and North and South America. Data from one of these – the French RMD cohort – have also recently been published in Annals of the Rheumatic Diseases, showing much the same findings but on a national level.
Hospitalization was the focus of a previous report because “you need large sample sizes” to look at endpoints that occur less frequently. When the first analysis was done, there were around 600 cases from 40 countries in the registry with sufficient data that could be used. Now, with a greater number of recorded cases, factors influencing the risk for death could be examined.
Death rate and risk factors found
Data on 3,729 COVID-19 cases in people with RMDs were included in the current analysis, all recorded in the first few months of the registry being open and up until July 1, 2020. In all, 390 (10.5%) of people died. While this is “clearly higher” than reported in the general population in most countries, the analysis was not designed to calculate a precise estimate.
“It should not be taken as an estimate of the overall death rate among patients with rheumatic diseases and COVID-19,” Dr. Machado and coauthors have been keen to point out.
“Age is always the biggest risk factor,” Dr. Machado explained. “There’s always a gradient: the older the patient, the worse the outcome.”
Indeed, there was a threefold increased risk for death among those aged 66-75 years versus those who were 65 years or younger (odds ratio, 3.00), and a sixfold increased risk for patients older than 75, compared with the younger age group (OR, 6.18).
Having both hypertension and cardiovascular disease was associated with an OR of 1.89, and coexisting chronic lung disease also significantly increased the chances of dying from COVID-19 (OR, 1.68).
Being of male sex was associated with a 46% increased risk for death from COVID-19 versus being of female sex.
The risk for COVID-19 death also rose with the use of corticosteroids. Compared with no steroid use, there was a 69% increased risk for with death at doses of 10 mg or more prednisolone equivalent per day.
“The finding about moderate to high doses of steroids being associated with a worse outcome is consistent with the first report; it was the same for hospitalization,” Dr. Machado observed.
The general consensus on steroid use in the COVID-19 setting is that they should be continued as needed, but at the lowest possible dose, as outlined in provisional recommendations set out by the recently renamed European Alliance of Associations for Rheumatology.
The GRA physician registry findings provide further support for this, suggesting that disease control should be optimized with disease-modifying antirheumatic drugs, ideally without increasing the dose of steroids.
Surprise over sulfasalazine risk
“Taking all medications into account – such as methotrexate, leflunomide, hydroxychloroquine, [tumor necrosis factor] blockers, interleukin-6 blockers, and [Janus kinase] inhibitors – it is quite reassuring because we did not see an association with worse outcome with those drugs overall,” Dr. Machado said.
However, treatment with rituximab (OR, 4.0), sulfasalazine (OR, 3.6), and immunosuppressive agents such as azathioprine, cyclophosphamide, cyclosporine, mycophenolate, or tacrolimus (OR, 2.2), were associated with higher odds of dying from COVID-19 when compared with treatment with methotrexate alone.
The findings for rituximab and immunosuppressant use were perhaps not unexpected, but the possible association between sulfasalazine and COVID-19 death was “a bit intriguing,” Dr. Machado observed. “Sulfasalazine is believed to have low immunosuppressive effect.”
This warrants further investigation, but there are likely a range of confounding factors at play. One could be that people considered to be at higher risk may have been more often prescribed sulfasalazine because it was thought to be less immunosuppressive. Another might be because people taking sulfasalazine were more likely to be smokers, and they were also not advised to protect themselves from exposure to the virus (shielding) during the first wave of the pandemic, at least not in the United Kingdom.
Rituximab caution and vaccination
“Rituximab is a concern,” Dr. Machado acknowledged. “It is a concern that rheumatologists are now aware of and they are addressing, but then it’s a concern for a very specific subgroup of patients.”
While rheumatologists are, and will continue to prescribe it, there will be even more careful consideration over when, in whom, and how to use it during, and possibly even after, the pandemic.
“COVID is here to stay, it will become endemic, and it’s going to be part of our lives like the flu virus is,” Dr. Machado predicted.
Then there is the issue on vaccinating people against COVID-19, should those on rituximab still receive it? The answer is a yes, but, as with other vaccinations it’s all about the timing of when the vaccination is given.
Societies such as the British Society for Rheumatology have already begun to include guidance on this, recommending one of the available COVID-19 vaccines is given at least a month before the next or first dose of rituximab is due. As rituximab is given every few months, with doses sometimes spaced as much as 9 months or even a year apart, this should not be too much of a problem, but it is “better to have the vaccine first,” Dr. Machado said.
Has COVID-19 care improved in RMDs?
In separate research published in The Lancet Rheumatology, April Jorge, MD, of Massachusetts General Hospital and Harvard Medical School, both in Boston, and associates found that the risks of severe COVID-19 outcomes have improved over time, although they still “remain substantial.”
Dr. Jorge and colleagues looked at temporal trends in COVID-19 outcomes in patients with RMDs over the course of the first 6 months of the pandemic in 2020, using data from a large, multicenter, electronic health record network (TriNetX).
They formed two patient cohorts – a late (diagnosed from April 20 to July 20) and an early (diagnosed from January 20 to April 20) cohort – to see if outcomes had improved and discovered lower relative risks among patients in the late cohort for hospitalization (0.67), admission to the ICU (0.56), mechanical ventilation (0.39), acute kidney injury (0.66), renal replacement (0.53), and death (0.39).
“These results are encouraging,” but it’s difficult to match these different populations of patients, Dr. Machado said. “There are always factors that you cannot match for” and were not included in the U.S. analysis.
While there are important caveats in how the analysis was performed and thus in interpreting these data, they do “suggest that one of the reasons why outcomes have improved is because we have become better at treating these patients,” Dr. Machado added.
“Our treatment has improved, and our capacity to treat the complications has improved. We understand better how the disease behaves – we know that they can have thromboembolic complications that we can manage, and we are now able to manage ventilation issues better.”
Moreover, Dr. Machado said that, not only were clinicians more aware of what they should or should not do, there were treatments that were being used routinely or in some cases based on recent clinical trial results. “I think we are indeed treating these patients better.”
The COVID-19 GRA physician registry is financially supported by the American College of Rheumatology and EULAR. Dr. Machado had no relevant conflicts of interest.
People with rheumatic and musculoskeletal diseases (RMDs) who contract the SARS-CoV-2 virus appear more likely to die from COVID-19 if their rheumatologic condition is not being well controlled at the time of their infection.
New data from the COVID-19 Global Rheumatology Alliance (GRA) physician registry reported in Annals of the Rheumatic Diseases have found that the odds of dying from COVID-19 were 87% higher in individuals recorded as having moderate to high disease activity versus those reported to be in remission or having low disease activity.
“I think this really highlights the importance of continuing to appropriately, and actively, treat our patients, and the importance of controlling their disease,” Pedro Machado, MD, PhD, said in an interview. Dr. Machado, an associate professor in rheumatology and muscle diseases at University College London and a consultant rheumatologist at several U.K. hospitals, has been involved in the GRA physician registry from the start, and sits on the GRA steering committee.
Alongside higher disease activity, several other important factors were found to be associated with increased odds of dying from COVID-19 – older age, male gender, and the presence of one or more comorbidities, such as hypertension combined with cardiovascular disease or chronic lung disease.
These demographic and disease-based factors have been linked to an increased risk for COVID-19–related hospitalization before, both in people with RMDs and in the general population, but the latest GRA physician registry data now take that a step further, and link them also to an increased risk for death, together with several other factors more specific to RMDs.
Logging COVID-19 rheumatologic cases
Since the start of the global pandemic, the potential effects that SARS-CoV-2 infection might have on people with RMDs in particular has concerned the rheumatology community. The main worries being that, either because of the underlying RMD itself or to its treatment, there may be immunoregulatory deficits or other risk factors that would make individuals more susceptible to not only infection but also to developing more severe COVID-19 than the general population.
These concerns led to the rapid formation of the GRA and the COVID-19 GRA physician registry in March 2020 to collect and analyze data on adults with rheumatic disease and confirmed or presumptive COVID-19. Entries into the registry are made by or under the direction of rheumatologists, and this is a voluntary process.
“This population cannot ever be entirely representative of the population of patients with rheumatic diseases,” Dr. Machado acknowledged. There will be selection and other biases that affect the reported data. That said, it’s the largest database of reported COVID-19 cases in adult rheumatology patients across the world, with more than 9,000 cases so far included from multiple registries, including those based in Europe and North and South America. Data from one of these – the French RMD cohort – have also recently been published in Annals of the Rheumatic Diseases, showing much the same findings but on a national level.
Hospitalization was the focus of a previous report because “you need large sample sizes” to look at endpoints that occur less frequently. When the first analysis was done, there were around 600 cases from 40 countries in the registry with sufficient data that could be used. Now, with a greater number of recorded cases, factors influencing the risk for death could be examined.
