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To improve psoriatic arthritis outcomes, address common comorbidities
Only about 30% or fewer of patients with psoriatic arthritis (PsA) on therapy achieve disease remission by any definition. One reason for this may be inadequate attention to common comorbid conditions, Alexis Ogdie, MD, MSCE, declared at the 2021 Rheumatology Winter Clinical Symposium.
“I believe that addressing off-target aspects of disease is really important to improving the patient experience of their disease. We might need to target these directly in order to improve outcomes,” said Dr. Ogdie, a rheumatologist and epidemiologist at the University of Pennsylvania, Philadelphia, who coauthored the current American College of Rheumatology/National Psoriasis Foundation PsA guidelines.
Since rheumatologists are by now well informed about the increased cardiovascular risk associated with PsA, she focused on two common comorbidities that get less attention, both of which are associated with worse clinical outcomes in PsA: obesity and mental health issues.
Anxiety and depression
Dr. Ogdie was first author of a large, population-based, longitudinal cohort study of cause-specific mortality in 8,706 U.K. patients with PsA, 41,752 with RA, and more than 81,000 controls. Particularly striking was the finding of elevated mortality because of suicide in the rheumatic disease patients: a 203% increased risk in the PsA population, compared with the general population, and a 147% greater risk in patients with RA.
Overall, 30%-40% of PsA patients have comorbid depression and/or anxiety.
“That’s pretty striking. It’s also true for rheumatoid arthritis and axial spondyloarthritis. And if you’re depressed, you’re much less likely to respond to therapy in the way that we are measuring response to therapy,” Dr. Ogdie said.
Her approach to screening for depression and anxiety in her PsA patients, and indeed in all her other patients, is to begin by normalizing the topic, explaining to them that these affective disorders are common among patients with these disorders. She lets her patients know they can talk to her about it. And she informs them that, while effective treatment of their rheumatic disease may improve their depression or anxiety, managing those is also important for improving their disease. Additionally, understanding whether depression is present is important prior to prescribing certain medications. Apremilast (Otezla), for example, can worsen preexisting depression.
“Ask about signs and symptoms of depression,” Dr. Ogdie urged her colleagues. “I do this at every single visit in my review of symptoms. This is one I don’t skip. I ask: ‘Do you have any symptoms of depression or anxiety?’ ”
Structured evidence-based screening tools, many of which are well suited for completion during a patient’s preappointment check-in survey, include the Patient Health Questionnaire–2, the PHQ-9, the Patient-Reported Outcomes Measure Information System–10, PROMIS–Depression, and Routine Assessment of Patient Index Data 3.
“I also really like the PROMIS-29. It covers many domains of interest: depression and anxiety, sleep, fatigue, pain, physical function. It gives a lot of information about what’s going on in a patient’s life right now,” according to the rheumatologist.
The main thing is to regularly screen for anxiety and depression and then refer symptomatic patients for further assessment and treatment. This is not something that all rheumatologists have been trained to do.
Obesity
Dr. Ogdie was lead author of a national CORRONA Registry study which concluded that obese patients with PsA were only half as likely to achieve remission on a tumor necrosis factor (TNF) inhibitor, compared with nonobese patients. She believes the same holds true for all other types of therapy: Across the board, obesity is associated with a poor response. And obesity is much more common in PsA patients than the general population in every age group. Moreover, obesity is associated with risk factors for cardiovascular disease and is associated with fatty liver disease, two other major comorbid conditions in the PsA population.
The CORRONA Registry findings are supportive of an earlier Italian prospective, observational study of 135 obese and an equal number of normal-weight PsA patients, all of whom started on a TNF inhibitor and were followed for 24 months. In a multivariate-adjusted analysis, obesity was independently associated with a 390% higher risk of not achieving minimal disease activity.
The same Italian group subsequently conducted a prospective dietary intervention study in 138 overweight or obese patients with PsA starting anti-TNF therapy. A total of 59% of participants randomized to either of the two dietary interventions experienced at least a 5% weight loss at 6 months. The key study finding: Compared with the subjects with less than 5% weight loss, those with 5%-10% weight loss were 275% more likely to achieve minimal disease activity at 6 months, and in those with greater than 10% weight loss the likelihood of attaining minimal disease activity increased by 567%.
“We’re talking about a disease where treatments tested in clinical trials have odds ratios in the 1.2 range, compared with other therapies, so this is a really striking difference,” she observed.
Several studies have demonstrated that obesity in psoriasis patients is a risk factor for developing PsA. Recently, U.K. investigators took things a step further, reporting in a huge observational study that obese or overweight psoriasis patients who reduced their body mass index over a 10-year period had a corresponding reduction in the risk of developing PsA, compared with overweight or obese psoriasis patients whose BMI remained steady over the same period.
What’s needed now is access to programs to help patients with PsA lose weight. Health insurers are often unwilling to provide coverage. “We have a really tough time getting the patients in to see a nutritionist unless they’re willing to pay out of pocket,” Dr. Ogdie said.
Physical activity is an important element in successful weight loss. It also is recommended in practice guidelines for patients with inflammatory arthritis because of its salutary effects on disease activity scores, pain and stiffness, sleep, and quality of life. But a recent survey conducted by Dr. Ogdie and coworkers concluded that patients with PsA and other forms of inflammatory arthritis don’t receive much exercise guidance from their rheumatologists. About 60% of subjects were inactive. Those who were physically active typically engaged in aerobic exercise but were much less likely to do the other guideline-recommended forms of exercise, namely flexibility, balance, and resistance training. The patients’ report of low engagement of their physicians “suggests an opportunity for more prescriptive exercise discussions,” according to the investigators.
Diabetes, a critical risk factor for cardiovascular disease, occurs at an increased incidence in PsA. This was demonstrated in a U.K. cohort study coauthored by Dr. Ogdie. The study, which included nearly 4,200 individuals with PsA, concluded that they had a 43% greater incidence of diabetes than the general population in an analysis adjusted for body mass index, smoking, alcohol use, and demographics.
New-onset diabetes can be readily picked up by rheumatologists based upon the laboratory work they often order at patient office visits, or during their review of symptoms, she noted, and added that the U.S. Preventive Services Task Force recommends ordering a hemoglobin A1c test every 3 years.
Dr. Ogdie reported receiving research grants and/or consulting fees from numerous pharmaceutical companies. Her research is also funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the Rheumatology Research Foundation, and the National Psoriasis Foundation.
Only about 30% or fewer of patients with psoriatic arthritis (PsA) on therapy achieve disease remission by any definition. One reason for this may be inadequate attention to common comorbid conditions, Alexis Ogdie, MD, MSCE, declared at the 2021 Rheumatology Winter Clinical Symposium.
“I believe that addressing off-target aspects of disease is really important to improving the patient experience of their disease. We might need to target these directly in order to improve outcomes,” said Dr. Ogdie, a rheumatologist and epidemiologist at the University of Pennsylvania, Philadelphia, who coauthored the current American College of Rheumatology/National Psoriasis Foundation PsA guidelines.
Since rheumatologists are by now well informed about the increased cardiovascular risk associated with PsA, she focused on two common comorbidities that get less attention, both of which are associated with worse clinical outcomes in PsA: obesity and mental health issues.
Anxiety and depression
Dr. Ogdie was first author of a large, population-based, longitudinal cohort study of cause-specific mortality in 8,706 U.K. patients with PsA, 41,752 with RA, and more than 81,000 controls. Particularly striking was the finding of elevated mortality because of suicide in the rheumatic disease patients: a 203% increased risk in the PsA population, compared with the general population, and a 147% greater risk in patients with RA.
Overall, 30%-40% of PsA patients have comorbid depression and/or anxiety.
“That’s pretty striking. It’s also true for rheumatoid arthritis and axial spondyloarthritis. And if you’re depressed, you’re much less likely to respond to therapy in the way that we are measuring response to therapy,” Dr. Ogdie said.
Her approach to screening for depression and anxiety in her PsA patients, and indeed in all her other patients, is to begin by normalizing the topic, explaining to them that these affective disorders are common among patients with these disorders. She lets her patients know they can talk to her about it. And she informs them that, while effective treatment of their rheumatic disease may improve their depression or anxiety, managing those is also important for improving their disease. Additionally, understanding whether depression is present is important prior to prescribing certain medications. Apremilast (Otezla), for example, can worsen preexisting depression.
“Ask about signs and symptoms of depression,” Dr. Ogdie urged her colleagues. “I do this at every single visit in my review of symptoms. This is one I don’t skip. I ask: ‘Do you have any symptoms of depression or anxiety?’ ”
Structured evidence-based screening tools, many of which are well suited for completion during a patient’s preappointment check-in survey, include the Patient Health Questionnaire–2, the PHQ-9, the Patient-Reported Outcomes Measure Information System–10, PROMIS–Depression, and Routine Assessment of Patient Index Data 3.
“I also really like the PROMIS-29. It covers many domains of interest: depression and anxiety, sleep, fatigue, pain, physical function. It gives a lot of information about what’s going on in a patient’s life right now,” according to the rheumatologist.
The main thing is to regularly screen for anxiety and depression and then refer symptomatic patients for further assessment and treatment. This is not something that all rheumatologists have been trained to do.
Obesity
Dr. Ogdie was lead author of a national CORRONA Registry study which concluded that obese patients with PsA were only half as likely to achieve remission on a tumor necrosis factor (TNF) inhibitor, compared with nonobese patients. She believes the same holds true for all other types of therapy: Across the board, obesity is associated with a poor response. And obesity is much more common in PsA patients than the general population in every age group. Moreover, obesity is associated with risk factors for cardiovascular disease and is associated with fatty liver disease, two other major comorbid conditions in the PsA population.
The CORRONA Registry findings are supportive of an earlier Italian prospective, observational study of 135 obese and an equal number of normal-weight PsA patients, all of whom started on a TNF inhibitor and were followed for 24 months. In a multivariate-adjusted analysis, obesity was independently associated with a 390% higher risk of not achieving minimal disease activity.
The same Italian group subsequently conducted a prospective dietary intervention study in 138 overweight or obese patients with PsA starting anti-TNF therapy. A total of 59% of participants randomized to either of the two dietary interventions experienced at least a 5% weight loss at 6 months. The key study finding: Compared with the subjects with less than 5% weight loss, those with 5%-10% weight loss were 275% more likely to achieve minimal disease activity at 6 months, and in those with greater than 10% weight loss the likelihood of attaining minimal disease activity increased by 567%.
“We’re talking about a disease where treatments tested in clinical trials have odds ratios in the 1.2 range, compared with other therapies, so this is a really striking difference,” she observed.
Several studies have demonstrated that obesity in psoriasis patients is a risk factor for developing PsA. Recently, U.K. investigators took things a step further, reporting in a huge observational study that obese or overweight psoriasis patients who reduced their body mass index over a 10-year period had a corresponding reduction in the risk of developing PsA, compared with overweight or obese psoriasis patients whose BMI remained steady over the same period.
What’s needed now is access to programs to help patients with PsA lose weight. Health insurers are often unwilling to provide coverage. “We have a really tough time getting the patients in to see a nutritionist unless they’re willing to pay out of pocket,” Dr. Ogdie said.
Physical activity is an important element in successful weight loss. It also is recommended in practice guidelines for patients with inflammatory arthritis because of its salutary effects on disease activity scores, pain and stiffness, sleep, and quality of life. But a recent survey conducted by Dr. Ogdie and coworkers concluded that patients with PsA and other forms of inflammatory arthritis don’t receive much exercise guidance from their rheumatologists. About 60% of subjects were inactive. Those who were physically active typically engaged in aerobic exercise but were much less likely to do the other guideline-recommended forms of exercise, namely flexibility, balance, and resistance training. The patients’ report of low engagement of their physicians “suggests an opportunity for more prescriptive exercise discussions,” according to the investigators.
Diabetes, a critical risk factor for cardiovascular disease, occurs at an increased incidence in PsA. This was demonstrated in a U.K. cohort study coauthored by Dr. Ogdie. The study, which included nearly 4,200 individuals with PsA, concluded that they had a 43% greater incidence of diabetes than the general population in an analysis adjusted for body mass index, smoking, alcohol use, and demographics.
New-onset diabetes can be readily picked up by rheumatologists based upon the laboratory work they often order at patient office visits, or during their review of symptoms, she noted, and added that the U.S. Preventive Services Task Force recommends ordering a hemoglobin A1c test every 3 years.
Dr. Ogdie reported receiving research grants and/or consulting fees from numerous pharmaceutical companies. Her research is also funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the Rheumatology Research Foundation, and the National Psoriasis Foundation.
Only about 30% or fewer of patients with psoriatic arthritis (PsA) on therapy achieve disease remission by any definition. One reason for this may be inadequate attention to common comorbid conditions, Alexis Ogdie, MD, MSCE, declared at the 2021 Rheumatology Winter Clinical Symposium.
“I believe that addressing off-target aspects of disease is really important to improving the patient experience of their disease. We might need to target these directly in order to improve outcomes,” said Dr. Ogdie, a rheumatologist and epidemiologist at the University of Pennsylvania, Philadelphia, who coauthored the current American College of Rheumatology/National Psoriasis Foundation PsA guidelines.
Since rheumatologists are by now well informed about the increased cardiovascular risk associated with PsA, she focused on two common comorbidities that get less attention, both of which are associated with worse clinical outcomes in PsA: obesity and mental health issues.
Anxiety and depression
Dr. Ogdie was first author of a large, population-based, longitudinal cohort study of cause-specific mortality in 8,706 U.K. patients with PsA, 41,752 with RA, and more than 81,000 controls. Particularly striking was the finding of elevated mortality because of suicide in the rheumatic disease patients: a 203% increased risk in the PsA population, compared with the general population, and a 147% greater risk in patients with RA.
Overall, 30%-40% of PsA patients have comorbid depression and/or anxiety.
“That’s pretty striking. It’s also true for rheumatoid arthritis and axial spondyloarthritis. And if you’re depressed, you’re much less likely to respond to therapy in the way that we are measuring response to therapy,” Dr. Ogdie said.
Her approach to screening for depression and anxiety in her PsA patients, and indeed in all her other patients, is to begin by normalizing the topic, explaining to them that these affective disorders are common among patients with these disorders. She lets her patients know they can talk to her about it. And she informs them that, while effective treatment of their rheumatic disease may improve their depression or anxiety, managing those is also important for improving their disease. Additionally, understanding whether depression is present is important prior to prescribing certain medications. Apremilast (Otezla), for example, can worsen preexisting depression.
“Ask about signs and symptoms of depression,” Dr. Ogdie urged her colleagues. “I do this at every single visit in my review of symptoms. This is one I don’t skip. I ask: ‘Do you have any symptoms of depression or anxiety?’ ”
Structured evidence-based screening tools, many of which are well suited for completion during a patient’s preappointment check-in survey, include the Patient Health Questionnaire–2, the PHQ-9, the Patient-Reported Outcomes Measure Information System–10, PROMIS–Depression, and Routine Assessment of Patient Index Data 3.
“I also really like the PROMIS-29. It covers many domains of interest: depression and anxiety, sleep, fatigue, pain, physical function. It gives a lot of information about what’s going on in a patient’s life right now,” according to the rheumatologist.
The main thing is to regularly screen for anxiety and depression and then refer symptomatic patients for further assessment and treatment. This is not something that all rheumatologists have been trained to do.
Obesity
Dr. Ogdie was lead author of a national CORRONA Registry study which concluded that obese patients with PsA were only half as likely to achieve remission on a tumor necrosis factor (TNF) inhibitor, compared with nonobese patients. She believes the same holds true for all other types of therapy: Across the board, obesity is associated with a poor response. And obesity is much more common in PsA patients than the general population in every age group. Moreover, obesity is associated with risk factors for cardiovascular disease and is associated with fatty liver disease, two other major comorbid conditions in the PsA population.
The CORRONA Registry findings are supportive of an earlier Italian prospective, observational study of 135 obese and an equal number of normal-weight PsA patients, all of whom started on a TNF inhibitor and were followed for 24 months. In a multivariate-adjusted analysis, obesity was independently associated with a 390% higher risk of not achieving minimal disease activity.
The same Italian group subsequently conducted a prospective dietary intervention study in 138 overweight or obese patients with PsA starting anti-TNF therapy. A total of 59% of participants randomized to either of the two dietary interventions experienced at least a 5% weight loss at 6 months. The key study finding: Compared with the subjects with less than 5% weight loss, those with 5%-10% weight loss were 275% more likely to achieve minimal disease activity at 6 months, and in those with greater than 10% weight loss the likelihood of attaining minimal disease activity increased by 567%.
“We’re talking about a disease where treatments tested in clinical trials have odds ratios in the 1.2 range, compared with other therapies, so this is a really striking difference,” she observed.
Several studies have demonstrated that obesity in psoriasis patients is a risk factor for developing PsA. Recently, U.K. investigators took things a step further, reporting in a huge observational study that obese or overweight psoriasis patients who reduced their body mass index over a 10-year period had a corresponding reduction in the risk of developing PsA, compared with overweight or obese psoriasis patients whose BMI remained steady over the same period.
What’s needed now is access to programs to help patients with PsA lose weight. Health insurers are often unwilling to provide coverage. “We have a really tough time getting the patients in to see a nutritionist unless they’re willing to pay out of pocket,” Dr. Ogdie said.
Physical activity is an important element in successful weight loss. It also is recommended in practice guidelines for patients with inflammatory arthritis because of its salutary effects on disease activity scores, pain and stiffness, sleep, and quality of life. But a recent survey conducted by Dr. Ogdie and coworkers concluded that patients with PsA and other forms of inflammatory arthritis don’t receive much exercise guidance from their rheumatologists. About 60% of subjects were inactive. Those who were physically active typically engaged in aerobic exercise but were much less likely to do the other guideline-recommended forms of exercise, namely flexibility, balance, and resistance training. The patients’ report of low engagement of their physicians “suggests an opportunity for more prescriptive exercise discussions,” according to the investigators.
Diabetes, a critical risk factor for cardiovascular disease, occurs at an increased incidence in PsA. This was demonstrated in a U.K. cohort study coauthored by Dr. Ogdie. The study, which included nearly 4,200 individuals with PsA, concluded that they had a 43% greater incidence of diabetes than the general population in an analysis adjusted for body mass index, smoking, alcohol use, and demographics.
New-onset diabetes can be readily picked up by rheumatologists based upon the laboratory work they often order at patient office visits, or during their review of symptoms, she noted, and added that the U.S. Preventive Services Task Force recommends ordering a hemoglobin A1c test every 3 years.
Dr. Ogdie reported receiving research grants and/or consulting fees from numerous pharmaceutical companies. Her research is also funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the Rheumatology Research Foundation, and the National Psoriasis Foundation.
FROM RWCS 2021
Novel lupus therapies take center stage
It’s been a banner year for treatment advances in systemic lupus erythematosus (SLE), with two drugs gaining approval for lupus nephritis while other promising molecules with novel mechanisms of action advanced smartly through the developmental pipeline, speakers agreed at the 2021 Rheumatology Winter Clinical Symposium.
“I think the most important thing in rheumatology in the last year is where we are now with lupus. With two drugs being approved for lupus nephritis, I think that’s really huge as we talk about treat-to-target,” said Alvin F. Wells, MD, PhD, a rheumatologist in Franklin, Wisc.
Martin Bergman, MD, concurred.
“Lupus has been blowing up in the past year. We have two new medications for lupus nephritis, we have two or three new mechanisms of action for therapy. I think that was one of the biggest things in rheumatology in the past year,” said Dr. Bergman, a rheumatologist at Drexel University in Philadelphia and in private practice in Ridley Park, Pa.
Together with Roy Fleischmann, MD, Dr. Wells spotlighted promising new molecules for the treatment of SLE, giant cell arteritis, vasculitis, rheumatoid arthritis, and osteoarthritis.
SLE
The two drugs approved in recent months specifically for lupus nephritis are voclosporin (Lupkynis) and belimumab (Benlysta), which has been approved for lupus for a decade. Voclosporin, an oral calcineurin inhibitor, is a modification of cyclosporine offering significant advantages over the older drug: It’s more potent, requires no dose titration, has a better safety profile, and is metabolized more quickly.
“A safer and easier-to-use calcineurin inhibitor is going to be huge,” Dr. Wells predicted.
Up for Food and Drug Administration review in the coming year on the basis of the positive phase 3 TULIP-1 and TULIP-2 trials is anifrolumab, a monoclonal antibody that binds to the type 1 interferon receptor subunit 1d. At 52 weeks in the pooled analysis, one or more SLE flares occurred in 33.6% of patients on anifrolumab and 42.9% of placebo-treated controls.
“This is not a blockbuster, but it’s a worthwhile addition, like belimumab,” according to Dr. Fleischmann, a rheumatologist at the University of Texas, Dallas.
Dr. Wells concurred, with a reservation: In a subgroup analysis of the TULIP trials, anifrolumab wasn’t significantly better than placebo in black patients, who tend to have more severe and tough-to-treat renal disease.
“Anifrolumab doesn’t look as effective as some other agents, and I’d be disinclined to give it to my black patients,” the rheumatologist said.
Dr. Fleischmann was far more enthusiastic about obinutuzumab (Gazyva), a humanized anti-CD20 monoclonal antibody already approved for the treatment of chronic lymphocytic leukemia and follicular lymphoma.
“It’s an anti-CD20, like rituximab. But it’s better than rituximab, it’s much more effective,” he said.
He pointed to the phase 2 NOBILITY trial, in which 125 patients with class III/IV lupus nephritis were randomized to a 1,000-mg infusion of obinutuzumab or placebo at weeks 0, 2, 24, and 26 and followed for 2 years. The complete renal response rate at 104 weeks in the obinutuzumab group was 41% and the partial renal response rate was 13%, compared to 23% and 6% in controls. The obinutuzumab group also did significantly better in terms of improvement in complement levels, double-stranded DNA, and estimated glomerular filtration rate. All this was accomplished even though the reduction in peripheral B cells dropped from 93% at week 24 to just 16% at week 104. This suggests that tissue levels of B cells in the kidney, joints, and skin may be more important than circulating B cell levels.
