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Analysis provides key questions – and answers – regarding future of JAK inhibitors for RA
MAUI, HAWAII – Now is a good time to assess the future of the Janus kinase inhibitor class of oral small-molecule medications for rheumatoid arthritis based on new evidence that addresses many of the key questions rheumatologists have about these agents, Dr. Roy Fleischmann said at the 2016 Rheumatology Winter Clinical Symposium.
Baricitinib is likely to win Food and Drug Administration approval within a year, and would join tofacitinib (Xeljanz) as the second Janus kinase (JAK) inhibitor. A once-daily formulation of tofacitinib also was recently approved. Additional investigational agents, filgotinib and ABT-494, are headed for phase III testing, noted Dr. Fleischmann of the University of Texas Southwestern Medical Center and co–medical director of the Metroplex Clinical Research Center, Dallas.
Here’s what rheumatologists want to know about the Janus associated kinase inhibitors, or Jakinibs:
Does Jakinib monotherapy look like a viable strategy?
Yes, according to Dr. Fleischmann, who pointed to the RA-BEGIN baricitinib trial and the DARWIN2 filgotinib trial, both presented at last fall’s American College of Rheumatology annual meeting in San Francisco.
Dr. Fleischmann presented the RA-BEGIN results at the American College of Rheumatology meeting. In this randomized trial conducted in methotrexate-naive rheumatoid arthritis patients, baricitinib 4 mg/day monotherapy outperformed methotrexate in terms of ACR response and demonstrated efficacy similar to baricitinib plus methotrexate, but with fewer side effects. Radiographic disease progression was significantly greater over 52 weeks with methotrexate than with baricitinib monotherapy, and significantly greater with baricitinib monotherapy than with combination therapy. However, baricitinib monotherapy was as effective as baricitinib in combination with methotrexate in slowing disease progression among patients who had elevated high-sensitivity C-reactive protein before treatment that normalized in response to therapy.
“So if baricitinib is approved and is available, I would use it as monotherapy initially and watch the C-reactive protein. If it drops to normal I’m fine, and if it doesn’t I’d add methotrexate for combination therapy,” according to the rheumatologist.
The randomized DARWIN2 trial included 283 methotrexate inadequate responders and showed that filgotinib is also effective as monotherapy.
“Tofacitinib, baricitinib, and filgotinib all work as monotherapy, and why shouldn’t they? There are no antibodies because these are small molecules,” Dr. Fleischmann commented.
A key safety finding in RA-BEAM, in his view, was that herpes zoster occurred in 1.4% of baricitinib-treated patients as well as in 1.2% of the adalimumab (Humira) arm.
“The message here, I think, is that we should be thinking about zoster in all patients with rheumatoid arthritis,” he said.
Is there a clinically meaningful efficacy difference between the Jakinibs?
Not so far, but as yet there have been no head-to-head trials.
How about in terms of safety?
“Safety may be the difference between these drugs. Efficacy doesn’t seem that different,” he said.
Based upon the clinical trials data to date, which involves hundreds of patients per Jakinib, it appears there is a hint of a difference, with less lymphopenia and anemia being seen with filgotinib, the most JAK 1–selective of the Jakinibs. Baricitinib is a JAK 1/2 inhibitor, tofacitinib a JAK 3/1/2 inhibitor, and ABT-494 is relatively JAK 1–selective. But definitive answers regarding comparative safety must await the creation of multi-thousand-patient postmarketing registries, in Dr. Fleischmann’s opinion.
Which is more effective: a Jakinib or a tumor necrosis factor inhibitor?
Only one clinical trial has addressed this question with sufficient power to yield a statistically significant answer. This was the RA-BEAM trial presented at the 2015 ACR meeting. RA-BEAM was a randomized head-to-head study of baricitinib plus methotrexate versus adalimumab plus methotrexate in 1,305 methotrexate inadequate responders. Baricitinib was the clear winner, with week 24 ACR 20 and ACR 50 responses of 70% and 45%, respectively, compared with 61% and 35% for adalimumab. Particularly impressive was baricitinib’s outperformance of adalimumab on the pain component of the ACR score.
“This is the first study to show a Jakinib plus methotrexate is actually superior to a TNF inhibitor plus methotrexate. And adalimumab is a really, really good drug. Is it a big difference? It’s not tremendous, but it’s a difference. Is it clinically significant? In that extra 9%-10% of patients, it obviously is; in most it’s probably not,” Dr. Fleischmann said.
Will an oral Jakinib be the first drug physicians prescribe in rheumatoid arthritis patients, or the last?
“The data so far shows that Jakinib monotherapy is very viable, as opposed to biologic monotherapy, which is viable but less so. RA-BEAM showed baricitinib was superior to a TNF inhibitor, and there are studies to suggest but don’t prove that tofacitinib is, too,” he said.
Dr. Fleischmann reported serving as a paid researcher for and/or consultant to numerous pharmaceutical companies, including most of those developing Jakinibs.
MAUI, HAWAII – Now is a good time to assess the future of the Janus kinase inhibitor class of oral small-molecule medications for rheumatoid arthritis based on new evidence that addresses many of the key questions rheumatologists have about these agents, Dr. Roy Fleischmann said at the 2016 Rheumatology Winter Clinical Symposium.
Baricitinib is likely to win Food and Drug Administration approval within a year, and would join tofacitinib (Xeljanz) as the second Janus kinase (JAK) inhibitor. A once-daily formulation of tofacitinib also was recently approved. Additional investigational agents, filgotinib and ABT-494, are headed for phase III testing, noted Dr. Fleischmann of the University of Texas Southwestern Medical Center and co–medical director of the Metroplex Clinical Research Center, Dallas.
Here’s what rheumatologists want to know about the Janus associated kinase inhibitors, or Jakinibs:
Does Jakinib monotherapy look like a viable strategy?
Yes, according to Dr. Fleischmann, who pointed to the RA-BEGIN baricitinib trial and the DARWIN2 filgotinib trial, both presented at last fall’s American College of Rheumatology annual meeting in San Francisco.
Dr. Fleischmann presented the RA-BEGIN results at the American College of Rheumatology meeting. In this randomized trial conducted in methotrexate-naive rheumatoid arthritis patients, baricitinib 4 mg/day monotherapy outperformed methotrexate in terms of ACR response and demonstrated efficacy similar to baricitinib plus methotrexate, but with fewer side effects. Radiographic disease progression was significantly greater over 52 weeks with methotrexate than with baricitinib monotherapy, and significantly greater with baricitinib monotherapy than with combination therapy. However, baricitinib monotherapy was as effective as baricitinib in combination with methotrexate in slowing disease progression among patients who had elevated high-sensitivity C-reactive protein before treatment that normalized in response to therapy.
“So if baricitinib is approved and is available, I would use it as monotherapy initially and watch the C-reactive protein. If it drops to normal I’m fine, and if it doesn’t I’d add methotrexate for combination therapy,” according to the rheumatologist.
The randomized DARWIN2 trial included 283 methotrexate inadequate responders and showed that filgotinib is also effective as monotherapy.
“Tofacitinib, baricitinib, and filgotinib all work as monotherapy, and why shouldn’t they? There are no antibodies because these are small molecules,” Dr. Fleischmann commented.
A key safety finding in RA-BEAM, in his view, was that herpes zoster occurred in 1.4% of baricitinib-treated patients as well as in 1.2% of the adalimumab (Humira) arm.
“The message here, I think, is that we should be thinking about zoster in all patients with rheumatoid arthritis,” he said.
Is there a clinically meaningful efficacy difference between the Jakinibs?
Not so far, but as yet there have been no head-to-head trials.
How about in terms of safety?
“Safety may be the difference between these drugs. Efficacy doesn’t seem that different,” he said.
Based upon the clinical trials data to date, which involves hundreds of patients per Jakinib, it appears there is a hint of a difference, with less lymphopenia and anemia being seen with filgotinib, the most JAK 1–selective of the Jakinibs. Baricitinib is a JAK 1/2 inhibitor, tofacitinib a JAK 3/1/2 inhibitor, and ABT-494 is relatively JAK 1–selective. But definitive answers regarding comparative safety must await the creation of multi-thousand-patient postmarketing registries, in Dr. Fleischmann’s opinion.
Which is more effective: a Jakinib or a tumor necrosis factor inhibitor?
Only one clinical trial has addressed this question with sufficient power to yield a statistically significant answer. This was the RA-BEAM trial presented at the 2015 ACR meeting. RA-BEAM was a randomized head-to-head study of baricitinib plus methotrexate versus adalimumab plus methotrexate in 1,305 methotrexate inadequate responders. Baricitinib was the clear winner, with week 24 ACR 20 and ACR 50 responses of 70% and 45%, respectively, compared with 61% and 35% for adalimumab. Particularly impressive was baricitinib’s outperformance of adalimumab on the pain component of the ACR score.
“This is the first study to show a Jakinib plus methotrexate is actually superior to a TNF inhibitor plus methotrexate. And adalimumab is a really, really good drug. Is it a big difference? It’s not tremendous, but it’s a difference. Is it clinically significant? In that extra 9%-10% of patients, it obviously is; in most it’s probably not,” Dr. Fleischmann said.
Will an oral Jakinib be the first drug physicians prescribe in rheumatoid arthritis patients, or the last?
“The data so far shows that Jakinib monotherapy is very viable, as opposed to biologic monotherapy, which is viable but less so. RA-BEAM showed baricitinib was superior to a TNF inhibitor, and there are studies to suggest but don’t prove that tofacitinib is, too,” he said.
Dr. Fleischmann reported serving as a paid researcher for and/or consultant to numerous pharmaceutical companies, including most of those developing Jakinibs.
MAUI, HAWAII – Now is a good time to assess the future of the Janus kinase inhibitor class of oral small-molecule medications for rheumatoid arthritis based on new evidence that addresses many of the key questions rheumatologists have about these agents, Dr. Roy Fleischmann said at the 2016 Rheumatology Winter Clinical Symposium.
Baricitinib is likely to win Food and Drug Administration approval within a year, and would join tofacitinib (Xeljanz) as the second Janus kinase (JAK) inhibitor. A once-daily formulation of tofacitinib also was recently approved. Additional investigational agents, filgotinib and ABT-494, are headed for phase III testing, noted Dr. Fleischmann of the University of Texas Southwestern Medical Center and co–medical director of the Metroplex Clinical Research Center, Dallas.
Here’s what rheumatologists want to know about the Janus associated kinase inhibitors, or Jakinibs:
Does Jakinib monotherapy look like a viable strategy?
Yes, according to Dr. Fleischmann, who pointed to the RA-BEGIN baricitinib trial and the DARWIN2 filgotinib trial, both presented at last fall’s American College of Rheumatology annual meeting in San Francisco.
Dr. Fleischmann presented the RA-BEGIN results at the American College of Rheumatology meeting. In this randomized trial conducted in methotrexate-naive rheumatoid arthritis patients, baricitinib 4 mg/day monotherapy outperformed methotrexate in terms of ACR response and demonstrated efficacy similar to baricitinib plus methotrexate, but with fewer side effects. Radiographic disease progression was significantly greater over 52 weeks with methotrexate than with baricitinib monotherapy, and significantly greater with baricitinib monotherapy than with combination therapy. However, baricitinib monotherapy was as effective as baricitinib in combination with methotrexate in slowing disease progression among patients who had elevated high-sensitivity C-reactive protein before treatment that normalized in response to therapy.
“So if baricitinib is approved and is available, I would use it as monotherapy initially and watch the C-reactive protein. If it drops to normal I’m fine, and if it doesn’t I’d add methotrexate for combination therapy,” according to the rheumatologist.
The randomized DARWIN2 trial included 283 methotrexate inadequate responders and showed that filgotinib is also effective as monotherapy.
“Tofacitinib, baricitinib, and filgotinib all work as monotherapy, and why shouldn’t they? There are no antibodies because these are small molecules,” Dr. Fleischmann commented.
A key safety finding in RA-BEAM, in his view, was that herpes zoster occurred in 1.4% of baricitinib-treated patients as well as in 1.2% of the adalimumab (Humira) arm.
“The message here, I think, is that we should be thinking about zoster in all patients with rheumatoid arthritis,” he said.
Is there a clinically meaningful efficacy difference between the Jakinibs?
Not so far, but as yet there have been no head-to-head trials.
How about in terms of safety?
“Safety may be the difference between these drugs. Efficacy doesn’t seem that different,” he said.
Based upon the clinical trials data to date, which involves hundreds of patients per Jakinib, it appears there is a hint of a difference, with less lymphopenia and anemia being seen with filgotinib, the most JAK 1–selective of the Jakinibs. Baricitinib is a JAK 1/2 inhibitor, tofacitinib a JAK 3/1/2 inhibitor, and ABT-494 is relatively JAK 1–selective. But definitive answers regarding comparative safety must await the creation of multi-thousand-patient postmarketing registries, in Dr. Fleischmann’s opinion.
Which is more effective: a Jakinib or a tumor necrosis factor inhibitor?
Only one clinical trial has addressed this question with sufficient power to yield a statistically significant answer. This was the RA-BEAM trial presented at the 2015 ACR meeting. RA-BEAM was a randomized head-to-head study of baricitinib plus methotrexate versus adalimumab plus methotrexate in 1,305 methotrexate inadequate responders. Baricitinib was the clear winner, with week 24 ACR 20 and ACR 50 responses of 70% and 45%, respectively, compared with 61% and 35% for adalimumab. Particularly impressive was baricitinib’s outperformance of adalimumab on the pain component of the ACR score.
“This is the first study to show a Jakinib plus methotrexate is actually superior to a TNF inhibitor plus methotrexate. And adalimumab is a really, really good drug. Is it a big difference? It’s not tremendous, but it’s a difference. Is it clinically significant? In that extra 9%-10% of patients, it obviously is; in most it’s probably not,” Dr. Fleischmann said.
Will an oral Jakinib be the first drug physicians prescribe in rheumatoid arthritis patients, or the last?
“The data so far shows that Jakinib monotherapy is very viable, as opposed to biologic monotherapy, which is viable but less so. RA-BEAM showed baricitinib was superior to a TNF inhibitor, and there are studies to suggest but don’t prove that tofacitinib is, too,” he said.
Dr. Fleischmann reported serving as a paid researcher for and/or consultant to numerous pharmaceutical companies, including most of those developing Jakinibs.
EXPERT ANALYSIS FROM RWCS 2016
The year in osteoarthritis
MAUI, HAWAII – One of the major happenings in the field of osteoarthritis in the past year was a disturbing report of dramatically increased risk of acute MI for at least 6 months after total knee replacement, panelists agreed at the 2016 Rheumatology Winter Clinical Symposium.
“What they found borders on frightening,” according to Dr. Martin J. Bergman of Drexel University, Philadelphia, and chief of rheumatology at Taylor Hospital in Ridley Park, Pa.