Death rate and risk factors found
Data on 3,729 COVID-19 cases in people with RMDs were included in the current analysis, all recorded in the first few months of the registry being open and up until July 1, 2020. In all, 390 (10.5%) of people died. While this is “clearly higher” than reported in the general population in most countries, the analysis was not designed to calculate a precise estimate.
“It should not be taken as an estimate of the overall death rate among patients with rheumatic diseases and COVID-19,” Dr. Machado and coauthors have been keen to point out.
“Age is always the biggest risk factor,” Dr. Machado explained. “There’s always a gradient: the older the patient, the worse the outcome.”
Indeed, there was a threefold increased risk for death among those aged 66-75 years versus those who were 65 years or younger (odds ratio, 3.00), and a sixfold increased risk for patients older than 75, compared with the younger age group (OR, 6.18).
Having both hypertension and cardiovascular disease was associated with an OR of 1.89, and coexisting chronic lung disease also significantly increased the chances of dying from COVID-19 (OR, 1.68).
Being of male sex was associated with a 46% increased risk for death from COVID-19 versus being of female sex.
The risk for COVID-19 death also rose with the use of corticosteroids. Compared with no steroid use, there was a 69% increased risk for with death at doses of 10 mg or more prednisolone equivalent per day.
“The finding about moderate to high doses of steroids being associated with a worse outcome is consistent with the first report; it was the same for hospitalization,” Dr. Machado observed.
The general consensus on steroid use in the COVID-19 setting is that they should be continued as needed, but at the lowest possible dose, as outlined in provisional recommendations set out by the recently renamed European Alliance of Associations for Rheumatology.
The GRA physician registry findings provide further support for this, suggesting that disease control should be optimized with disease-modifying antirheumatic drugs, ideally without increasing the dose of steroids.
Surprise over sulfasalazine risk
“Taking all medications into account – such as methotrexate, leflunomide, hydroxychloroquine, [tumor necrosis factor] blockers, interleukin-6 blockers, and [Janus kinase] inhibitors – it is quite reassuring because we did not see an association with worse outcome with those drugs overall,” Dr. Machado said.
However, treatment with rituximab (OR, 4.0), sulfasalazine (OR, 3.6), and immunosuppressive agents such as azathioprine, cyclophosphamide, cyclosporine, mycophenolate, or tacrolimus (OR, 2.2), were associated with higher odds of dying from COVID-19 when compared with treatment with methotrexate alone.
The findings for rituximab and immunosuppressant use were perhaps not unexpected, but the possible association between sulfasalazine and COVID-19 death was “a bit intriguing,” Dr. Machado observed. “Sulfasalazine is believed to have low immunosuppressive effect.”
This warrants further investigation, but there are likely a range of confounding factors at play. One could be that people considered to be at higher risk may have been more often prescribed sulfasalazine because it was thought to be less immunosuppressive. Another might be because people taking sulfasalazine were more likely to be smokers, and they were also not advised to protect themselves from exposure to the virus (shielding) during the first wave of the pandemic, at least not in the United Kingdom.
Rituximab caution and vaccination
“Rituximab is a concern,” Dr. Machado acknowledged. “It is a concern that rheumatologists are now aware of and they are addressing, but then it’s a concern for a very specific subgroup of patients.”
While rheumatologists are, and will continue to prescribe it, there will be even more careful consideration over when, in whom, and how to use it during, and possibly even after, the pandemic.
“COVID is here to stay, it will become endemic, and it’s going to be part of our lives like the flu virus is,” Dr. Machado predicted.
Then there is the issue on vaccinating people against COVID-19, should those on rituximab still receive it? The answer is a yes, but, as with other vaccinations it’s all about the timing of when the vaccination is given.
Societies such as the British Society for Rheumatology have already begun to include guidance on this, recommending one of the available COVID-19 vaccines is given at least a month before the next or first dose of rituximab is due. As rituximab is given every few months, with doses sometimes spaced as much as 9 months or even a year apart, this should not be too much of a problem, but it is “better to have the vaccine first,” Dr. Machado said.
Has COVID-19 care improved in RMDs?
In separate research published in The Lancet Rheumatology, April Jorge, MD, of Massachusetts General Hospital and Harvard Medical School, both in Boston, and associates found that the risks of severe COVID-19 outcomes have improved over time, although they still “remain substantial.”
Dr. Jorge and colleagues looked at temporal trends in COVID-19 outcomes in patients with RMDs over the course of the first 6 months of the pandemic in 2020, using data from a large, multicenter, electronic health record network (TriNetX).
They formed two patient cohorts – a late (diagnosed from April 20 to July 20) and an early (diagnosed from January 20 to April 20) cohort – to see if outcomes had improved and discovered lower relative risks among patients in the late cohort for hospitalization (0.67), admission to the ICU (0.56), mechanical ventilation (0.39), acute kidney injury (0.66), renal replacement (0.53), and death (0.39).
“These results are encouraging,” but it’s difficult to match these different populations of patients, Dr. Machado said. “There are always factors that you cannot match for” and were not included in the U.S. analysis.
While there are important caveats in how the analysis was performed and thus in interpreting these data, they do “suggest that one of the reasons why outcomes have improved is because we have become better at treating these patients,” Dr. Machado added.
“Our treatment has improved, and our capacity to treat the complications has improved. We understand better how the disease behaves – we know that they can have thromboembolic complications that we can manage, and we are now able to manage ventilation issues better.”
Moreover, Dr. Machado said that, not only were clinicians more aware of what they should or should not do, there were treatments that were being used routinely or in some cases based on recent clinical trial results. “I think we are indeed treating these patients better.”
The COVID-19 GRA physician registry is financially supported by the American College of Rheumatology and EULAR. Dr. Machado had no relevant conflicts of interest.
People with rheumatic and musculoskeletal diseases (RMDs) who contract the SARS-CoV-2 virus appear more likely to die from COVID-19 if their rheumatologic condition is not being well controlled at the time of their infection.
New data from the COVID-19 Global Rheumatology Alliance (GRA) physician registry reported in Annals of the Rheumatic Diseases have found that the odds of dying from COVID-19 were 87% higher in individuals recorded as having moderate to high disease activity versus those reported to be in remission or having low disease activity.
“I think this really highlights the importance of continuing to appropriately, and actively, treat our patients, and the importance of controlling their disease,” Pedro Machado, MD, PhD, said in an interview. Dr. Machado, an associate professor in rheumatology and muscle diseases at University College London and a consultant rheumatologist at several U.K. hospitals, has been involved in the GRA physician registry from the start, and sits on the GRA steering committee.
Alongside higher disease activity, several other important factors were found to be associated with increased odds of dying from COVID-19 – older age, male gender, and the presence of one or more comorbidities, such as hypertension combined with cardiovascular disease or chronic lung disease.
These demographic and disease-based factors have been linked to an increased risk for COVID-19–related hospitalization before, both in people with RMDs and in the general population, but the latest GRA physician registry data now take that a step further, and link them also to an increased risk for death, together with several other factors more specific to RMDs.
Logging COVID-19 rheumatologic cases
Since the start of the global pandemic, the potential effects that SARS-CoV-2 infection might have on people with RMDs in particular has concerned the rheumatology community. The main worries being that, either because of the underlying RMD itself or to its treatment, there may be immunoregulatory deficits or other risk factors that would make individuals more susceptible to not only infection but also to developing more severe COVID-19 than the general population.
These concerns led to the rapid formation of the GRA and the COVID-19 GRA physician registry in March 2020 to collect and analyze data on adults with rheumatic disease and confirmed or presumptive COVID-19. Entries into the registry are made by or under the direction of rheumatologists, and this is a voluntary process.
“This population cannot ever be entirely representative of the population of patients with rheumatic diseases,” Dr. Machado acknowledged. There will be selection and other biases that affect the reported data. That said, it’s the largest database of reported COVID-19 cases in adult rheumatology patients across the world, with more than 9,000 cases so far included from multiple registries, including those based in Europe and North and South America. Data from one of these – the French RMD cohort – have also recently been published in Annals of the Rheumatic Diseases, showing much the same findings but on a national level.
Hospitalization was the focus of a previous report because “you need large sample sizes” to look at endpoints that occur less frequently. When the first analysis was done, there were around 600 cases from 40 countries in the registry with sufficient data that could be used. Now, with a greater number of recorded cases, factors influencing the risk for death could be examined.
Death rate and risk factors found
Data on 3,729 COVID-19 cases in people with RMDs were included in the current analysis, all recorded in the first few months of the registry being open and up until July 1, 2020. In all, 390 (10.5%) of people died. While this is “clearly higher” than reported in the general population in most countries, the analysis was not designed to calculate a precise estimate.