“This looks like a very promising agent for patients with lupus nephritis,” Dr. Wells said. “The fact that they got this long-term effect for 2 years with just four infusions is really impressive.”
Another promising drug is iberdomide, an oral modulator of the E3 ubiquitin ligase complex which decreases plasmacytoid dendritic cells and B cells while increasing T regulatory cells. In a phase 2b clinical trial in 288 patients with active SLE, all on background standard-of-care therapy, a 4-point or greater reduction in the SLE Responder Index (SRI-4) at week 24 was achieved in 54.3% of the group on iberdomide at 0.45 mg/day, a significantly better result than the 34.9% rate with placebo. This absolute 19.4% difference was even greater in the subgroup of patients with a high baseline level of the transcription factor Aiolos, where the absolute improvement over placebo was 32.9%. Similarly, the benefit of iberdomide was also enhanced in patients with a high baseline level of type 1 interferon, where the absolute difference was 26.8%. This raises the prospect that a bioassay could be developed to predict the likelihood of a favorable clinical response to the drug. Iberdomide was well tolerated, with fewer severe adverse events than in the control group.
A humanized monoclonal antibody known for now as BIIB059 demonstrated efficacy and was well tolerated in the phase 2 LILAC trial. BIIB059 binds to blood dendritic cell antigen 2 (BDCA2), a receptor specific to plasmacytoid dendritic cells, resulting in decreased production of type 1 interferon and other inflammatory cytokines. The LILAC trial included 132 SLE patients with active arthritis and skin disease who received subcutaneous injections of BIIB059 at 450 mg or placebo every 4 weeks, with an extra dose at week 2. The primary endpoint was met, with an absolute 15-joint reduction in the total number of tender or swollen joints from baseline to week 24 in the BIIB059 group, compared to an 11.6-joint reduction with placebo. In addition, the likelihood of an SRI-4 response at week 24 was 3.49-fold greater with BIIB059 than with placebo.
Dr. Wells noted that the BIIB059 group showed continued improvement from week 12 to week 24, unlike the response pattern seen with many biologics for rheumatoid arthritis, where a plateau is reached by 8-12 weeks.
Vasculitis
The positive results for the C5a receptor inhibitor avacopan for treatment of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis in the phase-3 ADVOCATE trial have been hailed by some rheumatologists as a major breakthrough, but Dr. Fleischmann isn’t so sure.
The trial randomized 331 patients to oral avacopan at 30 mg twice daily or oral prednisone, with all patients on either cyclophosphamide or rituximab. Avacopan was noninferior to prednisone in terms of remission at week 26, but superior to prednisone for sustained taper at week 52. The rate of serious adverse events was 45.1% with prednisone and 42.2% in the avacopan arm.
“This is a drug that’s going to be much, much more expensive than prednisone. There were people in our group who were ecstatic that this drug is going to come, but how much it’s going to be used, I don’t know,” Dr. Fleischmann said.
Dr. Wells said cost-benefit analyses will be needed in order to learn if avacopan’s anticipated high sticker price is offset by the cost of serious corticosteroid side effects such as avascular necrosis.
Giant cell arteritis
Mavrilimumab is a human monoclonal antibody that inhibits human granulocyte macrophage colony stimulating factor receptor alpha. It demonstrated impressive efficacy in a phase 2, double-blind, randomized, placebo-controlled trial conducted in 70 patients with biopsy-confirmed giant cell arteritis. Participants were on corticosteroids until they went into remission and were then randomized to mavrilimumab or placebo, with the steroids stopped. By week 26, 19% of patients in the mavrilimumab arm had flared, as compared to 46.4% of controls.
“This is a game changer,” Dr. Wells declared. “I struggle with these patients because I can’t get the IL-6 drugs approved for them. I need something else.”
Dr. Fleischmann has a good idea how he’ll use mavrilimumab, if it wins approval: “I think this is clearly a drug you would use in a patient you can’t get off steroids and you’re having all the steroid toxicity. I don’t know that you’d use it right away.”
Osteoarthritis
Dr. Fleischmann predicted that tanezumab, a monoclonal antibody directed against nerve growth factor, will win FDA approval in 2021 for the treatment of osteoarthritis pain in patients with an inadequate response or intolerance to standard-of-care NSAIDs and opioids. But he cautioned his colleagues not to expect too much from the biologic, which has a long and checkered developmental history.
“It works better than placebo. It does not work better than an NSAID or an opioid. So it should be reasonable in patients who cannot take an NSAID or cannot or will not take an opioid,” he said.
There are safety issues to be aware of with tanezumab, he added: clinically significant increased risks of peripheral neuropathy and joint space narrowing.
Rheumatoid arthritis
Dr. Wells thought one of the most interesting novel therapies for RA in the past year didn’t involve a pharmaceutical, but rather noninvasive auricular branch stimulation of the vagus nerve. He cited an open-label, 12-week, uncontrolled study in 27 patients with active RA who wore an ear clip for vagal nerve stimulation for 12 weeks. The mean Disease Activity Score in 28 joints using C-reactive protein (DAS28-CRP) – the primary study endpoint – improved from 6.30 at baseline to 3.76 at week 12. The number of tender joints dropped from 12.17 to 4.7, while the swollen joint count went from 7.0 to 3.44. Pain scores improved from 75.23 to 43.3. Scores on the Health Assessment Questionnaire Disability Index improved from 1.59 to 1.05. There was no significant change in CRP. All in all, a modest clinical effect achieved noninvasively.
“The thing that did it for me was the effect on MRI from baseline: decreased synovitis, osteitis, and bone erosion scores,” Dr. Wells said. “This is noninvasive, so patients who want to do medical marijuana or CBD can put an earring on their auricular nerve.”
Dr. Fleischmann scoffed. “An open-label study, 27 patients? Let me see the real study,” he quipped.
Dr. Fleischmann reported receiving clinical trial research grants from and serving as a consultant to more than a dozen pharmaceutical companies. Dr. Wells serves as a consultant to MiCare Path.
It’s been a banner year for treatment advances in systemic lupus erythematosus (SLE), with two drugs gaining approval for lupus nephritis while other promising molecules with novel mechanisms of action advanced smartly through the developmental pipeline, speakers agreed at the 2021 Rheumatology Winter Clinical Symposium.
“I think the most important thing in rheumatology in the last year is where we are now with lupus. With two drugs being approved for lupus nephritis, I think that’s really huge as we talk about treat-to-target,” said Alvin F. Wells, MD, PhD, a rheumatologist in Franklin, Wisc.
Martin Bergman, MD, concurred.
“Lupus has been blowing up in the past year. We have two new medications for lupus nephritis, we have two or three new mechanisms of action for therapy. I think that was one of the biggest things in rheumatology in the past year,” said Dr. Bergman, a rheumatologist at Drexel University in Philadelphia and in private practice in Ridley Park, Pa.
Together with Roy Fleischmann, MD, Dr. Wells spotlighted promising new molecules for the treatment of SLE, giant cell arteritis, vasculitis, rheumatoid arthritis, and osteoarthritis.
SLE
The two drugs approved in recent months specifically for lupus nephritis are voclosporin (Lupkynis) and belimumab (Benlysta), which has been approved for lupus for a decade. Voclosporin, an oral calcineurin inhibitor, is a modification of cyclosporine offering significant advantages over the older drug: It’s more potent, requires no dose titration, has a better safety profile, and is metabolized more quickly.
“A safer and easier-to-use calcineurin inhibitor is going to be huge,” Dr. Wells predicted.
Up for Food and Drug Administration review in the coming year on the basis of the positive phase 3 TULIP-1 and TULIP-2 trials is anifrolumab, a monoclonal antibody that binds to the type 1 interferon receptor subunit 1d. At 52 weeks in the pooled analysis, one or more SLE flares occurred in 33.6% of patients on anifrolumab and 42.9% of placebo-treated controls.
“This is not a blockbuster, but it’s a worthwhile addition, like belimumab,” according to Dr. Fleischmann, a rheumatologist at the University of Texas, Dallas.
Dr. Wells concurred, with a reservation: In a subgroup analysis of the TULIP trials, anifrolumab wasn’t significantly better than placebo in black patients, who tend to have more severe and tough-to-treat renal disease.
“Anifrolumab doesn’t look as effective as some other agents, and I’d be disinclined to give it to my black patients,” the rheumatologist said.
Dr. Fleischmann was far more enthusiastic about obinutuzumab (Gazyva), a humanized anti-CD20 monoclonal antibody already approved for the treatment of chronic lymphocytic leukemia and follicular lymphoma.
“It’s an anti-CD20, like rituximab. But it’s better than rituximab, it’s much more effective,” he said.
He pointed to the phase 2 NOBILITY trial, in which 125 patients with class III/IV lupus nephritis were randomized to a 1,000-mg infusion of obinutuzumab or placebo at weeks 0, 2, 24, and 26 and followed for 2 years. The complete renal response rate at 104 weeks in the obinutuzumab group was 41% and the partial renal response rate was 13%, compared to 23% and 6% in controls. The obinutuzumab group also did significantly better in terms of improvement in complement levels, double-stranded DNA, and estimated glomerular filtration rate. All this was accomplished even though the reduction in peripheral B cells dropped from 93% at week 24 to just 16% at week 104. This suggests that tissue levels of B cells in the kidney, joints, and skin may be more important than circulating B cell levels.
“This looks like a very promising agent for patients with lupus nephritis,” Dr. Wells said. “The fact that they got this long-term effect for 2 years with just four infusions is really impressive.”
Another promising drug is iberdomide, an oral modulator of the E3 ubiquitin ligase complex which decreases plasmacytoid dendritic cells and B cells while increasing T regulatory cells. In a phase 2b clinical trial in 288 patients with active SLE, all on background standard-of-care therapy, a 4-point or greater reduction in the SLE Responder Index (SRI-4) at week 24 was achieved in 54.3% of the group on iberdomide at 0.45 mg/day, a significantly better result than the 34.9% rate with placebo. This absolute 19.4% difference was even greater in the subgroup of patients with a high baseline level of the transcription factor Aiolos, where the absolute improvement over placebo was 32.9%. Similarly, the benefit of iberdomide was also enhanced in patients with a high baseline level of type 1 interferon, where the absolute difference was 26.8%. This raises the prospect that a bioassay could be developed to predict the likelihood of a favorable clinical response to the drug. Iberdomide was well tolerated, with fewer severe adverse events than in the control group.
A humanized monoclonal antibody known for now as BIIB059 demonstrated efficacy and was well tolerated in the phase 2 LILAC trial. BIIB059 binds to blood dendritic cell antigen 2 (BDCA2), a receptor specific to plasmacytoid dendritic cells, resulting in decreased production of type 1 interferon and other inflammatory cytokines. The LILAC trial included 132 SLE patients with active arthritis and skin disease who received subcutaneous injections of BIIB059 at 450 mg or placebo every 4 weeks, with an extra dose at week 2. The primary endpoint was met, with an absolute 15-joint reduction in the total number of tender or swollen joints from baseline to week 24 in the BIIB059 group, compared to an 11.6-joint reduction with placebo. In addition, the likelihood of an SRI-4 response at week 24 was 3.49-fold greater with BIIB059 than with placebo.
Dr. Wells noted that the BIIB059 group showed continued improvement from week 12 to week 24, unlike the response pattern seen with many biologics for rheumatoid arthritis, where a plateau is reached by 8-12 weeks.
Vasculitis
The positive results for the C5a receptor inhibitor avacopan for treatment of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis in the phase-3 ADVOCATE trial have been hailed by some rheumatologists as a major breakthrough, but Dr. Fleischmann isn’t so sure.
The trial randomized 331 patients to oral avacopan at 30 mg twice daily or oral prednisone, with all patients on either cyclophosphamide or rituximab. Avacopan was noninferior to prednisone in terms of remission at week 26, but superior to prednisone for sustained taper at week 52. The rate of serious adverse events was 45.1% with prednisone and 42.2% in the avacopan arm.
“This is a drug that’s going to be much, much more expensive than prednisone. There were people in our group who were ecstatic that this drug is going to come, but how much it’s going to be used, I don’t know,” Dr. Fleischmann said.
Dr. Wells said cost-benefit analyses will be needed in order to learn if avacopan’s anticipated high sticker price is offset by the cost of serious corticosteroid side effects such as avascular necrosis.
Giant cell arteritis
Mavrilimumab is a human monoclonal antibody that inhibits human granulocyte macrophage colony stimulating factor receptor alpha. It demonstrated impressive efficacy in a phase 2, double-blind, randomized, placebo-controlled trial conducted in 70 patients with biopsy-confirmed giant cell arteritis. Participants were on corticosteroids until they went into remission and were then randomized to mavrilimumab or placebo, with the steroids stopped. By week 26, 19% of patients in the mavrilimumab arm had flared, as compared to 46.4% of controls.
“This is a game changer,” Dr. Wells declared. “I struggle with these patients because I can’t get the IL-6 drugs approved for them. I need something else.”
Dr. Fleischmann has a good idea how he’ll use mavrilimumab, if it wins approval: “I think this is clearly a drug you would use in a patient you can’t get off steroids and you’re having all the steroid toxicity. I don’t know that you’d use it right away.”
Osteoarthritis
Dr. Fleischmann predicted that tanezumab, a monoclonal antibody directed against nerve growth factor, will win FDA approval in 2021 for the treatment of osteoarthritis pain in patients with an inadequate response or intolerance to standard-of-care NSAIDs and opioids. But he cautioned his colleagues not to expect too much from the biologic, which has a long and checkered developmental history.
“It works better than placebo. It does not work better than an NSAID or an opioid. So it should be reasonable in patients who cannot take an NSAID or cannot or will not take an opioid,” he said.
There are safety issues to be aware of with tanezumab, he added: clinically significant increased risks of peripheral neuropathy and joint space narrowing.
Rheumatoid arthritis
Dr. Wells thought one of the most interesting novel therapies for RA in the past year didn’t involve a pharmaceutical, but rather noninvasive auricular branch stimulation of the vagus nerve. He cited an open-label, 12-week, uncontrolled study in 27 patients with active RA who wore an ear clip for vagal nerve stimulation for 12 weeks. The mean Disease Activity Score in 28 joints using C-reactive protein (DAS28-CRP) – the primary study endpoint – improved from 6.30 at baseline to 3.76 at week 12. The number of tender joints dropped from 12.17 to 4.7, while the swollen joint count went from 7.0 to 3.44. Pain scores improved from 75.23 to 43.3. Scores on the Health Assessment Questionnaire Disability Index improved from 1.59 to 1.05. There was no significant change in CRP. All in all, a modest clinical effect achieved noninvasively.
“The thing that did it for me was the effect on MRI from baseline: decreased synovitis, osteitis, and bone erosion scores,” Dr. Wells said. “This is noninvasive, so patients who want to do medical marijuana or CBD can put an earring on their auricular nerve.”
Dr. Fleischmann scoffed. “An open-label study, 27 patients? Let me see the real study,” he quipped.
Dr. Fleischmann reported receiving clinical trial research grants from and serving as a consultant to more than a dozen pharmaceutical companies. Dr. Wells serves as a consultant to MiCare Path.
It’s been a banner year for treatment advances in systemic lupus erythematosus (SLE), with two drugs gaining approval for lupus nephritis while other promising molecules with novel mechanisms of action advanced smartly through the developmental pipeline, speakers agreed at the 2021 Rheumatology Winter Clinical Symposium.
“I think the most important thing in rheumatology in the last year is where we are now with lupus. With two drugs being approved for lupus nephritis, I think that’s really huge as we talk about treat-to-target,” said Alvin F. Wells, MD, PhD, a rheumatologist in Franklin, Wisc.
Martin Bergman, MD, concurred.
“Lupus has been blowing up in the past year. We have two new medications for lupus nephritis, we have two or three new mechanisms of action for therapy. I think that was one of the biggest things in rheumatology in the past year,” said Dr. Bergman, a rheumatologist at Drexel University in Philadelphia and in private practice in Ridley Park, Pa.
Together with Roy Fleischmann, MD, Dr. Wells spotlighted promising new molecules for the treatment of SLE, giant cell arteritis, vasculitis, rheumatoid arthritis, and osteoarthritis.
SLE
The two drugs approved in recent months specifically for lupus nephritis are voclosporin (Lupkynis) and belimumab (Benlysta), which has been approved for lupus for a decade. Voclosporin, an oral calcineurin inhibitor, is a modification of cyclosporine offering significant advantages over the older drug: It’s more potent, requires no dose titration, has a better safety profile, and is metabolized more quickly.
“A safer and easier-to-use calcineurin inhibitor is going to be huge,” Dr. Wells predicted.
Up for Food and Drug Administration review in the coming year on the basis of the positive phase 3 TULIP-1 and TULIP-2 trials is anifrolumab, a monoclonal antibody that binds to the type 1 interferon receptor subunit 1d. At 52 weeks in the pooled analysis, one or more SLE flares occurred in 33.6% of patients on anifrolumab and 42.9% of placebo-treated controls.
“This is not a blockbuster, but it’s a worthwhile addition, like belimumab,” according to Dr. Fleischmann, a rheumatologist at the University of Texas, Dallas.
Dr. Wells concurred, with a reservation: In a subgroup analysis of the TULIP trials, anifrolumab wasn’t significantly better than placebo in black patients, who tend to have more severe and tough-to-treat renal disease.
“Anifrolumab doesn’t look as effective as some other agents, and I’d be disinclined to give it to my black patients,” the rheumatologist said.
Dr. Fleischmann was far more enthusiastic about obinutuzumab (Gazyva), a humanized anti-CD20 monoclonal antibody already approved for the treatment of chronic lymphocytic leukemia and follicular lymphoma.
“It’s an anti-CD20, like rituximab. But it’s better than rituximab, it’s much more effective,” he said.
He pointed to the phase 2 NOBILITY trial, in which 125 patients with class III/IV lupus nephritis were randomized to a 1,000-mg infusion of obinutuzumab or placebo at weeks 0, 2, 24, and 26 and followed for 2 years. The complete renal response rate at 104 weeks in the obinutuzumab group was 41% and the partial renal response rate was 13%, compared to 23% and 6% in controls. The obinutuzumab group also did significantly better in terms of improvement in complement levels, double-stranded DNA, and estimated glomerular filtration rate. All this was accomplished even though the reduction in peripheral B cells dropped from 93% at week 24 to just 16% at week 104. This suggests that tissue levels of B cells in the kidney, joints, and skin may be more important than circulating B cell levels.
“This looks like a very promising agent for patients with lupus nephritis,” Dr. Wells said. “The fact that they got this long-term effect for 2 years with just four infusions is really impressive.”
Another promising drug is iberdomide, an oral modulator of the E3 ubiquitin ligase complex which decreases plasmacytoid dendritic cells and B cells while increasing T regulatory cells. In a phase 2b clinical trial in 288 patients with active SLE, all on background standard-of-care therapy, a 4-point or greater reduction in the SLE Responder Index (SRI-4) at week 24 was achieved in 54.3% of the group on iberdomide at 0.45 mg/day, a significantly better result than the 34.9% rate with placebo. This absolute 19.4% difference was even greater in the subgroup of patients with a high baseline level of the transcription factor Aiolos, where the absolute improvement over placebo was 32.9%. Similarly, the benefit of iberdomide was also enhanced in patients with a high baseline level of type 1 interferon, where the absolute difference was 26.8%. This raises the prospect that a bioassay could be developed to predict the likelihood of a favorable clinical response to the drug. Iberdomide was well tolerated, with fewer severe adverse events than in the control group.
A humanized monoclonal antibody known for now as BIIB059 demonstrated efficacy and was well tolerated in the phase 2 LILAC trial. BIIB059 binds to blood dendritic cell antigen 2 (BDCA2), a receptor specific to plasmacytoid dendritic cells, resulting in decreased production of type 1 interferon and other inflammatory cytokines. The LILAC trial included 132 SLE patients with active arthritis and skin disease who received subcutaneous injections of BIIB059 at 450 mg or placebo every 4 weeks, with an extra dose at week 2. The primary endpoint was met, with an absolute 15-joint reduction in the total number of tender or swollen joints from baseline to week 24 in the BIIB059 group, compared to an 11.6-joint reduction with placebo. In addition, the likelihood of an SRI-4 response at week 24 was 3.49-fold greater with BIIB059 than with placebo.
Dr. Wells noted that the BIIB059 group showed continued improvement from week 12 to week 24, unlike the response pattern seen with many biologics for rheumatoid arthritis, where a plateau is reached by 8-12 weeks.
Vasculitis
The positive results for the C5a receptor inhibitor avacopan for treatment of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis in the phase-3 ADVOCATE trial have been hailed by some rheumatologists as a major breakthrough, but Dr. Fleischmann isn’t so sure.
The trial randomized 331 patients to oral avacopan at 30 mg twice daily or oral prednisone, with all patients on either cyclophosphamide or rituximab. Avacopan was noninferior to prednisone in terms of remission at week 26, but superior to prednisone for sustained taper at week 52. The rate of serious adverse events was 45.1% with prednisone and 42.2% in the avacopan arm.
“This is a drug that’s going to be much, much more expensive than prednisone. There were people in our group who were ecstatic that this drug is going to come, but how much it’s going to be used, I don’t know,” Dr. Fleischmann said.
Dr. Wells said cost-benefit analyses will be needed in order to learn if avacopan’s anticipated high sticker price is offset by the cost of serious corticosteroid side effects such as avascular necrosis.
Giant cell arteritis
Mavrilimumab is a human monoclonal antibody that inhibits human granulocyte macrophage colony stimulating factor receptor alpha. It demonstrated impressive efficacy in a phase 2, double-blind, randomized, placebo-controlled trial conducted in 70 patients with biopsy-confirmed giant cell arteritis. Participants were on corticosteroids until they went into remission and were then randomized to mavrilimumab or placebo, with the steroids stopped. By week 26, 19% of patients in the mavrilimumab arm had flared, as compared to 46.4% of controls.
“This is a game changer,” Dr. Wells declared. “I struggle with these patients because I can’t get the IL-6 drugs approved for them. I need something else.”
Dr. Fleischmann has a good idea how he’ll use mavrilimumab, if it wins approval: “I think this is clearly a drug you would use in a patient you can’t get off steroids and you’re having all the steroid toxicity. I don’t know that you’d use it right away.”
