Ankylosing spondylitis

Antibodies to the innovator infliximab drug Remicade found in rheumatoid arthritis and spondyloarthritis patients also cross-react with the infliximab biosimilar CT-P13, marketed as Remsima or Inflectra, suggesting that switches from the innovator drug to the biosimilar are not advisable in the presence of anti-infliximab antibodies.

Switching an antibody-positive patient from the innovator drug to the biosimilar could mean that existing infliximab antibodies will “interact with the new drug, enhance clearance, and potentially lead to loss of response and infusion-related reactions,” wrote first author M. Begoña Ruiz-Argüello, Ph.D., an employee of the molecular biology testing company Progenika-Grifols in Derio, Spain, and colleagues (Ann Rheum Dis. 2016 Mar 10. doi: 10.1136/annrheumdis-2015-208684).

©iStock/thinkstockphotos.com

In the current study, the investigators set out to discover whether anti-Remicade antibodies cross-reacted with the biosimilar CT-P13, which was approved by the European Medicines Agency in 2013 for the same indications as the originator infliximab biologic Remicade.

They retrospectively selected 250 patients with rheumatoid arthritis (RA) or spondyloarthritis (SpA) who were treated with Remicade and 77 control patients who were infliximab naive.

Antibodies to infliximab were measured at the same time using three bridging ELISA assays: one that used Remicade to detect antibodies (Promonitor-ANTI-IFX kit, Progenika-Grifols, Spain); one that used Remsima (Orion Pharma, Norway); and another that used Inflectra (Hospira, United States).

Overall, 126 (50.4%) patients tested positive for antibodies using the Promonitor-ANTI-IFX kit.

These patients also tested positive for antibodies when the Remsima and Inflectra assays were used. Median antibody concentrations between the assays were not statistically different (P greater than .05). No significant differences were observed between patients with RA and SpA (P greater than .05) or in patients on concomitant immunosuppressive treatment, such as methotrexate.

Contrary to previous research, patients who tested negative for antibodies with the Promonitor-ANTI-IFX kit also tested negative with the Remsima and Inflectra assays. “Although additional epitopes may be present in the biosimilar, results suggest that epitopes influencing the immune response to [infliximab] are also present in the biosimilar,” the researchers said.

The investigators said that their findings also supported the use of therapeutic drug monitoring before considering switching patients between drugs.

Although the researchers recommended not switching between Remicade and Remsima or Inflectra, a small subanalysis in their study suggests it would be okay to switch from adalimumab to the infliximab biosimilar. A control population of 19 patients involved in the study who were anti–adalimumab antibody positive tested negative for antibodies to infliximab across the three assays.

Six of the authors are full-time employees of Progenika Biopharma S.A., maker of the Remicade assay used in the study.

Antibodies to the innovator infliximab drug Remicade found in rheumatoid arthritis and spondyloarthritis patients also cross-react with the infliximab biosimilar CT-P13, marketed as Remsima or Inflectra, suggesting that switches from the innovator drug to the biosimilar are not advisable in the presence of anti-infliximab antibodies.

Switching an antibody-positive patient from the innovator drug to the biosimilar could mean that existing infliximab antibodies will “interact with the new drug, enhance clearance, and potentially lead to loss of response and infusion-related reactions,” wrote first author M. Begoña Ruiz-Argüello, Ph.D., an employee of the molecular biology testing company Progenika-Grifols in Derio, Spain, and colleagues (Ann Rheum Dis. 2016 Mar 10. doi: 10.1136/annrheumdis-2015-208684).

©iStock/thinkstockphotos.com

In the current study, the investigators set out to discover whether anti-Remicade antibodies cross-reacted with the biosimilar CT-P13, which was approved by the European Medicines Agency in 2013 for the same indications as the originator infliximab biologic Remicade.

They retrospectively selected 250 patients with rheumatoid arthritis (RA) or spondyloarthritis (SpA) who were treated with Remicade and 77 control patients who were infliximab naive.

Antibodies to infliximab were measured at the same time using three bridging ELISA assays: one that used Remicade to detect antibodies (Promonitor-ANTI-IFX kit, Progenika-Grifols, Spain); one that used Remsima (Orion Pharma, Norway); and another that used Inflectra (Hospira, United States).

Overall, 126 (50.4%) patients tested positive for antibodies using the Promonitor-ANTI-IFX kit.

These patients also tested positive for antibodies when the Remsima and Inflectra assays were used. Median antibody concentrations between the assays were not statistically different (P greater than .05). No significant differences were observed between patients with RA and SpA (P greater than .05) or in patients on concomitant immunosuppressive treatment, such as methotrexate.

Contrary to previous research, patients who tested negative for antibodies with the Promonitor-ANTI-IFX kit also tested negative with the Remsima and Inflectra assays. “Although additional epitopes may be present in the biosimilar, results suggest that epitopes influencing the immune response to [infliximab] are also present in the biosimilar,” the researchers said.

The investigators said that their findings also supported the use of therapeutic drug monitoring before considering switching patients between drugs.

Although the researchers recommended not switching between Remicade and Remsima or Inflectra, a small subanalysis in their study suggests it would be okay to switch from adalimumab to the infliximab biosimilar. A control population of 19 patients involved in the study who were anti–adalimumab antibody positive tested negative for antibodies to infliximab across the three assays.