“It should not be taken as an estimate of the overall death rate among patients with rheumatic diseases and COVID-19,” Dr. Machado and coauthors have been keen to point out.
“Age is always the biggest risk factor,” Dr. Machado explained. “There’s always a gradient: the older the patient, the worse the outcome.”
Indeed, there was a threefold increased risk for death among those aged 66-75 years versus those who were 65 years or younger (odds ratio, 3.00), and a sixfold increased risk for patients older than 75, compared with the younger age group (OR, 6.18).
Having both hypertension and cardiovascular disease was associated with an OR of 1.89, and coexisting chronic lung disease also significantly increased the chances of dying from COVID-19 (OR, 1.68).
Being of male sex was associated with a 46% increased risk for death from COVID-19 versus being of female sex.
The risk for COVID-19 death also rose with the use of corticosteroids. Compared with no steroid use, there was a 69% increased risk for with death at doses of 10 mg or more prednisolone equivalent per day.
“The finding about moderate to high doses of steroids being associated with a worse outcome is consistent with the first report; it was the same for hospitalization,” Dr. Machado observed.
The general consensus on steroid use in the COVID-19 setting is that they should be continued as needed, but at the lowest possible dose, as outlined in provisional recommendations set out by the recently renamed European Alliance of Associations for Rheumatology.
The GRA physician registry findings provide further support for this, suggesting that disease control should be optimized with disease-modifying antirheumatic drugs, ideally without increasing the dose of steroids.
Surprise over sulfasalazine risk
“Taking all medications into account – such as methotrexate, leflunomide, hydroxychloroquine, [tumor necrosis factor] blockers, interleukin-6 blockers, and [Janus kinase] inhibitors – it is quite reassuring because we did not see an association with worse outcome with those drugs overall,” Dr. Machado said.
However, treatment with rituximab (OR, 4.0), sulfasalazine (OR, 3.6), and immunosuppressive agents such as azathioprine, cyclophosphamide, cyclosporine, mycophenolate, or tacrolimus (OR, 2.2), were associated with higher odds of dying from COVID-19 when compared with treatment with methotrexate alone.
The findings for rituximab and immunosuppressant use were perhaps not unexpected, but the possible association between sulfasalazine and COVID-19 death was “a bit intriguing,” Dr. Machado observed. “Sulfasalazine is believed to have low immunosuppressive effect.”
This warrants further investigation, but there are likely a range of confounding factors at play. One could be that people considered to be at higher risk may have been more often prescribed sulfasalazine because it was thought to be less immunosuppressive. Another might be because people taking sulfasalazine were more likely to be smokers, and they were also not advised to protect themselves from exposure to the virus (shielding) during the first wave of the pandemic, at least not in the United Kingdom.
Rituximab caution and vaccination
“Rituximab is a concern,” Dr. Machado acknowledged. “It is a concern that rheumatologists are now aware of and they are addressing, but then it’s a concern for a very specific subgroup of patients.”
While rheumatologists are, and will continue to prescribe it, there will be even more careful consideration over when, in whom, and how to use it during, and possibly even after, the pandemic.
“COVID is here to stay, it will become endemic, and it’s going to be part of our lives like the flu virus is,” Dr. Machado predicted.
Then there is the issue on vaccinating people against COVID-19, should those on rituximab still receive it? The answer is a yes, but, as with other vaccinations it’s all about the timing of when the vaccination is given.
Societies such as the British Society for Rheumatology have already begun to include guidance on this, recommending one of the available COVID-19 vaccines is given at least a month before the next or first dose of rituximab is due. As rituximab is given every few months, with doses sometimes spaced as much as 9 months or even a year apart, this should not be too much of a problem, but it is “better to have the vaccine first,” Dr. Machado said.
Has COVID-19 care improved in RMDs?
In separate research published in The Lancet Rheumatology, April Jorge, MD, of Massachusetts General Hospital and Harvard Medical School, both in Boston, and associates found that the risks of severe COVID-19 outcomes have improved over time, although they still “remain substantial.”
Dr. Jorge and colleagues looked at temporal trends in COVID-19 outcomes in patients with RMDs over the course of the first 6 months of the pandemic in 2020, using data from a large, multicenter, electronic health record network (TriNetX).
They formed two patient cohorts – a late (diagnosed from April 20 to July 20) and an early (diagnosed from January 20 to April 20) cohort – to see if outcomes had improved and discovered lower relative risks among patients in the late cohort for hospitalization (0.67), admission to the ICU (0.56), mechanical ventilation (0.39), acute kidney injury (0.66), renal replacement (0.53), and death (0.39).
“These results are encouraging,” but it’s difficult to match these different populations of patients, Dr. Machado said. “There are always factors that you cannot match for” and were not included in the U.S. analysis.
While there are important caveats in how the analysis was performed and thus in interpreting these data, they do “suggest that one of the reasons why outcomes have improved is because we have become better at treating these patients,” Dr. Machado added.
“Our treatment has improved, and our capacity to treat the complications has improved. We understand better how the disease behaves – we know that they can have thromboembolic complications that we can manage, and we are now able to manage ventilation issues better.”
Moreover, Dr. Machado said that, not only were clinicians more aware of what they should or should not do, there were treatments that were being used routinely or in some cases based on recent clinical trial results. “I think we are indeed treating these patients better.”
The COVID-19 GRA physician registry is financially supported by the American College of Rheumatology and EULAR. Dr. Machado had no relevant conflicts of interest.
FROM ANNALS OF THE RHEUMATIC DISEASES
Data call for biologics trials in undertreated juvenile arthritis subtype
Children with enthesitis-related arthritis often have a high burden of disease and could benefit from medications currently approved for adults with spondyloarthritis, according to a review published in Arthritis Care & Research.
“Enthesitis-related arthritis (ERA) was the JIA [juvenile idiopathic arthritis] category applied to children with spondyloarthritis (SpA), recognizing enthesitis as a defining characteristic,” wrote Pamela F. Weiss, MD, of Children’s Hospital of Philadelphia, and colleagues.
The ERA criteria include “arthritis plus enthesitis; or arthritis or enthesitis plus at least two of the following: sacroiliac tenderness or inflammatory back pain, HLA-B27 positivity, first-degree relative with HLA-B27–associated disease, acute anterior uveitis, and arthritis in a male older than 6 years,” the review authors noted.
“None of the [Food and Drug Administration]–approved therapies for peripheral SpA or nonradiographic axial SpA” have been studied or approved for use in children with ERA, but data support biologic similarity to SpA in adults; notably, studies of the HLA-B27 allele have identified it as a risk factor for both SpA and ERA, they said.
Common factors in adult and childhood conditions
“The principal commonalities of children with ERA and axial arthritis, and adults with nonradiographic axial SpA, include enthesitis, arthritis, inflammatory back pain, anterior uveitis, HLA-B27 positivity, and family history of HLA-B27–associated disease,” the review authors wrote.
The first-line treatment for both ERA with axial arthritis and nonradiographic axial SpA is NSAIDs, followed by tumor necrosis factor (TNF) inhibitors if needed, they said. However, conventional disease-modifying antirheumatic drugs (cDMARDs) may be used in cases of peripheral disease affecting five or more joints. Studies of treatment response show similarities between ERA in children and SpA in adults, the authors added, with nearly half of adults with axial disease unable to achieve remission and approximately one-third of children with ERA failing to respond to therapy.
Clinical trials could improve options and outcomes for those with ERA who need advanced therapy and such trials should evaluate response of axial and peripheral disease separately, the review authors emphasized. For example, “Eligibility criteria for children with ERA and axial features could include the presence of some of the following disease features: active inflammatory sacroiliitis based on typical MRI changes according to ASAS/OMERACT [Assessment of SpondyloArthritis international Society/Outcome Measures in Rheumatology Clinical Trials] criteria; elevated CRP [C-reactive protein]; and inadequate response or intolerance to NSAIDs,” they noted. “Considering the similarities between adult spondyloarthritis and ERA in terms of etiology, genetics, pathogenesis, and clinical manifestations, it is evident that medications approved for axial or peripheral SpA should be studied in children with ERA involving axial or peripheral joints, respectively, with the intent to achieve labeling for use in children,” they concluded.
New data highlight ERA disease burden
The need for additional therapies for ERA patients gained more support from a recent study in which a majority of children with ERA or juvenile psoriatic arthritis (jPsA) used biologics, but those with sacroiliitis in particular showed a significant disease burden despite high biologic use.
The International Leagues Against Rheumatism criteria include seven categories of juvenile idiopathic arthritis, of which ERA and jPsA are the most common; however, characteristics of these children have not been well described, wrote Dax G. Rumsey, MD, of the University of Alberta, Edmonton, and colleagues.