Dr. Bergman and copanelist Dr. Orrin M. Troum of the University of Southern California in Los Angeles highlighted key developments in osteoarthritis during the past year, including two major studies on total knee replacement, the Food and Drug Administration’s updated stronger warning on the cardiac and stroke risks of NSAIDs, a randomized trial which effectively takes hydroxychloroquine (Plaquenil) off the treatment menu for hand osteoarthritis, and a reassuring report on the safety of repeated intra-articular corticosteroid injections in patients with synovitic knee osteoarthritis.
Acute MI risk after total knee replacement
British investigators utilizing the U.K. National Health Service database retrospectively identified 13,849 patients who underwent total knee replacement (TKR) and an equal number of nonsurgical controls propensity-matched for cardiovascular risk factors. These two very large groups were followed for 5 years.
During the first month after TKR, the acute MI risk was 8.75-fold greater than in the matched controls. The elevated risk gradually declined thereafter, but it remained significantly higher than in controls until 1 year after surgery. At 3 months post surgery the TKR group was at fourfold increased risk of MI, compared with controls, and at 6 months their risk was still nearly double that of controls (Arthritis Rheumatol. 2015 Oct;67[10]:2771-9).
The British investigators also found a prolonged postsurgical elevated risk of MI in a large group of patients who underwent total hip replacement, although the magnitude of the increased risk, compared with matched controls, wasn’t as large as that seen after TKR.
Dr. Troum commented that the increased risk of MI during the first year after TKR identified in this study is something physicians now need to bring up in the risk/benefit discussion with patients considering TKR.
“Also, this study underscores that it may behoove us to make sure that these presurgical patients are really well worked up by a cardiologist or their primary care physician to mitigate that coronary risk as much as possible,” he added.
Another key finding in the U.K. study was that unlike the acute MI risk, the risk of venous thromboembolism following TKR remained elevated throughout the full 5 years of follow-up.
“Once you’ve had that surgery, you are at increased risk for venous thromboembolism. I think that’s something we have to keep in mind when a patient comes in with a history of total knee replacement and a complaint of calf pain or swelling – at that point, you have to think about deep venous thrombosis,” Dr. Bergman said.
TKR – Why wait?
In a Danish trial of 100 knee osteoarthritis patients deemed eligible for TKR, participants were randomized to prompt TKR followed by a 3-month regimen of exercise, dietary weight loss, physical therapy, and pain medication or to the nonsurgical regimen alone. At 12 months of follow-up, the prompt TKR group showed significantly greater improvement in a standardized score encompassing pain, symptoms, quality of life, and activities of daily living, even though one-quarter of patients in the nonsurgical treatment group bailed and underwent TKR before 12 months was up (N Engl J Med. 2015 Oct 22;373[17]:1597-606).
“My conclusion is that once you’ve determined that a patient needs and wants a total knee replacement, the patient should probably get it. Delaying – trying other modalities in an effort to lose weight and improve function – is really not going to buy you much in the way of time,” Dr. Bergman observed.
Hydroxychloroquine for hand osteoarthritis
At the 2015 European League Against Rheumatism (EULAR) meeting in Rome, Dutch investigators presented a randomized, double-blind trial in which 196 patients with symptomatic hand osteoarthritis received 6 months of hydroxychloroquine at 400 mg/day or placebo. Unlike in mild rheumatoid arthritis or lupus, hydroxychloroquine had no beneficial effect on hand osteoarthritis pain, disability, or quality of life measures.
“Plaquenil [Hydroxychloroquine] is not a good choice for patients with osteoarthritis of the hand. I think it’s a dead therapy,” Dr. Troum declared.
FDA expands warning on NSAIDs’ cardiovascular risk
On July 9, 2015, the FDA announced updated labels for NSAIDs. The new warning states that MI and stroke risk can increase as early as in the first week of NSAID use and appear to be dose- and duration-related. The agency also warned that patients who take an NSAID after a first MI are more likely to die within 1 year.
“This really brought a lot of folks to my office,” Dr. Troum recalled.
“Absolutely, this was big stuff,” Dr. Bergman agreed. “This became a nightmare for many of us because all of a sudden patients were scared to death about taking their NSAIDs.”
Intra-articular corticosteroids for knee osteoarthritis don’t accelerate cartilage deterioration
At last fall’s American College of Rheumatology meeting in San Francisco, Jeffrey B. Driban, Ph.D., of Tufts Medical Center, Boston, presented a double-blind, randomized trial of intra-articular injections of triamcinolone hexacetonide 40 mg versus saline quarterly for 2 years in 140 patients with symptomatic knee osteoarthritis with ultrasound evidence of synovitis. Participants underwent annual evaluation of periarticular bone and cartilage changes via MRI and dual-energy x-ray absorptiometry.
After 2 years, there was no difference between the two groups in terms of pain scores, walk time, or other functional measures. The injections – eight in total over 2 years – were safe, with new-onset hypertension and hyperglycemia rates of 3% in this obese population. And most important of all, there were no major differences between the two groups in terms of quantitative or semiquantitative structural endpoints; in other words, the injections didn’t increase the rate of structural disease progression. The intra-articular steroid group showed a modestly greater rate of loss of cartilage thickness, which the investigators deemed of uncertain clinical significance.
“The structural changes were minimal,” Dr. Troum noted. “This is only a 2-year study, but I can say that I now feel more comfortable giving these injections in patients who for whatever reason can’t get surgery.”
Dr. Bergman said that many orthopedic surgeons talk up the potential risk that intra-articular steroid injections will accelerate cartilage damage. They place an arbitrary limit on the number of injections a patient can receive.
“I think this study really helps us push back and say, ‘No, I think you’re fine in getting this procedure,’” the rheumatologist commented.
Dr. Bergman and Dr. Troum reported having no financial conflicts regarding their presentation.
MAUI, HAWAII – One of the major happenings in the field of osteoarthritis in the past year was a disturbing report of dramatically increased risk of acute MI for at least 6 months after total knee replacement, panelists agreed at the 2016 Rheumatology Winter Clinical Symposium.
“What they found borders on frightening,” according to Dr. Martin J. Bergman of Drexel University, Philadelphia, and chief of rheumatology at Taylor Hospital in Ridley Park, Pa.
Dr. Bergman and copanelist Dr. Orrin M. Troum of the University of Southern California in Los Angeles highlighted key developments in osteoarthritis during the past year, including two major studies on total knee replacement, the Food and Drug Administration’s updated stronger warning on the cardiac and stroke risks of NSAIDs, a randomized trial which effectively takes hydroxychloroquine (Plaquenil) off the treatment menu for hand osteoarthritis, and a reassuring report on the safety of repeated intra-articular corticosteroid injections in patients with synovitic knee osteoarthritis.
Acute MI risk after total knee replacement
British investigators utilizing the U.K. National Health Service database retrospectively identified 13,849 patients who underwent total knee replacement (TKR) and an equal number of nonsurgical controls propensity-matched for cardiovascular risk factors. These two very large groups were followed for 5 years.
During the first month after TKR, the acute MI risk was 8.75-fold greater than in the matched controls. The elevated risk gradually declined thereafter, but it remained significantly higher than in controls until 1 year after surgery. At 3 months post surgery the TKR group was at fourfold increased risk of MI, compared with controls, and at 6 months their risk was still nearly double that of controls (Arthritis Rheumatol. 2015 Oct;67[10]:2771-9).
The British investigators also found a prolonged postsurgical elevated risk of MI in a large group of patients who underwent total hip replacement, although the magnitude of the increased risk, compared with matched controls, wasn’t as large as that seen after TKR.
Dr. Troum commented that the increased risk of MI during the first year after TKR identified in this study is something physicians now need to bring up in the risk/benefit discussion with patients considering TKR.
“Also, this study underscores that it may behoove us to make sure that these presurgical patients are really well worked up by a cardiologist or their primary care physician to mitigate that coronary risk as much as possible,” he added.
Another key finding in the U.K. study was that unlike the acute MI risk, the risk of venous thromboembolism following TKR remained elevated throughout the full 5 years of follow-up.
“Once you’ve had that surgery, you are at increased risk for venous thromboembolism. I think that’s something we have to keep in mind when a patient comes in with a history of total knee replacement and a complaint of calf pain or swelling – at that point, you have to think about deep venous thrombosis,” Dr. Bergman said.
TKR – Why wait?
In a Danish trial of 100 knee osteoarthritis patients deemed eligible for TKR, participants were randomized to prompt TKR followed by a 3-month regimen of exercise, dietary weight loss, physical therapy, and pain medication or to the nonsurgical regimen alone. At 12 months of follow-up, the prompt TKR group showed significantly greater improvement in a standardized score encompassing pain, symptoms, quality of life, and activities of daily living, even though one-quarter of patients in the nonsurgical treatment group bailed and underwent TKR before 12 months was up (N Engl J Med. 2015 Oct 22;373[17]:1597-606).
“My conclusion is that once you’ve determined that a patient needs and wants a total knee replacement, the patient should probably get it. Delaying – trying other modalities in an effort to lose weight and improve function – is really not going to buy you much in the way of time,” Dr. Bergman observed.
Hydroxychloroquine for hand osteoarthritis
At the 2015 European League Against Rheumatism (EULAR) meeting in Rome, Dutch investigators presented a randomized, double-blind trial in which 196 patients with symptomatic hand osteoarthritis received 6 months of hydroxychloroquine at 400 mg/day or placebo. Unlike in mild rheumatoid arthritis or lupus, hydroxychloroquine had no beneficial effect on hand osteoarthritis pain, disability, or quality of life measures.
“Plaquenil [Hydroxychloroquine] is not a good choice for patients with osteoarthritis of the hand. I think it’s a dead therapy,” Dr. Troum declared.
FDA expands warning on NSAIDs’ cardiovascular risk
On July 9, 2015, the FDA announced updated labels for NSAIDs. The new warning states that MI and stroke risk can increase as early as in the first week of NSAID use and appear to be dose- and duration-related. The agency also warned that patients who take an NSAID after a first MI are more likely to die within 1 year.
“This really brought a lot of folks to my office,” Dr. Troum recalled.
“Absolutely, this was big stuff,” Dr. Bergman agreed. “This became a nightmare for many of us because all of a sudden patients were scared to death about taking their NSAIDs.”
Intra-articular corticosteroids for knee osteoarthritis don’t accelerate cartilage deterioration
At last fall’s American College of Rheumatology meeting in San Francisco, Jeffrey B. Driban, Ph.D., of Tufts Medical Center, Boston, presented a double-blind, randomized trial of intra-articular injections of triamcinolone hexacetonide 40 mg versus saline quarterly for 2 years in 140 patients with symptomatic knee osteoarthritis with ultrasound evidence of synovitis. Participants underwent annual evaluation of periarticular bone and cartilage changes via MRI and dual-energy x-ray absorptiometry.
After 2 years, there was no difference between the two groups in terms of pain scores, walk time, or other functional measures. The injections – eight in total over 2 years – were safe, with new-onset hypertension and hyperglycemia rates of 3% in this obese population. And most important of all, there were no major differences between the two groups in terms of quantitative or semiquantitative structural endpoints; in other words, the injections didn’t increase the rate of structural disease progression. The intra-articular steroid group showed a modestly greater rate of loss of cartilage thickness, which the investigators deemed of uncertain clinical significance.
“The structural changes were minimal,” Dr. Troum noted. “This is only a 2-year study, but I can say that I now feel more comfortable giving these injections in patients who for whatever reason can’t get surgery.”
Dr. Bergman said that many orthopedic surgeons talk up the potential risk that intra-articular steroid injections will accelerate cartilage damage. They place an arbitrary limit on the number of injections a patient can receive.
“I think this study really helps us push back and say, ‘No, I think you’re fine in getting this procedure,’” the rheumatologist commented.
Dr. Bergman and Dr. Troum reported having no financial conflicts regarding their presentation.
MAUI, HAWAII – One of the major happenings in the field of osteoarthritis in the past year was a disturbing report of dramatically increased risk of acute MI for at least 6 months after total knee replacement, panelists agreed at the 2016 Rheumatology Winter Clinical Symposium.
“What they found borders on frightening,” according to Dr. Martin J. Bergman of Drexel University, Philadelphia, and chief of rheumatology at Taylor Hospital in Ridley Park, Pa.
Dr. Bergman and copanelist Dr. Orrin M. Troum of the University of Southern California in Los Angeles highlighted key developments in osteoarthritis during the past year, including two major studies on total knee replacement, the Food and Drug Administration’s updated stronger warning on the cardiac and stroke risks of NSAIDs, a randomized trial which effectively takes hydroxychloroquine (Plaquenil) off the treatment menu for hand osteoarthritis, and a reassuring report on the safety of repeated intra-articular corticosteroid injections in patients with synovitic knee osteoarthritis.
Acute MI risk after total knee replacement
British investigators utilizing the U.K. National Health Service database retrospectively identified 13,849 patients who underwent total knee replacement (TKR) and an equal number of nonsurgical controls propensity-matched for cardiovascular risk factors. These two very large groups were followed for 5 years.
During the first month after TKR, the acute MI risk was 8.75-fold greater than in the matched controls. The elevated risk gradually declined thereafter, but it remained significantly higher than in controls until 1 year after surgery. At 3 months post surgery the TKR group was at fourfold increased risk of MI, compared with controls, and at 6 months their risk was still nearly double that of controls (Arthritis Rheumatol. 2015 Oct;67[10]:2771-9).
The British investigators also found a prolonged postsurgical elevated risk of MI in a large group of patients who underwent total hip replacement, although the magnitude of the increased risk, compared with matched controls, wasn’t as large as that seen after TKR.
Dr. Troum commented that the increased risk of MI during the first year after TKR identified in this study is something physicians now need to bring up in the risk/benefit discussion with patients considering TKR.
“Also, this study underscores that it may behoove us to make sure that these presurgical patients are really well worked up by a cardiologist or their primary care physician to mitigate that coronary risk as much as possible,” he added.
Another key finding in the U.K. study was that unlike the acute MI risk, the risk of venous thromboembolism following TKR remained elevated throughout the full 5 years of follow-up.
“Once you’ve had that surgery, you are at increased risk for venous thromboembolism. I think that’s something we have to keep in mind when a patient comes in with a history of total knee replacement and a complaint of calf pain or swelling – at that point, you have to think about deep venous thrombosis,” Dr. Bergman said.
TKR – Why wait?
In a Danish trial of 100 knee osteoarthritis patients deemed eligible for TKR, participants were randomized to prompt TKR followed by a 3-month regimen of exercise, dietary weight loss, physical therapy, and pain medication or to the nonsurgical regimen alone. At 12 months of follow-up, the prompt TKR group showed significantly greater improvement in a standardized score encompassing pain, symptoms, quality of life, and activities of daily living, even though one-quarter of patients in the nonsurgical treatment group bailed and underwent TKR before 12 months was up (N Engl J Med. 2015 Oct 22;373[17]:1597-606).
“My conclusion is that once you’ve determined that a patient needs and wants a total knee replacement, the patient should probably get it. Delaying – trying other modalities in an effort to lose weight and improve function – is really not going to buy you much in the way of time,” Dr. Bergman observed.