Six of the authors are full-time employees of Progenika Biopharma S.A., maker of the Remicade assay used in the study.

Antibodies to the innovator infliximab drug Remicade found in rheumatoid arthritis and spondyloarthritis patients also cross-react with the infliximab biosimilar CT-P13, marketed as Remsima or Inflectra, suggesting that switches from the innovator drug to the biosimilar are not advisable in the presence of anti-infliximab antibodies.

Switching an antibody-positive patient from the innovator drug to the biosimilar could mean that existing infliximab antibodies will “interact with the new drug, enhance clearance, and potentially lead to loss of response and infusion-related reactions,” wrote first author M. Begoña Ruiz-Argüello, Ph.D., an employee of the molecular biology testing company Progenika-Grifols in Derio, Spain, and colleagues (Ann Rheum Dis. 2016 Mar 10. doi: 10.1136/annrheumdis-2015-208684).

©iStock/thinkstockphotos.com

In the current study, the investigators set out to discover whether anti-Remicade antibodies cross-reacted with the biosimilar CT-P13, which was approved by the European Medicines Agency in 2013 for the same indications as the originator infliximab biologic Remicade.

They retrospectively selected 250 patients with rheumatoid arthritis (RA) or spondyloarthritis (SpA) who were treated with Remicade and 77 control patients who were infliximab naive.

Antibodies to infliximab were measured at the same time using three bridging ELISA assays: one that used Remicade to detect antibodies (Promonitor-ANTI-IFX kit, Progenika-Grifols, Spain); one that used Remsima (Orion Pharma, Norway); and another that used Inflectra (Hospira, United States).

Overall, 126 (50.4%) patients tested positive for antibodies using the Promonitor-ANTI-IFX kit.

These patients also tested positive for antibodies when the Remsima and Inflectra assays were used. Median antibody concentrations between the assays were not statistically different (P greater than .05). No significant differences were observed between patients with RA and SpA (P greater than .05) or in patients on concomitant immunosuppressive treatment, such as methotrexate.

Contrary to previous research, patients who tested negative for antibodies with the Promonitor-ANTI-IFX kit also tested negative with the Remsima and Inflectra assays. “Although additional epitopes may be present in the biosimilar, results suggest that epitopes influencing the immune response to [infliximab] are also present in the biosimilar,” the researchers said.

The investigators said that their findings also supported the use of therapeutic drug monitoring before considering switching patients between drugs.

Although the researchers recommended not switching between Remicade and Remsima or Inflectra, a small subanalysis in their study suggests it would be okay to switch from adalimumab to the infliximab biosimilar. A control population of 19 patients involved in the study who were anti–adalimumab antibody positive tested negative for antibodies to infliximab across the three assays.

Six of the authors are full-time employees of Progenika Biopharma S.A., maker of the Remicade assay used in the study.

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.

Bruce Jancin/Frontline Medical News

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.

[email protected]

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.

Bruce Jancin/Frontline Medical News

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.

[email protected]

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.

Bruce Jancin/Frontline Medical News

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.

[email protected]

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.

jancin

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.

[email protected]

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.

jancin

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.

[email protected]

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.

jancin

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.

[email protected]

Sacroiliitis observed in patients with axial spondyloarthritis more often regressed rather than progressed on radiography over nearly 5 years of follow-up of the Assessment of SpondyloArthritis international Society (ASAS) cohort, which lead author Dr. Alexandre Sepriano and his colleagues called “strange” and “sobering.”

The findings call into question the reliability of plain pelvic radiographs for detecting subtle change in sacroiliitis and should prompt the evaluation of alternative imaging modalities such as MRI and low-dose CT, according to Dr. Sepriano of Leiden (the Netherlands) University Medical Center and his associates.

©Rocky89/Thinkstock.com

Determining the presence of radiographic sacroiliitis is prognostically relevant and can pave the way for treatment with biologics, but ambiguity in making this decision and in tracking progression has been revealed in the large inter-and intrareader variability found in previous studies. Furthermore, previous studies tracking progression of nonradiographic axial spondyloarthritis (axSpA) to radiographic axSpA have addressed only disease progression and ignored regression. While regression is likely to be rare, it cannot be ignored from a methodologic standpoint, the investigators wrote.

The researchers therefore set out in the current study to assess positive and negative changes in sacroiliitis on plain pelvic radiographs over time in 975 patients from the ASAS cohort who had chronic back pain of unknown origin or undiagnosed peripheral symptoms (Ann Rheum Dis. 2016 Feb 22. doi: 10.1136/annrheumdis-2015-208964).

Of the 357 of the patients who had paired plain pelvic radiographs available at baseline and follow-up, 17.4% (62/357) fulfilled the criteria for radiographic axSpA at baseline, as defined by modified New York criteria (mNY). At a mean follow-up of 4.4 years, this figure had risen to 22.4% (80/357), suggesting a net progression of 5%.

However, when the authors cross-tabulated their figures, more than half (36/62) of the patients considered mNY positive at baseline were assessed as mNY negative at follow-up. This would mean that radiographic sacroiliitis would have regressed in 58% of the cases; conversely, only 54 of 295 patients (18.3%) became mNY positive at follow-up.