“Children with ERA are more likely to have a clinical picture with predominantly peripheral arthritis, typically described as an oligoarthritis involving the lower limbs with high risk of axial disease, relative to the other categories of JIA,” and report more intense pain and worse health status, compared with children in other categories, the researchers wrote.
To more completely characterize children with ERA and jPsA, the researchers assessed 522 children with ERA and 380 with jPsA. The children were enrolled in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry. The findings were published in a brief report in Arthritis Care & Research.
Overall, 69% of the children took at least one biologic, including 72% with ERA and 64% with jPsA. Biologic use was even higher (81%) among the 28% of patients with sacroiliitis (40% of ERA patients and 12% of jPsA patients). Approximately 36% of the patients with sacroiliitis were positive for HLA-B27. In addition, Physician Global Assessment scores and clinical Juvenile Arthritis Disease Activity Score-10 (cJADAS10) scores were significantly higher at the first clinical visit with sacroiliitis, compared with the first visit without, which confirms “the clinical impression that active sacroiliitis significantly impacts children and their families,” the researchers said.
The average age at diagnosis was 10.8 years for ERA and 8.2 years for jPsA, and significantly more ERA patients were male (56% vs. 38%). However, more of the patients with sacroiliitis (54%) were female. More than half of the patients reported polyarticular involvement.
The study findings were limited by several factors, including the classification of ERA or jPsA and the reliance on physician diagnoses, as well as the variation in identifying sacroiliitis, the researchers said. However, the results increase understanding of the pathophysiology of ERA and jPsA to help determine optimal treatment, they concluded.
Data highlight research and treatment gaps
“Recent research demonstrates a large, unmet medical need in the treatment of JIA with 52%-65% of all JIA patients, including those with ERA and jPsA, having been treated with at least one biologic DMARD and 15%-19% having been treated with an FDA-unapproved biologic. In those with ERA or jPsA, 72%-79% of the children had been treated with a biologic DMARD, although no biologic DMARD has ever been FDA approved for these JIA categories,” Daniel J. Lovell, MD, and Hermine I. Brunner, MD, both with Cincinnati Children’s Hospital Medical Center, wrote in an editorial that accompanied the new study. Dr. Lovell and Dr. Brunner also were coauthors of the review article.
The new study supports findings from other recent publications, the editorialists noted. The new results showed “a significant proportion of the JIA population with active sacroiliitis with high disease burden despite very frequent (over 80% of the population) [treatment] with unstudied and unapproved biologic DMARDs,” they said. “These children with sacroiliitis had significantly greater disease burden with higher physician assessment of disease activity, higher parent assessment of disease impact, and higher disease activity as measured by the Juvenile Idiopathic Arthritis Disease Activity Score, compared to the children with ERA or jPsA without sacroiliitis,” they noted.
Previously, “the FDA granted pharmaceutical companies studying new treatments in adult SpA automatic full waivers from doing studies in children for new medications for ‘axial spondyloarthropathies including ankylosing spondylitis’ up until July 2020,” the editorialists said. However, “It is now time now for the pharmaceutical industry to perform FDA-monitored clinical trials of children and adolescents with SpA,” they emphasized. “This will allow for the scientific assessment of proper dosing, efficacy, and safety of the increasing number of new medications that are being licensed by the FDA for the treatment of SpA, such as the anti-TNF, anti–IL[interleukin]-17, and anti–IL-23 biologics, and perhaps JAK [Janus kinase] agents, to address this unmet medical need in these patients with juvenile SpA,” they concluded.
Dr. Weiss disclosed grant support from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), and financial relationships with Eli Lilly and Pfizer. Dr. Lovell disclosed relationships with companies including Abbott, AbbVie Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Hoffmann-La Roche, Janssen, Novartis, Pfizer, Takeda, UCB, and Wyeth, as well as serving on the data and safety monitoring board for Forest Research and NIAMS. Dr. Brunner disclosed relationships with companies including Ablynx, AbbVie, AstraZeneca-MedImmune, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, EMD Serono, F. Hoffmann-La Roche, Genzyme, GlaxoSmithKline, Merck, Novartis, R-Pharm, and Sanofi. The study by Dr. Rumsey and colleagues was supported by Amgen. Dr. Rumsey and colleagues had no relevant financial conflicts to disclose.
SOURCES: Weiss PF et al. Arthritis Care Res. 2020 Dec 5. doi: 10.1002/acr.24529; Rumsey DG et al. Arthritis Care Res. 2020 Dec. 16. doi: 10.1002/acr.24537; Lovell DJ and Brunner HI. Arthritis Care Res. 2020 Dec 16. doi: 10.1002/acr.24536.
Children with enthesitis-related arthritis often have a high burden of disease and could benefit from medications currently approved for adults with spondyloarthritis, according to a review published in Arthritis Care & Research.
“Enthesitis-related arthritis (ERA) was the JIA [juvenile idiopathic arthritis] category applied to children with spondyloarthritis (SpA), recognizing enthesitis as a defining characteristic,” wrote Pamela F. Weiss, MD, of Children’s Hospital of Philadelphia, and colleagues.
The ERA criteria include “arthritis plus enthesitis; or arthritis or enthesitis plus at least two of the following: sacroiliac tenderness or inflammatory back pain, HLA-B27 positivity, first-degree relative with HLA-B27–associated disease, acute anterior uveitis, and arthritis in a male older than 6 years,” the review authors noted.
“None of the [Food and Drug Administration]–approved therapies for peripheral SpA or nonradiographic axial SpA” have been studied or approved for use in children with ERA, but data support biologic similarity to SpA in adults; notably, studies of the HLA-B27 allele have identified it as a risk factor for both SpA and ERA, they said.
Common factors in adult and childhood conditions
“The principal commonalities of children with ERA and axial arthritis, and adults with nonradiographic axial SpA, include enthesitis, arthritis, inflammatory back pain, anterior uveitis, HLA-B27 positivity, and family history of HLA-B27–associated disease,” the review authors wrote.
The first-line treatment for both ERA with axial arthritis and nonradiographic axial SpA is NSAIDs, followed by tumor necrosis factor (TNF) inhibitors if needed, they said. However, conventional disease-modifying antirheumatic drugs (cDMARDs) may be used in cases of peripheral disease affecting five or more joints. Studies of treatment response show similarities between ERA in children and SpA in adults, the authors added, with nearly half of adults with axial disease unable to achieve remission and approximately one-third of children with ERA failing to respond to therapy.
Clinical trials could improve options and outcomes for those with ERA who need advanced therapy and such trials should evaluate response of axial and peripheral disease separately, the review authors emphasized. For example, “Eligibility criteria for children with ERA and axial features could include the presence of some of the following disease features: active inflammatory sacroiliitis based on typical MRI changes according to ASAS/OMERACT [Assessment of SpondyloArthritis international Society/Outcome Measures in Rheumatology Clinical Trials] criteria; elevated CRP [C-reactive protein]; and inadequate response or intolerance to NSAIDs,” they noted. “Considering the similarities between adult spondyloarthritis and ERA in terms of etiology, genetics, pathogenesis, and clinical manifestations, it is evident that medications approved for axial or peripheral SpA should be studied in children with ERA involving axial or peripheral joints, respectively, with the intent to achieve labeling for use in children,” they concluded.
New data highlight ERA disease burden
The need for additional therapies for ERA patients gained more support from a recent study in which a majority of children with ERA or juvenile psoriatic arthritis (jPsA) used biologics, but those with sacroiliitis in particular showed a significant disease burden despite high biologic use.
The International Leagues Against Rheumatism criteria include seven categories of juvenile idiopathic arthritis, of which ERA and jPsA are the most common; however, characteristics of these children have not been well described, wrote Dax G. Rumsey, MD, of the University of Alberta, Edmonton, and colleagues.
“Children with ERA are more likely to have a clinical picture with predominantly peripheral arthritis, typically described as an oligoarthritis involving the lower limbs with high risk of axial disease, relative to the other categories of JIA,” and report more intense pain and worse health status, compared with children in other categories, the researchers wrote.
To more completely characterize children with ERA and jPsA, the researchers assessed 522 children with ERA and 380 with jPsA. The children were enrolled in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry. The findings were published in a brief report in Arthritis Care & Research.
Overall, 69% of the children took at least one biologic, including 72% with ERA and 64% with jPsA. Biologic use was even higher (81%) among the 28% of patients with sacroiliitis (40% of ERA patients and 12% of jPsA patients). Approximately 36% of the patients with sacroiliitis were positive for HLA-B27. In addition, Physician Global Assessment scores and clinical Juvenile Arthritis Disease Activity Score-10 (cJADAS10) scores were significantly higher at the first clinical visit with sacroiliitis, compared with the first visit without, which confirms “the clinical impression that active sacroiliitis significantly impacts children and their families,” the researchers said.