Hydroxychloroquine for hand osteoarthritis
At the 2015 European League Against Rheumatism (EULAR) meeting in Rome, Dutch investigators presented a randomized, double-blind trial in which 196 patients with symptomatic hand osteoarthritis received 6 months of hydroxychloroquine at 400 mg/day or placebo. Unlike in mild rheumatoid arthritis or lupus, hydroxychloroquine had no beneficial effect on hand osteoarthritis pain, disability, or quality of life measures.
“Plaquenil [Hydroxychloroquine] is not a good choice for patients with osteoarthritis of the hand. I think it’s a dead therapy,” Dr. Troum declared.
FDA expands warning on NSAIDs’ cardiovascular risk
On July 9, 2015, the FDA announced updated labels for NSAIDs. The new warning states that MI and stroke risk can increase as early as in the first week of NSAID use and appear to be dose- and duration-related. The agency also warned that patients who take an NSAID after a first MI are more likely to die within 1 year.
“This really brought a lot of folks to my office,” Dr. Troum recalled.
“Absolutely, this was big stuff,” Dr. Bergman agreed. “This became a nightmare for many of us because all of a sudden patients were scared to death about taking their NSAIDs.”
Intra-articular corticosteroids for knee osteoarthritis don’t accelerate cartilage deterioration
At last fall’s American College of Rheumatology meeting in San Francisco, Jeffrey B. Driban, Ph.D., of Tufts Medical Center, Boston, presented a double-blind, randomized trial of intra-articular injections of triamcinolone hexacetonide 40 mg versus saline quarterly for 2 years in 140 patients with symptomatic knee osteoarthritis with ultrasound evidence of synovitis. Participants underwent annual evaluation of periarticular bone and cartilage changes via MRI and dual-energy x-ray absorptiometry.
After 2 years, there was no difference between the two groups in terms of pain scores, walk time, or other functional measures. The injections – eight in total over 2 years – were safe, with new-onset hypertension and hyperglycemia rates of 3% in this obese population. And most important of all, there were no major differences between the two groups in terms of quantitative or semiquantitative structural endpoints; in other words, the injections didn’t increase the rate of structural disease progression. The intra-articular steroid group showed a modestly greater rate of loss of cartilage thickness, which the investigators deemed of uncertain clinical significance.
“The structural changes were minimal,” Dr. Troum noted. “This is only a 2-year study, but I can say that I now feel more comfortable giving these injections in patients who for whatever reason can’t get surgery.”
Dr. Bergman said that many orthopedic surgeons talk up the potential risk that intra-articular steroid injections will accelerate cartilage damage. They place an arbitrary limit on the number of injections a patient can receive.
“I think this study really helps us push back and say, ‘No, I think you’re fine in getting this procedure,’” the rheumatologist commented.
Dr. Bergman and Dr. Troum reported having no financial conflicts regarding their presentation.
EXPERT ANALYSIS FROM RWCS 2016
Fresh evidence of methotrexate efficacy in psoriatic arthritis
MAUI, HAWAII – The effectiveness of methotrexate in psoriatic arthritis is a matter of debate, but Dr. Arthur Kavanaugh is a believer based in part upon a recent subanalysis of the TICOPA study.
Moreover, his new 5-year follow-up analysis from the GO-REVEAL study of golimumab (Simponi) with or without concomitant methotrexate suggests that methotrexate plus the tumor necrosis factor inhibitor provided synergistic efficacy, he said at the 2016 Rheumatology Winter Clinical Symposium.
The 5-year analysis doesn’t provide definitive proof of synergistic benefit because it wasn’t designed or powered with that endpoint in mind (Arthritis Care Res. 2016;68[2]:267–74). No randomized trial completed to date has been. But the first-ever trial set up to test the synergistic efficacy hypothesis is underway. It’s a 52-week, double-blind, multicenter, randomized trial of etanercept (Enbrel) and methotrexate versus either alone in combination with placebo. And while the Amgen-sponsored study won’t be completed until 2018, Dr. Kavanaugh is ready to predict the outcome based in part upon the message contained in his GO-REVEAL findings.
“I’m placing my bet down now that there will be synergy for the X-ray outcome of change in SHS [Sharp/van der Heijde Score] for sure, and maybe for clinical efficacy as well, both joints and skin,” declared Dr. Kavanaugh, the conference director and professor of medicine at the University of California, San Diego.
He pointed to a new subanalysis of the Tight Control of Psoriatic Arthritis (TICOPA) study reported by rheumatologists at the University of Leeds (England) as evidence that methotrexate is effective in psoriatic arthritis. Of the 188 patients in the tight control arm who received methotrexate in the first 12 weeks of the trial, 41% had an ACR 20 response, meaning a 20% improvement in disease signs and symptoms at 12 weeks. A total of 19% had an ACR 50 response. And 27% had at least a 75% improvement in Psoriasis Area and Severity Index, or PASI 75. A 63% reduction in the proportion of patients with dactylitis and a 26% decrease in the proportion of patients with enthesitis was observed in the early methotrexate group. There was a suggestion of a dose-response effect, with better outcomes seen in the 108 participants who received a mean dose greater than 15 mg/week (J Rheumatol. 2016 Feb;43[2]:356-61).
This is a more impressive result than earlier reported from the Methotrexate In Psoriatic Arthritis (MIPA) trial, where the ACR 20 response rate was only 34% (Rheumatology [Oxford]. 2012;51[8]:1368-77). That may well be because methotrexate was given at only 15 mg/week in MIPA, in Dr. Kavanaugh’s view.
“I think methotrexate can work for the peripheral arthritis. This TICOPA analysis gives us a sense of the extent of the improvement, and also the extent of improvement in the skin,” the rheumatologist commented.
Turning to the week 256 results of GO-REVEAL, he said there was no difference in clinical response between psoriatic arthritis patients on golimumab alone or golimumab plus methotrexate at baseline. But among patients who were doing well clinically, with an assessment of minimal disease activity (MDA) on three or more consecutive clinic visits, only those on golimumab plus methotrexate at baseline showed radiologic improvement. The 57 patients on combination therapy who achieved MDA on at least three consecutive visits showed a mean 1.29-point improvement in SHS; the 48 rated as having MDA on four or more consecutive occasions similarly had a mean 1.24-point improvement.
In contrast, the 59 participants who achieved MDA on three or more consecutive visits but were on golimumab without methotrexate at baseline had a 0.25-point increase in SHS, and the 47 who had MDA on at least four consecutive visits had a 0.38-point SHS bump.
Dr. Kavanaugh reported having financial relationships with roughly a dozen pharmaceutical companies
MAUI, HAWAII – The effectiveness of methotrexate in psoriatic arthritis is a matter of debate, but Dr. Arthur Kavanaugh is a believer based in part upon a recent subanalysis of the TICOPA study.
Moreover, his new 5-year follow-up analysis from the GO-REVEAL study of golimumab (Simponi) with or without concomitant methotrexate suggests that methotrexate plus the tumor necrosis factor inhibitor provided synergistic efficacy, he said at the 2016 Rheumatology Winter Clinical Symposium.
The 5-year analysis doesn’t provide definitive proof of synergistic benefit because it wasn’t designed or powered with that endpoint in mind (Arthritis Care Res. 2016;68[2]:267–74). No randomized trial completed to date has been. But the first-ever trial set up to test the synergistic efficacy hypothesis is underway. It’s a 52-week, double-blind, multicenter, randomized trial of etanercept (Enbrel) and methotrexate versus either alone in combination with placebo. And while the Amgen-sponsored study won’t be completed until 2018, Dr. Kavanaugh is ready to predict the outcome based in part upon the message contained in his GO-REVEAL findings.
“I’m placing my bet down now that there will be synergy for the X-ray outcome of change in SHS [Sharp/van der Heijde Score] for sure, and maybe for clinical efficacy as well, both joints and skin,” declared Dr. Kavanaugh, the conference director and professor of medicine at the University of California, San Diego.
He pointed to a new subanalysis of the Tight Control of Psoriatic Arthritis (TICOPA) study reported by rheumatologists at the University of Leeds (England) as evidence that methotrexate is effective in psoriatic arthritis. Of the 188 patients in the tight control arm who received methotrexate in the first 12 weeks of the trial, 41% had an ACR 20 response, meaning a 20% improvement in disease signs and symptoms at 12 weeks. A total of 19% had an ACR 50 response. And 27% had at least a 75% improvement in Psoriasis Area and Severity Index, or PASI 75. A 63% reduction in the proportion of patients with dactylitis and a 26% decrease in the proportion of patients with enthesitis was observed in the early methotrexate group. There was a suggestion of a dose-response effect, with better outcomes seen in the 108 participants who received a mean dose greater than 15 mg/week (J Rheumatol. 2016 Feb;43[2]:356-61).
This is a more impressive result than earlier reported from the Methotrexate In Psoriatic Arthritis (MIPA) trial, where the ACR 20 response rate was only 34% (Rheumatology [Oxford]. 2012;51[8]:1368-77). That may well be because methotrexate was given at only 15 mg/week in MIPA, in Dr. Kavanaugh’s view.
“I think methotrexate can work for the peripheral arthritis. This TICOPA analysis gives us a sense of the extent of the improvement, and also the extent of improvement in the skin,” the rheumatologist commented.
Turning to the week 256 results of GO-REVEAL, he said there was no difference in clinical response between psoriatic arthritis patients on golimumab alone or golimumab plus methotrexate at baseline. But among patients who were doing well clinically, with an assessment of minimal disease activity (MDA) on three or more consecutive clinic visits, only those on golimumab plus methotrexate at baseline showed radiologic improvement. The 57 patients on combination therapy who achieved MDA on at least three consecutive visits showed a mean 1.29-point improvement in SHS; the 48 rated as having MDA on four or more consecutive occasions similarly had a mean 1.24-point improvement.
In contrast, the 59 participants who achieved MDA on three or more consecutive visits but were on golimumab without methotrexate at baseline had a 0.25-point increase in SHS, and the 47 who had MDA on at least four consecutive visits had a 0.38-point SHS bump.
Dr. Kavanaugh reported having financial relationships with roughly a dozen pharmaceutical companies
MAUI, HAWAII – The effectiveness of methotrexate in psoriatic arthritis is a matter of debate, but Dr. Arthur Kavanaugh is a believer based in part upon a recent subanalysis of the TICOPA study.
Moreover, his new 5-year follow-up analysis from the GO-REVEAL study of golimumab (Simponi) with or without concomitant methotrexate suggests that methotrexate plus the tumor necrosis factor inhibitor provided synergistic efficacy, he said at the 2016 Rheumatology Winter Clinical Symposium.
The 5-year analysis doesn’t provide definitive proof of synergistic benefit because it wasn’t designed or powered with that endpoint in mind (Arthritis Care Res. 2016;68[2]:267–74). No randomized trial completed to date has been. But the first-ever trial set up to test the synergistic efficacy hypothesis is underway. It’s a 52-week, double-blind, multicenter, randomized trial of etanercept (Enbrel) and methotrexate versus either alone in combination with placebo. And while the Amgen-sponsored study won’t be completed until 2018, Dr. Kavanaugh is ready to predict the outcome based in part upon the message contained in his GO-REVEAL findings.
“I’m placing my bet down now that there will be synergy for the X-ray outcome of change in SHS [Sharp/van der Heijde Score] for sure, and maybe for clinical efficacy as well, both joints and skin,” declared Dr. Kavanaugh, the conference director and professor of medicine at the University of California, San Diego.
He pointed to a new subanalysis of the Tight Control of Psoriatic Arthritis (TICOPA) study reported by rheumatologists at the University of Leeds (England) as evidence that methotrexate is effective in psoriatic arthritis. Of the 188 patients in the tight control arm who received methotrexate in the first 12 weeks of the trial, 41% had an ACR 20 response, meaning a 20% improvement in disease signs and symptoms at 12 weeks. A total of 19% had an ACR 50 response. And 27% had at least a 75% improvement in Psoriasis Area and Severity Index, or PASI 75. A 63% reduction in the proportion of patients with dactylitis and a 26% decrease in the proportion of patients with enthesitis was observed in the early methotrexate group. There was a suggestion of a dose-response effect, with better outcomes seen in the 108 participants who received a mean dose greater than 15 mg/week (J Rheumatol. 2016 Feb;43[2]:356-61).
This is a more impressive result than earlier reported from the Methotrexate In Psoriatic Arthritis (MIPA) trial, where the ACR 20 response rate was only 34% (Rheumatology [Oxford]. 2012;51[8]:1368-77). That may well be because methotrexate was given at only 15 mg/week in MIPA, in Dr. Kavanaugh’s view.
“I think methotrexate can work for the peripheral arthritis. This TICOPA analysis gives us a sense of the extent of the improvement, and also the extent of improvement in the skin,” the rheumatologist commented.
Turning to the week 256 results of GO-REVEAL, he said there was no difference in clinical response between psoriatic arthritis patients on golimumab alone or golimumab plus methotrexate at baseline. But among patients who were doing well clinically, with an assessment of minimal disease activity (MDA) on three or more consecutive clinic visits, only those on golimumab plus methotrexate at baseline showed radiologic improvement. The 57 patients on combination therapy who achieved MDA on at least three consecutive visits showed a mean 1.29-point improvement in SHS; the 48 rated as having MDA on four or more consecutive occasions similarly had a mean 1.24-point improvement.
In contrast, the 59 participants who achieved MDA on three or more consecutive visits but were on golimumab without methotrexate at baseline had a 0.25-point increase in SHS, and the 47 who had MDA on at least four consecutive visits had a 0.38-point SHS bump.
Dr. Kavanaugh reported having financial relationships with roughly a dozen pharmaceutical companies
EXPERT ANALYSIS FROM RWCS 2016
Expert examines secukinumab’s role in ankylosing spondylitis treatment strategies
MAUI, HAWAII – The most important development within the past year in the treatment of ankylosing spondylitis was the Food and Drug Administration approval of secukinumab (Cosentyx) as the first non-tumor necrosis factor inhibitor biologic for this condition – but the interleukin-17A inhibitor is not going to immediately step into a role as a first-line therapy, Dr. Eric M. Ruderman predicted at the 2016 Rheumatology Winter Clinical Symposium.
“In all likelihood nobody’s going to use this as a first-line drug right out of the gate. It’s a drug you’re going to potentially go to in people who haven’t responded to the things that you’ve been comfortable using for the last 10 or 15 years. So the big practical issue becomes, ‘How does secukinumab perform in TNF inhibitor-naive patients versus prior TNF inhibitor inadequate responders?’ ” according to the rheumatologist, who is professor of medicine at Northwestern University in Chicago.
This question has been addressed in secondary analyses of the pivotal phase III MEASURE 1 and MEASURE 2 trials which have been presented at the annual European League Against Rheumatism and American College of Rheumatology meetings. The bottom line was that the therapeutic response rate in both trials was markedly lower in TNF inhibitor inadequate responders than in TNF inhibitor-naive subjects.
“But there still is a significant response rate in the inadequate responders. It’s clearly better than placebo. So this is a drug that may have a role in your practice at the point where patients have failed on one or two anti-TNF biologics,” according to Dr. Ruderman.