“If only positive change (progression) is valued and negative change is ignored, one would disregard measurement error and spuriously attribute part of the observed positive change to real progression,” the research team explained. “The most likely explanation of our strange and extreme observation is that subtle radiographic progression (the signal) – if truly present – cannot be reliably distinguished from measurement error (the noise). These sobering data clearly illustrate that more research is needed in visualising progression in axSpA.”

ASAS funded the study. The authors had no competing interests to declare.

Sacroiliitis observed in patients with axial spondyloarthritis more often regressed rather than progressed on radiography over nearly 5 years of follow-up of the Assessment of SpondyloArthritis international Society (ASAS) cohort, which lead author Dr. Alexandre Sepriano and his colleagues called “strange” and “sobering.”

The findings call into question the reliability of plain pelvic radiographs for detecting subtle change in sacroiliitis and should prompt the evaluation of alternative imaging modalities such as MRI and low-dose CT, according to Dr. Sepriano of Leiden (the Netherlands) University Medical Center and his associates.

©Rocky89/Thinkstock.com

Determining the presence of radiographic sacroiliitis is prognostically relevant and can pave the way for treatment with biologics, but ambiguity in making this decision and in tracking progression has been revealed in the large inter-and intrareader variability found in previous studies. Furthermore, previous studies tracking progression of nonradiographic axial spondyloarthritis (axSpA) to radiographic axSpA have addressed only disease progression and ignored regression. While regression is likely to be rare, it cannot be ignored from a methodologic standpoint, the investigators wrote.

The researchers therefore set out in the current study to assess positive and negative changes in sacroiliitis on plain pelvic radiographs over time in 975 patients from the ASAS cohort who had chronic back pain of unknown origin or undiagnosed peripheral symptoms (Ann Rheum Dis. 2016 Feb 22. doi: 10.1136/annrheumdis-2015-208964).

Of the 357 of the patients who had paired plain pelvic radiographs available at baseline and follow-up, 17.4% (62/357) fulfilled the criteria for radiographic axSpA at baseline, as defined by modified New York criteria (mNY). At a mean follow-up of 4.4 years, this figure had risen to 22.4% (80/357), suggesting a net progression of 5%.

However, when the authors cross-tabulated their figures, more than half (36/62) of the patients considered mNY positive at baseline were assessed as mNY negative at follow-up. This would mean that radiographic sacroiliitis would have regressed in 58% of the cases; conversely, only 54 of 295 patients (18.3%) became mNY positive at follow-up.

“If only positive change (progression) is valued and negative change is ignored, one would disregard measurement error and spuriously attribute part of the observed positive change to real progression,” the research team explained. “The most likely explanation of our strange and extreme observation is that subtle radiographic progression (the signal) – if truly present – cannot be reliably distinguished from measurement error (the noise). These sobering data clearly illustrate that more research is needed in visualising progression in axSpA.”

ASAS funded the study. The authors had no competing interests to declare.

Sacroiliitis observed in patients with axial spondyloarthritis more often regressed rather than progressed on radiography over nearly 5 years of follow-up of the Assessment of SpondyloArthritis international Society (ASAS) cohort, which lead author Dr. Alexandre Sepriano and his colleagues called “strange” and “sobering.”

The findings call into question the reliability of plain pelvic radiographs for detecting subtle change in sacroiliitis and should prompt the evaluation of alternative imaging modalities such as MRI and low-dose CT, according to Dr. Sepriano of Leiden (the Netherlands) University Medical Center and his associates.

©Rocky89/Thinkstock.com

Determining the presence of radiographic sacroiliitis is prognostically relevant and can pave the way for treatment with biologics, but ambiguity in making this decision and in tracking progression has been revealed in the large inter-and intrareader variability found in previous studies. Furthermore, previous studies tracking progression of nonradiographic axial spondyloarthritis (axSpA) to radiographic axSpA have addressed only disease progression and ignored regression. While regression is likely to be rare, it cannot be ignored from a methodologic standpoint, the investigators wrote.

The researchers therefore set out in the current study to assess positive and negative changes in sacroiliitis on plain pelvic radiographs over time in 975 patients from the ASAS cohort who had chronic back pain of unknown origin or undiagnosed peripheral symptoms (Ann Rheum Dis. 2016 Feb 22. doi: 10.1136/annrheumdis-2015-208964).

Of the 357 of the patients who had paired plain pelvic radiographs available at baseline and follow-up, 17.4% (62/357) fulfilled the criteria for radiographic axSpA at baseline, as defined by modified New York criteria (mNY). At a mean follow-up of 4.4 years, this figure had risen to 22.4% (80/357), suggesting a net progression of 5%.

However, when the authors cross-tabulated their figures, more than half (36/62) of the patients considered mNY positive at baseline were assessed as mNY negative at follow-up. This would mean that radiographic sacroiliitis would have regressed in 58% of the cases; conversely, only 54 of 295 patients (18.3%) became mNY positive at follow-up.

“If only positive change (progression) is valued and negative change is ignored, one would disregard measurement error and spuriously attribute part of the observed positive change to real progression,” the research team explained. “The most likely explanation of our strange and extreme observation is that subtle radiographic progression (the signal) – if truly present – cannot be reliably distinguished from measurement error (the noise). These sobering data clearly illustrate that more research is needed in visualising progression in axSpA.”

ASAS funded the study. The authors had no competing interests to declare.