The average age at diagnosis was 10.8 years for ERA and 8.2 years for jPsA, and significantly more ERA patients were male (56% vs. 38%). However, more of the patients with sacroiliitis (54%) were female. More than half of the patients reported polyarticular involvement.
The study findings were limited by several factors, including the classification of ERA or jPsA and the reliance on physician diagnoses, as well as the variation in identifying sacroiliitis, the researchers said. However, the results increase understanding of the pathophysiology of ERA and jPsA to help determine optimal treatment, they concluded.
Data highlight research and treatment gaps
“Recent research demonstrates a large, unmet medical need in the treatment of JIA with 52%-65% of all JIA patients, including those with ERA and jPsA, having been treated with at least one biologic DMARD and 15%-19% having been treated with an FDA-unapproved biologic. In those with ERA or jPsA, 72%-79% of the children had been treated with a biologic DMARD, although no biologic DMARD has ever been FDA approved for these JIA categories,” Daniel J. Lovell, MD, and Hermine I. Brunner, MD, both with Cincinnati Children’s Hospital Medical Center, wrote in an editorial that accompanied the new study. Dr. Lovell and Dr. Brunner also were coauthors of the review article.
The new study supports findings from other recent publications, the editorialists noted. The new results showed “a significant proportion of the JIA population with active sacroiliitis with high disease burden despite very frequent (over 80% of the population) [treatment] with unstudied and unapproved biologic DMARDs,” they said. “These children with sacroiliitis had significantly greater disease burden with higher physician assessment of disease activity, higher parent assessment of disease impact, and higher disease activity as measured by the Juvenile Idiopathic Arthritis Disease Activity Score, compared to the children with ERA or jPsA without sacroiliitis,” they noted.
Previously, “the FDA granted pharmaceutical companies studying new treatments in adult SpA automatic full waivers from doing studies in children for new medications for ‘axial spondyloarthropathies including ankylosing spondylitis’ up until July 2020,” the editorialists said. However, “It is now time now for the pharmaceutical industry to perform FDA-monitored clinical trials of children and adolescents with SpA,” they emphasized. “This will allow for the scientific assessment of proper dosing, efficacy, and safety of the increasing number of new medications that are being licensed by the FDA for the treatment of SpA, such as the anti-TNF, anti–IL[interleukin]-17, and anti–IL-23 biologics, and perhaps JAK [Janus kinase] agents, to address this unmet medical need in these patients with juvenile SpA,” they concluded.
Dr. Weiss disclosed grant support from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), and financial relationships with Eli Lilly and Pfizer. Dr. Lovell disclosed relationships with companies including Abbott, AbbVie Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Hoffmann-La Roche, Janssen, Novartis, Pfizer, Takeda, UCB, and Wyeth, as well as serving on the data and safety monitoring board for Forest Research and NIAMS. Dr. Brunner disclosed relationships with companies including Ablynx, AbbVie, AstraZeneca-MedImmune, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, EMD Serono, F. Hoffmann-La Roche, Genzyme, GlaxoSmithKline, Merck, Novartis, R-Pharm, and Sanofi. The study by Dr. Rumsey and colleagues was supported by Amgen. Dr. Rumsey and colleagues had no relevant financial conflicts to disclose.
SOURCES: Weiss PF et al. Arthritis Care Res. 2020 Dec 5. doi: 10.1002/acr.24529; Rumsey DG et al. Arthritis Care Res. 2020 Dec. 16. doi: 10.1002/acr.24537; Lovell DJ and Brunner HI. Arthritis Care Res. 2020 Dec 16. doi: 10.1002/acr.24536.
Children with enthesitis-related arthritis often have a high burden of disease and could benefit from medications currently approved for adults with spondyloarthritis, according to a review published in Arthritis Care & Research.
“Enthesitis-related arthritis (ERA) was the JIA [juvenile idiopathic arthritis] category applied to children with spondyloarthritis (SpA), recognizing enthesitis as a defining characteristic,” wrote Pamela F. Weiss, MD, of Children’s Hospital of Philadelphia, and colleagues.
The ERA criteria include “arthritis plus enthesitis; or arthritis or enthesitis plus at least two of the following: sacroiliac tenderness or inflammatory back pain, HLA-B27 positivity, first-degree relative with HLA-B27–associated disease, acute anterior uveitis, and arthritis in a male older than 6 years,” the review authors noted.
“None of the [Food and Drug Administration]–approved therapies for peripheral SpA or nonradiographic axial SpA” have been studied or approved for use in children with ERA, but data support biologic similarity to SpA in adults; notably, studies of the HLA-B27 allele have identified it as a risk factor for both SpA and ERA, they said.
Common factors in adult and childhood conditions
“The principal commonalities of children with ERA and axial arthritis, and adults with nonradiographic axial SpA, include enthesitis, arthritis, inflammatory back pain, anterior uveitis, HLA-B27 positivity, and family history of HLA-B27–associated disease,” the review authors wrote.
The first-line treatment for both ERA with axial arthritis and nonradiographic axial SpA is NSAIDs, followed by tumor necrosis factor (TNF) inhibitors if needed, they said. However, conventional disease-modifying antirheumatic drugs (cDMARDs) may be used in cases of peripheral disease affecting five or more joints. Studies of treatment response show similarities between ERA in children and SpA in adults, the authors added, with nearly half of adults with axial disease unable to achieve remission and approximately one-third of children with ERA failing to respond to therapy.
Clinical trials could improve options and outcomes for those with ERA who need advanced therapy and such trials should evaluate response of axial and peripheral disease separately, the review authors emphasized. For example, “Eligibility criteria for children with ERA and axial features could include the presence of some of the following disease features: active inflammatory sacroiliitis based on typical MRI changes according to ASAS/OMERACT [Assessment of SpondyloArthritis international Society/Outcome Measures in Rheumatology Clinical Trials] criteria; elevated CRP [C-reactive protein]; and inadequate response or intolerance to NSAIDs,” they noted. “Considering the similarities between adult spondyloarthritis and ERA in terms of etiology, genetics, pathogenesis, and clinical manifestations, it is evident that medications approved for axial or peripheral SpA should be studied in children with ERA involving axial or peripheral joints, respectively, with the intent to achieve labeling for use in children,” they concluded.
New data highlight ERA disease burden
The need for additional therapies for ERA patients gained more support from a recent study in which a majority of children with ERA or juvenile psoriatic arthritis (jPsA) used biologics, but those with sacroiliitis in particular showed a significant disease burden despite high biologic use.
The International Leagues Against Rheumatism criteria include seven categories of juvenile idiopathic arthritis, of which ERA and jPsA are the most common; however, characteristics of these children have not been well described, wrote Dax G. Rumsey, MD, of the University of Alberta, Edmonton, and colleagues.
“Children with ERA are more likely to have a clinical picture with predominantly peripheral arthritis, typically described as an oligoarthritis involving the lower limbs with high risk of axial disease, relative to the other categories of JIA,” and report more intense pain and worse health status, compared with children in other categories, the researchers wrote.
To more completely characterize children with ERA and jPsA, the researchers assessed 522 children with ERA and 380 with jPsA. The children were enrolled in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry. The findings were published in a brief report in Arthritis Care & Research.
Overall, 69% of the children took at least one biologic, including 72% with ERA and 64% with jPsA. Biologic use was even higher (81%) among the 28% of patients with sacroiliitis (40% of ERA patients and 12% of jPsA patients). Approximately 36% of the patients with sacroiliitis were positive for HLA-B27. In addition, Physician Global Assessment scores and clinical Juvenile Arthritis Disease Activity Score-10 (cJADAS10) scores were significantly higher at the first clinical visit with sacroiliitis, compared with the first visit without, which confirms “the clinical impression that active sacroiliitis significantly impacts children and their families,” the researchers said.
The average age at diagnosis was 10.8 years for ERA and 8.2 years for jPsA, and significantly more ERA patients were male (56% vs. 38%). However, more of the patients with sacroiliitis (54%) were female. More than half of the patients reported polyarticular involvement.
The study findings were limited by several factors, including the classification of ERA or jPsA and the reliance on physician diagnoses, as well as the variation in identifying sacroiliitis, the researchers said. However, the results increase understanding of the pathophysiology of ERA and jPsA to help determine optimal treatment, they concluded.
Data highlight research and treatment gaps
“Recent research demonstrates a large, unmet medical need in the treatment of JIA with 52%-65% of all JIA patients, including those with ERA and jPsA, having been treated with at least one biologic DMARD and 15%-19% having been treated with an FDA-unapproved biologic. In those with ERA or jPsA, 72%-79% of the children had been treated with a biologic DMARD, although no biologic DMARD has ever been FDA approved for these JIA categories,” Daniel J. Lovell, MD, and Hermine I. Brunner, MD, both with Cincinnati Children’s Hospital Medical Center, wrote in an editorial that accompanied the new study. Dr. Lovell and Dr. Brunner also were coauthors of the review article.