The difference between MEASURE 1 and MEASURE 2 is that MEASURE 1 entailed three intravenous loading doses of the biologic at 2-week intervals before switching to monthly subcutaneous dosing, while MEASURE 2 featured subcutaneous loading doses given weekly for 4 weeks before moving to monthly administration. Interestingly, the FDA approval of secukinumab at 150 mg doesn’t call for a loading dose, even though both pivotal trials relied on them, the rheumatologist observed.
At 16 weeks in MEASURE 1, 66% of TNF inhibitor-naive subjects on secukinumab 150 mg had at least a 20% improvement from baseline in ankylosing spondylitis signs and symptoms, or Assessment of Spondyloarthritis International Society (ASAS) 20, compared with 46% of TNF inhibitor inadequate responders. The week 16 ASAS 20 rate in MEASURE 2 was 68% in TNF inhibitor-naive patients and 50% in those with a prior inadequate response to TNF inhibitor therapy.
How should rheumatologists expect secukinumab to perform in daily clinical practice? In the 181 ankylosing spoindylitis patients who completed 52 weeks in the MEASURE 2 extension study, 74% of those on secukinumab at 150 mg had an ASAS 20 response. In both trials, the secukinumab side effect profile was “reasonably clean,” in Dr. Ruderman’s view, with serious adverse events that were similar to placebo.
Serial MRI scans showed rapid resolution of bone marrow edema and inflammation by 16 weeks, an effect sustained through 52 weeks.
The big unanswered question is whether secukinumab prevents radiographic progression of the disease. Serial cervical and spinal X-rays rated using the modified Stoke Ankylosing Spondylitis Spinal Score showed a mean increase of just 0.30 points at 2 years from a baseline of 10.22, with 80% of patients demonstrating no change over time. But there were no untreated controls for comparison in this analysis, so it’s not possible to say whether the drug actually slowed disease progression or that’s the natural history of disease in those subjects, Dr. Ruderman noted.
Effect of NSAID dosing frequency on progression
On the topic of preventing radiographic progression in ankylosing spondylitis, the rheumatologist highlighted a prospective study presented at last year’s EULAR meeting and published online last summer (Ann Rheum Dis. 2015 Aug 4. doi: 10.1136/annrheumdis-2015-207897) that demonstrated that continuous use of diclofenac didn’t do any better at preventing radiographic spinal disease progression than on-demand use of the nonsteroidal anti-inflammatory drug (NSAID) over the course of 2 years.
“There’s been a lot of noise in the ankylosing spondylitis community about the potential benefit of NSAIDs in preventing structural progression. Previous information suggested that staying on them continuously actually reduced radiographic progression. This diclofenac study has shaken things up a little. It raises the question of whether there is any added benefit for NSAIDs in terms of structural progression,” he commented.
Current ACR/SAA/SPARTAN guidelines, which predate the study, feature a conditional recommendation that patients with active ankylosing spondylitis stay on continuous NSAID therapy.
Secukinumab is also approved for treatment of psoriasis and psoriatic arthritis.
Dr. Ruderman reported serving as a consultant to and/or receiving research grants from numerous pharmaceutical companies, including Novartis, which markets secukinumab.
MAUI, HAWAII – The most important development within the past year in the treatment of ankylosing spondylitis was the Food and Drug Administration approval of secukinumab (Cosentyx) as the first non-tumor necrosis factor inhibitor biologic for this condition – but the interleukin-17A inhibitor is not going to immediately step into a role as a first-line therapy, Dr. Eric M. Ruderman predicted at the 2016 Rheumatology Winter Clinical Symposium.
“In all likelihood nobody’s going to use this as a first-line drug right out of the gate. It’s a drug you’re going to potentially go to in people who haven’t responded to the things that you’ve been comfortable using for the last 10 or 15 years. So the big practical issue becomes, ‘How does secukinumab perform in TNF inhibitor-naive patients versus prior TNF inhibitor inadequate responders?’ ” according to the rheumatologist, who is professor of medicine at Northwestern University in Chicago.
This question has been addressed in secondary analyses of the pivotal phase III MEASURE 1 and MEASURE 2 trials which have been presented at the annual European League Against Rheumatism and American College of Rheumatology meetings. The bottom line was that the therapeutic response rate in both trials was markedly lower in TNF inhibitor inadequate responders than in TNF inhibitor-naive subjects.
“But there still is a significant response rate in the inadequate responders. It’s clearly better than placebo. So this is a drug that may have a role in your practice at the point where patients have failed on one or two anti-TNF biologics,” according to Dr. Ruderman.
The difference between MEASURE 1 and MEASURE 2 is that MEASURE 1 entailed three intravenous loading doses of the biologic at 2-week intervals before switching to monthly subcutaneous dosing, while MEASURE 2 featured subcutaneous loading doses given weekly for 4 weeks before moving to monthly administration. Interestingly, the FDA approval of secukinumab at 150 mg doesn’t call for a loading dose, even though both pivotal trials relied on them, the rheumatologist observed.
At 16 weeks in MEASURE 1, 66% of TNF inhibitor-naive subjects on secukinumab 150 mg had at least a 20% improvement from baseline in ankylosing spondylitis signs and symptoms, or Assessment of Spondyloarthritis International Society (ASAS) 20, compared with 46% of TNF inhibitor inadequate responders. The week 16 ASAS 20 rate in MEASURE 2 was 68% in TNF inhibitor-naive patients and 50% in those with a prior inadequate response to TNF inhibitor therapy.
How should rheumatologists expect secukinumab to perform in daily clinical practice? In the 181 ankylosing spoindylitis patients who completed 52 weeks in the MEASURE 2 extension study, 74% of those on secukinumab at 150 mg had an ASAS 20 response. In both trials, the secukinumab side effect profile was “reasonably clean,” in Dr. Ruderman’s view, with serious adverse events that were similar to placebo.
Serial MRI scans showed rapid resolution of bone marrow edema and inflammation by 16 weeks, an effect sustained through 52 weeks.
The big unanswered question is whether secukinumab prevents radiographic progression of the disease. Serial cervical and spinal X-rays rated using the modified Stoke Ankylosing Spondylitis Spinal Score showed a mean increase of just 0.30 points at 2 years from a baseline of 10.22, with 80% of patients demonstrating no change over time. But there were no untreated controls for comparison in this analysis, so it’s not possible to say whether the drug actually slowed disease progression or that’s the natural history of disease in those subjects, Dr. Ruderman noted.
Effect of NSAID dosing frequency on progression
On the topic of preventing radiographic progression in ankylosing spondylitis, the rheumatologist highlighted a prospective study presented at last year’s EULAR meeting and published online last summer (Ann Rheum Dis. 2015 Aug 4. doi: 10.1136/annrheumdis-2015-207897) that demonstrated that continuous use of diclofenac didn’t do any better at preventing radiographic spinal disease progression than on-demand use of the nonsteroidal anti-inflammatory drug (NSAID) over the course of 2 years.
“There’s been a lot of noise in the ankylosing spondylitis community about the potential benefit of NSAIDs in preventing structural progression. Previous information suggested that staying on them continuously actually reduced radiographic progression. This diclofenac study has shaken things up a little. It raises the question of whether there is any added benefit for NSAIDs in terms of structural progression,” he commented.
Current ACR/SAA/SPARTAN guidelines, which predate the study, feature a conditional recommendation that patients with active ankylosing spondylitis stay on continuous NSAID therapy.
Secukinumab is also approved for treatment of psoriasis and psoriatic arthritis.
Dr. Ruderman reported serving as a consultant to and/or receiving research grants from numerous pharmaceutical companies, including Novartis, which markets secukinumab.
MAUI, HAWAII – The most important development within the past year in the treatment of ankylosing spondylitis was the Food and Drug Administration approval of secukinumab (Cosentyx) as the first non-tumor necrosis factor inhibitor biologic for this condition – but the interleukin-17A inhibitor is not going to immediately step into a role as a first-line therapy, Dr. Eric M. Ruderman predicted at the 2016 Rheumatology Winter Clinical Symposium.
“In all likelihood nobody’s going to use this as a first-line drug right out of the gate. It’s a drug you’re going to potentially go to in people who haven’t responded to the things that you’ve been comfortable using for the last 10 or 15 years. So the big practical issue becomes, ‘How does secukinumab perform in TNF inhibitor-naive patients versus prior TNF inhibitor inadequate responders?’ ” according to the rheumatologist, who is professor of medicine at Northwestern University in Chicago.
This question has been addressed in secondary analyses of the pivotal phase III MEASURE 1 and MEASURE 2 trials which have been presented at the annual European League Against Rheumatism and American College of Rheumatology meetings. The bottom line was that the therapeutic response rate in both trials was markedly lower in TNF inhibitor inadequate responders than in TNF inhibitor-naive subjects.
“But there still is a significant response rate in the inadequate responders. It’s clearly better than placebo. So this is a drug that may have a role in your practice at the point where patients have failed on one or two anti-TNF biologics,” according to Dr. Ruderman.
The difference between MEASURE 1 and MEASURE 2 is that MEASURE 1 entailed three intravenous loading doses of the biologic at 2-week intervals before switching to monthly subcutaneous dosing, while MEASURE 2 featured subcutaneous loading doses given weekly for 4 weeks before moving to monthly administration. Interestingly, the FDA approval of secukinumab at 150 mg doesn’t call for a loading dose, even though both pivotal trials relied on them, the rheumatologist observed.
At 16 weeks in MEASURE 1, 66% of TNF inhibitor-naive subjects on secukinumab 150 mg had at least a 20% improvement from baseline in ankylosing spondylitis signs and symptoms, or Assessment of Spondyloarthritis International Society (ASAS) 20, compared with 46% of TNF inhibitor inadequate responders. The week 16 ASAS 20 rate in MEASURE 2 was 68% in TNF inhibitor-naive patients and 50% in those with a prior inadequate response to TNF inhibitor therapy.
How should rheumatologists expect secukinumab to perform in daily clinical practice? In the 181 ankylosing spoindylitis patients who completed 52 weeks in the MEASURE 2 extension study, 74% of those on secukinumab at 150 mg had an ASAS 20 response. In both trials, the secukinumab side effect profile was “reasonably clean,” in Dr. Ruderman’s view, with serious adverse events that were similar to placebo.
Serial MRI scans showed rapid resolution of bone marrow edema and inflammation by 16 weeks, an effect sustained through 52 weeks.
The big unanswered question is whether secukinumab prevents radiographic progression of the disease. Serial cervical and spinal X-rays rated using the modified Stoke Ankylosing Spondylitis Spinal Score showed a mean increase of just 0.30 points at 2 years from a baseline of 10.22, with 80% of patients demonstrating no change over time. But there were no untreated controls for comparison in this analysis, so it’s not possible to say whether the drug actually slowed disease progression or that’s the natural history of disease in those subjects, Dr. Ruderman noted.
Effect of NSAID dosing frequency on progression
On the topic of preventing radiographic progression in ankylosing spondylitis, the rheumatologist highlighted a prospective study presented at last year’s EULAR meeting and published online last summer (Ann Rheum Dis. 2015 Aug 4. doi: 10.1136/annrheumdis-2015-207897) that demonstrated that continuous use of diclofenac didn’t do any better at preventing radiographic spinal disease progression than on-demand use of the nonsteroidal anti-inflammatory drug (NSAID) over the course of 2 years.
“There’s been a lot of noise in the ankylosing spondylitis community about the potential benefit of NSAIDs in preventing structural progression. Previous information suggested that staying on them continuously actually reduced radiographic progression. This diclofenac study has shaken things up a little. It raises the question of whether there is any added benefit for NSAIDs in terms of structural progression,” he commented.
Current ACR/SAA/SPARTAN guidelines, which predate the study, feature a conditional recommendation that patients with active ankylosing spondylitis stay on continuous NSAID therapy.
Secukinumab is also approved for treatment of psoriasis and psoriatic arthritis.
Dr. Ruderman reported serving as a consultant to and/or receiving research grants from numerous pharmaceutical companies, including Novartis, which markets secukinumab.
EXPERT ANALYSIS FROM RWCS 2016
New Tool Better Predicts Coronary Artery Disease in Lupus Patients
MAUI, HAWAII – Multiple studies have firmly established that the traditional Framingham Risk Score seriously underestimates the substantially increased risk of coronary artery disease present in patients with systemic lupus erythematosus (SLE). Nor is the American College of Cardiology/American Heart Association atherosclerotic cardiovascular disease risk score reliable in this population. But now physicians at the University of Toronto Lupus Clinic have come up with a more accurate risk prediction tool.
The new score is a straightforward modification of the Framingham Risk Score (FRS). It is calculated by multiplying the values for the items included in the classic FRS by two. It’s called, simply enough, the 2FRS, Dr. Dafna D. Gladman explained at the 2016 Rheumatology Winter Clinical Symposium.
In developing the 2FRS, she and her coinvestigators didn’t change the relative values of the individual components of the standard FRS. Instead, they calculated the standard baseline FRS values for 905 women with SLE who were prospectively followed at the Toronto Lupus Clinic. None had a prior history of CAD or diabetes when they enrolled in the cohort. Then the investigators tried multiplying those scores by 1.5, 2, 3, and 4 to learn which multiplier yielded the best sensitivity and specificity for prediction of coronary events, which occurred in 95 women during follow-up. Doubling the classic FRS score turned out to be the clear winner, according to Dr. Gladman, professor of medicine and codirector of the University of Toronto Lupus Clinic.
The classic FRS categorized 2.4% of the patients as being at moderate or high cardiovascular risk. With the 2FRS, this figure climbed to 17.3%. In a time-dependent covariant analysis for prediction of the first coronary event, a moderate/high score on the classic FRS was associated with a 3.2-fold increased risk, while a moderate/high score on the 2FRS conferred a 4.4-fold increased risk (J Rheumatol. 2016 Feb 15. doi: 10.3899/jrheum.150983).
The reason the classic FRS underestimates the true risk of atherosclerotic vascular events in lupus patients was illustrated in an earlier study by the Toronto group. Among 1,087 patients with no history of cardiovascular disease or diabetes when they enrolled at the clinic, 10.9% went on to experience an atherosclerotic vascular event during follow-up. In a multivariate analysis, disease-specific risk factors – namely, the presence of vasculitis or neuropsychiatric findings – proved to be more potent predictors of subsequent atherosclerotic vascular events than did the number of FRS risk factors or smoking status (J Rheumatol. 2007 Jan;34[1]:70-5).
It has long been known that mortality in SLE patients follows a bimodal pattern. Premature cardiovascular deaths explain a large portion of the second peak.
“In our total Toronto SLE cohort, we find there’s a fivefold increased risk for the development of acute MI compared to controls. The average age at which MI occurs is 69 for women in the general population, but it’s 49 for women in our lupus cohort,” according to Dr. Gladman.