The findings of a recent Cochrane review back up guidelines that recommend NSAIDs as an appropriate first-line treatment for people with axial spondyloarthritis (axSpA).

NSAIDs have been associated with a variety of gastrointestinal effects and an increased risk of cardiovascular events, heart failure, and renal toxicity, an international team of researchers led by Dr. Féline P.B. Kroon of the Leiden University Medical Center in the Netherlands noted in the review, published in the Journal of Rheumatology.

Denise Fulton/Frontline Medical News

“It is therefore crucial to know whether the benefits offset the risks, especially because the therapy is often given for extended periods of time,” the researchers wrote in background information to the article (J Rheumatol. 2016. doi: 10.3899/jrheum.150721).

The investigators analyzed the evidence to assess the benefits and harms of NSAIDs in controlling symptoms, disease activity, and radiographic progression in patients with axSpA.

Reviewing 29 randomized, controlled trials and two “quasi” RCT studies in a pooled analyses, the research team found that, compared with placebo, both traditional and cyclooxygenase-2 (COX-2) NSAIDs were consistently more efficacious at 6 weeks and equally safe after 12 weeks.

The researchers also observed no significant differences in benefits or harms between the two NSAID classes. An increased number of neurologic events were initially observed for indomethacin, but the finding was not statistically significant when studies with high or unclear risk of bias were excluded.

Two single studies included in the review also suggested NSAIDs might retard radiographic progression in the spine in axSpA, especially in certain subgroups of patients such as those with high C-reactive protein. Although this would most likely be best achieved by continuous rather than on-demand use, the researchers said.

“The results of the review are in keeping with current recommendations that NSAIDs are appropriate first-line treatments of patients with axSpA with active disease before tumor necrosis factor inhibitor biologicals are applied,” they concluded.

However, they said it was surprising that they were unable to confirm the safety concerns associated with traditional NSAIDs and COX-2 NSAIDs.

This finding could mean that short-term use of either class of NSAID in this population of patients is not associated with an increased risk of GI or other adverse events.

But it could also be because most patients with ankylosing spondylitis are younger and have fewer comorbidities than patients with other rheumatic diseases.

The finding that people with ankylosing spondylitis have fewer adverse events with biologics, compared with patients with other rheumatic diseases, supported this theory, they said.

“It is technically still possible that lack of statistical power is at the basis of this, but we feel it is more likely that in the studied population and within the studied time frame (i.e., short-term), the risks of GI or cardiovascular toxicity are really not increased,” they wrote.

The review had several limitations, including that many trials were older (61% of the included studies were published before 1990) and there were not sufficient data to draw conclusions on long-term safety.

The findings of a recent Cochrane review back up guidelines that recommend NSAIDs as an appropriate first-line treatment for people with axial spondyloarthritis (axSpA).

NSAIDs have been associated with a variety of gastrointestinal effects and an increased risk of cardiovascular events, heart failure, and renal toxicity, an international team of researchers led by Dr. Féline P.B. Kroon of the Leiden University Medical Center in the Netherlands noted in the review, published in the Journal of Rheumatology.

Denise Fulton/Frontline Medical News

“It is therefore crucial to know whether the benefits offset the risks, especially because the therapy is often given for extended periods of time,” the researchers wrote in background information to the article (J Rheumatol. 2016. doi: 10.3899/jrheum.150721).

The investigators analyzed the evidence to assess the benefits and harms of NSAIDs in controlling symptoms, disease activity, and radiographic progression in patients with axSpA.

Reviewing 29 randomized, controlled trials and two “quasi” RCT studies in a pooled analyses, the research team found that, compared with placebo, both traditional and cyclooxygenase-2 (COX-2) NSAIDs were consistently more efficacious at 6 weeks and equally safe after 12 weeks.

The researchers also observed no significant differences in benefits or harms between the two NSAID classes. An increased number of neurologic events were initially observed for indomethacin, but the finding was not statistically significant when studies with high or unclear risk of bias were excluded.

Two single studies included in the review also suggested NSAIDs might retard radiographic progression in the spine in axSpA, especially in certain subgroups of patients such as those with high C-reactive protein. Although this would most likely be best achieved by continuous rather than on-demand use, the researchers said.

“The results of the review are in keeping with current recommendations that NSAIDs are appropriate first-line treatments of patients with axSpA with active disease before tumor necrosis factor inhibitor biologicals are applied,” they concluded.

However, they said it was surprising that they were unable to confirm the safety concerns associated with traditional NSAIDs and COX-2 NSAIDs.

This finding could mean that short-term use of either class of NSAID in this population of patients is not associated with an increased risk of GI or other adverse events.

But it could also be because most patients with ankylosing spondylitis are younger and have fewer comorbidities than patients with other rheumatic diseases.

The finding that people with ankylosing spondylitis have fewer adverse events with biologics, compared with patients with other rheumatic diseases, supported this theory, they said.

“It is technically still possible that lack of statistical power is at the basis of this, but we feel it is more likely that in the studied population and within the studied time frame (i.e., short-term), the risks of GI or cardiovascular toxicity are really not increased,” they wrote.

The review had several limitations, including that many trials were older (61% of the included studies were published before 1990) and there were not sufficient data to draw conclusions on long-term safety.

The findings of a recent Cochrane review back up guidelines that recommend NSAIDs as an appropriate first-line treatment for people with axial spondyloarthritis (axSpA).