Osteoarthritis
Dr. Fleischmann predicted that tanezumab, a monoclonal antibody directed against nerve growth factor, will win FDA approval in 2021 for the treatment of osteoarthritis pain in patients with an inadequate response or intolerance to standard-of-care NSAIDs and opioids. But he cautioned his colleagues not to expect too much from the biologic, which has a long and checkered developmental history.
“It works better than placebo. It does not work better than an NSAID or an opioid. So it should be reasonable in patients who cannot take an NSAID or cannot or will not take an opioid,” he said.
There are safety issues to be aware of with tanezumab, he added: clinically significant increased risks of peripheral neuropathy and joint space narrowing.
Rheumatoid arthritis
Dr. Wells thought one of the most interesting novel therapies for RA in the past year didn’t involve a pharmaceutical, but rather noninvasive auricular branch stimulation of the vagus nerve. He cited an open-label, 12-week, uncontrolled study in 27 patients with active RA who wore an ear clip for vagal nerve stimulation for 12 weeks. The mean Disease Activity Score in 28 joints using C-reactive protein (DAS28-CRP) – the primary study endpoint – improved from 6.30 at baseline to 3.76 at week 12. The number of tender joints dropped from 12.17 to 4.7, while the swollen joint count went from 7.0 to 3.44. Pain scores improved from 75.23 to 43.3. Scores on the Health Assessment Questionnaire Disability Index improved from 1.59 to 1.05. There was no significant change in CRP. All in all, a modest clinical effect achieved noninvasively.
“The thing that did it for me was the effect on MRI from baseline: decreased synovitis, osteitis, and bone erosion scores,” Dr. Wells said. “This is noninvasive, so patients who want to do medical marijuana or CBD can put an earring on their auricular nerve.”
Dr. Fleischmann scoffed. “An open-label study, 27 patients? Let me see the real study,” he quipped.
Dr. Fleischmann reported receiving clinical trial research grants from and serving as a consultant to more than a dozen pharmaceutical companies. Dr. Wells serves as a consultant to MiCare Path.
FROM RWCS 2021
Recent psoriasis pathophysiology insights carry treatment implications
at MedscapeLive’s annual Las Vegas Dermatology Seminar, held virtually.
Among these unexpected developments was the startling finding that skin inflammation in mild psoriasis is at least as great as in severe disease; evidence that psoriasis may actually be an autoimmune disease rather than a nonspecific immune-mediated disease; and the newly appreciated importance of interleukin-19 (IL-19) in keratinocyte proliferation, according to Dr. Gordon, professor and chair of the department of dermatology at the Medical College of Wisconsin, Milwaukee.
“Our understanding of the pathophysiology of psoriasis is still a work in progress,” the dermatologist observed.
Immunoregulatory deficits in mild vs. severe psoriasis
Conventional wisdom has held that mild psoriasis as defined by limited affected body surface area involves less skin inflammation than more extensive severe psoriasis, so less-potent topical therapies are appropriate. Not so, according to Dr. Gordon, who highlighted work by James G. Krueger, MD, PhD, head of the laboratory of investigative dermatology at Rockefeller University, New York, and coinvestigators. They demonstrated that overall skin inflammation expressed as the sum of T-cell activation and IL-19-mediated epidermal responses didn’t differ in lesions of mild as compared with severe psoriasis. Indeed, mild skin lesions featured a greater number of T-cells, stronger expression of proinflammatory cytokine IL-17A, and greater expression of the central psoriasis transcriptome. The big difference between skin lesions of mild versus severe psoriasis was that severe psoriasis was characterized by strikingly weaker expression of immunoregulatory genes, including programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA4), than that of mild lesions.
The implication is that IL-17-targeted therapies may be of benefit in a much larger segment of the psoriatic population: namely, those with mild disease, who comprise the majority of psoriasis patients by a wide margin, according to the investigators.
Dr. Gordon concurs.
“The primary problem in psoriasis is not so much the inflammatory activity, but the ability to turn off the activity,” he explained. “That implies that if a patient wants to get clear or have significant improvement in disease, you can’t use a less effective medication just because they have less amount of disease. You’re going to need to treat it just as aggressively because the great majority of our medications block the proinflammatory pathways.”
The deficit in immunoregulatory action identified by Dr. Krueger and colleagues in patients with severe disease could provide a novel therapeutic target. If the deficient immunoregulation could be boosted, it might achieve disease control without need for continuous anti-inflammatory therapy.
Autoimmunity in psoriasis
“When I started work in psoriasis, we always thought there would be a common antigen for the immune process in the disease. We never found it. So for that reason, we sort of put it aside and called psoriasis a nonspecific immune-mediated disease,” Dr. Gordon recalled.
That view is being reexamined. “While we’re not completely certain, there is now some evidence that there might be autoimmunity in psoriasis,” he said.
He cited work by an international team of investigators who identified the cathelicidin antimicrobial peptide LL37 as being overexpressed in psoriatic skin, where it appears to serve as a T-cell autoantigen. LL37-specific CD4+ and CD8+ T-cells are skin homing: They can infiltrate lesional skin, where they produce interferon-gamma and proinflammatory Th17 cytokines. The investigators reported that levels of circulating LL37-specific T cells correlated with disease activity such that they were found in three-quarters of patients with moderate to severe plaque psoriasis.
“As LL37 is able to activate innate immune cells and break innate tolerance to self-nucleic acids, it represents an even more appealing target to treat psoriasis. Therapeutic targeting of LL37-specific T cells may provide new avenues to prevent or treat psoriasis without inducing indiscriminate immunosuppression,” the investigators concluded.
Similarly, German investigators have identified ADAMTS-like protein 5 (ADAMTSL5) as an autoantigen specific for melanocytes in psoriasis patients who possess the central psoriasis risk gene, known as HLA-C*06:02, which is present in two-thirds of patients with psoriasis. They proposed that their newly recognized autoimmune pathway may explain how HLA-C*06.02 predisposes to psoriasis.
Growing clinical relevance of IL-19
It’s now well-established that IL-17 is the pivotal force driving the changes in keratinocytes that define the visible expressions of psoriasis, including plaque scale and thickness, which are due to abnormal keratinocyte maturation and proliferation, respectively. Less well appreciated is the fact that IL-17-activated keratinocytes produce IL-19, which feeds back and further stimulates keratinocyte proliferation.
In light of mounting evidence that IL-19 plays an important role in the pathogenesis of psoriasis and that naked eye assessment of visible psoriasis may not reflect the true extent of inflammation, Brian J. Nickoloff, MD, PhD, and coworkers at Lilly Research Laboratories have developed a novel serum IL-19 immunoassay that appears to provide a much-needed objective biomarker of disease activity in psoriasis patients. They demonstrated that serum IL-19 levels correlated with Psoriasis Area and Severity Index scores, and that treatment with the anti-IL-17A biologic ixekizumab (Taltz) led to rapid reduction of IL-19 down to a normal level.
Moreover, following withdrawal of ixekizumab, IL-19 levels rose prior to clinical relapse, then dropped again in response to retreatment. The hope is that this assay will serve as an accurate tool for assessment of response to therapy.
Dr. Gordon reported receiving research funding and/or honoraria from more than a dozen pharmaceutical companies involved in psoriasis therapy.
MedscapeLive and this news organization are owned by the same parent company.
at MedscapeLive’s annual Las Vegas Dermatology Seminar, held virtually.
Among these unexpected developments was the startling finding that skin inflammation in mild psoriasis is at least as great as in severe disease; evidence that psoriasis may actually be an autoimmune disease rather than a nonspecific immune-mediated disease; and the newly appreciated importance of interleukin-19 (IL-19) in keratinocyte proliferation, according to Dr. Gordon, professor and chair of the department of dermatology at the Medical College of Wisconsin, Milwaukee.
“Our understanding of the pathophysiology of psoriasis is still a work in progress,” the dermatologist observed.
Immunoregulatory deficits in mild vs. severe psoriasis
Conventional wisdom has held that mild psoriasis as defined by limited affected body surface area involves less skin inflammation than more extensive severe psoriasis, so less-potent topical therapies are appropriate. Not so, according to Dr. Gordon, who highlighted work by James G. Krueger, MD, PhD, head of the laboratory of investigative dermatology at Rockefeller University, New York, and coinvestigators. They demonstrated that overall skin inflammation expressed as the sum of T-cell activation and IL-19-mediated epidermal responses didn’t differ in lesions of mild as compared with severe psoriasis. Indeed, mild skin lesions featured a greater number of T-cells, stronger expression of proinflammatory cytokine IL-17A, and greater expression of the central psoriasis transcriptome. The big difference between skin lesions of mild versus severe psoriasis was that severe psoriasis was characterized by strikingly weaker expression of immunoregulatory genes, including programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA4), than that of mild lesions.
The implication is that IL-17-targeted therapies may be of benefit in a much larger segment of the psoriatic population: namely, those with mild disease, who comprise the majority of psoriasis patients by a wide margin, according to the investigators.
Dr. Gordon concurs.
“The primary problem in psoriasis is not so much the inflammatory activity, but the ability to turn off the activity,” he explained. “That implies that if a patient wants to get clear or have significant improvement in disease, you can’t use a less effective medication just because they have less amount of disease. You’re going to need to treat it just as aggressively because the great majority of our medications block the proinflammatory pathways.”
The deficit in immunoregulatory action identified by Dr. Krueger and colleagues in patients with severe disease could provide a novel therapeutic target. If the deficient immunoregulation could be boosted, it might achieve disease control without need for continuous anti-inflammatory therapy.
Autoimmunity in psoriasis
“When I started work in psoriasis, we always thought there would be a common antigen for the immune process in the disease. We never found it. So for that reason, we sort of put it aside and called psoriasis a nonspecific immune-mediated disease,” Dr. Gordon recalled.
That view is being reexamined. “While we’re not completely certain, there is now some evidence that there might be autoimmunity in psoriasis,” he said.
He cited work by an international team of investigators who identified the cathelicidin antimicrobial peptide LL37 as being overexpressed in psoriatic skin, where it appears to serve as a T-cell autoantigen. LL37-specific CD4+ and CD8+ T-cells are skin homing: They can infiltrate lesional skin, where they produce interferon-gamma and proinflammatory Th17 cytokines. The investigators reported that levels of circulating LL37-specific T cells correlated with disease activity such that they were found in three-quarters of patients with moderate to severe plaque psoriasis.
“As LL37 is able to activate innate immune cells and break innate tolerance to self-nucleic acids, it represents an even more appealing target to treat psoriasis. Therapeutic targeting of LL37-specific T cells may provide new avenues to prevent or treat psoriasis without inducing indiscriminate immunosuppression,” the investigators concluded.
Similarly, German investigators have identified ADAMTS-like protein 5 (ADAMTSL5) as an autoantigen specific for melanocytes in psoriasis patients who possess the central psoriasis risk gene, known as HLA-C*06:02, which is present in two-thirds of patients with psoriasis. They proposed that their newly recognized autoimmune pathway may explain how HLA-C*06.02 predisposes to psoriasis.
Growing clinical relevance of IL-19
It’s now well-established that IL-17 is the pivotal force driving the changes in keratinocytes that define the visible expressions of psoriasis, including plaque scale and thickness, which are due to abnormal keratinocyte maturation and proliferation, respectively. Less well appreciated is the fact that IL-17-activated keratinocytes produce IL-19, which feeds back and further stimulates keratinocyte proliferation.
In light of mounting evidence that IL-19 plays an important role in the pathogenesis of psoriasis and that naked eye assessment of visible psoriasis may not reflect the true extent of inflammation, Brian J. Nickoloff, MD, PhD, and coworkers at Lilly Research Laboratories have developed a novel serum IL-19 immunoassay that appears to provide a much-needed objective biomarker of disease activity in psoriasis patients. They demonstrated that serum IL-19 levels correlated with Psoriasis Area and Severity Index scores, and that treatment with the anti-IL-17A biologic ixekizumab (Taltz) led to rapid reduction of IL-19 down to a normal level.
Moreover, following withdrawal of ixekizumab, IL-19 levels rose prior to clinical relapse, then dropped again in response to retreatment. The hope is that this assay will serve as an accurate tool for assessment of response to therapy.
Dr. Gordon reported receiving research funding and/or honoraria from more than a dozen pharmaceutical companies involved in psoriasis therapy.
MedscapeLive and this news organization are owned by the same parent company.
at MedscapeLive’s annual Las Vegas Dermatology Seminar, held virtually.
Among these unexpected developments was the startling finding that skin inflammation in mild psoriasis is at least as great as in severe disease; evidence that psoriasis may actually be an autoimmune disease rather than a nonspecific immune-mediated disease; and the newly appreciated importance of interleukin-19 (IL-19) in keratinocyte proliferation, according to Dr. Gordon, professor and chair of the department of dermatology at the Medical College of Wisconsin, Milwaukee.
“Our understanding of the pathophysiology of psoriasis is still a work in progress,” the dermatologist observed.
Immunoregulatory deficits in mild vs. severe psoriasis
Conventional wisdom has held that mild psoriasis as defined by limited affected body surface area involves less skin inflammation than more extensive severe psoriasis, so less-potent topical therapies are appropriate. Not so, according to Dr. Gordon, who highlighted work by James G. Krueger, MD, PhD, head of the laboratory of investigative dermatology at Rockefeller University, New York, and coinvestigators. They demonstrated that overall skin inflammation expressed as the sum of T-cell activation and IL-19-mediated epidermal responses didn’t differ in lesions of mild as compared with severe psoriasis. Indeed, mild skin lesions featured a greater number of T-cells, stronger expression of proinflammatory cytokine IL-17A, and greater expression of the central psoriasis transcriptome. The big difference between skin lesions of mild versus severe psoriasis was that severe psoriasis was characterized by strikingly weaker expression of immunoregulatory genes, including programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA4), than that of mild lesions.
The implication is that IL-17-targeted therapies may be of benefit in a much larger segment of the psoriatic population: namely, those with mild disease, who comprise the majority of psoriasis patients by a wide margin, according to the investigators.
Dr. Gordon concurs.
“The primary problem in psoriasis is not so much the inflammatory activity, but the ability to turn off the activity,” he explained. “That implies that if a patient wants to get clear or have significant improvement in disease, you can’t use a less effective medication just because they have less amount of disease. You’re going to need to treat it just as aggressively because the great majority of our medications block the proinflammatory pathways.”
The deficit in immunoregulatory action identified by Dr. Krueger and colleagues in patients with severe disease could provide a novel therapeutic target. If the deficient immunoregulation could be boosted, it might achieve disease control without need for continuous anti-inflammatory therapy.
Autoimmunity in psoriasis
“When I started work in psoriasis, we always thought there would be a common antigen for the immune process in the disease. We never found it. So for that reason, we sort of put it aside and called psoriasis a nonspecific immune-mediated disease,” Dr. Gordon recalled.
That view is being reexamined. “While we’re not completely certain, there is now some evidence that there might be autoimmunity in psoriasis,” he said.
He cited work by an international team of investigators who identified the cathelicidin antimicrobial peptide LL37 as being overexpressed in psoriatic skin, where it appears to serve as a T-cell autoantigen. LL37-specific CD4+ and CD8+ T-cells are skin homing: They can infiltrate lesional skin, where they produce interferon-gamma and proinflammatory Th17 cytokines. The investigators reported that levels of circulating LL37-specific T cells correlated with disease activity such that they were found in three-quarters of patients with moderate to severe plaque psoriasis.
“As LL37 is able to activate innate immune cells and break innate tolerance to self-nucleic acids, it represents an even more appealing target to treat psoriasis. Therapeutic targeting of LL37-specific T cells may provide new avenues to prevent or treat psoriasis without inducing indiscriminate immunosuppression,” the investigators concluded.
Similarly, German investigators have identified ADAMTS-like protein 5 (ADAMTSL5) as an autoantigen specific for melanocytes in psoriasis patients who possess the central psoriasis risk gene, known as HLA-C*06:02, which is present in two-thirds of patients with psoriasis. They proposed that their newly recognized autoimmune pathway may explain how HLA-C*06.02 predisposes to psoriasis.
Growing clinical relevance of IL-19
It’s now well-established that IL-17 is the pivotal force driving the changes in keratinocytes that define the visible expressions of psoriasis, including plaque scale and thickness, which are due to abnormal keratinocyte maturation and proliferation, respectively. Less well appreciated is the fact that IL-17-activated keratinocytes produce IL-19, which feeds back and further stimulates keratinocyte proliferation.
In light of mounting evidence that IL-19 plays an important role in the pathogenesis of psoriasis and that naked eye assessment of visible psoriasis may not reflect the true extent of inflammation, Brian J. Nickoloff, MD, PhD, and coworkers at Lilly Research Laboratories have developed a novel serum IL-19 immunoassay that appears to provide a much-needed objective biomarker of disease activity in psoriasis patients. They demonstrated that serum IL-19 levels correlated with Psoriasis Area and Severity Index scores, and that treatment with the anti-IL-17A biologic ixekizumab (Taltz) led to rapid reduction of IL-19 down to a normal level.
Moreover, following withdrawal of ixekizumab, IL-19 levels rose prior to clinical relapse, then dropped again in response to retreatment. The hope is that this assay will serve as an accurate tool for assessment of response to therapy.
Dr. Gordon reported receiving research funding and/or honoraria from more than a dozen pharmaceutical companies involved in psoriasis therapy.
MedscapeLive and this news organization are owned by the same parent company.
FROM MEDSCAPELIVE LAS VEGAS DERMATOLOGY SEMINAR
RA experts highlight key developments over the past year
A massive Swedish cohort study suggesting that biologic agents reduce the known excess risk of lymphoma in patients with rheumatoid arthritis was hailed as one of the high points of the last year by speakers at the 2021 Rheumatology Winter Clinical Symposium.
The speakers gave additional shout-outs regarding other key developments in RA during the pandemic year, including two huge studies showing that even low-dose corticosteroids at 5 mg/day or less carry the price of increased risk of cardiovascular disease and serious infections; Swedish data showing that RA disease activity can be used for venous thromboembolism (VTE) risk stratification; evidence from the venerable BeST study showing at 17 years of follow-up that treat-to-target strategies didn’t prevent an increased mortality risk of RA compared to the general population; and a signal that artificial intelligence using machine learning will become useful in clinical practice sooner than many realize.
Also, the speakers offered kudos to the investigators in the SEAM-RA trial, whose results they expect to be practice changing. In addition, they praised the SELECT-CHOICE trial for providing insight into the relative safety and efficacy of upadacitinib (Rinvoq) and abatacept (Orencia) as second- or third-line therapy in RA. And they warned their colleagues of rocky upcoming months for tofacitinib (Xeljanz) as the Food and Drug Administration reviews concerning new data from a long-term postmarketing safety trial.
Swedes show biologics may reduce excess lymphoma risk in RA
Decades ago, Swedish investigators harnessed their nation’s comprehensive linked health registries to demonstrate that patients with RA are inherently at greater risk for developing lymphoma. Now the Swedes have used the registries to identify a strong signal that this excess risk of lymphoma is reduced in RA patients treated with biologic drugs.
The study included 16,392 RA patients who initiated treatment with a biologic during the study period, 55,253 who were biologic-naive, and 229,047 age- and sex-matched controls from the general population. During the years 2006-2016, there was an adjusted 31% reduction in the risk of incident lymphoma in RA patients who started a first biologic agent, compared with those who did not, and a 54% reduction in lymphoma in biologic-treated patients, compared with those who switched from one conventional synthetic disease-modifying antirheumatic drug (DMARD) to another.
Moreover, while RA patients with 0-2 years of accumulated time on biologics were at a statistically significant 3.42-fold increased risk of lymphoma, compared with the matched general population, that risk shrunk with longer exposure to these medications, dropping to a nonsignificant 1.53-fold increase with 3-4 years of biologic exposure and a 1.04-fold risk with 5 years or more. The lymphoma risks didn’t vary significantly among the TNF inhibitors, nor with the use of TNF inhibitors versus other biologics.
“I think this is really quite encouraging,” said John J. Cush, MD, professor of internal medicine at the University of Texas, Dallas. “If the lymphoma risk was related to inflammation, I think you’d see results like this. It really does speak to the fact that control of inflammation over time does lessen one’s risk of cancer.”
Arthur Kavanaugh, MD, observed that patients with RA continue to ask their rheumatologists if going on a TNF inhibitor will increase their risk of lymphoma, so these Swedish data are going to be useful in conversations in the clinic.
“I thought this study was very exciting,” said Dr. Kavanaugh, professor of medicine at the University of California, San Diego, and director of RWCS. “Maybe we can make the case now that the longer you’re on biologic therapies and the more recently you’re being treated, the better you do in terms of lymphoma risk.”
Beware underappreciated hazards of very-low-dose glucocorticoids
The increased risk of osteoporotic fractures associated with corticosteroid therapy gets tons of attention. But the past year brought two cautionary studies that newly identified significantly increased risks of cardiovascular events and serious infection as well, even at doses of less than 5 mg/day, which have traditionally been believed safe long term.
Investigators at the University of Leeds (England) conducted a population-based cohort study in which they used the U.K. Clinical Practice Research Datalink to analyze the oral corticosteroid dose-dependent cardiovascular risk in 25,324 patients with RA and 62,470 with five other immune-mediated inflammatory diseases: inflammatory bowel disease, giant cell arteritis, polymyalgia rheumatica, systemic lupus erythematosus, and vasculitis. None had known cardiovascular disease at baseline. The analysis accounted for changes in oral steroid dose over time and for the use of potentially confounding medications.
Over a median 5 years of follow-up, a strong steroid dose-dependent risk of acute MI, heart failure, atrial fibrillation, cerebrovascular disease, and abdominal aortic aneurysm was evident in patients with any of the six of the immune-mediated inflammatory diseases. The 1-year adjusted cumulative risk of major adverse cardiovascular events jumped from 1.4% during periods of nonuse to 8.9% at a daily dose of 25 mg or more. Notably, when patients were on oral steroids at doses less than 5 mg/day, their risk of one or more of these major adverse cardiovascular events was 74% greater than when off steroids.