In yet another study focusing on atherosclerotic comorbidity in lupus patients, the Toronto group showed that carotid total plaque area as measured by high-resolution ultrasound correlated significantly better – by nearly fivefold – with clinical ischemic cardiovascular events than did carotid intima-media thickness, suggesting total plaque area may be the better tool for investigating atherosclerotic vascular disease as expressed in SLE patients. Carotid plaque also displayed a much stronger correlation with conventional cardiovascular risk factors, including hypertension and elevated LDL cholesterol, in the lupus patients (Lupus. 2014 Oct;23[11]:1142-8).
Dr. Gladman reported receiving research grants from GlaxoSmithKline and Janssen and serving as a consultant to those pharmaceutical companies as well as to Bristol-Myers Squibb and UCB.
MAUI, HAWAII – Multiple studies have firmly established that the traditional Framingham Risk Score seriously underestimates the substantially increased risk of coronary artery disease present in patients with systemic lupus erythematosus (SLE). Nor is the American College of Cardiology/American Heart Association atherosclerotic cardiovascular disease risk score reliable in this population. But now physicians at the University of Toronto Lupus Clinic have come up with a more accurate risk prediction tool.
The new score is a straightforward modification of the Framingham Risk Score (FRS). It is calculated by multiplying the values for the items included in the classic FRS by two. It’s called, simply enough, the 2FRS, Dr. Dafna D. Gladman explained at the 2016 Rheumatology Winter Clinical Symposium.
In developing the 2FRS, she and her coinvestigators didn’t change the relative values of the individual components of the standard FRS. Instead, they calculated the standard baseline FRS values for 905 women with SLE who were prospectively followed at the Toronto Lupus Clinic. None had a prior history of CAD or diabetes when they enrolled in the cohort. Then the investigators tried multiplying those scores by 1.5, 2, 3, and 4 to learn which multiplier yielded the best sensitivity and specificity for prediction of coronary events, which occurred in 95 women during follow-up. Doubling the classic FRS score turned out to be the clear winner, according to Dr. Gladman, professor of medicine and codirector of the University of Toronto Lupus Clinic.
The classic FRS categorized 2.4% of the patients as being at moderate or high cardiovascular risk. With the 2FRS, this figure climbed to 17.3%. In a time-dependent covariant analysis for prediction of the first coronary event, a moderate/high score on the classic FRS was associated with a 3.2-fold increased risk, while a moderate/high score on the 2FRS conferred a 4.4-fold increased risk (J Rheumatol. 2016 Feb 15. doi: 10.3899/jrheum.150983).
The reason the classic FRS underestimates the true risk of atherosclerotic vascular events in lupus patients was illustrated in an earlier study by the Toronto group. Among 1,087 patients with no history of cardiovascular disease or diabetes when they enrolled at the clinic, 10.9% went on to experience an atherosclerotic vascular event during follow-up. In a multivariate analysis, disease-specific risk factors – namely, the presence of vasculitis or neuropsychiatric findings – proved to be more potent predictors of subsequent atherosclerotic vascular events than did the number of FRS risk factors or smoking status (J Rheumatol. 2007 Jan;34[1]:70-5).
It has long been known that mortality in SLE patients follows a bimodal pattern. Premature cardiovascular deaths explain a large portion of the second peak.
“In our total Toronto SLE cohort, we find there’s a fivefold increased risk for the development of acute MI compared to controls. The average age at which MI occurs is 69 for women in the general population, but it’s 49 for women in our lupus cohort,” according to Dr. Gladman.
In yet another study focusing on atherosclerotic comorbidity in lupus patients, the Toronto group showed that carotid total plaque area as measured by high-resolution ultrasound correlated significantly better – by nearly fivefold – with clinical ischemic cardiovascular events than did carotid intima-media thickness, suggesting total plaque area may be the better tool for investigating atherosclerotic vascular disease as expressed in SLE patients. Carotid plaque also displayed a much stronger correlation with conventional cardiovascular risk factors, including hypertension and elevated LDL cholesterol, in the lupus patients (Lupus. 2014 Oct;23[11]:1142-8).
Dr. Gladman reported receiving research grants from GlaxoSmithKline and Janssen and serving as a consultant to those pharmaceutical companies as well as to Bristol-Myers Squibb and UCB.
MAUI, HAWAII – Multiple studies have firmly established that the traditional Framingham Risk Score seriously underestimates the substantially increased risk of coronary artery disease present in patients with systemic lupus erythematosus (SLE). Nor is the American College of Cardiology/American Heart Association atherosclerotic cardiovascular disease risk score reliable in this population. But now physicians at the University of Toronto Lupus Clinic have come up with a more accurate risk prediction tool.
The new score is a straightforward modification of the Framingham Risk Score (FRS). It is calculated by multiplying the values for the items included in the classic FRS by two. It’s called, simply enough, the 2FRS, Dr. Dafna D. Gladman explained at the 2016 Rheumatology Winter Clinical Symposium.
In developing the 2FRS, she and her coinvestigators didn’t change the relative values of the individual components of the standard FRS. Instead, they calculated the standard baseline FRS values for 905 women with SLE who were prospectively followed at the Toronto Lupus Clinic. None had a prior history of CAD or diabetes when they enrolled in the cohort. Then the investigators tried multiplying those scores by 1.5, 2, 3, and 4 to learn which multiplier yielded the best sensitivity and specificity for prediction of coronary events, which occurred in 95 women during follow-up. Doubling the classic FRS score turned out to be the clear winner, according to Dr. Gladman, professor of medicine and codirector of the University of Toronto Lupus Clinic.
The classic FRS categorized 2.4% of the patients as being at moderate or high cardiovascular risk. With the 2FRS, this figure climbed to 17.3%. In a time-dependent covariant analysis for prediction of the first coronary event, a moderate/high score on the classic FRS was associated with a 3.2-fold increased risk, while a moderate/high score on the 2FRS conferred a 4.4-fold increased risk (J Rheumatol. 2016 Feb 15. doi: 10.3899/jrheum.150983).
The reason the classic FRS underestimates the true risk of atherosclerotic vascular events in lupus patients was illustrated in an earlier study by the Toronto group. Among 1,087 patients with no history of cardiovascular disease or diabetes when they enrolled at the clinic, 10.9% went on to experience an atherosclerotic vascular event during follow-up. In a multivariate analysis, disease-specific risk factors – namely, the presence of vasculitis or neuropsychiatric findings – proved to be more potent predictors of subsequent atherosclerotic vascular events than did the number of FRS risk factors or smoking status (J Rheumatol. 2007 Jan;34[1]:70-5).
It has long been known that mortality in SLE patients follows a bimodal pattern. Premature cardiovascular deaths explain a large portion of the second peak.
“In our total Toronto SLE cohort, we find there’s a fivefold increased risk for the development of acute MI compared to controls. The average age at which MI occurs is 69 for women in the general population, but it’s 49 for women in our lupus cohort,” according to Dr. Gladman.
In yet another study focusing on atherosclerotic comorbidity in lupus patients, the Toronto group showed that carotid total plaque area as measured by high-resolution ultrasound correlated significantly better – by nearly fivefold – with clinical ischemic cardiovascular events than did carotid intima-media thickness, suggesting total plaque area may be the better tool for investigating atherosclerotic vascular disease as expressed in SLE patients. Carotid plaque also displayed a much stronger correlation with conventional cardiovascular risk factors, including hypertension and elevated LDL cholesterol, in the lupus patients (Lupus. 2014 Oct;23[11]:1142-8).
Dr. Gladman reported receiving research grants from GlaxoSmithKline and Janssen and serving as a consultant to those pharmaceutical companies as well as to Bristol-Myers Squibb and UCB.
EXPERT ANALYSIS FROM RWCS 2016
New tool better predicts coronary artery disease in lupus patients
MAUI, HAWAII – Multiple studies have firmly established that the traditional Framingham Risk Score seriously underestimates the substantially increased risk of coronary artery disease present in patients with systemic lupus erythematosus (SLE). Nor is the American College of Cardiology/American Heart Association atherosclerotic cardiovascular disease risk score reliable in this population. But now physicians at the University of Toronto Lupus Clinic have come up with a more accurate risk prediction tool.
The new score is a straightforward modification of the Framingham Risk Score (FRS). It is calculated by multiplying the values for the items included in the classic FRS by two. It’s called, simply enough, the 2FRS, Dr. Dafna D. Gladman explained at the 2016 Rheumatology Winter Clinical Symposium.
In developing the 2FRS, she and her coinvestigators didn’t change the relative values of the individual components of the standard FRS. Instead, they calculated the standard baseline FRS values for 905 women with SLE who were prospectively followed at the Toronto Lupus Clinic. None had a prior history of CAD or diabetes when they enrolled in the cohort. Then the investigators tried multiplying those scores by 1.5, 2, 3, and 4 to learn which multiplier yielded the best sensitivity and specificity for prediction of coronary events, which occurred in 95 women during follow-up. Doubling the classic FRS score turned out to be the clear winner, according to Dr. Gladman, professor of medicine and codirector of the University of Toronto Lupus Clinic.
The classic FRS categorized 2.4% of the patients as being at moderate or high cardiovascular risk. With the 2FRS, this figure climbed to 17.3%. In a time-dependent covariant analysis for prediction of the first coronary event, a moderate/high score on the classic FRS was associated with a 3.2-fold increased risk, while a moderate/high score on the 2FRS conferred a 4.4-fold increased risk (J Rheumatol. 2016 Feb 15. doi: 10.3899/jrheum.150983).
The reason the classic FRS underestimates the true risk of atherosclerotic vascular events in lupus patients was illustrated in an earlier study by the Toronto group. Among 1,087 patients with no history of cardiovascular disease or diabetes when they enrolled at the clinic, 10.9% went on to experience an atherosclerotic vascular event during follow-up. In a multivariate analysis, disease-specific risk factors – namely, the presence of vasculitis or neuropsychiatric findings – proved to be more potent predictors of subsequent atherosclerotic vascular events than did the number of FRS risk factors or smoking status (J Rheumatol. 2007 Jan;34[1]:70-5).
It has long been known that mortality in SLE patients follows a bimodal pattern. Premature cardiovascular deaths explain a large portion of the second peak.
“In our total Toronto SLE cohort, we find there’s a fivefold increased risk for the development of acute MI compared to controls. The average age at which MI occurs is 69 for women in the general population, but it’s 49 for women in our lupus cohort,” according to Dr. Gladman.
In yet another study focusing on atherosclerotic comorbidity in lupus patients, the Toronto group showed that carotid total plaque area as measured by high-resolution ultrasound correlated significantly better – by nearly fivefold – with clinical ischemic cardiovascular events than did carotid intima-media thickness, suggesting total plaque area may be the better tool for investigating atherosclerotic vascular disease as expressed in SLE patients. Carotid plaque also displayed a much stronger correlation with conventional cardiovascular risk factors, including hypertension and elevated LDL cholesterol, in the lupus patients (Lupus. 2014 Oct;23[11]:1142-8).
Dr. Gladman reported receiving research grants from GlaxoSmithKline and Janssen and serving as a consultant to those pharmaceutical companies as well as to Bristol-Myers Squibb and UCB.
MAUI, HAWAII – Multiple studies have firmly established that the traditional Framingham Risk Score seriously underestimates the substantially increased risk of coronary artery disease present in patients with systemic lupus erythematosus (SLE). Nor is the American College of Cardiology/American Heart Association atherosclerotic cardiovascular disease risk score reliable in this population. But now physicians at the University of Toronto Lupus Clinic have come up with a more accurate risk prediction tool.
The new score is a straightforward modification of the Framingham Risk Score (FRS). It is calculated by multiplying the values for the items included in the classic FRS by two. It’s called, simply enough, the 2FRS, Dr. Dafna D. Gladman explained at the 2016 Rheumatology Winter Clinical Symposium.
In developing the 2FRS, she and her coinvestigators didn’t change the relative values of the individual components of the standard FRS. Instead, they calculated the standard baseline FRS values for 905 women with SLE who were prospectively followed at the Toronto Lupus Clinic. None had a prior history of CAD or diabetes when they enrolled in the cohort. Then the investigators tried multiplying those scores by 1.5, 2, 3, and 4 to learn which multiplier yielded the best sensitivity and specificity for prediction of coronary events, which occurred in 95 women during follow-up. Doubling the classic FRS score turned out to be the clear winner, according to Dr. Gladman, professor of medicine and codirector of the University of Toronto Lupus Clinic.
The classic FRS categorized 2.4% of the patients as being at moderate or high cardiovascular risk. With the 2FRS, this figure climbed to 17.3%. In a time-dependent covariant analysis for prediction of the first coronary event, a moderate/high score on the classic FRS was associated with a 3.2-fold increased risk, while a moderate/high score on the 2FRS conferred a 4.4-fold increased risk (J Rheumatol. 2016 Feb 15. doi: 10.3899/jrheum.150983).
The reason the classic FRS underestimates the true risk of atherosclerotic vascular events in lupus patients was illustrated in an earlier study by the Toronto group. Among 1,087 patients with no history of cardiovascular disease or diabetes when they enrolled at the clinic, 10.9% went on to experience an atherosclerotic vascular event during follow-up. In a multivariate analysis, disease-specific risk factors – namely, the presence of vasculitis or neuropsychiatric findings – proved to be more potent predictors of subsequent atherosclerotic vascular events than did the number of FRS risk factors or smoking status (J Rheumatol. 2007 Jan;34[1]:70-5).
It has long been known that mortality in SLE patients follows a bimodal pattern. Premature cardiovascular deaths explain a large portion of the second peak.
“In our total Toronto SLE cohort, we find there’s a fivefold increased risk for the development of acute MI compared to controls. The average age at which MI occurs is 69 for women in the general population, but it’s 49 for women in our lupus cohort,” according to Dr. Gladman.
In yet another study focusing on atherosclerotic comorbidity in lupus patients, the Toronto group showed that carotid total plaque area as measured by high-resolution ultrasound correlated significantly better – by nearly fivefold – with clinical ischemic cardiovascular events than did carotid intima-media thickness, suggesting total plaque area may be the better tool for investigating atherosclerotic vascular disease as expressed in SLE patients. Carotid plaque also displayed a much stronger correlation with conventional cardiovascular risk factors, including hypertension and elevated LDL cholesterol, in the lupus patients (Lupus. 2014 Oct;23[11]:1142-8).
Dr. Gladman reported receiving research grants from GlaxoSmithKline and Janssen and serving as a consultant to those pharmaceutical companies as well as to Bristol-Myers Squibb and UCB.
MAUI, HAWAII – Multiple studies have firmly established that the traditional Framingham Risk Score seriously underestimates the substantially increased risk of coronary artery disease present in patients with systemic lupus erythematosus (SLE). Nor is the American College of Cardiology/American Heart Association atherosclerotic cardiovascular disease risk score reliable in this population. But now physicians at the University of Toronto Lupus Clinic have come up with a more accurate risk prediction tool.
The new score is a straightforward modification of the Framingham Risk Score (FRS). It is calculated by multiplying the values for the items included in the classic FRS by two. It’s called, simply enough, the 2FRS, Dr. Dafna D. Gladman explained at the 2016 Rheumatology Winter Clinical Symposium.