NSAIDs have been associated with a variety of gastrointestinal effects and an increased risk of cardiovascular events, heart failure, and renal toxicity, an international team of researchers led by Dr. Féline P.B. Kroon of the Leiden University Medical Center in the Netherlands noted in the review, published in the Journal of Rheumatology.

Denise Fulton/Frontline Medical News

“It is therefore crucial to know whether the benefits offset the risks, especially because the therapy is often given for extended periods of time,” the researchers wrote in background information to the article (J Rheumatol. 2016. doi: 10.3899/jrheum.150721).

The investigators analyzed the evidence to assess the benefits and harms of NSAIDs in controlling symptoms, disease activity, and radiographic progression in patients with axSpA.

Reviewing 29 randomized, controlled trials and two “quasi” RCT studies in a pooled analyses, the research team found that, compared with placebo, both traditional and cyclooxygenase-2 (COX-2) NSAIDs were consistently more efficacious at 6 weeks and equally safe after 12 weeks.

The researchers also observed no significant differences in benefits or harms between the two NSAID classes. An increased number of neurologic events were initially observed for indomethacin, but the finding was not statistically significant when studies with high or unclear risk of bias were excluded.

Two single studies included in the review also suggested NSAIDs might retard radiographic progression in the spine in axSpA, especially in certain subgroups of patients such as those with high C-reactive protein. Although this would most likely be best achieved by continuous rather than on-demand use, the researchers said.

“The results of the review are in keeping with current recommendations that NSAIDs are appropriate first-line treatments of patients with axSpA with active disease before tumor necrosis factor inhibitor biologicals are applied,” they concluded.

However, they said it was surprising that they were unable to confirm the safety concerns associated with traditional NSAIDs and COX-2 NSAIDs.

This finding could mean that short-term use of either class of NSAID in this population of patients is not associated with an increased risk of GI or other adverse events.

But it could also be because most patients with ankylosing spondylitis are younger and have fewer comorbidities than patients with other rheumatic diseases.

The finding that people with ankylosing spondylitis have fewer adverse events with biologics, compared with patients with other rheumatic diseases, supported this theory, they said.

“It is technically still possible that lack of statistical power is at the basis of this, but we feel it is more likely that in the studied population and within the studied time frame (i.e., short-term), the risks of GI or cardiovascular toxicity are really not increased,” they wrote.

The review had several limitations, including that many trials were older (61% of the included studies were published before 1990) and there were not sufficient data to draw conclusions on long-term safety.

The U.S. program to develop biosimilar agents – somewhat akin to generic drugs for complex, biologic molecules that have come off patent protection – is gathering momentum, with the first U.S. biosimilar, Zarxio, approved by the Food and Drug Administration in March 2015 and with the second, a biosimilar to infliximab, recommended by an FDA advisory committee on Feb. 9 of this year.

What’s striking about the burgeoning biosimilar development process, created by the Affordable Care Act, is how it has morphed the FDA from its traditional role as an objective arbiter of a drug’s safety and efficacy into an active partner in shepherding biosimilars onto the market.

As explained on Feb. 4 in testimony before a Congressional committee by Dr. Janet Woodcock, director of the FDA Center for Drug Evaluation and Research, the Biologic Price Competition and Innovation Act that was part of the Affordable Care Act launched a new U.S. drug-development pathway expressly for biosimilars. To implement that law, the FDA created an entirely new infrastructure within the agency – the Biosimilar Product Development Program – to help guide prospective manufacturers (called sponsors) of biosimilars through the regulatory and research hurdles to get a new biosimilar approved and into the hands of U.S. patients.

According to Dr. Woodcock, this program involves many steps where FDA staffers provide “review” and “advice” to sponsors on the studies they need to conduct and the analysis they need to perform to get their new products to market. The sponsor joins this program by paying an upfront fee that the FDA uses to keep the program running. Once a sponsor of a prospective biosimilar is in the program, the FDA’s staff helps guide the biosimilar development to a smooth conclusion.

To some extent, the FDA staff fills a similar role for conventional drug-development enterprises, conferring with manufacturers from the outset on matters such as the types and design of studies needed to insure success. What’s different about the biosimilar program is that conventional-drug development went on well before the FDA (or its predecessor) entered the scene, and the U.S. government created the FDA to police and regulate the drug production industry and protect the public against unscrupulous manufacturers of ineffective or dangerous drugs.

In contrast, the FDA itself created this new biosimilar development structure, and Dr. Woodcock noted that the in-depth review and advice meetings that the FDA offers to prospective biosimilar sponsors “has no counterpart in the Prescription Drug User Fee Act program and is unique” to the biosimilar program.

The consequence of having the FDA create the biosimilar development program from the ground up and structure it to provide such intimate input from the agency to sponsors at every step of the way seems to give the agency a notable and somewhat unnerving investment in the program’s success.

Dr. Woodcock called the approval of Zarxio an “exciting accomplishment,” and in her testimony before Congress she trumpeted the fact that as of January 2016 the biosimilar program was working on 59 proposed products that would mimic 18 different reference-product biologics. She also said that the FDA is “excited about the growing demand” for biosimilar-oriented meetings and marketing applications.