A separate red flag regarding low-dose glucocorticoids was raised by a retrospective cohort study of the 1-year risk of hospitalization for serious infection in 172,041 RA patients in the Medicare claims database for the years 2005-2015. After 6 months of stable use of DMARDs, 47.1% of those patients were on corticosteroids. Their 1-year cumulative incidence of severe infection resulting in hospitalization was 11% if their dose was 5 mg/day or less, 14.4% at >5 to 10 mg/day, and 17.7% at >10 mg/day, all significantly greater than the 8.6% rate in patients not on steroids. The same pattern held true when the investigators separately scrutinized 44,118 RA patients in the Optum Clinformatics Data Mart database for the years 2006-2015.
“This is a really important paper telling us what you’ve always known, which is that there’s a dose-related increase in serious infections in people on steroids. Everybody knows that, but usually people think of 10 mg/day and above,” Dr. Cush said. “This is a little bit sobering for those of you who think, ‘Well, I’m doing OK using 2.5 or 4 mg/day.’ In this study, even at doses of 5 mg/day or less, there’s a significant increase in serious hospitalizable infections.”
Taken together, the message of these two huge studies is clear, he added: “The idea is we probably shouldn’t be using steroids.”
Given the large array of therapies now available to address various aspects of the inflammatory and immune responses in RA, Dr. Kavanaugh asked, why do so many rheumatologists still maintain their patients on low-dose steroids?
”Because when we find something that works, we stick to it,” Dr. Cush replied.
RA disease activity predicts VTE risk
The risk of VTE climbs with RA disease activity such that patients with high disease activity – defined using the erythrocyte sedimentation rate-based Disease Activity Score in 28 joints (DAS28-ESR) – have double the VTE risk of those in disease remission, according to a Swedish nationwide cohort study using data from the Swedish Rheumatology Quality Register. The investigators concluded that RA disease activity can be used in clinical practice as an additional tool for VTE risk stratification, alongside such established risk factors as immobilization, age, surgery, and comorbid conditions.
The study included 46,316 patients with RA who collectively experienced 2,241 VTE events within 1 year after one of their collective 322,601 visits to their rheumatologist. The overall cumulative 1-year incidence of VTE in the RA population was 0.71%, versus 0.36% in a control group composed of 215,843 randomly selected age- and sex-matched individuals drawn from the general Swedish population. That translates to an adjusted 1.88-fold increased risk in the RA group.
The VTE incidence was 0.52% in the year following a rheumatologist visit at which RA patients were found to be in DAS28-ESR remission. The adjusted risk for VTE climbed significantly in stepwise fashion with increasing disease activity: 12% greater risk with DAS28-ESR low disease activity, 48% greater risk with moderate disease activity, and 2.03-fold greater risk with high disease activity.
SEAM-RA shows which drug to withdraw to maintain remission gained on combo therapy
The SEAM-RA trial presented at the 2020 annual meeting of the American College of Rheumatology (ACR) and published shortly afterward in Arthritis & Rheumatology provides guidance on how to best implement a drug tapering strategy in patients who have achieved sustained remission on combination therapy with etanercept (Enbrel) and methotrexate. The purpose of such a strategy is to reduce patients’ medication burden and exposure to safety concerns inherent in continuing therapy. SEAM-RA included 371 RA patients in sustained disease remission during 24 weeks of open-label treatment with etanercept plus methotrexate. At that point, they were randomized 2:2:1 to 48 weeks of double-blind methotrexate monotherapy with etanercept withdrawal, etanercept monotherapy, or continued combination therapy. Those who experienced disease worsening on double-blind monotherapy were eligible for combination rescue therapy with both drugs.
The primary endpoint was maintenance of remission without disease worsening at week 48. This was accomplished in 52.9% of the combination therapy group, with a similar 49.5% success rate in patients on etanercept monotherapy, both significantly better than the 28.7% rate with methotrexate monotherapy. The inference is that biologic monotherapy might be an advantageous strategy for maintenance after achieving prolonged remission on combination therapy.
“This study could impact guidelines,” Dr. Cush predicted.
Among the key study findings, in his view, was that disease worsening occurred early following the switch to methotrexate monotherapy: typically within the first 2-4 weeks. And combination rescue therapy worked: Almost 75% of patients were able to recapture disease remission regardless of which drug they’d been on as monotherapy, and almost 90% of patients on rescue therapy achieved a low-disease-activity state.
Still, just over half of patients were able to maintain long-term remission after downshifting to etanercept monotherapy, Dr. Kavanaugh noted. “The bedeviling thing is we don’t know which patients can do this,” he said.
This was made abundantly clear in PREDICTRA, a phase 4, double-blind study in which 122 RA patients in sustained remission on 40 mg of adalimumab (Humira) every 2 weeks were randomized 5:1 to adalimumab taper or withdrawal for 36 weeks. Overall, 36% of the taper group and 45% of those who halted the biologic flared within 36 weeks. Nothing on an extensive list of candidate baseline predictors predicted flare in either group.
”I think the interesting thing here is that nothing predicted it, not drug levels, antidrug antibodies, not even MRI evidence of inflammation while in remission. The lack of predictors of who’s going to do well off therapy makes us crazy,” Dr. Kavanaugh said. Also noteworthy was that when full-dose, open-label adalimumab was reinstituted as rescue therapy in patients who flared, only half of them regained remission during the following 4 months, he observed.
Dr. Cush didn’t mince words regarding his view of the concept underlying PREDICTRA.
“Why are we even talking about this? We spend our whole lives trying to get these patients into remission, we’re heavily invested in combination therapy, we’re very proud of our great successes, and now we want to find data to condone, ‘Let’s get off drug therapy?’ ” he argued.
“There are untold consequences to this,” the rheumatologist continued. “There are cardiovascular consequences, and we’ve seen the x-ray studies that show that patients may be doing clinically better but still have x-ray worsening because you’ve withdrawn the TNF inhibitor. I think this is all nonsense, and I’m totally against it.”
Making a SELECT-CHOICE in refractory RA
In patients whose RA has proved refractory to one or more biologics, opting for the oral Janus kinase inhibitor upadacitinib as next-line therapy is significantly more effective than turning to the T-cell costimulation modulator abatacept, but at the cost of a doubled risk of severe adverse events, according to the findings of the phase 3, double-blind, 24-week, randomized SELECT-CHOICE trial.
In this 612-patient study, the week-12 clinical remission rate as defined by a C-reactive protein (CRP)-based DAS28 below 2.6 was 30% in the upadacitinib arm, compared to 13.3% with abatacept. At week 24, the remission rates were 46% and 31%, respectively. However, the severe adverse event rate was 6.3% in the upadacitinib group, including one death, one stroke, and two cases of VTE, compared to 3.2% with abatacept.
“Maybe this is a win for upadacitinib, but abatacept is a win when it comes to safety,” Dr. Cush said. “So the question is, when you’re making your second or third change in a biologic DMARD, are you going for safety or are you going for efficacy?”
Make way for machine learning
Studies of machine learning and artificial intelligence aimed at developing a more individualized treatment approach are popping up with increasing frequency at the major rheumatology meetings.
“This is really, I think, the future because for most of us, in most of our choices, as great as all of us are in managing RA, it is a crystal ball and a coin toss as to whether our next therapy is going to work,” Dr. Cush said.
He highlighted a study presented at the 2020 ACR annual meeting as an example of how machine learning can generate better evidence for selecting therapies. An international team of investigators used artificial intelligence to develop a simple rule to predict an RA patient’s likely response to the interleukin-6 receptor inhibitor sarilumab (Kevzara). The researchers developed a list of 42 candidate predictors of an ACR20 response, including demographics, biomarkers, and disease activity scores, then applied machine learning to data from the 1,197-patient, phase 3 MOBILITY trial of sarilumab versus placebo in order to generate a predictive rule of better outcomes.
Out of the 42 candidate predictive values, the best predictive rule turned out to be the combination of the presence of anti-citrullinated protein antibodies and a baseline CRP level greater than 12.3 mg/L. This rule was then put to the test using data from four phase 3 clinical trials in which 34%-51% of RA patients randomized to sarilumab were rule-positive. The rule-positive patients had worse baseline prognostic factors and more severe RA. Yet rule-positive patients had a better outcome than that of those who were rule-negative. For example, a week-24 ACR70 response was achieved in 34% of rule-positive patients, nearly fivefold greater than the 7% rate in the rule-negative group.
Treat-to-target strategies don’t tame excess mortality in RA
At a mean of 17 years of follow-up in the Dutch BeST study – a pioneering treat-to-target study in RA – patients with early RA who were assigned to one of four treat-to-target strategies for 10 years showed excess mortality compared to the general age- and sex-matched Dutch population, Johanna M. Maassen, MD, reported at the 2020 annual meeting of the European Alliance of Associations for Rheumatology (EULAR). Indeed, mortality was 37% higher in the RA patients than in the comparator population, with no significant differences in survival curves evident between the four tight-control strategies.
“This raises the question of whether survival in patients not strictly treated to target would have been even lower. Are we not doing as well as we think we’re doing?” Dr. Kavanaugh said.
“This is very sobering. It tells us we really do need to be better at managing RA. And I would say based on this data we need to be better at managing RA really early to get better outcomes really late,” said Dr. Cush. “The damage that led to cardiovascular risk could have been incurred earlier on and then carried forward when you look out to 15-20 years.”
More trouble for tofacitinib
Tofacitinib faces an uncertain future following Pfizer’s late-January press release announcing that the JAK inhibitor failed to meet noninferiority compared to anti-TNF therapy in terms of adjudicated major adverse cardiovascular events (MACE) and adjudicated malignancies in an FDA-mandated postmarketing safety study. The study, known as ORAL Surveillance, or Study A3921133 – ‘1133’ for short – randomized 4,362 RA patients aged 50 years or older with at least one additional cardiovascular risk factor to tofacitinib at 5 or 10 mg twice daily or to a TNF inhibitor.
The Pfizer press release was soon followed by an FDA safety warning and announcement that the agency is reviewing the full study data before making any final recommendations. The FDA already requires black box warnings for tofacitinib regarding increased risks of blood clots and death, but only at the 10-mg twice-daily dose. In the ORAL Surveillance study, however, the primary endpoint was noninferiority of the combined tofacitinib doses, and there was no evidence of a difference in endpoints between the 5- and 10-mg twice-daily doses.
Only the topline results released in the Pfizer press release are publicly available so far. The combined tofacitinib doses were associated with a 1.33-fold greater risk of adjudicated MACE and a 1.48-fold increase in adjudicated malignancies other than nonmelanoma skin cancer, compared to adalimumab or etanercept.
The jury is still out pending release of the full study data, in Dr. Kavanaugh’s view.
“When I get to look at the data, I want to see who are the people who had the events, their characteristics,” he said.
Alexis R. Ogdie-Beatty, MD, said the study’s topline results “make me a little nervous.
“The effect size is pretty large. It’s in the 1.4 range, which means there might be something there for real,” said Dr. Ogdie-Beatty, a rheumatologist and epidemiologist at the University of Pennsylvania, Philadelphia.
In contrast, Eric M. Ruderman, MD, said he’s not concerned “just yet” about the results.
“Frankly, the FDA was just plain wrong in their press release because the confidence intervals for the MACE events crossed 1.0 meaningfully [0.91, 1.94], so there’s nothing there. And the confidence intervals hit 1.0 for the malignancies,” observed Dr. Ruderman, professor of medicine at Northwestern University, Chicago.
This was a nearly 4,400-patient study, and given that it couldn’t convincingly show a safety risk, such risk – if it even exists – would seem to be tiny, he added.
“It’s probably not going to change the way we prescribe these drugs. So I don’t see that trial taking away from the big run for JAK inhibitors we’re going to see in the next year,” the rheumatologist said.
The speakers reported having financial relationships with numerous pharmaceutical companies.
A massive Swedish cohort study suggesting that biologic agents reduce the known excess risk of lymphoma in patients with rheumatoid arthritis was hailed as one of the high points of the last year by speakers at the 2021 Rheumatology Winter Clinical Symposium.
The speakers gave additional shout-outs regarding other key developments in RA during the pandemic year, including two huge studies showing that even low-dose corticosteroids at 5 mg/day or less carry the price of increased risk of cardiovascular disease and serious infections; Swedish data showing that RA disease activity can be used for venous thromboembolism (VTE) risk stratification; evidence from the venerable BeST study showing at 17 years of follow-up that treat-to-target strategies didn’t prevent an increased mortality risk of RA compared to the general population; and a signal that artificial intelligence using machine learning will become useful in clinical practice sooner than many realize.
Also, the speakers offered kudos to the investigators in the SEAM-RA trial, whose results they expect to be practice changing. In addition, they praised the SELECT-CHOICE trial for providing insight into the relative safety and efficacy of upadacitinib (Rinvoq) and abatacept (Orencia) as second- or third-line therapy in RA. And they warned their colleagues of rocky upcoming months for tofacitinib (Xeljanz) as the Food and Drug Administration reviews concerning new data from a long-term postmarketing safety trial.
Swedes show biologics may reduce excess lymphoma risk in RA
Decades ago, Swedish investigators harnessed their nation’s comprehensive linked health registries to demonstrate that patients with RA are inherently at greater risk for developing lymphoma. Now the Swedes have used the registries to identify a strong signal that this excess risk of lymphoma is reduced in RA patients treated with biologic drugs.
The study included 16,392 RA patients who initiated treatment with a biologic during the study period, 55,253 who were biologic-naive, and 229,047 age- and sex-matched controls from the general population. During the years 2006-2016, there was an adjusted 31% reduction in the risk of incident lymphoma in RA patients who started a first biologic agent, compared with those who did not, and a 54% reduction in lymphoma in biologic-treated patients, compared with those who switched from one conventional synthetic disease-modifying antirheumatic drug (DMARD) to another.
Moreover, while RA patients with 0-2 years of accumulated time on biologics were at a statistically significant 3.42-fold increased risk of lymphoma, compared with the matched general population, that risk shrunk with longer exposure to these medications, dropping to a nonsignificant 1.53-fold increase with 3-4 years of biologic exposure and a 1.04-fold risk with 5 years or more. The lymphoma risks didn’t vary significantly among the TNF inhibitors, nor with the use of TNF inhibitors versus other biologics.
“I think this is really quite encouraging,” said John J. Cush, MD, professor of internal medicine at the University of Texas, Dallas. “If the lymphoma risk was related to inflammation, I think you’d see results like this. It really does speak to the fact that control of inflammation over time does lessen one’s risk of cancer.”
Arthur Kavanaugh, MD, observed that patients with RA continue to ask their rheumatologists if going on a TNF inhibitor will increase their risk of lymphoma, so these Swedish data are going to be useful in conversations in the clinic.
“I thought this study was very exciting,” said Dr. Kavanaugh, professor of medicine at the University of California, San Diego, and director of RWCS. “Maybe we can make the case now that the longer you’re on biologic therapies and the more recently you’re being treated, the better you do in terms of lymphoma risk.”
Beware underappreciated hazards of very-low-dose glucocorticoids
The increased risk of osteoporotic fractures associated with corticosteroid therapy gets tons of attention. But the past year brought two cautionary studies that newly identified significantly increased risks of cardiovascular events and serious infection as well, even at doses of less than 5 mg/day, which have traditionally been believed safe long term.
Investigators at the University of Leeds (England) conducted a population-based cohort study in which they used the U.K. Clinical Practice Research Datalink to analyze the oral corticosteroid dose-dependent cardiovascular risk in 25,324 patients with RA and 62,470 with five other immune-mediated inflammatory diseases: inflammatory bowel disease, giant cell arteritis, polymyalgia rheumatica, systemic lupus erythematosus, and vasculitis. None had known cardiovascular disease at baseline. The analysis accounted for changes in oral steroid dose over time and for the use of potentially confounding medications.
Over a median 5 years of follow-up, a strong steroid dose-dependent risk of acute MI, heart failure, atrial fibrillation, cerebrovascular disease, and abdominal aortic aneurysm was evident in patients with any of the six of the immune-mediated inflammatory diseases. The 1-year adjusted cumulative risk of major adverse cardiovascular events jumped from 1.4% during periods of nonuse to 8.9% at a daily dose of 25 mg or more. Notably, when patients were on oral steroids at doses less than 5 mg/day, their risk of one or more of these major adverse cardiovascular events was 74% greater than when off steroids.
A separate red flag regarding low-dose glucocorticoids was raised by a retrospective cohort study of the 1-year risk of hospitalization for serious infection in 172,041 RA patients in the Medicare claims database for the years 2005-2015. After 6 months of stable use of DMARDs, 47.1% of those patients were on corticosteroids. Their 1-year cumulative incidence of severe infection resulting in hospitalization was 11% if their dose was 5 mg/day or less, 14.4% at >5 to 10 mg/day, and 17.7% at >10 mg/day, all significantly greater than the 8.6% rate in patients not on steroids. The same pattern held true when the investigators separately scrutinized 44,118 RA patients in the Optum Clinformatics Data Mart database for the years 2006-2015.
“This is a really important paper telling us what you’ve always known, which is that there’s a dose-related increase in serious infections in people on steroids. Everybody knows that, but usually people think of 10 mg/day and above,” Dr. Cush said. “This is a little bit sobering for those of you who think, ‘Well, I’m doing OK using 2.5 or 4 mg/day.’ In this study, even at doses of 5 mg/day or less, there’s a significant increase in serious hospitalizable infections.”
Taken together, the message of these two huge studies is clear, he added: “The idea is we probably shouldn’t be using steroids.”
Given the large array of therapies now available to address various aspects of the inflammatory and immune responses in RA, Dr. Kavanaugh asked, why do so many rheumatologists still maintain their patients on low-dose steroids?
”Because when we find something that works, we stick to it,” Dr. Cush replied.
RA disease activity predicts VTE risk
The risk of VTE climbs with RA disease activity such that patients with high disease activity – defined using the erythrocyte sedimentation rate-based Disease Activity Score in 28 joints (DAS28-ESR) – have double the VTE risk of those in disease remission, according to a Swedish nationwide cohort study using data from the Swedish Rheumatology Quality Register. The investigators concluded that RA disease activity can be used in clinical practice as an additional tool for VTE risk stratification, alongside such established risk factors as immobilization, age, surgery, and comorbid conditions.
The study included 46,316 patients with RA who collectively experienced 2,241 VTE events within 1 year after one of their collective 322,601 visits to their rheumatologist. The overall cumulative 1-year incidence of VTE in the RA population was 0.71%, versus 0.36% in a control group composed of 215,843 randomly selected age- and sex-matched individuals drawn from the general Swedish population. That translates to an adjusted 1.88-fold increased risk in the RA group.
The VTE incidence was 0.52% in the year following a rheumatologist visit at which RA patients were found to be in DAS28-ESR remission. The adjusted risk for VTE climbed significantly in stepwise fashion with increasing disease activity: 12% greater risk with DAS28-ESR low disease activity, 48% greater risk with moderate disease activity, and 2.03-fold greater risk with high disease activity.
SEAM-RA shows which drug to withdraw to maintain remission gained on combo therapy
The SEAM-RA trial presented at the 2020 annual meeting of the American College of Rheumatology (ACR) and published shortly afterward in Arthritis & Rheumatology provides guidance on how to best implement a drug tapering strategy in patients who have achieved sustained remission on combination therapy with etanercept (Enbrel) and methotrexate. The purpose of such a strategy is to reduce patients’ medication burden and exposure to safety concerns inherent in continuing therapy. SEAM-RA included 371 RA patients in sustained disease remission during 24 weeks of open-label treatment with etanercept plus methotrexate. At that point, they were randomized 2:2:1 to 48 weeks of double-blind methotrexate monotherapy with etanercept withdrawal, etanercept monotherapy, or continued combination therapy. Those who experienced disease worsening on double-blind monotherapy were eligible for combination rescue therapy with both drugs.
The primary endpoint was maintenance of remission without disease worsening at week 48. This was accomplished in 52.9% of the combination therapy group, with a similar 49.5% success rate in patients on etanercept monotherapy, both significantly better than the 28.7% rate with methotrexate monotherapy. The inference is that biologic monotherapy might be an advantageous strategy for maintenance after achieving prolonged remission on combination therapy.
“This study could impact guidelines,” Dr. Cush predicted.
Among the key study findings, in his view, was that disease worsening occurred early following the switch to methotrexate monotherapy: typically within the first 2-4 weeks. And combination rescue therapy worked: Almost 75% of patients were able to recapture disease remission regardless of which drug they’d been on as monotherapy, and almost 90% of patients on rescue therapy achieved a low-disease-activity state.
Still, just over half of patients were able to maintain long-term remission after downshifting to etanercept monotherapy, Dr. Kavanaugh noted. “The bedeviling thing is we don’t know which patients can do this,” he said.
This was made abundantly clear in PREDICTRA, a phase 4, double-blind study in which 122 RA patients in sustained remission on 40 mg of adalimumab (Humira) every 2 weeks were randomized 5:1 to adalimumab taper or withdrawal for 36 weeks. Overall, 36% of the taper group and 45% of those who halted the biologic flared within 36 weeks. Nothing on an extensive list of candidate baseline predictors predicted flare in either group.
”I think the interesting thing here is that nothing predicted it, not drug levels, antidrug antibodies, not even MRI evidence of inflammation while in remission. The lack of predictors of who’s going to do well off therapy makes us crazy,” Dr. Kavanaugh said. Also noteworthy was that when full-dose, open-label adalimumab was reinstituted as rescue therapy in patients who flared, only half of them regained remission during the following 4 months, he observed.
Dr. Cush didn’t mince words regarding his view of the concept underlying PREDICTRA.
“Why are we even talking about this? We spend our whole lives trying to get these patients into remission, we’re heavily invested in combination therapy, we’re very proud of our great successes, and now we want to find data to condone, ‘Let’s get off drug therapy?’ ” he argued.
“There are untold consequences to this,” the rheumatologist continued. “There are cardiovascular consequences, and we’ve seen the x-ray studies that show that patients may be doing clinically better but still have x-ray worsening because you’ve withdrawn the TNF inhibitor. I think this is all nonsense, and I’m totally against it.”