In developing the 2FRS, she and her coinvestigators didn’t change the relative values of the individual components of the standard FRS. Instead, they calculated the standard baseline FRS values for 905 women with SLE who were prospectively followed at the Toronto Lupus Clinic. None had a prior history of CAD or diabetes when they enrolled in the cohort. Then the investigators tried multiplying those scores by 1.5, 2, 3, and 4 to learn which multiplier yielded the best sensitivity and specificity for prediction of coronary events, which occurred in 95 women during follow-up. Doubling the classic FRS score turned out to be the clear winner, according to Dr. Gladman, professor of medicine and codirector of the University of Toronto Lupus Clinic.
The classic FRS categorized 2.4% of the patients as being at moderate or high cardiovascular risk. With the 2FRS, this figure climbed to 17.3%. In a time-dependent covariant analysis for prediction of the first coronary event, a moderate/high score on the classic FRS was associated with a 3.2-fold increased risk, while a moderate/high score on the 2FRS conferred a 4.4-fold increased risk (J Rheumatol. 2016 Feb 15. doi: 10.3899/jrheum.150983).
The reason the classic FRS underestimates the true risk of atherosclerotic vascular events in lupus patients was illustrated in an earlier study by the Toronto group. Among 1,087 patients with no history of cardiovascular disease or diabetes when they enrolled at the clinic, 10.9% went on to experience an atherosclerotic vascular event during follow-up. In a multivariate analysis, disease-specific risk factors – namely, the presence of vasculitis or neuropsychiatric findings – proved to be more potent predictors of subsequent atherosclerotic vascular events than did the number of FRS risk factors or smoking status (J Rheumatol. 2007 Jan;34[1]:70-5).
It has long been known that mortality in SLE patients follows a bimodal pattern. Premature cardiovascular deaths explain a large portion of the second peak.
“In our total Toronto SLE cohort, we find there’s a fivefold increased risk for the development of acute MI compared to controls. The average age at which MI occurs is 69 for women in the general population, but it’s 49 for women in our lupus cohort,” according to Dr. Gladman.
In yet another study focusing on atherosclerotic comorbidity in lupus patients, the Toronto group showed that carotid total plaque area as measured by high-resolution ultrasound correlated significantly better – by nearly fivefold – with clinical ischemic cardiovascular events than did carotid intima-media thickness, suggesting total plaque area may be the better tool for investigating atherosclerotic vascular disease as expressed in SLE patients. Carotid plaque also displayed a much stronger correlation with conventional cardiovascular risk factors, including hypertension and elevated LDL cholesterol, in the lupus patients (Lupus. 2014 Oct;23[11]:1142-8).
Dr. Gladman reported receiving research grants from GlaxoSmithKline and Janssen and serving as a consultant to those pharmaceutical companies as well as to Bristol-Myers Squibb and UCB.
EXPERT ANALYSIS FROM RWCS 2016
Expert advises how to use shingles vaccine in rheumatology patients
MAUI, HAWAII – The herpes zoster vaccine is particularly important in patients with rheumatic diseases because their risks of shingles and postherpetic neuralgia are substantially higher than in the general population, Dr. John J. Cush observed at the 2016 Rheumatology Winter Clinical Symposium.
This is a live attenuated virus vaccine, and the rules regarding its use in patients with rheumatic diseases are fairly complicated. Here’s what physicians need to know: the Centers for Disease Control and Prevention and the Advisory Committee on Immunization Practices say the shingles vaccine can safely be given to patients on prednisone at less than 20 mg/day, azathioprine at up to 3 mg/kg/day, or methotrexate at up to 0.4 mg/kg/week, which works out to about 25 mg/week in anyone weighing more than 136 pounds.
However, the shingles vaccine is contraindicated in patients on recombinant biologic agents, including tumor necrosis factor (TNF) inhibitors, abatacept (Orencia), rituximab (Rituxan), or Janus kinase inhibitors, explained Dr. Cush, professor of medicine and rheumatology at Baylor University, Dallas, and director of clinical rheumatology at the Baylor Research Institute.
The lifetime risk of shingles in the general population is roughly one in three. The risk in patients with rheumatoid arthritis is roughly twice that of the age-matched general population, and the risks are substantially greater than that in individuals with other rheumatic diseases, including lupus and granulomatosis with polyangiitis.
Payers cover the vaccine in patients age 60 or older. The vaccine is approved for and has been shown to be effective in 50- to 59-year-olds as well, but that typically entails an out-of-pocket expense of around $200.
Given that close to 60% of all rheumatoid arthritis patients will eventually be placed on biologic therapy, Dr. Cush believes in seizing any opportunity to give the shingles vaccine in age-appropriate patients beforehand. However, he advises against temporarily stopping a biologic for the express purpose of administering the live virus vaccine.
“Find the opportunity: between changes in medication, after they have surgery, during a lapse in therapy,” he suggested.
It’s recommended that Zostavax be deferred until after a patient has been off biologic therapy or high-dose steroids for at least 4 weeks, and that a biologic agent shouldn’t be started for 2-4 weeks after vaccination.
The shingles vaccine can safely be given with multiple inactivated virus vaccines such as an influenza vaccine or pneumococcal vaccine on a single day.
Controversy surrounds the issue of whether TNF inhibitors increase the risk of shingles. Several retrospective studies have reported they do. But the largest retrospective study, involving more than 33,000 new users of anti-TNF agents, found that patients with rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, and other inflammatory diseases who initiated anti-TNF therapy weren’t at any higher risk of herpes zoster than those who started on methotrexate or other nonbiologic disease-modifying antirheumatic drugs (JAMA. 2013 Mar 6;309[9]:887-95). The lead investigator in this study, Dr. Kevin L. Winthrop of Oregon Health and Science University, Portland, is currently conducting a prospective study in an effort to confirm these findings.
The recommendation against giving the zoster vaccine to patients while on biologics is based upon the theoretical risk that exposure to the live attenuated virus will trigger an acute shingles attack. However, when Dr. Cush conducted a survey of his fellow rheumatologists, they reported that among more than a collective 200 patients inadvertently given the vaccine while on biologic therapy, not one case of shingles subsequently occurred over the short term.
More persuasively, Dr. Jeffrey R. Curtis of the University of Alabama at Birmingham and coinvestigators conducted a formal retrospective study of close to a half-million Medicare patients and found there were no cases of herpes zoster or varicella within 42 days following inadvertent vaccination of 633 patients while on biologics. During a median 2-year follow-up of Medicare patients with rheumatoid arthritis and other immune-mediated diseases, herpes zoster vaccination was associated with a 39% reduction in the risk of shingles (JAMA. 2012 Jul 4;308[1]:43-9).
“You shouldn’t be vaccinating for herpes zoster while patients are on a biologic, but you know what? If it happens, don’t wig out. Move on and try to avoid it,” Dr. Cush advised.
In any event, this is an issue that is eventually likely to go away. An inactivated virus vaccine for the prevention of shingles is now in clinical trials. It appears to be more effective than the current vaccine, according to the rheumatologist.
He reported having no financial interests relevant to his presentation.
MAUI, HAWAII – The herpes zoster vaccine is particularly important in patients with rheumatic diseases because their risks of shingles and postherpetic neuralgia are substantially higher than in the general population, Dr. John J. Cush observed at the 2016 Rheumatology Winter Clinical Symposium.
This is a live attenuated virus vaccine, and the rules regarding its use in patients with rheumatic diseases are fairly complicated. Here’s what physicians need to know: the Centers for Disease Control and Prevention and the Advisory Committee on Immunization Practices say the shingles vaccine can safely be given to patients on prednisone at less than 20 mg/day, azathioprine at up to 3 mg/kg/day, or methotrexate at up to 0.4 mg/kg/week, which works out to about 25 mg/week in anyone weighing more than 136 pounds.
However, the shingles vaccine is contraindicated in patients on recombinant biologic agents, including tumor necrosis factor (TNF) inhibitors, abatacept (Orencia), rituximab (Rituxan), or Janus kinase inhibitors, explained Dr. Cush, professor of medicine and rheumatology at Baylor University, Dallas, and director of clinical rheumatology at the Baylor Research Institute.
The lifetime risk of shingles in the general population is roughly one in three. The risk in patients with rheumatoid arthritis is roughly twice that of the age-matched general population, and the risks are substantially greater than that in individuals with other rheumatic diseases, including lupus and granulomatosis with polyangiitis.
Payers cover the vaccine in patients age 60 or older. The vaccine is approved for and has been shown to be effective in 50- to 59-year-olds as well, but that typically entails an out-of-pocket expense of around $200.
Given that close to 60% of all rheumatoid arthritis patients will eventually be placed on biologic therapy, Dr. Cush believes in seizing any opportunity to give the shingles vaccine in age-appropriate patients beforehand. However, he advises against temporarily stopping a biologic for the express purpose of administering the live virus vaccine.
“Find the opportunity: between changes in medication, after they have surgery, during a lapse in therapy,” he suggested.
It’s recommended that Zostavax be deferred until after a patient has been off biologic therapy or high-dose steroids for at least 4 weeks, and that a biologic agent shouldn’t be started for 2-4 weeks after vaccination.
The shingles vaccine can safely be given with multiple inactivated virus vaccines such as an influenza vaccine or pneumococcal vaccine on a single day.
Controversy surrounds the issue of whether TNF inhibitors increase the risk of shingles. Several retrospective studies have reported they do. But the largest retrospective study, involving more than 33,000 new users of anti-TNF agents, found that patients with rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, and other inflammatory diseases who initiated anti-TNF therapy weren’t at any higher risk of herpes zoster than those who started on methotrexate or other nonbiologic disease-modifying antirheumatic drugs (JAMA. 2013 Mar 6;309[9]:887-95). The lead investigator in this study, Dr. Kevin L. Winthrop of Oregon Health and Science University, Portland, is currently conducting a prospective study in an effort to confirm these findings.
The recommendation against giving the zoster vaccine to patients while on biologics is based upon the theoretical risk that exposure to the live attenuated virus will trigger an acute shingles attack. However, when Dr. Cush conducted a survey of his fellow rheumatologists, they reported that among more than a collective 200 patients inadvertently given the vaccine while on biologic therapy, not one case of shingles subsequently occurred over the short term.
More persuasively, Dr. Jeffrey R. Curtis of the University of Alabama at Birmingham and coinvestigators conducted a formal retrospective study of close to a half-million Medicare patients and found there were no cases of herpes zoster or varicella within 42 days following inadvertent vaccination of 633 patients while on biologics. During a median 2-year follow-up of Medicare patients with rheumatoid arthritis and other immune-mediated diseases, herpes zoster vaccination was associated with a 39% reduction in the risk of shingles (JAMA. 2012 Jul 4;308[1]:43-9).
“You shouldn’t be vaccinating for herpes zoster while patients are on a biologic, but you know what? If it happens, don’t wig out. Move on and try to avoid it,” Dr. Cush advised.
In any event, this is an issue that is eventually likely to go away. An inactivated virus vaccine for the prevention of shingles is now in clinical trials. It appears to be more effective than the current vaccine, according to the rheumatologist.
He reported having no financial interests relevant to his presentation.
MAUI, HAWAII – The herpes zoster vaccine is particularly important in patients with rheumatic diseases because their risks of shingles and postherpetic neuralgia are substantially higher than in the general population, Dr. John J. Cush observed at the 2016 Rheumatology Winter Clinical Symposium.
This is a live attenuated virus vaccine, and the rules regarding its use in patients with rheumatic diseases are fairly complicated. Here’s what physicians need to know: the Centers for Disease Control and Prevention and the Advisory Committee on Immunization Practices say the shingles vaccine can safely be given to patients on prednisone at less than 20 mg/day, azathioprine at up to 3 mg/kg/day, or methotrexate at up to 0.4 mg/kg/week, which works out to about 25 mg/week in anyone weighing more than 136 pounds.
However, the shingles vaccine is contraindicated in patients on recombinant biologic agents, including tumor necrosis factor (TNF) inhibitors, abatacept (Orencia), rituximab (Rituxan), or Janus kinase inhibitors, explained Dr. Cush, professor of medicine and rheumatology at Baylor University, Dallas, and director of clinical rheumatology at the Baylor Research Institute.
The lifetime risk of shingles in the general population is roughly one in three. The risk in patients with rheumatoid arthritis is roughly twice that of the age-matched general population, and the risks are substantially greater than that in individuals with other rheumatic diseases, including lupus and granulomatosis with polyangiitis.
Payers cover the vaccine in patients age 60 or older. The vaccine is approved for and has been shown to be effective in 50- to 59-year-olds as well, but that typically entails an out-of-pocket expense of around $200.
Given that close to 60% of all rheumatoid arthritis patients will eventually be placed on biologic therapy, Dr. Cush believes in seizing any opportunity to give the shingles vaccine in age-appropriate patients beforehand. However, he advises against temporarily stopping a biologic for the express purpose of administering the live virus vaccine.
“Find the opportunity: between changes in medication, after they have surgery, during a lapse in therapy,” he suggested.
It’s recommended that Zostavax be deferred until after a patient has been off biologic therapy or high-dose steroids for at least 4 weeks, and that a biologic agent shouldn’t be started for 2-4 weeks after vaccination.
The shingles vaccine can safely be given with multiple inactivated virus vaccines such as an influenza vaccine or pneumococcal vaccine on a single day.
Controversy surrounds the issue of whether TNF inhibitors increase the risk of shingles. Several retrospective studies have reported they do. But the largest retrospective study, involving more than 33,000 new users of anti-TNF agents, found that patients with rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, and other inflammatory diseases who initiated anti-TNF therapy weren’t at any higher risk of herpes zoster than those who started on methotrexate or other nonbiologic disease-modifying antirheumatic drugs (JAMA. 2013 Mar 6;309[9]:887-95). The lead investigator in this study, Dr. Kevin L. Winthrop of Oregon Health and Science University, Portland, is currently conducting a prospective study in an effort to confirm these findings.
The recommendation against giving the zoster vaccine to patients while on biologics is based upon the theoretical risk that exposure to the live attenuated virus will trigger an acute shingles attack. However, when Dr. Cush conducted a survey of his fellow rheumatologists, they reported that among more than a collective 200 patients inadvertently given the vaccine while on biologic therapy, not one case of shingles subsequently occurred over the short term.
More persuasively, Dr. Jeffrey R. Curtis of the University of Alabama at Birmingham and coinvestigators conducted a formal retrospective study of close to a half-million Medicare patients and found there were no cases of herpes zoster or varicella within 42 days following inadvertent vaccination of 633 patients while on biologics. During a median 2-year follow-up of Medicare patients with rheumatoid arthritis and other immune-mediated diseases, herpes zoster vaccination was associated with a 39% reduction in the risk of shingles (JAMA. 2012 Jul 4;308[1]:43-9).
“You shouldn’t be vaccinating for herpes zoster while patients are on a biologic, but you know what? If it happens, don’t wig out. Move on and try to avoid it,” Dr. Cush advised.