The new study supports findings from other recent publications, the editorialists noted. The new results showed “a significant proportion of the JIA population with active sacroiliitis with high disease burden despite very frequent (over 80% of the population) [treatment] with unstudied and unapproved biologic DMARDs,” they said. “These children with sacroiliitis had significantly greater disease burden with higher physician assessment of disease activity, higher parent assessment of disease impact, and higher disease activity as measured by the Juvenile Idiopathic Arthritis Disease Activity Score, compared to the children with ERA or jPsA without sacroiliitis,” they noted.
Previously, “the FDA granted pharmaceutical companies studying new treatments in adult SpA automatic full waivers from doing studies in children for new medications for ‘axial spondyloarthropathies including ankylosing spondylitis’ up until July 2020,” the editorialists said. However, “It is now time now for the pharmaceutical industry to perform FDA-monitored clinical trials of children and adolescents with SpA,” they emphasized. “This will allow for the scientific assessment of proper dosing, efficacy, and safety of the increasing number of new medications that are being licensed by the FDA for the treatment of SpA, such as the anti-TNF, anti–IL[interleukin]-17, and anti–IL-23 biologics, and perhaps JAK [Janus kinase] agents, to address this unmet medical need in these patients with juvenile SpA,” they concluded.
Dr. Weiss disclosed grant support from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), and financial relationships with Eli Lilly and Pfizer. Dr. Lovell disclosed relationships with companies including Abbott, AbbVie Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Hoffmann-La Roche, Janssen, Novartis, Pfizer, Takeda, UCB, and Wyeth, as well as serving on the data and safety monitoring board for Forest Research and NIAMS. Dr. Brunner disclosed relationships with companies including Ablynx, AbbVie, AstraZeneca-MedImmune, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, EMD Serono, F. Hoffmann-La Roche, Genzyme, GlaxoSmithKline, Merck, Novartis, R-Pharm, and Sanofi. The study by Dr. Rumsey and colleagues was supported by Amgen. Dr. Rumsey and colleagues had no relevant financial conflicts to disclose.
SOURCES: Weiss PF et al. Arthritis Care Res. 2020 Dec 5. doi: 10.1002/acr.24529; Rumsey DG et al. Arthritis Care Res. 2020 Dec. 16. doi: 10.1002/acr.24537; Lovell DJ and Brunner HI. Arthritis Care Res. 2020 Dec 16. doi: 10.1002/acr.24536.
FROM ARTHRITIS CARE & RESEARCH
EULAR recommendations define strategies to improve adherence in RMDs
Clinicians who care for patients with rheumatic and musculoskeletal diseases (RMDs) can now refer to a new set of strategies and points to consider from a European League Against Rheumatism (EULAR) task force in building a patient-centered approach to improve adherence to treatments.
Nonadherence to treatments is concerning given that 30%-80% of patients who have RMDs are thought to not follow a recommended treatment plan according to their physicians’ instructions, according to first author Valentin Ritschl of the Medical University of Vienna and colleagues.
“The problem of poor adherence is addressed in some EULAR recommendations/points to consider on the management of specific health conditions or on the role of professionals,” Mr. Ritschl said in an interview. “However, all these recommendations focus on limited aspects of nonadherence and do not cover the multifaceted nature of this phenomenon.”
Mr. Ritschl and colleagues conducted an extensive systematic literature review, the results of which they presented to a task force consisting of a panel of international experts hailing from 12 different countries. The task force included rheumatologists and other health professionals in rheumatology, as well as patient representatives.
The collaboration resulted in investigators crafting a definition of adherence in addition to drafting four overarching principles and nine points to consider, which were published Dec. 18 in Annals of the Rheumatic Diseases.
They defined adherence as “the extent to which a person’s behavior corresponds with the agreed prescription, of pharmacological or nonpharmacological treatments, by a health care provider.”
The four overarching principles emphasize the following concepts: that adherence affects outcomes in people who have RMDs; the importance of shared decision-making, with the understanding that the adherence describes the patient’s behavior “following an agreed prescription”; that numerous factors can affect adherence; and the notion of adherence being a dynamic process that, consequently, requires continuous evaluation.
Among the nine points to consider, Mr. Ritschl and coauthors encouraged all health care providers involved in caring for RMD patients to assume responsibility for promoting adherence. Practitioners should also strive to create an ongoing, open dialogue to discuss adherence, especially in cases in which the patient’s RMD is not well controlled. The patient-centered recommendations include taking into account the patient’s goals and preferences because these greatly contribute to the patient’s ability to adhere to any medication regimen. Another arm of that exploration also requires the medical professional to evaluate any circumstances that could bear a negative effect on the patient’s adherence – whether it be medication access issues related to cost or availability, or functional challenges such as memory, motivation, or complexity of the medication regimen.
Mr. Ritschl believed the task force’s recommendations will add value and help improve overall outcomes in RMD population management.
“Until today, there are no recommendations or points to consider developed in order to support our patients to be adherent to the agreed treatment plan,” he said. “In our project/initiative, we therefore developed for the first time points to consider to detect, assess, and manage nonadherence in people with RMDs.”
Additionally, the recommendations offer some strategic insights to help improve clinical trials because the deleterious effects of nonadherence also affect study results.
Looking ahead, Mr. Ritschl said randomized, controlled trials are necessary to test strategies that might improve adherence. He strongly emphasized the importance of designing future research studies that are heavily patient centered and effective for shared decision-making.
The project was funded by EULAR. Mr. Ritschl reported having no disclosures, but many of his coauthors reported financial relationships with pharmaceutical companies.
SOURCE: Ritschl V et al. Ann Rheum Dis. 2020 Dec 18. doi: 10.1136/annrheumdis-2020-218986.
Clinicians who care for patients with rheumatic and musculoskeletal diseases (RMDs) can now refer to a new set of strategies and points to consider from a European League Against Rheumatism (EULAR) task force in building a patient-centered approach to improve adherence to treatments.
Nonadherence to treatments is concerning given that 30%-80% of patients who have RMDs are thought to not follow a recommended treatment plan according to their physicians’ instructions, according to first author Valentin Ritschl of the Medical University of Vienna and colleagues.
“The problem of poor adherence is addressed in some EULAR recommendations/points to consider on the management of specific health conditions or on the role of professionals,” Mr. Ritschl said in an interview. “However, all these recommendations focus on limited aspects of nonadherence and do not cover the multifaceted nature of this phenomenon.”
Mr. Ritschl and colleagues conducted an extensive systematic literature review, the results of which they presented to a task force consisting of a panel of international experts hailing from 12 different countries. The task force included rheumatologists and other health professionals in rheumatology, as well as patient representatives.
The collaboration resulted in investigators crafting a definition of adherence in addition to drafting four overarching principles and nine points to consider, which were published Dec. 18 in Annals of the Rheumatic Diseases.
They defined adherence as “the extent to which a person’s behavior corresponds with the agreed prescription, of pharmacological or nonpharmacological treatments, by a health care provider.”
The four overarching principles emphasize the following concepts: that adherence affects outcomes in people who have RMDs; the importance of shared decision-making, with the understanding that the adherence describes the patient’s behavior “following an agreed prescription”; that numerous factors can affect adherence; and the notion of adherence being a dynamic process that, consequently, requires continuous evaluation.
Among the nine points to consider, Mr. Ritschl and coauthors encouraged all health care providers involved in caring for RMD patients to assume responsibility for promoting adherence. Practitioners should also strive to create an ongoing, open dialogue to discuss adherence, especially in cases in which the patient’s RMD is not well controlled. The patient-centered recommendations include taking into account the patient’s goals and preferences because these greatly contribute to the patient’s ability to adhere to any medication regimen. Another arm of that exploration also requires the medical professional to evaluate any circumstances that could bear a negative effect on the patient’s adherence – whether it be medication access issues related to cost or availability, or functional challenges such as memory, motivation, or complexity of the medication regimen.
Mr. Ritschl believed the task force’s recommendations will add value and help improve overall outcomes in RMD population management.
“Until today, there are no recommendations or points to consider developed in order to support our patients to be adherent to the agreed treatment plan,” he said. “In our project/initiative, we therefore developed for the first time points to consider to detect, assess, and manage nonadherence in people with RMDs.”
Additionally, the recommendations offer some strategic insights to help improve clinical trials because the deleterious effects of nonadherence also affect study results.
Looking ahead, Mr. Ritschl said randomized, controlled trials are necessary to test strategies that might improve adherence. He strongly emphasized the importance of designing future research studies that are heavily patient centered and effective for shared decision-making.