Making a SELECT-CHOICE in refractory RA
In patients whose RA has proved refractory to one or more biologics, opting for the oral Janus kinase inhibitor upadacitinib as next-line therapy is significantly more effective than turning to the T-cell costimulation modulator abatacept, but at the cost of a doubled risk of severe adverse events, according to the findings of the phase 3, double-blind, 24-week, randomized SELECT-CHOICE trial.
In this 612-patient study, the week-12 clinical remission rate as defined by a C-reactive protein (CRP)-based DAS28 below 2.6 was 30% in the upadacitinib arm, compared to 13.3% with abatacept. At week 24, the remission rates were 46% and 31%, respectively. However, the severe adverse event rate was 6.3% in the upadacitinib group, including one death, one stroke, and two cases of VTE, compared to 3.2% with abatacept.
“Maybe this is a win for upadacitinib, but abatacept is a win when it comes to safety,” Dr. Cush said. “So the question is, when you’re making your second or third change in a biologic DMARD, are you going for safety or are you going for efficacy?”
Make way for machine learning
Studies of machine learning and artificial intelligence aimed at developing a more individualized treatment approach are popping up with increasing frequency at the major rheumatology meetings.
“This is really, I think, the future because for most of us, in most of our choices, as great as all of us are in managing RA, it is a crystal ball and a coin toss as to whether our next therapy is going to work,” Dr. Cush said.
He highlighted a study presented at the 2020 ACR annual meeting as an example of how machine learning can generate better evidence for selecting therapies. An international team of investigators used artificial intelligence to develop a simple rule to predict an RA patient’s likely response to the interleukin-6 receptor inhibitor sarilumab (Kevzara). The researchers developed a list of 42 candidate predictors of an ACR20 response, including demographics, biomarkers, and disease activity scores, then applied machine learning to data from the 1,197-patient, phase 3 MOBILITY trial of sarilumab versus placebo in order to generate a predictive rule of better outcomes.
Out of the 42 candidate predictive values, the best predictive rule turned out to be the combination of the presence of anti-citrullinated protein antibodies and a baseline CRP level greater than 12.3 mg/L. This rule was then put to the test using data from four phase 3 clinical trials in which 34%-51% of RA patients randomized to sarilumab were rule-positive. The rule-positive patients had worse baseline prognostic factors and more severe RA. Yet rule-positive patients had a better outcome than that of those who were rule-negative. For example, a week-24 ACR70 response was achieved in 34% of rule-positive patients, nearly fivefold greater than the 7% rate in the rule-negative group.
Treat-to-target strategies don’t tame excess mortality in RA
At a mean of 17 years of follow-up in the Dutch BeST study – a pioneering treat-to-target study in RA – patients with early RA who were assigned to one of four treat-to-target strategies for 10 years showed excess mortality compared to the general age- and sex-matched Dutch population, Johanna M. Maassen, MD, reported at the 2020 annual meeting of the European Alliance of Associations for Rheumatology (EULAR). Indeed, mortality was 37% higher in the RA patients than in the comparator population, with no significant differences in survival curves evident between the four tight-control strategies.
“This raises the question of whether survival in patients not strictly treated to target would have been even lower. Are we not doing as well as we think we’re doing?” Dr. Kavanaugh said.
“This is very sobering. It tells us we really do need to be better at managing RA. And I would say based on this data we need to be better at managing RA really early to get better outcomes really late,” said Dr. Cush. “The damage that led to cardiovascular risk could have been incurred earlier on and then carried forward when you look out to 15-20 years.”
More trouble for tofacitinib
Tofacitinib faces an uncertain future following Pfizer’s late-January press release announcing that the JAK inhibitor failed to meet noninferiority compared to anti-TNF therapy in terms of adjudicated major adverse cardiovascular events (MACE) and adjudicated malignancies in an FDA-mandated postmarketing safety study. The study, known as ORAL Surveillance, or Study A3921133 – ‘1133’ for short – randomized 4,362 RA patients aged 50 years or older with at least one additional cardiovascular risk factor to tofacitinib at 5 or 10 mg twice daily or to a TNF inhibitor.
The Pfizer press release was soon followed by an FDA safety warning and announcement that the agency is reviewing the full study data before making any final recommendations. The FDA already requires black box warnings for tofacitinib regarding increased risks of blood clots and death, but only at the 10-mg twice-daily dose. In the ORAL Surveillance study, however, the primary endpoint was noninferiority of the combined tofacitinib doses, and there was no evidence of a difference in endpoints between the 5- and 10-mg twice-daily doses.
Only the topline results released in the Pfizer press release are publicly available so far. The combined tofacitinib doses were associated with a 1.33-fold greater risk of adjudicated MACE and a 1.48-fold increase in adjudicated malignancies other than nonmelanoma skin cancer, compared to adalimumab or etanercept.
The jury is still out pending release of the full study data, in Dr. Kavanaugh’s view.
“When I get to look at the data, I want to see who are the people who had the events, their characteristics,” he said.
Alexis R. Ogdie-Beatty, MD, said the study’s topline results “make me a little nervous.
“The effect size is pretty large. It’s in the 1.4 range, which means there might be something there for real,” said Dr. Ogdie-Beatty, a rheumatologist and epidemiologist at the University of Pennsylvania, Philadelphia.
In contrast, Eric M. Ruderman, MD, said he’s not concerned “just yet” about the results.
“Frankly, the FDA was just plain wrong in their press release because the confidence intervals for the MACE events crossed 1.0 meaningfully [0.91, 1.94], so there’s nothing there. And the confidence intervals hit 1.0 for the malignancies,” observed Dr. Ruderman, professor of medicine at Northwestern University, Chicago.
This was a nearly 4,400-patient study, and given that it couldn’t convincingly show a safety risk, such risk – if it even exists – would seem to be tiny, he added.
“It’s probably not going to change the way we prescribe these drugs. So I don’t see that trial taking away from the big run for JAK inhibitors we’re going to see in the next year,” the rheumatologist said.
The speakers reported having financial relationships with numerous pharmaceutical companies.
A massive Swedish cohort study suggesting that biologic agents reduce the known excess risk of lymphoma in patients with rheumatoid arthritis was hailed as one of the high points of the last year by speakers at the 2021 Rheumatology Winter Clinical Symposium.
The speakers gave additional shout-outs regarding other key developments in RA during the pandemic year, including two huge studies showing that even low-dose corticosteroids at 5 mg/day or less carry the price of increased risk of cardiovascular disease and serious infections; Swedish data showing that RA disease activity can be used for venous thromboembolism (VTE) risk stratification; evidence from the venerable BeST study showing at 17 years of follow-up that treat-to-target strategies didn’t prevent an increased mortality risk of RA compared to the general population; and a signal that artificial intelligence using machine learning will become useful in clinical practice sooner than many realize.
Also, the speakers offered kudos to the investigators in the SEAM-RA trial, whose results they expect to be practice changing. In addition, they praised the SELECT-CHOICE trial for providing insight into the relative safety and efficacy of upadacitinib (Rinvoq) and abatacept (Orencia) as second- or third-line therapy in RA. And they warned their colleagues of rocky upcoming months for tofacitinib (Xeljanz) as the Food and Drug Administration reviews concerning new data from a long-term postmarketing safety trial.
Swedes show biologics may reduce excess lymphoma risk in RA
Decades ago, Swedish investigators harnessed their nation’s comprehensive linked health registries to demonstrate that patients with RA are inherently at greater risk for developing lymphoma. Now the Swedes have used the registries to identify a strong signal that this excess risk of lymphoma is reduced in RA patients treated with biologic drugs.
The study included 16,392 RA patients who initiated treatment with a biologic during the study period, 55,253 who were biologic-naive, and 229,047 age- and sex-matched controls from the general population. During the years 2006-2016, there was an adjusted 31% reduction in the risk of incident lymphoma in RA patients who started a first biologic agent, compared with those who did not, and a 54% reduction in lymphoma in biologic-treated patients, compared with those who switched from one conventional synthetic disease-modifying antirheumatic drug (DMARD) to another.
Moreover, while RA patients with 0-2 years of accumulated time on biologics were at a statistically significant 3.42-fold increased risk of lymphoma, compared with the matched general population, that risk shrunk with longer exposure to these medications, dropping to a nonsignificant 1.53-fold increase with 3-4 years of biologic exposure and a 1.04-fold risk with 5 years or more. The lymphoma risks didn’t vary significantly among the TNF inhibitors, nor with the use of TNF inhibitors versus other biologics.
“I think this is really quite encouraging,” said John J. Cush, MD, professor of internal medicine at the University of Texas, Dallas. “If the lymphoma risk was related to inflammation, I think you’d see results like this. It really does speak to the fact that control of inflammation over time does lessen one’s risk of cancer.”
Arthur Kavanaugh, MD, observed that patients with RA continue to ask their rheumatologists if going on a TNF inhibitor will increase their risk of lymphoma, so these Swedish data are going to be useful in conversations in the clinic.
“I thought this study was very exciting,” said Dr. Kavanaugh, professor of medicine at the University of California, San Diego, and director of RWCS. “Maybe we can make the case now that the longer you’re on biologic therapies and the more recently you’re being treated, the better you do in terms of lymphoma risk.”
Beware underappreciated hazards of very-low-dose glucocorticoids
The increased risk of osteoporotic fractures associated with corticosteroid therapy gets tons of attention. But the past year brought two cautionary studies that newly identified significantly increased risks of cardiovascular events and serious infection as well, even at doses of less than 5 mg/day, which have traditionally been believed safe long term.
Investigators at the University of Leeds (England) conducted a population-based cohort study in which they used the U.K. Clinical Practice Research Datalink to analyze the oral corticosteroid dose-dependent cardiovascular risk in 25,324 patients with RA and 62,470 with five other immune-mediated inflammatory diseases: inflammatory bowel disease, giant cell arteritis, polymyalgia rheumatica, systemic lupus erythematosus, and vasculitis. None had known cardiovascular disease at baseline. The analysis accounted for changes in oral steroid dose over time and for the use of potentially confounding medications.
Over a median 5 years of follow-up, a strong steroid dose-dependent risk of acute MI, heart failure, atrial fibrillation, cerebrovascular disease, and abdominal aortic aneurysm was evident in patients with any of the six of the immune-mediated inflammatory diseases. The 1-year adjusted cumulative risk of major adverse cardiovascular events jumped from 1.4% during periods of nonuse to 8.9% at a daily dose of 25 mg or more. Notably, when patients were on oral steroids at doses less than 5 mg/day, their risk of one or more of these major adverse cardiovascular events was 74% greater than when off steroids.
A separate red flag regarding low-dose glucocorticoids was raised by a retrospective cohort study of the 1-year risk of hospitalization for serious infection in 172,041 RA patients in the Medicare claims database for the years 2005-2015. After 6 months of stable use of DMARDs, 47.1% of those patients were on corticosteroids. Their 1-year cumulative incidence of severe infection resulting in hospitalization was 11% if their dose was 5 mg/day or less, 14.4% at >5 to 10 mg/day, and 17.7% at >10 mg/day, all significantly greater than the 8.6% rate in patients not on steroids. The same pattern held true when the investigators separately scrutinized 44,118 RA patients in the Optum Clinformatics Data Mart database for the years 2006-2015.
“This is a really important paper telling us what you’ve always known, which is that there’s a dose-related increase in serious infections in people on steroids. Everybody knows that, but usually people think of 10 mg/day and above,” Dr. Cush said. “This is a little bit sobering for those of you who think, ‘Well, I’m doing OK using 2.5 or 4 mg/day.’ In this study, even at doses of 5 mg/day or less, there’s a significant increase in serious hospitalizable infections.”
Taken together, the message of these two huge studies is clear, he added: “The idea is we probably shouldn’t be using steroids.”
Given the large array of therapies now available to address various aspects of the inflammatory and immune responses in RA, Dr. Kavanaugh asked, why do so many rheumatologists still maintain their patients on low-dose steroids?
”Because when we find something that works, we stick to it,” Dr. Cush replied.
RA disease activity predicts VTE risk
The risk of VTE climbs with RA disease activity such that patients with high disease activity – defined using the erythrocyte sedimentation rate-based Disease Activity Score in 28 joints (DAS28-ESR) – have double the VTE risk of those in disease remission, according to a Swedish nationwide cohort study using data from the Swedish Rheumatology Quality Register. The investigators concluded that RA disease activity can be used in clinical practice as an additional tool for VTE risk stratification, alongside such established risk factors as immobilization, age, surgery, and comorbid conditions.
The study included 46,316 patients with RA who collectively experienced 2,241 VTE events within 1 year after one of their collective 322,601 visits to their rheumatologist. The overall cumulative 1-year incidence of VTE in the RA population was 0.71%, versus 0.36% in a control group composed of 215,843 randomly selected age- and sex-matched individuals drawn from the general Swedish population. That translates to an adjusted 1.88-fold increased risk in the RA group.
The VTE incidence was 0.52% in the year following a rheumatologist visit at which RA patients were found to be in DAS28-ESR remission. The adjusted risk for VTE climbed significantly in stepwise fashion with increasing disease activity: 12% greater risk with DAS28-ESR low disease activity, 48% greater risk with moderate disease activity, and 2.03-fold greater risk with high disease activity.
SEAM-RA shows which drug to withdraw to maintain remission gained on combo therapy
The SEAM-RA trial presented at the 2020 annual meeting of the American College of Rheumatology (ACR) and published shortly afterward in Arthritis & Rheumatology provides guidance on how to best implement a drug tapering strategy in patients who have achieved sustained remission on combination therapy with etanercept (Enbrel) and methotrexate. The purpose of such a strategy is to reduce patients’ medication burden and exposure to safety concerns inherent in continuing therapy. SEAM-RA included 371 RA patients in sustained disease remission during 24 weeks of open-label treatment with etanercept plus methotrexate. At that point, they were randomized 2:2:1 to 48 weeks of double-blind methotrexate monotherapy with etanercept withdrawal, etanercept monotherapy, or continued combination therapy. Those who experienced disease worsening on double-blind monotherapy were eligible for combination rescue therapy with both drugs.
The primary endpoint was maintenance of remission without disease worsening at week 48. This was accomplished in 52.9% of the combination therapy group, with a similar 49.5% success rate in patients on etanercept monotherapy, both significantly better than the 28.7% rate with methotrexate monotherapy. The inference is that biologic monotherapy might be an advantageous strategy for maintenance after achieving prolonged remission on combination therapy.
“This study could impact guidelines,” Dr. Cush predicted.
Among the key study findings, in his view, was that disease worsening occurred early following the switch to methotrexate monotherapy: typically within the first 2-4 weeks. And combination rescue therapy worked: Almost 75% of patients were able to recapture disease remission regardless of which drug they’d been on as monotherapy, and almost 90% of patients on rescue therapy achieved a low-disease-activity state.
Still, just over half of patients were able to maintain long-term remission after downshifting to etanercept monotherapy, Dr. Kavanaugh noted. “The bedeviling thing is we don’t know which patients can do this,” he said.
This was made abundantly clear in PREDICTRA, a phase 4, double-blind study in which 122 RA patients in sustained remission on 40 mg of adalimumab (Humira) every 2 weeks were randomized 5:1 to adalimumab taper or withdrawal for 36 weeks. Overall, 36% of the taper group and 45% of those who halted the biologic flared within 36 weeks. Nothing on an extensive list of candidate baseline predictors predicted flare in either group.
”I think the interesting thing here is that nothing predicted it, not drug levels, antidrug antibodies, not even MRI evidence of inflammation while in remission. The lack of predictors of who’s going to do well off therapy makes us crazy,” Dr. Kavanaugh said. Also noteworthy was that when full-dose, open-label adalimumab was reinstituted as rescue therapy in patients who flared, only half of them regained remission during the following 4 months, he observed.
Dr. Cush didn’t mince words regarding his view of the concept underlying PREDICTRA.
“Why are we even talking about this? We spend our whole lives trying to get these patients into remission, we’re heavily invested in combination therapy, we’re very proud of our great successes, and now we want to find data to condone, ‘Let’s get off drug therapy?’ ” he argued.
“There are untold consequences to this,” the rheumatologist continued. “There are cardiovascular consequences, and we’ve seen the x-ray studies that show that patients may be doing clinically better but still have x-ray worsening because you’ve withdrawn the TNF inhibitor. I think this is all nonsense, and I’m totally against it.”
Making a SELECT-CHOICE in refractory RA
In patients whose RA has proved refractory to one or more biologics, opting for the oral Janus kinase inhibitor upadacitinib as next-line therapy is significantly more effective than turning to the T-cell costimulation modulator abatacept, but at the cost of a doubled risk of severe adverse events, according to the findings of the phase 3, double-blind, 24-week, randomized SELECT-CHOICE trial.
In this 612-patient study, the week-12 clinical remission rate as defined by a C-reactive protein (CRP)-based DAS28 below 2.6 was 30% in the upadacitinib arm, compared to 13.3% with abatacept. At week 24, the remission rates were 46% and 31%, respectively. However, the severe adverse event rate was 6.3% in the upadacitinib group, including one death, one stroke, and two cases of VTE, compared to 3.2% with abatacept.
“Maybe this is a win for upadacitinib, but abatacept is a win when it comes to safety,” Dr. Cush said. “So the question is, when you’re making your second or third change in a biologic DMARD, are you going for safety or are you going for efficacy?”
Make way for machine learning
Studies of machine learning and artificial intelligence aimed at developing a more individualized treatment approach are popping up with increasing frequency at the major rheumatology meetings.
“This is really, I think, the future because for most of us, in most of our choices, as great as all of us are in managing RA, it is a crystal ball and a coin toss as to whether our next therapy is going to work,” Dr. Cush said.
He highlighted a study presented at the 2020 ACR annual meeting as an example of how machine learning can generate better evidence for selecting therapies. An international team of investigators used artificial intelligence to develop a simple rule to predict an RA patient’s likely response to the interleukin-6 receptor inhibitor sarilumab (Kevzara). The researchers developed a list of 42 candidate predictors of an ACR20 response, including demographics, biomarkers, and disease activity scores, then applied machine learning to data from the 1,197-patient, phase 3 MOBILITY trial of sarilumab versus placebo in order to generate a predictive rule of better outcomes.
Out of the 42 candidate predictive values, the best predictive rule turned out to be the combination of the presence of anti-citrullinated protein antibodies and a baseline CRP level greater than 12.3 mg/L. This rule was then put to the test using data from four phase 3 clinical trials in which 34%-51% of RA patients randomized to sarilumab were rule-positive. The rule-positive patients had worse baseline prognostic factors and more severe RA. Yet rule-positive patients had a better outcome than that of those who were rule-negative. For example, a week-24 ACR70 response was achieved in 34% of rule-positive patients, nearly fivefold greater than the 7% rate in the rule-negative group.
Treat-to-target strategies don’t tame excess mortality in RA
At a mean of 17 years of follow-up in the Dutch BeST study – a pioneering treat-to-target study in RA – patients with early RA who were assigned to one of four treat-to-target strategies for 10 years showed excess mortality compared to the general age- and sex-matched Dutch population, Johanna M. Maassen, MD, reported at the 2020 annual meeting of the European Alliance of Associations for Rheumatology (EULAR). Indeed, mortality was 37% higher in the RA patients than in the comparator population, with no significant differences in survival curves evident between the four tight-control strategies.
“This raises the question of whether survival in patients not strictly treated to target would have been even lower. Are we not doing as well as we think we’re doing?” Dr. Kavanaugh said.
“This is very sobering. It tells us we really do need to be better at managing RA. And I would say based on this data we need to be better at managing RA really early to get better outcomes really late,” said Dr. Cush. “The damage that led to cardiovascular risk could have been incurred earlier on and then carried forward when you look out to 15-20 years.”
More trouble for tofacitinib
Tofacitinib faces an uncertain future following Pfizer’s late-January press release announcing that the JAK inhibitor failed to meet noninferiority compared to anti-TNF therapy in terms of adjudicated major adverse cardiovascular events (MACE) and adjudicated malignancies in an FDA-mandated postmarketing safety study. The study, known as ORAL Surveillance, or Study A3921133 – ‘1133’ for short – randomized 4,362 RA patients aged 50 years or older with at least one additional cardiovascular risk factor to tofacitinib at 5 or 10 mg twice daily or to a TNF inhibitor.
The Pfizer press release was soon followed by an FDA safety warning and announcement that the agency is reviewing the full study data before making any final recommendations. The FDA already requires black box warnings for tofacitinib regarding increased risks of blood clots and death, but only at the 10-mg twice-daily dose. In the ORAL Surveillance study, however, the primary endpoint was noninferiority of the combined tofacitinib doses, and there was no evidence of a difference in endpoints between the 5- and 10-mg twice-daily doses.
Only the topline results released in the Pfizer press release are publicly available so far. The combined tofacitinib doses were associated with a 1.33-fold greater risk of adjudicated MACE and a 1.48-fold increase in adjudicated malignancies other than nonmelanoma skin cancer, compared to adalimumab or etanercept.
The jury is still out pending release of the full study data, in Dr. Kavanaugh’s view.
“When I get to look at the data, I want to see who are the people who had the events, their characteristics,” he said.
Alexis R. Ogdie-Beatty, MD, said the study’s topline results “make me a little nervous.
“The effect size is pretty large. It’s in the 1.4 range, which means there might be something there for real,” said Dr. Ogdie-Beatty, a rheumatologist and epidemiologist at the University of Pennsylvania, Philadelphia.
In contrast, Eric M. Ruderman, MD, said he’s not concerned “just yet” about the results.
“Frankly, the FDA was just plain wrong in their press release because the confidence intervals for the MACE events crossed 1.0 meaningfully [0.91, 1.94], so there’s nothing there. And the confidence intervals hit 1.0 for the malignancies,” observed Dr. Ruderman, professor of medicine at Northwestern University, Chicago.
This was a nearly 4,400-patient study, and given that it couldn’t convincingly show a safety risk, such risk – if it even exists – would seem to be tiny, he added.
“It’s probably not going to change the way we prescribe these drugs. So I don’t see that trial taking away from the big run for JAK inhibitors we’re going to see in the next year,” the rheumatologist said.