In any event, this is an issue that is eventually likely to go away. An inactivated virus vaccine for the prevention of shingles is now in clinical trials. It appears to be more effective than the current vaccine, according to the rheumatologist.
He reported having no financial interests relevant to his presentation.
EXPERT ANALYSIS FROM RWCS 2016
Uveitis in juvenile idiopathic arthritis may be preventable
MAUI, HAWAII – Uveitis is a common, highly destructive manifestation of juvenile idiopathic arthritis that is readily treatable when caught early, Dr. Anne M. Stevens said at the 2016 Rheumatology Winter Clinical Symposium.
Moreover, recent evidence from Germany suggests that uveitis may actually be preventable through early aggressive anti-inflammatory therapy, noted Dr. Stevens, a pediatric rheumatologist at Seattle Children’s Hospital and the University of Washington.
She cited a report from investigators participating in the National Pediatric Rheumatological Database in Germany. This large study included 3,512 juvenile idiopathic arthritis (JIA) patients with a mean age at arthritis onset of 7.8 years, a disease duration of less than 12 months at enrollment, and a mean follow-up of 3.6 years.
Uveitis occurred in 5.1% of patients within the first year after onset of JIA, and in another 7.1% following the first year. The key finding in the German study was that aggressive disease-modifying antirheumatic drug (DMARD) therapy during the year prior to uveitis significantly reduced the likelihood of developing this complication. Children on methotrexate during that time period were 37% less likely to develop uveitis than were those not on a DMARD. Moreover, patients placed on methotrexate within the first year after being diagnosed with JIA had a 71% relative risk reduction.
Patients on a tumor necrosis factor inhibitor during the year prior to uveitis had a 44% reduction in the risk of developing the eye complication. Most impressive of all, children on both methotrexate and a TNF inhibitor during the year prior to uveitis had a whopping 90% reduction in the risk of developing uveitis, compared with those not on a DMARD (Arthritis Care Res [Hoboken]. 2016 Jan;68[1]:46-54).
“I was fascinated by this study showing that treatment with two types of therapy may be preventive,” Dr. Stevens commented. “If this is substantiated in another large population-based cohort, it will be interesting to see if practice moves to treating the ANA [antinuclear antibody]–positive oligo JIA patients very early with TNF [tumor necrosis factor] inhibitors and methotrexate to prevent uveitis.”
The logic behind this aggressive preventive therapy lies in the fact that while uveitis occurs in about 20% of patients with oligoarticular JIA overall, roughly 90% of cases involve ANA-positive patients. For this reason, guidelines recommend slit lamp examinations every 3 months for a year in patients with young-onset, ANA-positive JIA.
“Imagine trying to do a slit lamp exam on a 2-year-old. It really helps to send these kids to a pediatric ophthalmologist who’s done a lot of them,” she advised.
The uveitis of JIA is typically anterior, asymptomatic, and low grade. It’s also a leading cause of blindness in childhood. Complications include band keratopathy, glaucomatous optic neuropathy, cataracts, and maculopathy.
“If we catch uveitis early, we can treat this disease really well now,” according to Dr. Stevens.
The initial therapy is short-term topical steroids. It’s important to keep in touch with the ophthalmologist regarding the slit lamp findings, however, because ophthalmologists generally tend to favor longer-term topical steroid therapy, while rheumatologists are appropriately primed to push on to more aggressive systemic therapy very quickly.
The first-line systemic agent for treatment of uveitis in patients with JIA is methotrexate at 1 mg/kg/week. If that doesn’t achieve satisfactory results, pediatric rheumatologists are quick to move on to second-line therapy with cyclosporine, azathioprine, or mycophenolate (CellCept).
“We move on fairly quickly if need be to TNF inhibitors, and we go with very high doses. The literature for infliximab [Remicade] is supportive of 20 mg/kg every 4 weeks. That’s what I use,” she continued.
High-dose adalimumab (Humira) is another option (J Rheumatol. 2013 Jan;40[1]:74-9). However, etanercept (Enbrel) is not effective for this condition. The use of abatacept (Orencia) or rituximab (Rituxan) in refractory patients is supported by favorable case reports.
Dr. Stevens reported having no financial interests relevant to her presentation.
MAUI, HAWAII – Uveitis is a common, highly destructive manifestation of juvenile idiopathic arthritis that is readily treatable when caught early, Dr. Anne M. Stevens said at the 2016 Rheumatology Winter Clinical Symposium.
Moreover, recent evidence from Germany suggests that uveitis may actually be preventable through early aggressive anti-inflammatory therapy, noted Dr. Stevens, a pediatric rheumatologist at Seattle Children’s Hospital and the University of Washington.
She cited a report from investigators participating in the National Pediatric Rheumatological Database in Germany. This large study included 3,512 juvenile idiopathic arthritis (JIA) patients with a mean age at arthritis onset of 7.8 years, a disease duration of less than 12 months at enrollment, and a mean follow-up of 3.6 years.
Uveitis occurred in 5.1% of patients within the first year after onset of JIA, and in another 7.1% following the first year. The key finding in the German study was that aggressive disease-modifying antirheumatic drug (DMARD) therapy during the year prior to uveitis significantly reduced the likelihood of developing this complication. Children on methotrexate during that time period were 37% less likely to develop uveitis than were those not on a DMARD. Moreover, patients placed on methotrexate within the first year after being diagnosed with JIA had a 71% relative risk reduction.
Patients on a tumor necrosis factor inhibitor during the year prior to uveitis had a 44% reduction in the risk of developing the eye complication. Most impressive of all, children on both methotrexate and a TNF inhibitor during the year prior to uveitis had a whopping 90% reduction in the risk of developing uveitis, compared with those not on a DMARD (Arthritis Care Res [Hoboken]. 2016 Jan;68[1]:46-54).
“I was fascinated by this study showing that treatment with two types of therapy may be preventive,” Dr. Stevens commented. “If this is substantiated in another large population-based cohort, it will be interesting to see if practice moves to treating the ANA [antinuclear antibody]–positive oligo JIA patients very early with TNF [tumor necrosis factor] inhibitors and methotrexate to prevent uveitis.”
The logic behind this aggressive preventive therapy lies in the fact that while uveitis occurs in about 20% of patients with oligoarticular JIA overall, roughly 90% of cases involve ANA-positive patients. For this reason, guidelines recommend slit lamp examinations every 3 months for a year in patients with young-onset, ANA-positive JIA.
“Imagine trying to do a slit lamp exam on a 2-year-old. It really helps to send these kids to a pediatric ophthalmologist who’s done a lot of them,” she advised.
The uveitis of JIA is typically anterior, asymptomatic, and low grade. It’s also a leading cause of blindness in childhood. Complications include band keratopathy, glaucomatous optic neuropathy, cataracts, and maculopathy.
“If we catch uveitis early, we can treat this disease really well now,” according to Dr. Stevens.
The initial therapy is short-term topical steroids. It’s important to keep in touch with the ophthalmologist regarding the slit lamp findings, however, because ophthalmologists generally tend to favor longer-term topical steroid therapy, while rheumatologists are appropriately primed to push on to more aggressive systemic therapy very quickly.
The first-line systemic agent for treatment of uveitis in patients with JIA is methotrexate at 1 mg/kg/week. If that doesn’t achieve satisfactory results, pediatric rheumatologists are quick to move on to second-line therapy with cyclosporine, azathioprine, or mycophenolate (CellCept).
“We move on fairly quickly if need be to TNF inhibitors, and we go with very high doses. The literature for infliximab [Remicade] is supportive of 20 mg/kg every 4 weeks. That’s what I use,” she continued.
High-dose adalimumab (Humira) is another option (J Rheumatol. 2013 Jan;40[1]:74-9). However, etanercept (Enbrel) is not effective for this condition. The use of abatacept (Orencia) or rituximab (Rituxan) in refractory patients is supported by favorable case reports.
Dr. Stevens reported having no financial interests relevant to her presentation.
MAUI, HAWAII – Uveitis is a common, highly destructive manifestation of juvenile idiopathic arthritis that is readily treatable when caught early, Dr. Anne M. Stevens said at the 2016 Rheumatology Winter Clinical Symposium.
Moreover, recent evidence from Germany suggests that uveitis may actually be preventable through early aggressive anti-inflammatory therapy, noted Dr. Stevens, a pediatric rheumatologist at Seattle Children’s Hospital and the University of Washington.
She cited a report from investigators participating in the National Pediatric Rheumatological Database in Germany. This large study included 3,512 juvenile idiopathic arthritis (JIA) patients with a mean age at arthritis onset of 7.8 years, a disease duration of less than 12 months at enrollment, and a mean follow-up of 3.6 years.
Uveitis occurred in 5.1% of patients within the first year after onset of JIA, and in another 7.1% following the first year. The key finding in the German study was that aggressive disease-modifying antirheumatic drug (DMARD) therapy during the year prior to uveitis significantly reduced the likelihood of developing this complication. Children on methotrexate during that time period were 37% less likely to develop uveitis than were those not on a DMARD. Moreover, patients placed on methotrexate within the first year after being diagnosed with JIA had a 71% relative risk reduction.
Patients on a tumor necrosis factor inhibitor during the year prior to uveitis had a 44% reduction in the risk of developing the eye complication. Most impressive of all, children on both methotrexate and a TNF inhibitor during the year prior to uveitis had a whopping 90% reduction in the risk of developing uveitis, compared with those not on a DMARD (Arthritis Care Res [Hoboken]. 2016 Jan;68[1]:46-54).
“I was fascinated by this study showing that treatment with two types of therapy may be preventive,” Dr. Stevens commented. “If this is substantiated in another large population-based cohort, it will be interesting to see if practice moves to treating the ANA [antinuclear antibody]–positive oligo JIA patients very early with TNF [tumor necrosis factor] inhibitors and methotrexate to prevent uveitis.”
The logic behind this aggressive preventive therapy lies in the fact that while uveitis occurs in about 20% of patients with oligoarticular JIA overall, roughly 90% of cases involve ANA-positive patients. For this reason, guidelines recommend slit lamp examinations every 3 months for a year in patients with young-onset, ANA-positive JIA.
“Imagine trying to do a slit lamp exam on a 2-year-old. It really helps to send these kids to a pediatric ophthalmologist who’s done a lot of them,” she advised.
The uveitis of JIA is typically anterior, asymptomatic, and low grade. It’s also a leading cause of blindness in childhood. Complications include band keratopathy, glaucomatous optic neuropathy, cataracts, and maculopathy.
“If we catch uveitis early, we can treat this disease really well now,” according to Dr. Stevens.
The initial therapy is short-term topical steroids. It’s important to keep in touch with the ophthalmologist regarding the slit lamp findings, however, because ophthalmologists generally tend to favor longer-term topical steroid therapy, while rheumatologists are appropriately primed to push on to more aggressive systemic therapy very quickly.
The first-line systemic agent for treatment of uveitis in patients with JIA is methotrexate at 1 mg/kg/week. If that doesn’t achieve satisfactory results, pediatric rheumatologists are quick to move on to second-line therapy with cyclosporine, azathioprine, or mycophenolate (CellCept).
“We move on fairly quickly if need be to TNF inhibitors, and we go with very high doses. The literature for infliximab [Remicade] is supportive of 20 mg/kg every 4 weeks. That’s what I use,” she continued.
High-dose adalimumab (Humira) is another option (J Rheumatol. 2013 Jan;40[1]:74-9). However, etanercept (Enbrel) is not effective for this condition. The use of abatacept (Orencia) or rituximab (Rituxan) in refractory patients is supported by favorable case reports.
Dr. Stevens reported having no financial interests relevant to her presentation.
EXPERT ANALYSIS FROM RWCS 2016
Keep cancer prominent in differential diagnoses of pediatric rheumatic complaints
MAUI, HAWAII – The first thing nonpediatric rheumatologists need to understand about a child who presents with rheumatic complaints is the importance of ruling out malignancy, Dr. Anne M. Stevens stressed at the 2016 Rheumatology Winter Clinical Symposium.
“This is something I think we in pediatric rheumatology worry about a lot more than adult rheumatologists: malignancy and how to distinguish it from rheumatic diseases,” said Dr. Stevens, a pediatric rheumatologist at Seattle Children’s Hospital and the University of Washington.
And with there being only about 250 pediatric rheumatologists in the entire United States, and a handful of states having none at all, it’s important that physicians in other specialties be familiar with key differences between pediatric and adult rheumatic diseases, she added.
A diverse group of malignancies in children and teens can present with swollen joints or other rheumatic features. One of the biggest red flags suggestive of an underlying malignancy is disproportionate pain, especially nonarticular bone pain or tenderness or back pain as a major presenting feature.
The source of this bone or back pain may be a reactive arthritis in response to local bony changes caused by an osteosarcoma or neuroblastoma, or malignant effusions as a result of leukemia or lymphoma, Dr. Stevens explained.
Other atypical features that get her thinking about the possibility of underlying malignancy rather than juvenile idiopathic arthritis include weight loss, night sweats, fatigue, fever, and night pain. Overall, young patients with an undetected cancer just seem sicker than those with rheumatic disease, she continued.
In a classic retrospective study of 29 children and teens who initially presented to pediatric rheumatologists at the University of British Columbia and were ultimately found to have malignancy, the most common provisional rheumatologic diagnosis was juvenile rheumatoid arthritis in 12 of the 29. Five patients were thought by referring physicians to have a connective tissue disease, and three each were believed to have discitis or spondyloarthropathy. Other provisional diagnoses included systemic lupus erythematosus in two patients; Kawasaki disease in two; and Lyme disease, mixed connective tissue disease, and dermatomyositis in one each.
The final diagnoses included leukemia in 13 patients, neuroblastoma in 6, lymphoma in 3, Ewing sarcoma in 3, and single cases of ependymoma, thalamic glioma, epithelioma, and sarcoma (J Pediatr. 1999 Jan;134[1]:53-7).
Working backwards, the investigators developed a set of clinical clues helpful in detecting malignancy. Nonarticular bone pain was a prominent presenting complaint in 20 of the 29, bone tenderness in 8, and back pain in 9.
“Bone tenderness is not seen in juvenile idiopathic arthritis at all, and children under about age 10 just don’t get low back pain. That really alerts us to malignancy concern,” Dr. Stevens said.
Night sweats were present in four patients, severe constitutional symptoms in nine.
Two patients had true juvenile idiopathic arthritis, so that finding doesn’t rule out malignancy.
Surprisingly, the CBC was normal in three-quarters of patients. Antinuclear antibody testing is not helpful, as it can be strongly positive in the setting of pediatric malignancy, but lactate dehydrogenase and uric acid tests are important in making the differential diagnosis.
If there are any surprising findings raising concerns about possible malignancy, a bone marrow biopsy is essential.
“We have a lot of fights with our hematologists when we’re trying to get a bone marrow biopsy and they say, ‘No, the CBC is normal so you don’t need a bone marrow biopsy.’ But you have to get that bone marrow biopsy. A strategy that works is for us to say, ‘Could you please include a note in the chart that it’s okay for us to give steroids because you’re sure it’s not a lymphoma?’ Then we usually get it scheduled for the next day,” Dr. Stevens said.