Don’t get me wrong: I think that the biosimilar concept is great, and has the potential to make what have become life-changing treatments more affordable and more available. And making the FDA such an active participant in getting biosimilar drugs created and approved is undoubtedly the most efficient way to accomplish this.

But in the process, the biosimilar program has changed the FDA from its more disengaged role as objective pharmaceutical judge into an active and seemingly not completely neutral codeveloper, risking at least the appearance of lost impartiality. Given that the FDA now wears two very different hats, we need to trust that the integrity and dedication of its staff will keep them from confusing their roles as proponent and gatekeeper.

[email protected]

On Twitter @mitchelzoler

The U.S. program to develop biosimilar agents – somewhat akin to generic drugs for complex, biologic molecules that have come off patent protection – is gathering momentum, with the first U.S. biosimilar, Zarxio, approved by the Food and Drug Administration in March 2015 and with the second, a biosimilar to infliximab, recommended by an FDA advisory committee on Feb. 9 of this year.

What’s striking about the burgeoning biosimilar development process, created by the Affordable Care Act, is how it has morphed the FDA from its traditional role as an objective arbiter of a drug’s safety and efficacy into an active partner in shepherding biosimilars onto the market.

As explained on Feb. 4 in testimony before a Congressional committee by Dr. Janet Woodcock, director of the FDA Center for Drug Evaluation and Research, the Biologic Price Competition and Innovation Act that was part of the Affordable Care Act launched a new U.S. drug-development pathway expressly for biosimilars. To implement that law, the FDA created an entirely new infrastructure within the agency – the Biosimilar Product Development Program – to help guide prospective manufacturers (called sponsors) of biosimilars through the regulatory and research hurdles to get a new biosimilar approved and into the hands of U.S. patients.

According to Dr. Woodcock, this program involves many steps where FDA staffers provide “review” and “advice” to sponsors on the studies they need to conduct and the analysis they need to perform to get their new products to market. The sponsor joins this program by paying an upfront fee that the FDA uses to keep the program running. Once a sponsor of a prospective biosimilar is in the program, the FDA’s staff helps guide the biosimilar development to a smooth conclusion.

To some extent, the FDA staff fills a similar role for conventional drug-development enterprises, conferring with manufacturers from the outset on matters such as the types and design of studies needed to insure success. What’s different about the biosimilar program is that conventional-drug development went on well before the FDA (or its predecessor) entered the scene, and the U.S. government created the FDA to police and regulate the drug production industry and protect the public against unscrupulous manufacturers of ineffective or dangerous drugs.

In contrast, the FDA itself created this new biosimilar development structure, and Dr. Woodcock noted that the in-depth review and advice meetings that the FDA offers to prospective biosimilar sponsors “has no counterpart in the Prescription Drug User Fee Act program and is unique” to the biosimilar program.

The consequence of having the FDA create the biosimilar development program from the ground up and structure it to provide such intimate input from the agency to sponsors at every step of the way seems to give the agency a notable and somewhat unnerving investment in the program’s success.

Dr. Woodcock called the approval of Zarxio an “exciting accomplishment,” and in her testimony before Congress she trumpeted the fact that as of January 2016 the biosimilar program was working on 59 proposed products that would mimic 18 different reference-product biologics. She also said that the FDA is “excited about the growing demand” for biosimilar-oriented meetings and marketing applications.

Don’t get me wrong: I think that the biosimilar concept is great, and has the potential to make what have become life-changing treatments more affordable and more available. And making the FDA such an active participant in getting biosimilar drugs created and approved is undoubtedly the most efficient way to accomplish this.

But in the process, the biosimilar program has changed the FDA from its more disengaged role as objective pharmaceutical judge into an active and seemingly not completely neutral codeveloper, risking at least the appearance of lost impartiality. Given that the FDA now wears two very different hats, we need to trust that the integrity and dedication of its staff will keep them from confusing their roles as proponent and gatekeeper.

[email protected]

On Twitter @mitchelzoler

The U.S. program to develop biosimilar agents – somewhat akin to generic drugs for complex, biologic molecules that have come off patent protection – is gathering momentum, with the first U.S. biosimilar, Zarxio, approved by the Food and Drug Administration in March 2015 and with the second, a biosimilar to infliximab, recommended by an FDA advisory committee on Feb. 9 of this year.

What’s striking about the burgeoning biosimilar development process, created by the Affordable Care Act, is how it has morphed the FDA from its traditional role as an objective arbiter of a drug’s safety and efficacy into an active partner in shepherding biosimilars onto the market.

As explained on Feb. 4 in testimony before a Congressional committee by Dr. Janet Woodcock, director of the FDA Center for Drug Evaluation and Research, the Biologic Price Competition and Innovation Act that was part of the Affordable Care Act launched a new U.S. drug-development pathway expressly for biosimilars. To implement that law, the FDA created an entirely new infrastructure within the agency – the Biosimilar Product Development Program – to help guide prospective manufacturers (called sponsors) of biosimilars through the regulatory and research hurdles to get a new biosimilar approved and into the hands of U.S. patients.

According to Dr. Woodcock, this program involves many steps where FDA staffers provide “review” and “advice” to sponsors on the studies they need to conduct and the analysis they need to perform to get their new products to market. The sponsor joins this program by paying an upfront fee that the FDA uses to keep the program running. Once a sponsor of a prospective biosimilar is in the program, the FDA’s staff helps guide the biosimilar development to a smooth conclusion.