The speakers reported having financial relationships with numerous 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
Romosozumab may not increase cardiovascular risk after all
The potent anabolic, antiosteoporosis agent romosozumab has been saddled with an Food and Drug Administration–mandated black-box warning for increased cardiovascular risk that may not be warranted, Glenn Haugeberg, MD, PhD, asserted at the 2021 Rheumatology Winter Clinical Symposium.
The black-box warning states that romosozumab (Evenity), a monoclonal antibody approved in 2019 for fracture prevention in patients with osteoporosis, may increase the risk of MI, stroke, and cardiovascular death. The warning arose from FDA concerns raised by the results of the phase 3 ARCH trial in which 4,093 postmenopausal women at high fracture risk were randomized to monthly subcutaneous injections of romosozumab or weekly dosing of the oral bisphosphonate alendronate (Fosamax) for 1 year, followed by 12 months of open-label alendronate for all. Alarm bells went off at the FDA because during year 1, the incidence of adjudicated major adverse cardiovascular events was 2.5% in the romosozumab arm, compared with 1.9% with alendronate.
Could a cardioprotective effect of bisphosphonates explain cardiovascular concerns?
However, evidence from multiple animal and human studies suggests that bisphosphonates actually have a cardioprotective effect. For example, a Taiwanese population-based cohort study of 1,548 patients on bisphosphonate therapy for osteoporotic fractures and 4,644 individuals with hip or vertebral fractures who were not on a bisphosphonate showed a 65% reduction in the risk of acute MI during 2 years of follow-up in those who received a bisphosphonate.
“That may explain the ARCH finding. It may – I say may – be that this concern in the ARCH study can be explained by the positive effect of the bisphosphonates on cardiovascular events,” according to Dr. Haugeberg, head of the division of rheumatology at the Southern Norway Hospital Trust, Kristiansand, and professor of medicine at the Norwegian University of Science and Technology, Trondheim.
He noted that, in the FRAME trial, another pivotal phase 3 trial of romosozumab, there was no signal of increased cardiovascular risk, compared with placebo. In FRAME, which included 7,180 osteoporotic postmenopausal women, rates of major adverse cardiovascular events and other adverse events were balanced between the two study arms at 12 months. Indeed, the incidence of adjudicated serious cardiovascular events was 0.5% with romosozumab and 0.4% with placebo injections. After 12 months, all participants were transitioned to denosumab (Prolia) for another 12 months. At 24 months, there remained no significant between-group difference in cardiovascular events, cancer, osteoarthritis, hyperostosis, or other major adverse events.
Potency of romosozumab
Romosozumab’s efficacy for fracture prevention in these two pivotal trials was striking. The risk of new vertebral fractures was reduced by 73% with romosozumab, compared with placebo at 12 months in FRAME, and by 75% at 24 months in the romosozumab-to-denosumab group.
“FRAME was a 12-month study for the primary endpoint. The bisphosphonate studies typically had a 3-year design in order to show benefit, but here you see only 12-month follow-up. This illustrates the potency of this drug. We saw rapid increase in bone density and a huge decrease in new vertebral fractures versus placebo in the first 12 months, then during follow-up with denosumab the reduction in fractures was maintained,” the rheumatologist commented.
In the ARCH trial, where romosozumab went head to head with a very effective oral bisphosphonate, the risk of new vertebral fractures was 48% lower at 24 months in the romosozumab-to-alendronate group than in women on alendronate for the full 24 months, while the risk of hip fractures was reduced by 38%.
Romosozumab is a humanized monoclonal antibody with a novel mechanism of anabolic action: This agent binds to sclerostin, which is produced in osteocytes. When sclerostin binds to receptors on osteoblasts it reduces their activity, thereby inhibiting bone formation. Romosozumab takes away this inhibition of osteoblasts, boosting their activity. The result is increased bone formation accompanied by decreased bone resorption. This allows for a logical treatment approach: first using an anabolic agent – in this instance, subcutaneously injected romosozumab at 210 mg once monthly for 12 months – then switching to an antiresorptive agent in order to maintain the gain in bone mineral density and decrease fracture risk. This is the same treatment strategy recommended when using the anabolic agents teriparatide (Forteo) and abaloparatide (Tymlos); however, those parathyroid hormone and parathyroid hormone–related protein analogs are seldom used in Norway because their cost is substantially greater than for romosozumab, he explained.
Updated Endocrine Society guidelines
Dr. Haugeberg called romosozumab “a new and wonderful drug.” The Endocrine Society also considers romosozumab an important new drug, as evidenced by the release of an 8-page update of the group’s clinical practice guideline on the pharmacologic management of osteoporosis in postmenopausal women; the update was devoted specifically to the use of romosozumab. The update, published in response to the biologic’s recent approval by U.S., Canadian, and European regulatory agencies, came just 10 months after release of the Endocrine Society’s comprehensive 28-page clinical practice guideline.
Dr. Haugeberg is a fan of the Endocrine Society guideline, which recommends romosozumab as a first-line therapy in postmenopausal women at very high risk of osteoporotic fracture, defined as those with a history of multiple vertebral fractures or severe osteoporosis with a T score of –2.5 or less at the hip or spine plus fractures. The updated guideline also recommends consideration of the antisclerostin biologic in high-risk patients who have failed on antiresorptive treatments.
The practice guideline states that the issue of a possible cardioprotective effect of alendronate in the ARCH trial “remains uncertain at this time.”
“Women at high risk of cardiovascular disease and stroke should not be considered for romosozumab pending further studies on cardiovascular risk associated with this treatment,” according to the Endocrine Society.
Dr. Haugeberg reported receiving research grants from Pfizer and Biogen and serving as a consultant to and/or on speakers’ bureaus for Amgen, which markets romosozumab, and more than a dozen other pharmaceutical companies.
The potent anabolic, antiosteoporosis agent romosozumab has been saddled with an Food and Drug Administration–mandated black-box warning for increased cardiovascular risk that may not be warranted, Glenn Haugeberg, MD, PhD, asserted at the 2021 Rheumatology Winter Clinical Symposium.
The black-box warning states that romosozumab (Evenity), a monoclonal antibody approved in 2019 for fracture prevention in patients with osteoporosis, may increase the risk of MI, stroke, and cardiovascular death. The warning arose from FDA concerns raised by the results of the phase 3 ARCH trial in which 4,093 postmenopausal women at high fracture risk were randomized to monthly subcutaneous injections of romosozumab or weekly dosing of the oral bisphosphonate alendronate (Fosamax) for 1 year, followed by 12 months of open-label alendronate for all. Alarm bells went off at the FDA because during year 1, the incidence of adjudicated major adverse cardiovascular events was 2.5% in the romosozumab arm, compared with 1.9% with alendronate.
Could a cardioprotective effect of bisphosphonates explain cardiovascular concerns?
However, evidence from multiple animal and human studies suggests that bisphosphonates actually have a cardioprotective effect. For example, a Taiwanese population-based cohort study of 1,548 patients on bisphosphonate therapy for osteoporotic fractures and 4,644 individuals with hip or vertebral fractures who were not on a bisphosphonate showed a 65% reduction in the risk of acute MI during 2 years of follow-up in those who received a bisphosphonate.
“That may explain the ARCH finding. It may – I say may – be that this concern in the ARCH study can be explained by the positive effect of the bisphosphonates on cardiovascular events,” according to Dr. Haugeberg, head of the division of rheumatology at the Southern Norway Hospital Trust, Kristiansand, and professor of medicine at the Norwegian University of Science and Technology, Trondheim.
He noted that, in the FRAME trial, another pivotal phase 3 trial of romosozumab, there was no signal of increased cardiovascular risk, compared with placebo. In FRAME, which included 7,180 osteoporotic postmenopausal women, rates of major adverse cardiovascular events and other adverse events were balanced between the two study arms at 12 months. Indeed, the incidence of adjudicated serious cardiovascular events was 0.5% with romosozumab and 0.4% with placebo injections. After 12 months, all participants were transitioned to denosumab (Prolia) for another 12 months. At 24 months, there remained no significant between-group difference in cardiovascular events, cancer, osteoarthritis, hyperostosis, or other major adverse events.
Potency of romosozumab
Romosozumab’s efficacy for fracture prevention in these two pivotal trials was striking. The risk of new vertebral fractures was reduced by 73% with romosozumab, compared with placebo at 12 months in FRAME, and by 75% at 24 months in the romosozumab-to-denosumab group.
“FRAME was a 12-month study for the primary endpoint. The bisphosphonate studies typically had a 3-year design in order to show benefit, but here you see only 12-month follow-up. This illustrates the potency of this drug. We saw rapid increase in bone density and a huge decrease in new vertebral fractures versus placebo in the first 12 months, then during follow-up with denosumab the reduction in fractures was maintained,” the rheumatologist commented.
In the ARCH trial, where romosozumab went head to head with a very effective oral bisphosphonate, the risk of new vertebral fractures was 48% lower at 24 months in the romosozumab-to-alendronate group than in women on alendronate for the full 24 months, while the risk of hip fractures was reduced by 38%.
Romosozumab is a humanized monoclonal antibody with a novel mechanism of anabolic action: This agent binds to sclerostin, which is produced in osteocytes. When sclerostin binds to receptors on osteoblasts it reduces their activity, thereby inhibiting bone formation. Romosozumab takes away this inhibition of osteoblasts, boosting their activity. The result is increased bone formation accompanied by decreased bone resorption. This allows for a logical treatment approach: first using an anabolic agent – in this instance, subcutaneously injected romosozumab at 210 mg once monthly for 12 months – then switching to an antiresorptive agent in order to maintain the gain in bone mineral density and decrease fracture risk. This is the same treatment strategy recommended when using the anabolic agents teriparatide (Forteo) and abaloparatide (Tymlos); however, those parathyroid hormone and parathyroid hormone–related protein analogs are seldom used in Norway because their cost is substantially greater than for romosozumab, he explained.
Updated Endocrine Society guidelines
Dr. Haugeberg called romosozumab “a new and wonderful drug.” The Endocrine Society also considers romosozumab an important new drug, as evidenced by the release of an 8-page update of the group’s clinical practice guideline on the pharmacologic management of osteoporosis in postmenopausal women; the update was devoted specifically to the use of romosozumab. The update, published in response to the biologic’s recent approval by U.S., Canadian, and European regulatory agencies, came just 10 months after release of the Endocrine Society’s comprehensive 28-page clinical practice guideline.
Dr. Haugeberg is a fan of the Endocrine Society guideline, which recommends romosozumab as a first-line therapy in postmenopausal women at very high risk of osteoporotic fracture, defined as those with a history of multiple vertebral fractures or severe osteoporosis with a T score of –2.5 or less at the hip or spine plus fractures. The updated guideline also recommends consideration of the antisclerostin biologic in high-risk patients who have failed on antiresorptive treatments.
The practice guideline states that the issue of a possible cardioprotective effect of alendronate in the ARCH trial “remains uncertain at this time.”
“Women at high risk of cardiovascular disease and stroke should not be considered for romosozumab pending further studies on cardiovascular risk associated with this treatment,” according to the Endocrine Society.
Dr. Haugeberg reported receiving research grants from Pfizer and Biogen and serving as a consultant to and/or on speakers’ bureaus for Amgen, which markets romosozumab, and more than a dozen other pharmaceutical companies.
The potent anabolic, antiosteoporosis agent romosozumab has been saddled with an Food and Drug Administration–mandated black-box warning for increased cardiovascular risk that may not be warranted, Glenn Haugeberg, MD, PhD, asserted at the 2021 Rheumatology Winter Clinical Symposium.
The black-box warning states that romosozumab (Evenity), a monoclonal antibody approved in 2019 for fracture prevention in patients with osteoporosis, may increase the risk of MI, stroke, and cardiovascular death. The warning arose from FDA concerns raised by the results of the phase 3 ARCH trial in which 4,093 postmenopausal women at high fracture risk were randomized to monthly subcutaneous injections of romosozumab or weekly dosing of the oral bisphosphonate alendronate (Fosamax) for 1 year, followed by 12 months of open-label alendronate for all. Alarm bells went off at the FDA because during year 1, the incidence of adjudicated major adverse cardiovascular events was 2.5% in the romosozumab arm, compared with 1.9% with alendronate.
Could a cardioprotective effect of bisphosphonates explain cardiovascular concerns?
However, evidence from multiple animal and human studies suggests that bisphosphonates actually have a cardioprotective effect. For example, a Taiwanese population-based cohort study of 1,548 patients on bisphosphonate therapy for osteoporotic fractures and 4,644 individuals with hip or vertebral fractures who were not on a bisphosphonate showed a 65% reduction in the risk of acute MI during 2 years of follow-up in those who received a bisphosphonate.
“That may explain the ARCH finding. It may – I say may – be that this concern in the ARCH study can be explained by the positive effect of the bisphosphonates on cardiovascular events,” according to Dr. Haugeberg, head of the division of rheumatology at the Southern Norway Hospital Trust, Kristiansand, and professor of medicine at the Norwegian University of Science and Technology, Trondheim.
He noted that, in the FRAME trial, another pivotal phase 3 trial of romosozumab, there was no signal of increased cardiovascular risk, compared with placebo. In FRAME, which included 7,180 osteoporotic postmenopausal women, rates of major adverse cardiovascular events and other adverse events were balanced between the two study arms at 12 months. Indeed, the incidence of adjudicated serious cardiovascular events was 0.5% with romosozumab and 0.4% with placebo injections. After 12 months, all participants were transitioned to denosumab (Prolia) for another 12 months. At 24 months, there remained no significant between-group difference in cardiovascular events, cancer, osteoarthritis, hyperostosis, or other major adverse events.
Potency of romosozumab
Romosozumab’s efficacy for fracture prevention in these two pivotal trials was striking. The risk of new vertebral fractures was reduced by 73% with romosozumab, compared with placebo at 12 months in FRAME, and by 75% at 24 months in the romosozumab-to-denosumab group.
“FRAME was a 12-month study for the primary endpoint. The bisphosphonate studies typically had a 3-year design in order to show benefit, but here you see only 12-month follow-up. This illustrates the potency of this drug. We saw rapid increase in bone density and a huge decrease in new vertebral fractures versus placebo in the first 12 months, then during follow-up with denosumab the reduction in fractures was maintained,” the rheumatologist commented.
In the ARCH trial, where romosozumab went head to head with a very effective oral bisphosphonate, the risk of new vertebral fractures was 48% lower at 24 months in the romosozumab-to-alendronate group than in women on alendronate for the full 24 months, while the risk of hip fractures was reduced by 38%.
Romosozumab is a humanized monoclonal antibody with a novel mechanism of anabolic action: This agent binds to sclerostin, which is produced in osteocytes. When sclerostin binds to receptors on osteoblasts it reduces their activity, thereby inhibiting bone formation. Romosozumab takes away this inhibition of osteoblasts, boosting their activity. The result is increased bone formation accompanied by decreased bone resorption. This allows for a logical treatment approach: first using an anabolic agent – in this instance, subcutaneously injected romosozumab at 210 mg once monthly for 12 months – then switching to an antiresorptive agent in order to maintain the gain in bone mineral density and decrease fracture risk. This is the same treatment strategy recommended when using the anabolic agents teriparatide (Forteo) and abaloparatide (Tymlos); however, those parathyroid hormone and parathyroid hormone–related protein analogs are seldom used in Norway because their cost is substantially greater than for romosozumab, he explained.
Updated Endocrine Society guidelines
Dr. Haugeberg called romosozumab “a new and wonderful drug.” The Endocrine Society also considers romosozumab an important new drug, as evidenced by the release of an 8-page update of the group’s clinical practice guideline on the pharmacologic management of osteoporosis in postmenopausal women; the update was devoted specifically to the use of romosozumab. The update, published in response to the biologic’s recent approval by U.S., Canadian, and European regulatory agencies, came just 10 months after release of the Endocrine Society’s comprehensive 28-page clinical practice guideline.
Dr. Haugeberg is a fan of the Endocrine Society guideline, which recommends romosozumab as a first-line therapy in postmenopausal women at very high risk of osteoporotic fracture, defined as those with a history of multiple vertebral fractures or severe osteoporosis with a T score of –2.5 or less at the hip or spine plus fractures. The updated guideline also recommends consideration of the antisclerostin biologic in high-risk patients who have failed on antiresorptive treatments.
The practice guideline states that the issue of a possible cardioprotective effect of alendronate in the ARCH trial “remains uncertain at this time.”
“Women at high risk of cardiovascular disease and stroke should not be considered for romosozumab pending further studies on cardiovascular risk associated with this treatment,” according to the Endocrine Society.
Dr. Haugeberg reported receiving research grants from Pfizer and Biogen and serving as a consultant to and/or on speakers’ bureaus for Amgen, which markets romosozumab, and more than a dozen other pharmaceutical companies.
FROM RWCS 2021
Consider home subcutaneous immune globulin for refractory dermatomyositis
Home-based subcutaneous immune globulin therapy is a promising alternative to intravenous immune globulin therapy for patients with refractory dermatomyositis or polymyositis, Anna Postolova, MD, MPH, declared at the 2021 Rheumatology Winter Clinical Symposium.
“This is really exciting. I think in the years to come we may see a change to having our patients be able to do immune globulin therapy at home,” said Dr. Postolova, a rheumatologist and allergist/immunologist at Stanford (Calif.) Health Care.
“The technology is there. I think our patients might feel more comfortable getting immune globulin at home,” she said. “I would love to switch more patients from IVIg to SCIg [subcutaneous immune globulin] in my practice.”
A few caveats: SCIg remains off label for treatment of dermatomyositis (DM) or polymyositis (PM). Its approved indication is as replacement therapy in patients with primary or secondary immunodeficiency diseases. IVIg is approved for this indication, but is also approved for DM/PM refractory to high-dose corticosteroids and immunosuppressants. Yet SCIg is clearly effective for these autoimmune inflammatory diseases, albeit to date the supporting evidence comes chiefly from observational studies and anecdotal experience.
“I don’t know if insurers will cover it, but they should because it’s obviously a lot cheaper to do it at home,” she noted.
SCIg advantages
SCIg offers compelling advantages over IVIg in addition to its substantially lower cost. These include far fewer systemic side effects, shorter infusion time, greater bioavailability, and better quality of life. Patients self-administer SCIg at home, avoiding the inconvenience of IVIg therapy, which entails travel time for once-monthly hospitalization or long hours spent in an infusion center, she explained.
French investigators recently documented a previously unappreciated further advantage of home-based SCIg. They convened a focus group of patients with DM or PM experienced with both IVIg and home SCIg and determined that participants uniformly preferred home SCIg. The patients cited a new and welcome feeling of autonomy and control.
“All patients with experience of IVIg and SCIg expressed a clear preference for SCIg, which was described to be easy, less disruptive for daily life, well tolerated, and less time-consuming. Preference was mainly related to a restoration of autonomy. Home-based self-administration reinforced the feeling of independence,” according to the investigators.
Available products
Six preparations of SCIg are commercially available. Most are in 10% concentration, as are all IVIg products. However, a 20% formulation of SCIg known as Hizentra allows for a smaller infusion volume and quicker completion of a treatment session. And one SCIg product, HyQvia, uses recombinant human hyaluronidase-facilitated 10% immune globulin, allowing home infusion of large volumes of sustained-release immune globulin on a once-monthly basis.
The relatively recent introduction of home SCIg for treatment of autoimmune inflammatory diseases, including DM, PM, and chronic inflammatory demyelinating polyneuropathy, has been pioneered mainly by European investigators. The treatment is often given by programmable mechanical pump once weekly. Italian investigators have reported efficacy in DM using 0.2 g/kg per week, which is about half the monthly total dose of IVIg employed. The infusion rate is 10-40 mL/hour, with a volume of around 35 mL per injection site.
Alternatively, SCIg can be delivered by rapid push infusions of smaller volumes with a syringe two or three times per week; that’s the regimen that was used at 2 g/kg over the course of a month by patients in the French focus group study, who didn’t mind the more frequent dosing.
“As they have had severe long-lasting symptoms, SCIg was perceived as a curative rather than a preventive therapy,” according to the French investigators.
More than 40% of patients experience adverse reactions to IVIg. These often involve headaches, nausea, back or abdominal pain, arthralgias, and/or difficulty breathing. Thromboembolic events and acute renal failure occur occasionally. For this reason, many physicians give a prophylactic dose of corticosteroids an hour before a patient’s first dose of IVIg. These systemic side effects are so rare with SCIg that Dr. Postolova has never pretreated with steroids, even though the main reason she resorts to the home therapy is a patient’s track record of poor tolerance of IVIg. The lower abdomen and thigh are the most commonly used subcutaneous infusion sites. Mild local infusion site reactions are fairly common.
Formulating IVIg and SCIg is a complex process that entails plasma procurement and pooling, fractionation, and purification. It takes 10,000-60,000 plasma donations to make one lot of IVIg. Donations are accepted only from repeated donors. Samples are held for 6 months and tested for infectious agents. However, efforts are underway to develop bioengineered recombinant immune globulin products that don’t require donated plasma. These products are being designed to capture and enhance the most important mechanisms of benefit of plasma-derived immunoglobulins using Fc fragments that target key receptors, rather than relying on full-length immune globulin. The goal is enhanced efficacy at much lower doses than with IVIg or SCIg.
Dr. Postolova reported having no financial conflicts regarding her presentation.
Home-based subcutaneous immune globulin therapy is a promising alternative to intravenous immune globulin therapy for patients with refractory dermatomyositis or polymyositis, Anna Postolova, MD, MPH, declared at the 2021 Rheumatology Winter Clinical Symposium.
“This is really exciting. I think in the years to come we may see a change to having our patients be able to do immune globulin therapy at home,” said Dr. Postolova, a rheumatologist and allergist/immunologist at Stanford (Calif.) Health Care.
“The technology is there. I think our patients might feel more comfortable getting immune globulin at home,” she said. “I would love to switch more patients from IVIg to SCIg [subcutaneous immune globulin] in my practice.”
A few caveats: SCIg remains off label for treatment of dermatomyositis (DM) or polymyositis (PM). Its approved indication is as replacement therapy in patients with primary or secondary immunodeficiency diseases. IVIg is approved for this indication, but is also approved for DM/PM refractory to high-dose corticosteroids and immunosuppressants. Yet SCIg is clearly effective for these autoimmune inflammatory diseases, albeit to date the supporting evidence comes chiefly from observational studies and anecdotal experience.