She reported having no relevant financial disclosures.
MAUI, HAWAII – The first thing nonpediatric rheumatologists need to understand about a child who presents with rheumatic complaints is the importance of ruling out malignancy, Dr. Anne M. Stevens stressed at the 2016 Rheumatology Winter Clinical Symposium.
“This is something I think we in pediatric rheumatology worry about a lot more than adult rheumatologists: malignancy and how to distinguish it from rheumatic diseases,” said Dr. Stevens, a pediatric rheumatologist at Seattle Children’s Hospital and the University of Washington.
And with there being only about 250 pediatric rheumatologists in the entire United States, and a handful of states having none at all, it’s important that physicians in other specialties be familiar with key differences between pediatric and adult rheumatic diseases, she added.
A diverse group of malignancies in children and teens can present with swollen joints or other rheumatic features. One of the biggest red flags suggestive of an underlying malignancy is disproportionate pain, especially nonarticular bone pain or tenderness or back pain as a major presenting feature.
The source of this bone or back pain may be a reactive arthritis in response to local bony changes caused by an osteosarcoma or neuroblastoma, or malignant effusions as a result of leukemia or lymphoma, Dr. Stevens explained.
Other atypical features that get her thinking about the possibility of underlying malignancy rather than juvenile idiopathic arthritis include weight loss, night sweats, fatigue, fever, and night pain. Overall, young patients with an undetected cancer just seem sicker than those with rheumatic disease, she continued.
In a classic retrospective study of 29 children and teens who initially presented to pediatric rheumatologists at the University of British Columbia and were ultimately found to have malignancy, the most common provisional rheumatologic diagnosis was juvenile rheumatoid arthritis in 12 of the 29. Five patients were thought by referring physicians to have a connective tissue disease, and three each were believed to have discitis or spondyloarthropathy. Other provisional diagnoses included systemic lupus erythematosus in two patients; Kawasaki disease in two; and Lyme disease, mixed connective tissue disease, and dermatomyositis in one each.
The final diagnoses included leukemia in 13 patients, neuroblastoma in 6, lymphoma in 3, Ewing sarcoma in 3, and single cases of ependymoma, thalamic glioma, epithelioma, and sarcoma (J Pediatr. 1999 Jan;134[1]:53-7).
Working backwards, the investigators developed a set of clinical clues helpful in detecting malignancy. Nonarticular bone pain was a prominent presenting complaint in 20 of the 29, bone tenderness in 8, and back pain in 9.
“Bone tenderness is not seen in juvenile idiopathic arthritis at all, and children under about age 10 just don’t get low back pain. That really alerts us to malignancy concern,” Dr. Stevens said.
Night sweats were present in four patients, severe constitutional symptoms in nine.
Two patients had true juvenile idiopathic arthritis, so that finding doesn’t rule out malignancy.
Surprisingly, the CBC was normal in three-quarters of patients. Antinuclear antibody testing is not helpful, as it can be strongly positive in the setting of pediatric malignancy, but lactate dehydrogenase and uric acid tests are important in making the differential diagnosis.
If there are any surprising findings raising concerns about possible malignancy, a bone marrow biopsy is essential.
“We have a lot of fights with our hematologists when we’re trying to get a bone marrow biopsy and they say, ‘No, the CBC is normal so you don’t need a bone marrow biopsy.’ But you have to get that bone marrow biopsy. A strategy that works is for us to say, ‘Could you please include a note in the chart that it’s okay for us to give steroids because you’re sure it’s not a lymphoma?’ Then we usually get it scheduled for the next day,” Dr. Stevens said.
She reported having no relevant financial disclosures.
MAUI, HAWAII – The first thing nonpediatric rheumatologists need to understand about a child who presents with rheumatic complaints is the importance of ruling out malignancy, Dr. Anne M. Stevens stressed at the 2016 Rheumatology Winter Clinical Symposium.
“This is something I think we in pediatric rheumatology worry about a lot more than adult rheumatologists: malignancy and how to distinguish it from rheumatic diseases,” said Dr. Stevens, a pediatric rheumatologist at Seattle Children’s Hospital and the University of Washington.
And with there being only about 250 pediatric rheumatologists in the entire United States, and a handful of states having none at all, it’s important that physicians in other specialties be familiar with key differences between pediatric and adult rheumatic diseases, she added.
A diverse group of malignancies in children and teens can present with swollen joints or other rheumatic features. One of the biggest red flags suggestive of an underlying malignancy is disproportionate pain, especially nonarticular bone pain or tenderness or back pain as a major presenting feature.
The source of this bone or back pain may be a reactive arthritis in response to local bony changes caused by an osteosarcoma or neuroblastoma, or malignant effusions as a result of leukemia or lymphoma, Dr. Stevens explained.
Other atypical features that get her thinking about the possibility of underlying malignancy rather than juvenile idiopathic arthritis include weight loss, night sweats, fatigue, fever, and night pain. Overall, young patients with an undetected cancer just seem sicker than those with rheumatic disease, she continued.
In a classic retrospective study of 29 children and teens who initially presented to pediatric rheumatologists at the University of British Columbia and were ultimately found to have malignancy, the most common provisional rheumatologic diagnosis was juvenile rheumatoid arthritis in 12 of the 29. Five patients were thought by referring physicians to have a connective tissue disease, and three each were believed to have discitis or spondyloarthropathy. Other provisional diagnoses included systemic lupus erythematosus in two patients; Kawasaki disease in two; and Lyme disease, mixed connective tissue disease, and dermatomyositis in one each.
The final diagnoses included leukemia in 13 patients, neuroblastoma in 6, lymphoma in 3, Ewing sarcoma in 3, and single cases of ependymoma, thalamic glioma, epithelioma, and sarcoma (J Pediatr. 1999 Jan;134[1]:53-7).
Working backwards, the investigators developed a set of clinical clues helpful in detecting malignancy. Nonarticular bone pain was a prominent presenting complaint in 20 of the 29, bone tenderness in 8, and back pain in 9.
“Bone tenderness is not seen in juvenile idiopathic arthritis at all, and children under about age 10 just don’t get low back pain. That really alerts us to malignancy concern,” Dr. Stevens said.
Night sweats were present in four patients, severe constitutional symptoms in nine.
Two patients had true juvenile idiopathic arthritis, so that finding doesn’t rule out malignancy.
Surprisingly, the CBC was normal in three-quarters of patients. Antinuclear antibody testing is not helpful, as it can be strongly positive in the setting of pediatric malignancy, but lactate dehydrogenase and uric acid tests are important in making the differential diagnosis.
If there are any surprising findings raising concerns about possible malignancy, a bone marrow biopsy is essential.
“We have a lot of fights with our hematologists when we’re trying to get a bone marrow biopsy and they say, ‘No, the CBC is normal so you don’t need a bone marrow biopsy.’ But you have to get that bone marrow biopsy. A strategy that works is for us to say, ‘Could you please include a note in the chart that it’s okay for us to give steroids because you’re sure it’s not a lymphoma?’ Then we usually get it scheduled for the next day,” Dr. Stevens said.
She reported having no relevant financial disclosures.
EXPERT ANALYSIS FROM RWCS 2016
Romosozumab, coming ACR guidelines mark recent high points in osteoporosis
MAUI, HAWAII – The investigational bone-building agent romosozumab provided the therapeutic highlight in the field of osteoporosis during the past year, Dr. Martin J. Bergman said at the 2016 Rheumatology Winter Clinical Symposium.
Romosozumab is a monoclonal antibody directed against sclerostin, a glycoprotein that prevents mesenchymal cells from becoming osteoblasts. By inhibiting sclerostin, romosozumab promotes osteoblast production. The result is increased bone mineral density and bone formation coupled with decreased bone resorption, providing physicians with a promising new avenue for rapidly building strong bone, explained Dr. Bergman of Drexel University in Philadelphia and chief of the section of rheumatology at Taylor Hospital in Ridley Park, Pa.
Romosozumab caught his eye in a 12-month randomized trial presented last fall at the annual meeting of the American College of Rheumatology. The 430 postmenopausal participants were assigned to blinded romosozumab at 210 mg delivered by subcutaneous injection once per month, blinded placebo, or open-label teriparatide (Forteo). The primary endpoint in this secondary analysis was change in bone strength as measured using the Food and Drug Administration–approved method of finite element analysis based upon quantitative CT imaging.
Romosozumab boosted bone strength at the spine by 27.3% at 12 months, compared with a 3.9% reduction from baseline with placebo and an 18.5% increase with teriparatide. At the hip, romosozumab delivered a 3.6% increase in bone strength versus no significant change from baseline in the other two study arms. Thus, romosozumab increased bone strength both in the cortical and trabecular compartments even more than did teriparatide, the most potent drug currently available for building bone mass.
“The numbers are very impressive,” Dr. Bergman observed. “Trabecular bone, cortical bone, whole bone – across the board, we haven’t seen similar numbers before. I think this is going to be a very exciting new approach to the treatment of osteoporosis. We need to keep an eye on this.”
Romosozumab, which is being codeveloped by Amgen and UCB, is now in phase III testing.
The other big news in osteoporosis is that later this year the ACR will undertake a revision of its 2010 guidelines for the prevention and treatment of glucocorticoid-induced osteoporosis (Arthritis Care Res [Hoboken]. 2010 Nov;62[11]:1515-26).
Among the actions that need to be taken are the incorporation of denosumab (Prolia) and ibandronate (Boniva) into the treatment recommendations, as well as clarification of the recommendation for supplemental calcium in light of recent evidence of an association between high serum calcium and increased cardiovascular risk. Most of the lifestyle modification recommendations in the current guidelines are supported by a weak level of evidence C, meaning “expert opinion,” and the hope is that the evidence has become stronger since 2010, he said.
Dr. Bergman reported having no financial conflicts regarding his presentation.
MAUI, HAWAII – The investigational bone-building agent romosozumab provided the therapeutic highlight in the field of osteoporosis during the past year, Dr. Martin J. Bergman said at the 2016 Rheumatology Winter Clinical Symposium.
Romosozumab is a monoclonal antibody directed against sclerostin, a glycoprotein that prevents mesenchymal cells from becoming osteoblasts. By inhibiting sclerostin, romosozumab promotes osteoblast production. The result is increased bone mineral density and bone formation coupled with decreased bone resorption, providing physicians with a promising new avenue for rapidly building strong bone, explained Dr. Bergman of Drexel University in Philadelphia and chief of the section of rheumatology at Taylor Hospital in Ridley Park, Pa.
Romosozumab caught his eye in a 12-month randomized trial presented last fall at the annual meeting of the American College of Rheumatology. The 430 postmenopausal participants were assigned to blinded romosozumab at 210 mg delivered by subcutaneous injection once per month, blinded placebo, or open-label teriparatide (Forteo). The primary endpoint in this secondary analysis was change in bone strength as measured using the Food and Drug Administration–approved method of finite element analysis based upon quantitative CT imaging.
Romosozumab boosted bone strength at the spine by 27.3% at 12 months, compared with a 3.9% reduction from baseline with placebo and an 18.5% increase with teriparatide. At the hip, romosozumab delivered a 3.6% increase in bone strength versus no significant change from baseline in the other two study arms. Thus, romosozumab increased bone strength both in the cortical and trabecular compartments even more than did teriparatide, the most potent drug currently available for building bone mass.
“The numbers are very impressive,” Dr. Bergman observed. “Trabecular bone, cortical bone, whole bone – across the board, we haven’t seen similar numbers before. I think this is going to be a very exciting new approach to the treatment of osteoporosis. We need to keep an eye on this.”
Romosozumab, which is being codeveloped by Amgen and UCB, is now in phase III testing.
The other big news in osteoporosis is that later this year the ACR will undertake a revision of its 2010 guidelines for the prevention and treatment of glucocorticoid-induced osteoporosis (Arthritis Care Res [Hoboken]. 2010 Nov;62[11]:1515-26).
Among the actions that need to be taken are the incorporation of denosumab (Prolia) and ibandronate (Boniva) into the treatment recommendations, as well as clarification of the recommendation for supplemental calcium in light of recent evidence of an association between high serum calcium and increased cardiovascular risk. Most of the lifestyle modification recommendations in the current guidelines are supported by a weak level of evidence C, meaning “expert opinion,” and the hope is that the evidence has become stronger since 2010, he said.
Dr. Bergman reported having no financial conflicts regarding his presentation.
MAUI, HAWAII – The investigational bone-building agent romosozumab provided the therapeutic highlight in the field of osteoporosis during the past year, Dr. Martin J. Bergman said at the 2016 Rheumatology Winter Clinical Symposium.
Romosozumab is a monoclonal antibody directed against sclerostin, a glycoprotein that prevents mesenchymal cells from becoming osteoblasts. By inhibiting sclerostin, romosozumab promotes osteoblast production. The result is increased bone mineral density and bone formation coupled with decreased bone resorption, providing physicians with a promising new avenue for rapidly building strong bone, explained Dr. Bergman of Drexel University in Philadelphia and chief of the section of rheumatology at Taylor Hospital in Ridley Park, Pa.
Romosozumab caught his eye in a 12-month randomized trial presented last fall at the annual meeting of the American College of Rheumatology. The 430 postmenopausal participants were assigned to blinded romosozumab at 210 mg delivered by subcutaneous injection once per month, blinded placebo, or open-label teriparatide (Forteo). The primary endpoint in this secondary analysis was change in bone strength as measured using the Food and Drug Administration–approved method of finite element analysis based upon quantitative CT imaging.
Romosozumab boosted bone strength at the spine by 27.3% at 12 months, compared with a 3.9% reduction from baseline with placebo and an 18.5% increase with teriparatide. At the hip, romosozumab delivered a 3.6% increase in bone strength versus no significant change from baseline in the other two study arms. Thus, romosozumab increased bone strength both in the cortical and trabecular compartments even more than did teriparatide, the most potent drug currently available for building bone mass.
“The numbers are very impressive,” Dr. Bergman observed. “Trabecular bone, cortical bone, whole bone – across the board, we haven’t seen similar numbers before. I think this is going to be a very exciting new approach to the treatment of osteoporosis. We need to keep an eye on this.”
Romosozumab, which is being codeveloped by Amgen and UCB, is now in phase III testing.
The other big news in osteoporosis is that later this year the ACR will undertake a revision of its 2010 guidelines for the prevention and treatment of glucocorticoid-induced osteoporosis (Arthritis Care Res [Hoboken]. 2010 Nov;62[11]:1515-26).
Among the actions that need to be taken are the incorporation of denosumab (Prolia) and ibandronate (Boniva) into the treatment recommendations, as well as clarification of the recommendation for supplemental calcium in light of recent evidence of an association between high serum calcium and increased cardiovascular risk. Most of the lifestyle modification recommendations in the current guidelines are supported by a weak level of evidence C, meaning “expert opinion,” and the hope is that the evidence has become stronger since 2010, he said.
Dr. Bergman reported having no financial conflicts regarding his presentation.
EXPERT ANALYSIS FROM RWCS 2016