To some extent, the FDA staff fills a similar role for conventional drug-development enterprises, conferring with manufacturers from the outset on matters such as the types and design of studies needed to insure success. What’s different about the biosimilar program is that conventional-drug development went on well before the FDA (or its predecessor) entered the scene, and the U.S. government created the FDA to police and regulate the drug production industry and protect the public against unscrupulous manufacturers of ineffective or dangerous drugs.

In contrast, the FDA itself created this new biosimilar development structure, and Dr. Woodcock noted that the in-depth review and advice meetings that the FDA offers to prospective biosimilar sponsors “has no counterpart in the Prescription Drug User Fee Act program and is unique” to the biosimilar program.

The consequence of having the FDA create the biosimilar development program from the ground up and structure it to provide such intimate input from the agency to sponsors at every step of the way seems to give the agency a notable and somewhat unnerving investment in the program’s success.

Dr. Woodcock called the approval of Zarxio an “exciting accomplishment,” and in her testimony before Congress she trumpeted the fact that as of January 2016 the biosimilar program was working on 59 proposed products that would mimic 18 different reference-product biologics. She also said that the FDA is “excited about the growing demand” for biosimilar-oriented meetings and marketing applications.

Don’t get me wrong: I think that the biosimilar concept is great, and has the potential to make what have become life-changing treatments more affordable and more available. And making the FDA such an active participant in getting biosimilar drugs created and approved is undoubtedly the most efficient way to accomplish this.

But in the process, the biosimilar program has changed the FDA from its more disengaged role as objective pharmaceutical judge into an active and seemingly not completely neutral codeveloper, risking at least the appearance of lost impartiality. Given that the FDA now wears two very different hats, we need to trust that the integrity and dedication of its staff will keep them from confusing their roles as proponent and gatekeeper.

[email protected]

On Twitter @mitchelzoler

The presence of fibromyalgia in patients who are undergoing treatment of spondyloarthritis (SpA) is associated with higher measures of disease activity and shorter duration of first-time treatment with tumor necrosis factor inhibitors, according to results of a study measuring the impact and prevalence of fibromyalgia coexisting with SpA.

The results confirm “that the existence of concomitant FM [fibromyalgia] in SpA might complicate the evaluation of treatment response and [suggest] that coexistence of FM should be carefully screened when initiating a TNFi [tumor necrosis factor inhibitor] and/or evaluating its treatment effect, especially in the presence of peripheral and/or enthesitic symptoms and in the presence of very severe disease activity and patient-reported scores,” wrote Dr. Natalia Bello and her colleagues at Cochin Hospital, Paris (Arthritis Res Ther. 2016 Feb 9;18:42. doi: 10.1186/s13075-016-0943-z).

©Zerbor/Thinkstock

They recruited patients from Cochin Hospital, a tertiary care facility, and its rheumatology department’s outpatient clinic. Rather than use the 1990 American College of Rheumatology (ACR) classification criteria of FM or the 2010 ACR or modified 2010 ACR diagnostic criteria, which were developed for research and classification purposes, the investigators diagnosed FM based on a score of 5 or 6 on the six-question, self-reported Fibromyalgia Rapid Screening Tool (FiRST), which has 90.5% sensitivity and 85.7% specificity for FM. Patients’ SpA diagnoses were made by their rheumatologists. Overall, 30% of the cohort was female and had a mean age of 43 years.

The overall FM prevalence in the cohort was 21.4% (42 of 196 patients) and did not differ significantly according to whether the patients met either the clinical or imaging ASAS (Assessment of Spondyloarthritis International Society) criteria (21.3% vs. 18.8%, respectively) or whether they did or did not fulfill the ASAS criteria (21.1% vs. 30.0%, respectively).

Previous studies have shown the prevalence of FM at 12.6%-15.0% in SpA patients. Classifying axial SpA based on the clinical arm criteria alone has been controversial, the investigators said, mainly because it does not require an objective sign of inflammation (abnormal C-reactive protein or presence of inflammatory lesions seen on MRI of the sacroiliac joint) or structural damage in the sacroiliac joint seen on pelvic radiographs. But at least in this study there was no difference in FM prevalence in regard to whether patients met either the imaging and clinical arms of the ASAS classification criteria for axial SpA or both.

The study, according to the best knowledge of the investigators, is the first “to evaluate the prevalence of FM in a population of patients with SpA with regard to the fulfillment of the ASAS classification criteria.”

FM patients had as expected a significantly higher rate of either history of depression, or use of psychotropic drugs or strong opioids, compared with patients without FM (67% vs. 35%; P less than .01). Rates of exposure to treatment with different drug types (nonsteroidal anti-inflammatory drugs or conventional antirheumatic disease-modifying drugs) did not differ between those with and without FM, but FM patients switched significantly more often from their first TNFi (15.2% vs. 4.0%) and used it for a significantly shorter mean duration (1.7 vs. 3.5 years). The percentage of patients still taking their first TNFi after 2 years also was significantly lower among FM patients (28.1% vs. 41.7%).

Within the entire cohort, FM patients more often had enthesitis (59.5% vs. 39.0%, P  =  .01), a higher total Bath Ankylosing Spondylitis Disease Activity Index (4.7 vs. 2.6; P less than .01), higher global visual analog scale (5.9 vs. 3.0; P less than .01), and higher Bath Ankylosing Spondylitis Functional Index (4.8 vs. 2.0; P less than .01).