“I don’t know if insurers will cover it, but they should because it’s obviously a lot cheaper to do it at home,” she noted.
SCIg advantages
SCIg offers compelling advantages over IVIg in addition to its substantially lower cost. These include far fewer systemic side effects, shorter infusion time, greater bioavailability, and better quality of life. Patients self-administer SCIg at home, avoiding the inconvenience of IVIg therapy, which entails travel time for once-monthly hospitalization or long hours spent in an infusion center, she explained.
French investigators recently documented a previously unappreciated further advantage of home-based SCIg. They convened a focus group of patients with DM or PM experienced with both IVIg and home SCIg and determined that participants uniformly preferred home SCIg. The patients cited a new and welcome feeling of autonomy and control.
“All patients with experience of IVIg and SCIg expressed a clear preference for SCIg, which was described to be easy, less disruptive for daily life, well tolerated, and less time-consuming. Preference was mainly related to a restoration of autonomy. Home-based self-administration reinforced the feeling of independence,” according to the investigators.
Available products
Six preparations of SCIg are commercially available. Most are in 10% concentration, as are all IVIg products. However, a 20% formulation of SCIg known as Hizentra allows for a smaller infusion volume and quicker completion of a treatment session. And one SCIg product, HyQvia, uses recombinant human hyaluronidase-facilitated 10% immune globulin, allowing home infusion of large volumes of sustained-release immune globulin on a once-monthly basis.
The relatively recent introduction of home SCIg for treatment of autoimmune inflammatory diseases, including DM, PM, and chronic inflammatory demyelinating polyneuropathy, has been pioneered mainly by European investigators. The treatment is often given by programmable mechanical pump once weekly. Italian investigators have reported efficacy in DM using 0.2 g/kg per week, which is about half the monthly total dose of IVIg employed. The infusion rate is 10-40 mL/hour, with a volume of around 35 mL per injection site.
Alternatively, SCIg can be delivered by rapid push infusions of smaller volumes with a syringe two or three times per week; that’s the regimen that was used at 2 g/kg over the course of a month by patients in the French focus group study, who didn’t mind the more frequent dosing.
“As they have had severe long-lasting symptoms, SCIg was perceived as a curative rather than a preventive therapy,” according to the French investigators.
More than 40% of patients experience adverse reactions to IVIg. These often involve headaches, nausea, back or abdominal pain, arthralgias, and/or difficulty breathing. Thromboembolic events and acute renal failure occur occasionally. For this reason, many physicians give a prophylactic dose of corticosteroids an hour before a patient’s first dose of IVIg. These systemic side effects are so rare with SCIg that Dr. Postolova has never pretreated with steroids, even though the main reason she resorts to the home therapy is a patient’s track record of poor tolerance of IVIg. The lower abdomen and thigh are the most commonly used subcutaneous infusion sites. Mild local infusion site reactions are fairly common.
Formulating IVIg and SCIg is a complex process that entails plasma procurement and pooling, fractionation, and purification. It takes 10,000-60,000 plasma donations to make one lot of IVIg. Donations are accepted only from repeated donors. Samples are held for 6 months and tested for infectious agents. However, efforts are underway to develop bioengineered recombinant immune globulin products that don’t require donated plasma. These products are being designed to capture and enhance the most important mechanisms of benefit of plasma-derived immunoglobulins using Fc fragments that target key receptors, rather than relying on full-length immune globulin. The goal is enhanced efficacy at much lower doses than with IVIg or SCIg.
Dr. Postolova reported having no financial conflicts regarding her presentation.
Home-based subcutaneous immune globulin therapy is a promising alternative to intravenous immune globulin therapy for patients with refractory dermatomyositis or polymyositis, Anna Postolova, MD, MPH, declared at the 2021 Rheumatology Winter Clinical Symposium.
“This is really exciting. I think in the years to come we may see a change to having our patients be able to do immune globulin therapy at home,” said Dr. Postolova, a rheumatologist and allergist/immunologist at Stanford (Calif.) Health Care.
“The technology is there. I think our patients might feel more comfortable getting immune globulin at home,” she said. “I would love to switch more patients from IVIg to SCIg [subcutaneous immune globulin] in my practice.”
A few caveats: SCIg remains off label for treatment of dermatomyositis (DM) or polymyositis (PM). Its approved indication is as replacement therapy in patients with primary or secondary immunodeficiency diseases. IVIg is approved for this indication, but is also approved for DM/PM refractory to high-dose corticosteroids and immunosuppressants. Yet SCIg is clearly effective for these autoimmune inflammatory diseases, albeit to date the supporting evidence comes chiefly from observational studies and anecdotal experience.
“I don’t know if insurers will cover it, but they should because it’s obviously a lot cheaper to do it at home,” she noted.
SCIg advantages
SCIg offers compelling advantages over IVIg in addition to its substantially lower cost. These include far fewer systemic side effects, shorter infusion time, greater bioavailability, and better quality of life. Patients self-administer SCIg at home, avoiding the inconvenience of IVIg therapy, which entails travel time for once-monthly hospitalization or long hours spent in an infusion center, she explained.
French investigators recently documented a previously unappreciated further advantage of home-based SCIg. They convened a focus group of patients with DM or PM experienced with both IVIg and home SCIg and determined that participants uniformly preferred home SCIg. The patients cited a new and welcome feeling of autonomy and control.
“All patients with experience of IVIg and SCIg expressed a clear preference for SCIg, which was described to be easy, less disruptive for daily life, well tolerated, and less time-consuming. Preference was mainly related to a restoration of autonomy. Home-based self-administration reinforced the feeling of independence,” according to the investigators.
Available products
Six preparations of SCIg are commercially available. Most are in 10% concentration, as are all IVIg products. However, a 20% formulation of SCIg known as Hizentra allows for a smaller infusion volume and quicker completion of a treatment session. And one SCIg product, HyQvia, uses recombinant human hyaluronidase-facilitated 10% immune globulin, allowing home infusion of large volumes of sustained-release immune globulin on a once-monthly basis.
The relatively recent introduction of home SCIg for treatment of autoimmune inflammatory diseases, including DM, PM, and chronic inflammatory demyelinating polyneuropathy, has been pioneered mainly by European investigators. The treatment is often given by programmable mechanical pump once weekly. Italian investigators have reported efficacy in DM using 0.2 g/kg per week, which is about half the monthly total dose of IVIg employed. The infusion rate is 10-40 mL/hour, with a volume of around 35 mL per injection site.
Alternatively, SCIg can be delivered by rapid push infusions of smaller volumes with a syringe two or three times per week; that’s the regimen that was used at 2 g/kg over the course of a month by patients in the French focus group study, who didn’t mind the more frequent dosing.
“As they have had severe long-lasting symptoms, SCIg was perceived as a curative rather than a preventive therapy,” according to the French investigators.
More than 40% of patients experience adverse reactions to IVIg. These often involve headaches, nausea, back or abdominal pain, arthralgias, and/or difficulty breathing. Thromboembolic events and acute renal failure occur occasionally. For this reason, many physicians give a prophylactic dose of corticosteroids an hour before a patient’s first dose of IVIg. These systemic side effects are so rare with SCIg that Dr. Postolova has never pretreated with steroids, even though the main reason she resorts to the home therapy is a patient’s track record of poor tolerance of IVIg. The lower abdomen and thigh are the most commonly used subcutaneous infusion sites. Mild local infusion site reactions are fairly common.
Formulating IVIg and SCIg is a complex process that entails plasma procurement and pooling, fractionation, and purification. It takes 10,000-60,000 plasma donations to make one lot of IVIg. Donations are accepted only from repeated donors. Samples are held for 6 months and tested for infectious agents. However, efforts are underway to develop bioengineered recombinant immune globulin products that don’t require donated plasma. These products are being designed to capture and enhance the most important mechanisms of benefit of plasma-derived immunoglobulins using Fc fragments that target key receptors, rather than relying on full-length immune globulin. The goal is enhanced efficacy at much lower doses than with IVIg or SCIg.
Dr. Postolova reported having no financial conflicts regarding her presentation.
FROM RWCS 2021
Molecular insights suggest novel therapies for hidradenitis suppurativa
at the virtual annual congress of the European Academy of Dermatology and Venereology.
He presented highlights of a multicenter translational study, which utilized whole transcriptome analysis of lesional and nonlesional skin from patients with HS and normal controls along with quantitative real-time PCR and immunohistochemistry. The purpose was to further define the molecular taxonomy of this inflammatory disease. And while this objective was achieved, the results also underscored a truism regarding the painful and scarring disease: “HS is characterized by an ever-growing complexity, which translates into multiple potential mechanistic drivers,” observed Dr. da Costa, head of immunology precision medicine at AstraZeneca in Gothenburg, Sweden.
Indeed, the study identified a panel of immune-related drivers in HS that influence innate immunity and cell differentiation in follicular and epidermal keratinocytes. The research by Dr. da Costa and coinvestigators identified a broad array of promising novel therapeutic targets in HS.
“Our findings provide evidence of an inflammatory process coupled with impaired barrier function, altered epidermal cell differentiation, and possibly abnormal microbiome activity which can be seen at the follicular and epidermal keratinocytes and also to a minor degree at the level of the skin glands,” Dr. da Costa said.
There is a huge unmet need for new therapies for HS, since at present adalimumab (Humira) is the only approved medication for this debilitating inflammatory disease. Some good news that emerged from this translational study is that some of the novel molecular mediators implicated in HS are targeted by multiple Food and Drug Administration–approved therapies that have other indications. From a drug development standpoint, repurposing a commercially available drug for a novel indication is a much more efficient and less costly endeavor than is necessary to establish the safety and efficacy of an unproven new agent.
The translational work demonstrated that the proteins calgranulin-A and -B and serpin-B4 were strongly expressed in the hair root sheaths of patients with HS. Connexin-32 and koebnerisin were present in stratum granulosum, matrix metallopeptidase-9 was strongly expressed in resident monocytes, small prolin-rich protein 3 in apocrine sweat glands and ducts as well as in sebaceous glands and ducts, and transcobalamin-1 was prominent in stratum spinosum.
Of the 19 key molecular mediators of HS identified in the study, FDA-approved agents are already available that target 12 of them. For example, apremilast (Otezla) targets interferon-gamma and tumor necrosis factor–alpha. Gentamicin targets growth arrest-specific 6 (GAS6) and interleukin-17 (IL-17). Secukinumab (Cosentyx) and ixekizumab (Taltz) target IL-17A, and brodalumab (Siliq) more broadly targets IL-17A as well as all the other IL-17 receptors. Thalidomide targets hepatocyte growth factor (HGF) and TNF-alpha. Spironolactone targets androgen receptor (AR) and TNF-alpha. Colchicine targets tubulin. Anakinra (Kineret) homes in on the IL-1 receptor. And prednisone targets NFxB.
Other key molecular mediators of HS, which are targeted by commercially available drugs, include epidermal growth factor (EGF), macrophage colony-stimulating factor (MCSF), epiregulin (EREG), fibroblast growth factor 1 (FGF1), FGF2, insulin-like growth factor 2 (IGF2), and IL-6, according to Dr. da Costa.
In addition, clinical trials are underway in HS involving totally investigational agents, including several Janus kinase inhibitors and tyrosine kinase 2 inhibitors.
The work described by Dr. da Costa had multiple funding sources, including the European Hidradenitis Suppurativa Foundation, the University of Copenhagen, the Icahn School of Medicine at Mount Sinai, AstraZeneca, and the German Federal Ministry of Education and Research. Dr. da Costa is an employee of AstraZeneca, Gothenburg, Sweden.
at the virtual annual congress of the European Academy of Dermatology and Venereology.
He presented highlights of a multicenter translational study, which utilized whole transcriptome analysis of lesional and nonlesional skin from patients with HS and normal controls along with quantitative real-time PCR and immunohistochemistry. The purpose was to further define the molecular taxonomy of this inflammatory disease. And while this objective was achieved, the results also underscored a truism regarding the painful and scarring disease: “HS is characterized by an ever-growing complexity, which translates into multiple potential mechanistic drivers,” observed Dr. da Costa, head of immunology precision medicine at AstraZeneca in Gothenburg, Sweden.
Indeed, the study identified a panel of immune-related drivers in HS that influence innate immunity and cell differentiation in follicular and epidermal keratinocytes. The research by Dr. da Costa and coinvestigators identified a broad array of promising novel therapeutic targets in HS.
“Our findings provide evidence of an inflammatory process coupled with impaired barrier function, altered epidermal cell differentiation, and possibly abnormal microbiome activity which can be seen at the follicular and epidermal keratinocytes and also to a minor degree at the level of the skin glands,” Dr. da Costa said.
There is a huge unmet need for new therapies for HS, since at present adalimumab (Humira) is the only approved medication for this debilitating inflammatory disease. Some good news that emerged from this translational study is that some of the novel molecular mediators implicated in HS are targeted by multiple Food and Drug Administration–approved therapies that have other indications. From a drug development standpoint, repurposing a commercially available drug for a novel indication is a much more efficient and less costly endeavor than is necessary to establish the safety and efficacy of an unproven new agent.
The translational work demonstrated that the proteins calgranulin-A and -B and serpin-B4 were strongly expressed in the hair root sheaths of patients with HS. Connexin-32 and koebnerisin were present in stratum granulosum, matrix metallopeptidase-9 was strongly expressed in resident monocytes, small prolin-rich protein 3 in apocrine sweat glands and ducts as well as in sebaceous glands and ducts, and transcobalamin-1 was prominent in stratum spinosum.
Of the 19 key molecular mediators of HS identified in the study, FDA-approved agents are already available that target 12 of them. For example, apremilast (Otezla) targets interferon-gamma and tumor necrosis factor–alpha. Gentamicin targets growth arrest-specific 6 (GAS6) and interleukin-17 (IL-17). Secukinumab (Cosentyx) and ixekizumab (Taltz) target IL-17A, and brodalumab (Siliq) more broadly targets IL-17A as well as all the other IL-17 receptors. Thalidomide targets hepatocyte growth factor (HGF) and TNF-alpha. Spironolactone targets androgen receptor (AR) and TNF-alpha. Colchicine targets tubulin. Anakinra (Kineret) homes in on the IL-1 receptor. And prednisone targets NFxB.
Other key molecular mediators of HS, which are targeted by commercially available drugs, include epidermal growth factor (EGF), macrophage colony-stimulating factor (MCSF), epiregulin (EREG), fibroblast growth factor 1 (FGF1), FGF2, insulin-like growth factor 2 (IGF2), and IL-6, according to Dr. da Costa.
In addition, clinical trials are underway in HS involving totally investigational agents, including several Janus kinase inhibitors and tyrosine kinase 2 inhibitors.
The work described by Dr. da Costa had multiple funding sources, including the European Hidradenitis Suppurativa Foundation, the University of Copenhagen, the Icahn School of Medicine at Mount Sinai, AstraZeneca, and the German Federal Ministry of Education and Research. Dr. da Costa is an employee of AstraZeneca, Gothenburg, Sweden.
at the virtual annual congress of the European Academy of Dermatology and Venereology.
He presented highlights of a multicenter translational study, which utilized whole transcriptome analysis of lesional and nonlesional skin from patients with HS and normal controls along with quantitative real-time PCR and immunohistochemistry. The purpose was to further define the molecular taxonomy of this inflammatory disease. And while this objective was achieved, the results also underscored a truism regarding the painful and scarring disease: “HS is characterized by an ever-growing complexity, which translates into multiple potential mechanistic drivers,” observed Dr. da Costa, head of immunology precision medicine at AstraZeneca in Gothenburg, Sweden.
Indeed, the study identified a panel of immune-related drivers in HS that influence innate immunity and cell differentiation in follicular and epidermal keratinocytes. The research by Dr. da Costa and coinvestigators identified a broad array of promising novel therapeutic targets in HS.
“Our findings provide evidence of an inflammatory process coupled with impaired barrier function, altered epidermal cell differentiation, and possibly abnormal microbiome activity which can be seen at the follicular and epidermal keratinocytes and also to a minor degree at the level of the skin glands,” Dr. da Costa said.
There is a huge unmet need for new therapies for HS, since at present adalimumab (Humira) is the only approved medication for this debilitating inflammatory disease. Some good news that emerged from this translational study is that some of the novel molecular mediators implicated in HS are targeted by multiple Food and Drug Administration–approved therapies that have other indications. From a drug development standpoint, repurposing a commercially available drug for a novel indication is a much more efficient and less costly endeavor than is necessary to establish the safety and efficacy of an unproven new agent.
The translational work demonstrated that the proteins calgranulin-A and -B and serpin-B4 were strongly expressed in the hair root sheaths of patients with HS. Connexin-32 and koebnerisin were present in stratum granulosum, matrix metallopeptidase-9 was strongly expressed in resident monocytes, small prolin-rich protein 3 in apocrine sweat glands and ducts as well as in sebaceous glands and ducts, and transcobalamin-1 was prominent in stratum spinosum.
Of the 19 key molecular mediators of HS identified in the study, FDA-approved agents are already available that target 12 of them. For example, apremilast (Otezla) targets interferon-gamma and tumor necrosis factor–alpha. Gentamicin targets growth arrest-specific 6 (GAS6) and interleukin-17 (IL-17). Secukinumab (Cosentyx) and ixekizumab (Taltz) target IL-17A, and brodalumab (Siliq) more broadly targets IL-17A as well as all the other IL-17 receptors. Thalidomide targets hepatocyte growth factor (HGF) and TNF-alpha. Spironolactone targets androgen receptor (AR) and TNF-alpha. Colchicine targets tubulin. Anakinra (Kineret) homes in on the IL-1 receptor. And prednisone targets NFxB.
Other key molecular mediators of HS, which are targeted by commercially available drugs, include epidermal growth factor (EGF), macrophage colony-stimulating factor (MCSF), epiregulin (EREG), fibroblast growth factor 1 (FGF1), FGF2, insulin-like growth factor 2 (IGF2), and IL-6, according to Dr. da Costa.
In addition, clinical trials are underway in HS involving totally investigational agents, including several Janus kinase inhibitors and tyrosine kinase 2 inhibitors.
The work described by Dr. da Costa had multiple funding sources, including the European Hidradenitis Suppurativa Foundation, the University of Copenhagen, the Icahn School of Medicine at Mount Sinai, AstraZeneca, and the German Federal Ministry of Education and Research. Dr. da Costa is an employee of AstraZeneca, Gothenburg, Sweden.
FROM THE EADV CONGRESS
Anybody for a nanobody? Novel psoriasis therapy impresses in phase 2b
in a phase 2b randomized trial, Kim A. Papp, MD, PhD, reported at the annual congress of the European Academy of Dermatology and Venereology.
A nanobody is a tiny antibody fragment with a much smaller molecular weight than the monoclonal antibodies utilized today in treating psoriasis or atopic dermatitis. The sonelokinab nanobody, derived from animals in the camel family, is a recombinant sequence-optimized nanobody specific for human IL-17F, IL-17A, the heterodimer IL-17A/F, and serum albumin. The binding to serum albumin give sonelokinab a lengthy half-life of 10-12 hours, which may be therapeutically relevant, explained Dr. Papp, president and founder of Probity Medical Research in Waterloo, Ont.
He presented the 24-week results of a multicenter, double-blind, double-dummy randomized trial including 313 North American and European adults with an average 18-year history of psoriasis and a baseline Psoriasis Area and Severity Index (PASI) score of about 21. They were randomized to one of six treatment arms for the first 12 weeks: subcutaneous injection of sonelokinab at 30, 60, or 120 mg at weeks 0, 2, 4, and 8; enhanced–loading-dose sonelokinab at 120 mg every 2 weeks through week 10; the IL-17A inhibitor secukinumab (Cosentyx) at its standard dosing as an active comparator; or placebo. Data analysis was by rigorous nonresponder imputation, meaning anyone who didn’t complete the study was scored as a nonresponder.
“This yields a conservative data analysis somewhat biased against sonelokinab,” the dermatologist pointed out.
The primary outcome in the trial was the week-12 rate of an Investigator’s Global Assessment score of 0 or 1, indicative of clear or almost clear skin. This was achieved in 88.2% of patients in the highest-dose arm of sonelokinab. That group also had a week-12 PASI 90 response rate of 76.5% and a PASI 100 response rate of 33.3%. By comparison, patients on standard-dose secukinumab had a less robust week-12 IGA 0/1 rate of 77.4%, a PASI 90 of 64.2%, and a PASI 100 of 28.3%. Of note, however, this secukinumab performance was better than seen in the 30-mg sonelokinab group, and comparable to outcomes with 60 mg of sonelokinab.
Dose escalation was performed from weeks 12-24. Patients with a week-12 IGA score greater than 1 after being on sonelokinab at 30 or 60 mg were upgraded to 120 mg at week 12 and again every 4 weeks thereafter. Placebo-treated controls were switched to 120 mg at weeks 12, 14, 16, and every 4 weeks thereafter. The group on the enhanced–loading-dose sonelokinab moved to 120 mg every 4 weeks, while those who had gotten four doses of sonelokinab at 120 mg during the first 12 weeks were switched to 120 mg every 8 weeks. The secukinumab group remained on the approved dosing through week 24.
At week 24, superior outcomes were seen in the enhanced–loading-dose sonelokinab group, with an IGA 0/1 response rate of 94.2%, a PASI 90 of 90.4%, and a PASI 100 of 56.9%. The corresponding week-24 rates in patients on 120 mg of sonelokinab every 8 weeks from week 12 on were 80.4%, 79.2%, and 40.4%, outcomes similar to those seen with secukinumab.
The rapidity of response to sonelokinab at 120 mg was striking, with approximately one-third of treated patients achieving a PASI 90 response by week 4.
“This could reflect the smaller molecular profile. There is possibly rapid increased absorption or bioavailability, quicker time to achieving serum half-life, better penetration into target tissue, and perhaps more effective engagement at the target. All of those things are possibilities. These are things that are yet to be explored, but it’s very enticing to see that uncharacteristically rapid initial response. It’s all very gratifying – and tantalizing,” Dr. Papp said in response to an audience question.