The project was funded by EULAR. Mr. Ritschl reported having no disclosures, but many of his coauthors reported financial relationships with pharmaceutical companies.
SOURCE: Ritschl V et al. Ann Rheum Dis. 2020 Dec 18. doi: 10.1136/annrheumdis-2020-218986.
Clinicians who care for patients with rheumatic and musculoskeletal diseases (RMDs) can now refer to a new set of strategies and points to consider from a European League Against Rheumatism (EULAR) task force in building a patient-centered approach to improve adherence to treatments.
Nonadherence to treatments is concerning given that 30%-80% of patients who have RMDs are thought to not follow a recommended treatment plan according to their physicians’ instructions, according to first author Valentin Ritschl of the Medical University of Vienna and colleagues.
“The problem of poor adherence is addressed in some EULAR recommendations/points to consider on the management of specific health conditions or on the role of professionals,” Mr. Ritschl said in an interview. “However, all these recommendations focus on limited aspects of nonadherence and do not cover the multifaceted nature of this phenomenon.”
Mr. Ritschl and colleagues conducted an extensive systematic literature review, the results of which they presented to a task force consisting of a panel of international experts hailing from 12 different countries. The task force included rheumatologists and other health professionals in rheumatology, as well as patient representatives.
The collaboration resulted in investigators crafting a definition of adherence in addition to drafting four overarching principles and nine points to consider, which were published Dec. 18 in Annals of the Rheumatic Diseases.
They defined adherence as “the extent to which a person’s behavior corresponds with the agreed prescription, of pharmacological or nonpharmacological treatments, by a health care provider.”
The four overarching principles emphasize the following concepts: that adherence affects outcomes in people who have RMDs; the importance of shared decision-making, with the understanding that the adherence describes the patient’s behavior “following an agreed prescription”; that numerous factors can affect adherence; and the notion of adherence being a dynamic process that, consequently, requires continuous evaluation.
Among the nine points to consider, Mr. Ritschl and coauthors encouraged all health care providers involved in caring for RMD patients to assume responsibility for promoting adherence. Practitioners should also strive to create an ongoing, open dialogue to discuss adherence, especially in cases in which the patient’s RMD is not well controlled. The patient-centered recommendations include taking into account the patient’s goals and preferences because these greatly contribute to the patient’s ability to adhere to any medication regimen. Another arm of that exploration also requires the medical professional to evaluate any circumstances that could bear a negative effect on the patient’s adherence – whether it be medication access issues related to cost or availability, or functional challenges such as memory, motivation, or complexity of the medication regimen.
Mr. Ritschl believed the task force’s recommendations will add value and help improve overall outcomes in RMD population management.
“Until today, there are no recommendations or points to consider developed in order to support our patients to be adherent to the agreed treatment plan,” he said. “In our project/initiative, we therefore developed for the first time points to consider to detect, assess, and manage nonadherence in people with RMDs.”
Additionally, the recommendations offer some strategic insights to help improve clinical trials because the deleterious effects of nonadherence also affect study results.
Looking ahead, Mr. Ritschl said randomized, controlled trials are necessary to test strategies that might improve adherence. He strongly emphasized the importance of designing future research studies that are heavily patient centered and effective for shared decision-making.
The project was funded by EULAR. Mr. Ritschl reported having no disclosures, but many of his coauthors reported financial relationships with pharmaceutical companies.
SOURCE: Ritschl V et al. Ann Rheum Dis. 2020 Dec 18. doi: 10.1136/annrheumdis-2020-218986.
FROM ANNALS OF THE RHEUMATIC DISEASES
Etanercept may not help some with suspected nonradiographic axial spondyloarthritis
Treatment with etanercept does not appear to achieve significant clinical improvement in patients suspected of having nonradiographic axial spondyloarthritis (nr-axSpA) but without positive MRI signs of sacroiliitis and/or elevated C-reactive protein (CRP) levels, research suggests.
A paper published in Arthritis & Rheumatology presents the outcomes of a randomized, double-blind, placebo-controlled trial of a 16-week course of etanercept at 25 mg twice weekly in 80 tumor necrosis factor inhibitor (TNFi)–naive patients with suspected nr-axSpA. Patients all had chronic inflammatory back pain, at least two spondyloarthritis features – such as HLA-B27 positivity, asymmetrical arthritis, or family history of ankylosing spondylitis – as well as high disease activity and insufficient response to at least two NSAIDs. These patients meet the “clinical arm” of Assessment of SpondyloArthritis international Society (ASAS) criteria for classifying axSpA at an early stage of disease but not “imaging-arm” requirements for the presence of active inflammatory lesions of the sacroiliac joints (SIJ) on MRI and one additional SpA feature.
Whether these imaging criteria and objective evidence of elevated inflammation are necessary to fulfill when considering TNFi treatment for patients with suspected nr-axSpA in daily practice is an important question to address, the authors pointed out, because “in many studies, the presence of a positive MRI-SIJ is one of the prerequisites to start a TNF inhibitor treatment in patients with nr-axSpA.” In addition, starting a TNFi is dependent on failure of at least two NSAIDs and an elevated CRP level when the MRI is negative, which is problematic since in some studies raised CRP levels were found in only 30% of the nr-axSpA patients and 59%-64% of nr-axSpA patients with high disease activity do not have active inflammatory SIJ lesions on MRI. On top of these concerns is the fact that many people who do not have axSpA show false-positive results of bone marrow edema on MRI of the SIJ, such as postpartum women, recreational runners, professional athletes, and army recruits undergoing physical training, they added.
In the current study at the end of the 16-week course of treatment, researchers found no statistically significant difference between the treatment and placebo group in the number of patients who achieved a 20% improvement in ASAS response criteria (16.7% vs. 11.1%; P = .5), nor in those who had at least 40% improvement (8.3% in both groups). This was regardless of sex, age, NSAID or disease-modifying antirheumatic drug use, HLA-B27 status, or other clinical factors.
Similarly, there was no statistically significant difference between the two groups in the number of patients who met response criteria for the Ankylosing Spondylitis Disease Activity Score based on CRP for either clinical improvement or major improvement.
Participants underwent MRI at baseline and at 16 and 24 weeks, which revealed similar numbers of active inflammatory SIJ lesions in each group. The two groups also had similar Spondyloarthritis Research Consortium of Canada scores at baseline and 16 weeks, but a slightly – yet statistically significant – higher score in the etanercept group at 24 weeks.
However, during the first 16 weeks of the study, patients in the etanercept group showed greater improvements in pain and erythrocyte sedimentation rate (ESR), compared with those in the placebo group.
After the 16-week treatment course, participants were followed for another 8 weeks. During this time, participants in the etanercept group showed a worsening in their mean Bath Ankylosing Spondylitis Metrology Index score, CRP level, and ESR, compared with the placebo group.
While the number of participants who experienced an adverse event by 16 weeks was similar in both groups, more patients in the etanercept group experienced an adverse effect likely related to the study drug.
Study results in the context of previous findings
Commenting on their findings, first author Tamara Rusman, of the Amsterdam University Medical Center, and coauthors wrote that the results suggested early treatment with etanercept in patients without a positive MRI and raised CRP levels was not effective.
However, they acknowledged that two previous placebo-controlled studies had specifically included patients with nr-axSpA and found a significantly better treatment response to TNF inhibitors than to placebo. One of these studies included a significant number of patients with MRI-detected active inflammatory SIJ lesions at baseline, which is a known predictor of treatment response.
“The relatively low number of patients with either a positive MRI-SIJ (23%) and/or elevated CRP level (13%) at baseline in our study could be an explanation for the absence of a treatment effect in favor of etanercept,” they wrote.
They also raised the possibility that their choice of study population didn’t truly capture patients with nr-axSpA, and that it was not powered to compare patients with or without a positive MRI or raised CRP level at baseline.
“It would be interesting to know whether our study results will be replicated by others in comparable study populations with equal numbers of patients with and without a positive MRI-SIJ and raised CRP in the future,” they wrote.
The study was supported by an unrestricted financial grant from Pfizer and ReumaNederland. No conflicts of interest were declared.
SOURCE: Rusman T et al. Arthritis Rheumatol. 2020 Dec 5. doi: 10.1002/art.41607.
Treatment with etanercept does not appear to achieve significant clinical improvement in patients suspected of having nonradiographic axial spondyloarthritis (nr-axSpA) but without positive MRI signs of sacroiliitis and/or elevated C-reactive protein (CRP) levels, research suggests.