The safety profile of sonelokinab was reassuring. The most common adverse events were nasopharyngitis in 13.5% of patients and pruritus in 6.7%, with most cases being mild or moderate. As with other IL-17 blockers, there was an increase in oral candidiasis. This side effect appeared to occur in dose-dependent fashion: The incidence was zero in the 30-mg group, 1.9% with 60 mg, 3.8% with sonelokinab at 120 mg without an enhanced loading dose, and 5.9% with the enhanced loading dose.
The study was conducted by Avillion in partnership with Merck. Dr. Papp reported receiving research funding from and serving as a consultant to those and numerous other pharmaceutical companies.
in a phase 2b randomized trial, Kim A. Papp, MD, PhD, reported at the annual congress of the European Academy of Dermatology and Venereology.
A nanobody is a tiny antibody fragment with a much smaller molecular weight than the monoclonal antibodies utilized today in treating psoriasis or atopic dermatitis. The sonelokinab nanobody, derived from animals in the camel family, is a recombinant sequence-optimized nanobody specific for human IL-17F, IL-17A, the heterodimer IL-17A/F, and serum albumin. The binding to serum albumin give sonelokinab a lengthy half-life of 10-12 hours, which may be therapeutically relevant, explained Dr. Papp, president and founder of Probity Medical Research in Waterloo, Ont.
He presented the 24-week results of a multicenter, double-blind, double-dummy randomized trial including 313 North American and European adults with an average 18-year history of psoriasis and a baseline Psoriasis Area and Severity Index (PASI) score of about 21. They were randomized to one of six treatment arms for the first 12 weeks: subcutaneous injection of sonelokinab at 30, 60, or 120 mg at weeks 0, 2, 4, and 8; enhanced–loading-dose sonelokinab at 120 mg every 2 weeks through week 10; the IL-17A inhibitor secukinumab (Cosentyx) at its standard dosing as an active comparator; or placebo. Data analysis was by rigorous nonresponder imputation, meaning anyone who didn’t complete the study was scored as a nonresponder.
“This yields a conservative data analysis somewhat biased against sonelokinab,” the dermatologist pointed out.
The primary outcome in the trial was the week-12 rate of an Investigator’s Global Assessment score of 0 or 1, indicative of clear or almost clear skin. This was achieved in 88.2% of patients in the highest-dose arm of sonelokinab. That group also had a week-12 PASI 90 response rate of 76.5% and a PASI 100 response rate of 33.3%. By comparison, patients on standard-dose secukinumab had a less robust week-12 IGA 0/1 rate of 77.4%, a PASI 90 of 64.2%, and a PASI 100 of 28.3%. Of note, however, this secukinumab performance was better than seen in the 30-mg sonelokinab group, and comparable to outcomes with 60 mg of sonelokinab.
Dose escalation was performed from weeks 12-24. Patients with a week-12 IGA score greater than 1 after being on sonelokinab at 30 or 60 mg were upgraded to 120 mg at week 12 and again every 4 weeks thereafter. Placebo-treated controls were switched to 120 mg at weeks 12, 14, 16, and every 4 weeks thereafter. The group on the enhanced–loading-dose sonelokinab moved to 120 mg every 4 weeks, while those who had gotten four doses of sonelokinab at 120 mg during the first 12 weeks were switched to 120 mg every 8 weeks. The secukinumab group remained on the approved dosing through week 24.
At week 24, superior outcomes were seen in the enhanced–loading-dose sonelokinab group, with an IGA 0/1 response rate of 94.2%, a PASI 90 of 90.4%, and a PASI 100 of 56.9%. The corresponding week-24 rates in patients on 120 mg of sonelokinab every 8 weeks from week 12 on were 80.4%, 79.2%, and 40.4%, outcomes similar to those seen with secukinumab.
The rapidity of response to sonelokinab at 120 mg was striking, with approximately one-third of treated patients achieving a PASI 90 response by week 4.
“This could reflect the smaller molecular profile. There is possibly rapid increased absorption or bioavailability, quicker time to achieving serum half-life, better penetration into target tissue, and perhaps more effective engagement at the target. All of those things are possibilities. These are things that are yet to be explored, but it’s very enticing to see that uncharacteristically rapid initial response. It’s all very gratifying – and tantalizing,” Dr. Papp said in response to an audience question.
The safety profile of sonelokinab was reassuring. The most common adverse events were nasopharyngitis in 13.5% of patients and pruritus in 6.7%, with most cases being mild or moderate. As with other IL-17 blockers, there was an increase in oral candidiasis. This side effect appeared to occur in dose-dependent fashion: The incidence was zero in the 30-mg group, 1.9% with 60 mg, 3.8% with sonelokinab at 120 mg without an enhanced loading dose, and 5.9% with the enhanced loading dose.
The study was conducted by Avillion in partnership with Merck. Dr. Papp reported receiving research funding from and serving as a consultant to those and numerous other pharmaceutical companies.
in a phase 2b randomized trial, Kim A. Papp, MD, PhD, reported at the annual congress of the European Academy of Dermatology and Venereology.
A nanobody is a tiny antibody fragment with a much smaller molecular weight than the monoclonal antibodies utilized today in treating psoriasis or atopic dermatitis. The sonelokinab nanobody, derived from animals in the camel family, is a recombinant sequence-optimized nanobody specific for human IL-17F, IL-17A, the heterodimer IL-17A/F, and serum albumin. The binding to serum albumin give sonelokinab a lengthy half-life of 10-12 hours, which may be therapeutically relevant, explained Dr. Papp, president and founder of Probity Medical Research in Waterloo, Ont.
He presented the 24-week results of a multicenter, double-blind, double-dummy randomized trial including 313 North American and European adults with an average 18-year history of psoriasis and a baseline Psoriasis Area and Severity Index (PASI) score of about 21. They were randomized to one of six treatment arms for the first 12 weeks: subcutaneous injection of sonelokinab at 30, 60, or 120 mg at weeks 0, 2, 4, and 8; enhanced–loading-dose sonelokinab at 120 mg every 2 weeks through week 10; the IL-17A inhibitor secukinumab (Cosentyx) at its standard dosing as an active comparator; or placebo. Data analysis was by rigorous nonresponder imputation, meaning anyone who didn’t complete the study was scored as a nonresponder.
“This yields a conservative data analysis somewhat biased against sonelokinab,” the dermatologist pointed out.
The primary outcome in the trial was the week-12 rate of an Investigator’s Global Assessment score of 0 or 1, indicative of clear or almost clear skin. This was achieved in 88.2% of patients in the highest-dose arm of sonelokinab. That group also had a week-12 PASI 90 response rate of 76.5% and a PASI 100 response rate of 33.3%. By comparison, patients on standard-dose secukinumab had a less robust week-12 IGA 0/1 rate of 77.4%, a PASI 90 of 64.2%, and a PASI 100 of 28.3%. Of note, however, this secukinumab performance was better than seen in the 30-mg sonelokinab group, and comparable to outcomes with 60 mg of sonelokinab.
Dose escalation was performed from weeks 12-24. Patients with a week-12 IGA score greater than 1 after being on sonelokinab at 30 or 60 mg were upgraded to 120 mg at week 12 and again every 4 weeks thereafter. Placebo-treated controls were switched to 120 mg at weeks 12, 14, 16, and every 4 weeks thereafter. The group on the enhanced–loading-dose sonelokinab moved to 120 mg every 4 weeks, while those who had gotten four doses of sonelokinab at 120 mg during the first 12 weeks were switched to 120 mg every 8 weeks. The secukinumab group remained on the approved dosing through week 24.
At week 24, superior outcomes were seen in the enhanced–loading-dose sonelokinab group, with an IGA 0/1 response rate of 94.2%, a PASI 90 of 90.4%, and a PASI 100 of 56.9%. The corresponding week-24 rates in patients on 120 mg of sonelokinab every 8 weeks from week 12 on were 80.4%, 79.2%, and 40.4%, outcomes similar to those seen with secukinumab.
The rapidity of response to sonelokinab at 120 mg was striking, with approximately one-third of treated patients achieving a PASI 90 response by week 4.
“This could reflect the smaller molecular profile. There is possibly rapid increased absorption or bioavailability, quicker time to achieving serum half-life, better penetration into target tissue, and perhaps more effective engagement at the target. All of those things are possibilities. These are things that are yet to be explored, but it’s very enticing to see that uncharacteristically rapid initial response. It’s all very gratifying – and tantalizing,” Dr. Papp said in response to an audience question.
The safety profile of sonelokinab was reassuring. The most common adverse events were nasopharyngitis in 13.5% of patients and pruritus in 6.7%, with most cases being mild or moderate. As with other IL-17 blockers, there was an increase in oral candidiasis. This side effect appeared to occur in dose-dependent fashion: The incidence was zero in the 30-mg group, 1.9% with 60 mg, 3.8% with sonelokinab at 120 mg without an enhanced loading dose, and 5.9% with the enhanced loading dose.
The study was conducted by Avillion in partnership with Merck. Dr. Papp reported receiving research funding from and serving as a consultant to those and numerous other pharmaceutical companies.
FROM the eadv congress
Neoadjuvant immunotherapy shows promise in stage III melanoma
The next dramatic , John M. Kirkwood, MD, predicted at a virtual forum on cutaneous malignancies jointly presented by the Postgraduate Institute for Medicine and Global Academy for Medical Education.
These agents have already demonstrated profound efficacy, first in stage IV metastatic disease and more recently as adjuvant therapy for resected stage III melanoma. Now, there is a great interest in learning whether by prescribing them preoperatively, patients might reduce their risk of advancing to metastatic disease. And neoadjuvant therapy offers an extremely attractive feature: It yields results in an accelerated fashion.
“The major problem with postoperative adjuvant trials in melanoma since 1984 is the long time to maturity. Many of us don’t want to wait the full 9 or 10 years for a full-bore, phase 3 adjuvant trial in stage III melanoma to mature,” explained Dr. Kirkwood, professor of medicine, dermatology, and translational science and coleader of the melanoma and skin cancer program at the University of Pittsburgh. “The opportunity to treat a patient who presents with a bulky lymph node, has a biopsy, and then can be treated for 3 or 6 weeks or sometimes even longer periods with a therapy that’s promising allows us to ask what’s going on in the tumor tissue, what’s going on in the clinical response at 3 or 6 weeks, and if there’s pathological complete or near-complete response under the microscope.”
Because pathological complete response is a strong predictor of relapse-free survival, this neoadjuvant-forward therapeutic strategy has the potential to provide patients and their physicians with an early forecast of likely clinical outcome only 4-6 weeks into treatment. Also, there is both preclinical and clinical evidence that neoadjuvant therapy may offer a survival advantage over adjuvant therapy, perhaps as a result of early treatment of micrometastatic disease. Another benefit of neoadjuvant therapy for melanoma is the resultant tumor shrinkage, which can permit less extensive surgery.
Dr. Kirkwood highlighted a phase 2 clinical trial conducted at the University of Pittsburgh to illustrate the potential of neoadjuvant therapy in melanoma. The ongoing single-arm study includes 32 patients with stage IIIB or IIIC resectable melanoma along with accessible tumor for biopsy and intratumoral injections of CMP-001, a toll-like receptor 9 agonist. According to the Eighth Edition of the American Joint Committee on Cancer staging manual, stage IIIB melanoma has a 10-year mortality of 23%, and stage IIIC disease has 40%.
CMP-001 triggers type 1 interferon production through activation of plasmacytoid dendritic cells. The resultant inflammatory response draws T cells into the tumor to enhance the response to immunotherapy, which in this study was nivolumab (Opdivo), a human programmed death ligand 1 (PD-L1)–blocking antibody. The neoadjuvant regimen consisted of seven once-weekly intratumoral injections of CMP-001, plus three 240-mg doses of nivolumab given at 2-week intervals. This was followed by resection, then 1 year of adjuvant therapy with nivolumab at 480 mg every 4 weeks and intratumoral CMP-001 every 4 weeks.
In an interim analysis, a major pathologic response occurred in an impressive 15 of 21 patients (71%) after 6 weeks of neoadjuvant therapy. Thirteen of the 15 had a pathologic complete response. Encouragingly, no one with a pathologic complete or near-complete response has relapsed to date.
“A pathologic complete response or near-complete response with neoadjuvant therapy appears to be a biomarker of durable disease control and is associated with excellent outcomes,” Dr. Kirkwood observed, adding that the Pittsburgh experience has been mirrored in reports from the Netherlands, Australia, and University of Texas M.D. Anderson Cancer Center, Houston, involving other neoadjuvant agents.
Other potential early biomarkers of favorable outcome with neoadjuvant therapy include CD8+ T cells in the tumor at baseline, tumor mutational burden, T-cell clonality, and a T-cell–inflamed gene-expression profile.
There were no dose-limiting toxicities or delays in surgery related to the neoadjuvant treatment.
Of note, imaging often inaccurately showed only a partial response in patients who actually had a pathologic complete response, meaning totally devoid of tumor, Dr. Kirkwood said.
Corroboration of these findings is planned in the national multicenter ECOG-ACRIN neoadjuvant trial EA6194.
“Consider referring to this trial any patients who present with bulky nodal disease for whom a treatment assessment at 4-6 weeks is desired in order to predict what the outcome may be,” he suggested.
Dr. Kirkwood reported receiving research grants from Amgen, BMS, Castle Biosciences, Checkmate, Immunocore, Iovance, and Novartis and serving as a consultant to a handful of companies.
Global Academy for Medical Education and this news organization are owned by the same company.
The next dramatic , John M. Kirkwood, MD, predicted at a virtual forum on cutaneous malignancies jointly presented by the Postgraduate Institute for Medicine and Global Academy for Medical Education.
These agents have already demonstrated profound efficacy, first in stage IV metastatic disease and more recently as adjuvant therapy for resected stage III melanoma. Now, there is a great interest in learning whether by prescribing them preoperatively, patients might reduce their risk of advancing to metastatic disease. And neoadjuvant therapy offers an extremely attractive feature: It yields results in an accelerated fashion.
“The major problem with postoperative adjuvant trials in melanoma since 1984 is the long time to maturity. Many of us don’t want to wait the full 9 or 10 years for a full-bore, phase 3 adjuvant trial in stage III melanoma to mature,” explained Dr. Kirkwood, professor of medicine, dermatology, and translational science and coleader of the melanoma and skin cancer program at the University of Pittsburgh. “The opportunity to treat a patient who presents with a bulky lymph node, has a biopsy, and then can be treated for 3 or 6 weeks or sometimes even longer periods with a therapy that’s promising allows us to ask what’s going on in the tumor tissue, what’s going on in the clinical response at 3 or 6 weeks, and if there’s pathological complete or near-complete response under the microscope.”
Because pathological complete response is a strong predictor of relapse-free survival, this neoadjuvant-forward therapeutic strategy has the potential to provide patients and their physicians with an early forecast of likely clinical outcome only 4-6 weeks into treatment. Also, there is both preclinical and clinical evidence that neoadjuvant therapy may offer a survival advantage over adjuvant therapy, perhaps as a result of early treatment of micrometastatic disease. Another benefit of neoadjuvant therapy for melanoma is the resultant tumor shrinkage, which can permit less extensive surgery.
Dr. Kirkwood highlighted a phase 2 clinical trial conducted at the University of Pittsburgh to illustrate the potential of neoadjuvant therapy in melanoma. The ongoing single-arm study includes 32 patients with stage IIIB or IIIC resectable melanoma along with accessible tumor for biopsy and intratumoral injections of CMP-001, a toll-like receptor 9 agonist. According to the Eighth Edition of the American Joint Committee on Cancer staging manual, stage IIIB melanoma has a 10-year mortality of 23%, and stage IIIC disease has 40%.
CMP-001 triggers type 1 interferon production through activation of plasmacytoid dendritic cells. The resultant inflammatory response draws T cells into the tumor to enhance the response to immunotherapy, which in this study was nivolumab (Opdivo), a human programmed death ligand 1 (PD-L1)–blocking antibody. The neoadjuvant regimen consisted of seven once-weekly intratumoral injections of CMP-001, plus three 240-mg doses of nivolumab given at 2-week intervals. This was followed by resection, then 1 year of adjuvant therapy with nivolumab at 480 mg every 4 weeks and intratumoral CMP-001 every 4 weeks.
In an interim analysis, a major pathologic response occurred in an impressive 15 of 21 patients (71%) after 6 weeks of neoadjuvant therapy. Thirteen of the 15 had a pathologic complete response. Encouragingly, no one with a pathologic complete or near-complete response has relapsed to date.
“A pathologic complete response or near-complete response with neoadjuvant therapy appears to be a biomarker of durable disease control and is associated with excellent outcomes,” Dr. Kirkwood observed, adding that the Pittsburgh experience has been mirrored in reports from the Netherlands, Australia, and University of Texas M.D. Anderson Cancer Center, Houston, involving other neoadjuvant agents.
Other potential early biomarkers of favorable outcome with neoadjuvant therapy include CD8+ T cells in the tumor at baseline, tumor mutational burden, T-cell clonality, and a T-cell–inflamed gene-expression profile.
There were no dose-limiting toxicities or delays in surgery related to the neoadjuvant treatment.
Of note, imaging often inaccurately showed only a partial response in patients who actually had a pathologic complete response, meaning totally devoid of tumor, Dr. Kirkwood said.
Corroboration of these findings is planned in the national multicenter ECOG-ACRIN neoadjuvant trial EA6194.
“Consider referring to this trial any patients who present with bulky nodal disease for whom a treatment assessment at 4-6 weeks is desired in order to predict what the outcome may be,” he suggested.
Dr. Kirkwood reported receiving research grants from Amgen, BMS, Castle Biosciences, Checkmate, Immunocore, Iovance, and Novartis and serving as a consultant to a handful of companies.
Global Academy for Medical Education and this news organization are owned by the same company.
The next dramatic , John M. Kirkwood, MD, predicted at a virtual forum on cutaneous malignancies jointly presented by the Postgraduate Institute for Medicine and Global Academy for Medical Education.
These agents have already demonstrated profound efficacy, first in stage IV metastatic disease and more recently as adjuvant therapy for resected stage III melanoma. Now, there is a great interest in learning whether by prescribing them preoperatively, patients might reduce their risk of advancing to metastatic disease. And neoadjuvant therapy offers an extremely attractive feature: It yields results in an accelerated fashion.
“The major problem with postoperative adjuvant trials in melanoma since 1984 is the long time to maturity. Many of us don’t want to wait the full 9 or 10 years for a full-bore, phase 3 adjuvant trial in stage III melanoma to mature,” explained Dr. Kirkwood, professor of medicine, dermatology, and translational science and coleader of the melanoma and skin cancer program at the University of Pittsburgh. “The opportunity to treat a patient who presents with a bulky lymph node, has a biopsy, and then can be treated for 3 or 6 weeks or sometimes even longer periods with a therapy that’s promising allows us to ask what’s going on in the tumor tissue, what’s going on in the clinical response at 3 or 6 weeks, and if there’s pathological complete or near-complete response under the microscope.”
Because pathological complete response is a strong predictor of relapse-free survival, this neoadjuvant-forward therapeutic strategy has the potential to provide patients and their physicians with an early forecast of likely clinical outcome only 4-6 weeks into treatment. Also, there is both preclinical and clinical evidence that neoadjuvant therapy may offer a survival advantage over adjuvant therapy, perhaps as a result of early treatment of micrometastatic disease. Another benefit of neoadjuvant therapy for melanoma is the resultant tumor shrinkage, which can permit less extensive surgery.
Dr. Kirkwood highlighted a phase 2 clinical trial conducted at the University of Pittsburgh to illustrate the potential of neoadjuvant therapy in melanoma. The ongoing single-arm study includes 32 patients with stage IIIB or IIIC resectable melanoma along with accessible tumor for biopsy and intratumoral injections of CMP-001, a toll-like receptor 9 agonist. According to the Eighth Edition of the American Joint Committee on Cancer staging manual, stage IIIB melanoma has a 10-year mortality of 23%, and stage IIIC disease has 40%.
CMP-001 triggers type 1 interferon production through activation of plasmacytoid dendritic cells. The resultant inflammatory response draws T cells into the tumor to enhance the response to immunotherapy, which in this study was nivolumab (Opdivo), a human programmed death ligand 1 (PD-L1)–blocking antibody. The neoadjuvant regimen consisted of seven once-weekly intratumoral injections of CMP-001, plus three 240-mg doses of nivolumab given at 2-week intervals. This was followed by resection, then 1 year of adjuvant therapy with nivolumab at 480 mg every 4 weeks and intratumoral CMP-001 every 4 weeks.
In an interim analysis, a major pathologic response occurred in an impressive 15 of 21 patients (71%) after 6 weeks of neoadjuvant therapy. Thirteen of the 15 had a pathologic complete response. Encouragingly, no one with a pathologic complete or near-complete response has relapsed to date.
“A pathologic complete response or near-complete response with neoadjuvant therapy appears to be a biomarker of durable disease control and is associated with excellent outcomes,” Dr. Kirkwood observed, adding that the Pittsburgh experience has been mirrored in reports from the Netherlands, Australia, and University of Texas M.D. Anderson Cancer Center, Houston, involving other neoadjuvant agents.
Other potential early biomarkers of favorable outcome with neoadjuvant therapy include CD8+ T cells in the tumor at baseline, tumor mutational burden, T-cell clonality, and a T-cell–inflamed gene-expression profile.
There were no dose-limiting toxicities or delays in surgery related to the neoadjuvant treatment.
Of note, imaging often inaccurately showed only a partial response in patients who actually had a pathologic complete response, meaning totally devoid of tumor, Dr. Kirkwood said.
Corroboration of these findings is planned in the national multicenter ECOG-ACRIN neoadjuvant trial EA6194.
“Consider referring to this trial any patients who present with bulky nodal disease for whom a treatment assessment at 4-6 weeks is desired in order to predict what the outcome may be,” he suggested.
Dr. Kirkwood reported receiving research grants from Amgen, BMS, Castle Biosciences, Checkmate, Immunocore, Iovance, and Novartis and serving as a consultant to a handful of companies.
Global Academy for Medical Education and this news organization are owned by the same company.
FROM THE CUTANEOUS MALIGNANCIES FORUM