A paper published in Arthritis & Rheumatology presents the outcomes of a randomized, double-blind, placebo-controlled trial of a 16-week course of etanercept at 25 mg twice weekly in 80 tumor necrosis factor inhibitor (TNFi)–naive patients with suspected nr-axSpA. Patients all had chronic inflammatory back pain, at least two spondyloarthritis features – such as HLA-B27 positivity, asymmetrical arthritis, or family history of ankylosing spondylitis – as well as high disease activity and insufficient response to at least two NSAIDs. These patients meet the “clinical arm” of Assessment of SpondyloArthritis international Society (ASAS) criteria for classifying axSpA at an early stage of disease but not “imaging-arm” requirements for the presence of active inflammatory lesions of the sacroiliac joints (SIJ) on MRI and one additional SpA feature.
Whether these imaging criteria and objective evidence of elevated inflammation are necessary to fulfill when considering TNFi treatment for patients with suspected nr-axSpA in daily practice is an important question to address, the authors pointed out, because “in many studies, the presence of a positive MRI-SIJ is one of the prerequisites to start a TNF inhibitor treatment in patients with nr-axSpA.” In addition, starting a TNFi is dependent on failure of at least two NSAIDs and an elevated CRP level when the MRI is negative, which is problematic since in some studies raised CRP levels were found in only 30% of the nr-axSpA patients and 59%-64% of nr-axSpA patients with high disease activity do not have active inflammatory SIJ lesions on MRI. On top of these concerns is the fact that many people who do not have axSpA show false-positive results of bone marrow edema on MRI of the SIJ, such as postpartum women, recreational runners, professional athletes, and army recruits undergoing physical training, they added.
In the current study at the end of the 16-week course of treatment, researchers found no statistically significant difference between the treatment and placebo group in the number of patients who achieved a 20% improvement in ASAS response criteria (16.7% vs. 11.1%; P = .5), nor in those who had at least 40% improvement (8.3% in both groups). This was regardless of sex, age, NSAID or disease-modifying antirheumatic drug use, HLA-B27 status, or other clinical factors.
Similarly, there was no statistically significant difference between the two groups in the number of patients who met response criteria for the Ankylosing Spondylitis Disease Activity Score based on CRP for either clinical improvement or major improvement.
Participants underwent MRI at baseline and at 16 and 24 weeks, which revealed similar numbers of active inflammatory SIJ lesions in each group. The two groups also had similar Spondyloarthritis Research Consortium of Canada scores at baseline and 16 weeks, but a slightly – yet statistically significant – higher score in the etanercept group at 24 weeks.
However, during the first 16 weeks of the study, patients in the etanercept group showed greater improvements in pain and erythrocyte sedimentation rate (ESR), compared with those in the placebo group.
After the 16-week treatment course, participants were followed for another 8 weeks. During this time, participants in the etanercept group showed a worsening in their mean Bath Ankylosing Spondylitis Metrology Index score, CRP level, and ESR, compared with the placebo group.
While the number of participants who experienced an adverse event by 16 weeks was similar in both groups, more patients in the etanercept group experienced an adverse effect likely related to the study drug.
Study results in the context of previous findings
Commenting on their findings, first author Tamara Rusman, of the Amsterdam University Medical Center, and coauthors wrote that the results suggested early treatment with etanercept in patients without a positive MRI and raised CRP levels was not effective.
However, they acknowledged that two previous placebo-controlled studies had specifically included patients with nr-axSpA and found a significantly better treatment response to TNF inhibitors than to placebo. One of these studies included a significant number of patients with MRI-detected active inflammatory SIJ lesions at baseline, which is a known predictor of treatment response.
“The relatively low number of patients with either a positive MRI-SIJ (23%) and/or elevated CRP level (13%) at baseline in our study could be an explanation for the absence of a treatment effect in favor of etanercept,” they wrote.
They also raised the possibility that their choice of study population didn’t truly capture patients with nr-axSpA, and that it was not powered to compare patients with or without a positive MRI or raised CRP level at baseline.
“It would be interesting to know whether our study results will be replicated by others in comparable study populations with equal numbers of patients with and without a positive MRI-SIJ and raised CRP in the future,” they wrote.
The study was supported by an unrestricted financial grant from Pfizer and ReumaNederland. No conflicts of interest were declared.
SOURCE: Rusman T et al. Arthritis Rheumatol. 2020 Dec 5. doi: 10.1002/art.41607.
Treatment with etanercept does not appear to achieve significant clinical improvement in patients suspected of having nonradiographic axial spondyloarthritis (nr-axSpA) but without positive MRI signs of sacroiliitis and/or elevated C-reactive protein (CRP) levels, research suggests.
A paper published in Arthritis & Rheumatology presents the outcomes of a randomized, double-blind, placebo-controlled trial of a 16-week course of etanercept at 25 mg twice weekly in 80 tumor necrosis factor inhibitor (TNFi)–naive patients with suspected nr-axSpA. Patients all had chronic inflammatory back pain, at least two spondyloarthritis features – such as HLA-B27 positivity, asymmetrical arthritis, or family history of ankylosing spondylitis – as well as high disease activity and insufficient response to at least two NSAIDs. These patients meet the “clinical arm” of Assessment of SpondyloArthritis international Society (ASAS) criteria for classifying axSpA at an early stage of disease but not “imaging-arm” requirements for the presence of active inflammatory lesions of the sacroiliac joints (SIJ) on MRI and one additional SpA feature.
Whether these imaging criteria and objective evidence of elevated inflammation are necessary to fulfill when considering TNFi treatment for patients with suspected nr-axSpA in daily practice is an important question to address, the authors pointed out, because “in many studies, the presence of a positive MRI-SIJ is one of the prerequisites to start a TNF inhibitor treatment in patients with nr-axSpA.” In addition, starting a TNFi is dependent on failure of at least two NSAIDs and an elevated CRP level when the MRI is negative, which is problematic since in some studies raised CRP levels were found in only 30% of the nr-axSpA patients and 59%-64% of nr-axSpA patients with high disease activity do not have active inflammatory SIJ lesions on MRI. On top of these concerns is the fact that many people who do not have axSpA show false-positive results of bone marrow edema on MRI of the SIJ, such as postpartum women, recreational runners, professional athletes, and army recruits undergoing physical training, they added.
In the current study at the end of the 16-week course of treatment, researchers found no statistically significant difference between the treatment and placebo group in the number of patients who achieved a 20% improvement in ASAS response criteria (16.7% vs. 11.1%; P = .5), nor in those who had at least 40% improvement (8.3% in both groups). This was regardless of sex, age, NSAID or disease-modifying antirheumatic drug use, HLA-B27 status, or other clinical factors.
Similarly, there was no statistically significant difference between the two groups in the number of patients who met response criteria for the Ankylosing Spondylitis Disease Activity Score based on CRP for either clinical improvement or major improvement.
Participants underwent MRI at baseline and at 16 and 24 weeks, which revealed similar numbers of active inflammatory SIJ lesions in each group. The two groups also had similar Spondyloarthritis Research Consortium of Canada scores at baseline and 16 weeks, but a slightly – yet statistically significant – higher score in the etanercept group at 24 weeks.
However, during the first 16 weeks of the study, patients in the etanercept group showed greater improvements in pain and erythrocyte sedimentation rate (ESR), compared with those in the placebo group.
After the 16-week treatment course, participants were followed for another 8 weeks. During this time, participants in the etanercept group showed a worsening in their mean Bath Ankylosing Spondylitis Metrology Index score, CRP level, and ESR, compared with the placebo group.
While the number of participants who experienced an adverse event by 16 weeks was similar in both groups, more patients in the etanercept group experienced an adverse effect likely related to the study drug.
Study results in the context of previous findings
Commenting on their findings, first author Tamara Rusman, of the Amsterdam University Medical Center, and coauthors wrote that the results suggested early treatment with etanercept in patients without a positive MRI and raised CRP levels was not effective.
However, they acknowledged that two previous placebo-controlled studies had specifically included patients with nr-axSpA and found a significantly better treatment response to TNF inhibitors than to placebo. One of these studies included a significant number of patients with MRI-detected active inflammatory SIJ lesions at baseline, which is a known predictor of treatment response.
“The relatively low number of patients with either a positive MRI-SIJ (23%) and/or elevated CRP level (13%) at baseline in our study could be an explanation for the absence of a treatment effect in favor of etanercept,” they wrote.
They also raised the possibility that their choice of study population didn’t truly capture patients with nr-axSpA, and that it was not powered to compare patients with or without a positive MRI or raised CRP level at baseline.
“It would be interesting to know whether our study results will be replicated by others in comparable study populations with equal numbers of patients with and without a positive MRI-SIJ and raised CRP in the future,” they wrote.
The study was supported by an unrestricted financial grant from Pfizer and ReumaNederland. No conflicts of interest were declared.
SOURCE: Rusman T et al. Arthritis Rheumatol. 2020 Dec 5. doi: 10.1002/art.41607.
FROM ARTHRITIS & RHEUMATOLOGY