The authors suggested that FM patients’ higher rates of peripheral symptoms and enthesitis may warrant the use of the FiRST questionnaire in clinical practice before starting a TNFi in SpA patients to detect potentially coexisting FM.

The authors had no conflicts of interest to declare.

[email protected]

The presence of fibromyalgia in patients who are undergoing treatment of spondyloarthritis (SpA) is associated with higher measures of disease activity and shorter duration of first-time treatment with tumor necrosis factor inhibitors, according to results of a study measuring the impact and prevalence of fibromyalgia coexisting with SpA.

The results confirm “that the existence of concomitant FM [fibromyalgia] in SpA might complicate the evaluation of treatment response and [suggest] that coexistence of FM should be carefully screened when initiating a TNFi [tumor necrosis factor inhibitor] and/or evaluating its treatment effect, especially in the presence of peripheral and/or enthesitic symptoms and in the presence of very severe disease activity and patient-reported scores,” wrote Dr. Natalia Bello and her colleagues at Cochin Hospital, Paris (Arthritis Res Ther. 2016 Feb 9;18:42. doi: 10.1186/s13075-016-0943-z).

©Zerbor/Thinkstock

They recruited patients from Cochin Hospital, a tertiary care facility, and its rheumatology department’s outpatient clinic. Rather than use the 1990 American College of Rheumatology (ACR) classification criteria of FM or the 2010 ACR or modified 2010 ACR diagnostic criteria, which were developed for research and classification purposes, the investigators diagnosed FM based on a score of 5 or 6 on the six-question, self-reported Fibromyalgia Rapid Screening Tool (FiRST), which has 90.5% sensitivity and 85.7% specificity for FM. Patients’ SpA diagnoses were made by their rheumatologists. Overall, 30% of the cohort was female and had a mean age of 43 years.

The overall FM prevalence in the cohort was 21.4% (42 of 196 patients) and did not differ significantly according to whether the patients met either the clinical or imaging ASAS (Assessment of Spondyloarthritis International Society) criteria (21.3% vs. 18.8%, respectively) or whether they did or did not fulfill the ASAS criteria (21.1% vs. 30.0%, respectively).

Previous studies have shown the prevalence of FM at 12.6%-15.0% in SpA patients. Classifying axial SpA based on the clinical arm criteria alone has been controversial, the investigators said, mainly because it does not require an objective sign of inflammation (abnormal C-reactive protein or presence of inflammatory lesions seen on MRI of the sacroiliac joint) or structural damage in the sacroiliac joint seen on pelvic radiographs. But at least in this study there was no difference in FM prevalence in regard to whether patients met either the imaging and clinical arms of the ASAS classification criteria for axial SpA or both.

The study, according to the best knowledge of the investigators, is the first “to evaluate the prevalence of FM in a population of patients with SpA with regard to the fulfillment of the ASAS classification criteria.”

FM patients had as expected a significantly higher rate of either history of depression, or use of psychotropic drugs or strong opioids, compared with patients without FM (67% vs. 35%; P less than .01). Rates of exposure to treatment with different drug types (nonsteroidal anti-inflammatory drugs or conventional antirheumatic disease-modifying drugs) did not differ between those with and without FM, but FM patients switched significantly more often from their first TNFi (15.2% vs. 4.0%) and used it for a significantly shorter mean duration (1.7 vs. 3.5 years). The percentage of patients still taking their first TNFi after 2 years also was significantly lower among FM patients (28.1% vs. 41.7%).

Within the entire cohort, FM patients more often had enthesitis (59.5% vs. 39.0%, P  =  .01), a higher total Bath Ankylosing Spondylitis Disease Activity Index (4.7 vs. 2.6; P less than .01), higher global visual analog scale (5.9 vs. 3.0; P less than .01), and higher Bath Ankylosing Spondylitis Functional Index (4.8 vs. 2.0; P less than .01).

The authors suggested that FM patients’ higher rates of peripheral symptoms and enthesitis may warrant the use of the FiRST questionnaire in clinical practice before starting a TNFi in SpA patients to detect potentially coexisting FM.

The authors had no conflicts of interest to declare.

[email protected]

The presence of fibromyalgia in patients who are undergoing treatment of spondyloarthritis (SpA) is associated with higher measures of disease activity and shorter duration of first-time treatment with tumor necrosis factor inhibitors, according to results of a study measuring the impact and prevalence of fibromyalgia coexisting with SpA.

The results confirm “that the existence of concomitant FM [fibromyalgia] in SpA might complicate the evaluation of treatment response and [suggest] that coexistence of FM should be carefully screened when initiating a TNFi [tumor necrosis factor inhibitor] and/or evaluating its treatment effect, especially in the presence of peripheral and/or enthesitic symptoms and in the presence of very severe disease activity and patient-reported scores,” wrote Dr. Natalia Bello and her colleagues at Cochin Hospital, Paris (Arthritis Res Ther. 2016 Feb 9;18:42. doi: 10.1186/s13075-016-0943-z).

©Zerbor/Thinkstock

They recruited patients from Cochin Hospital, a tertiary care facility, and its rheumatology department’s outpatient clinic. Rather than use the 1990 American College of Rheumatology (ACR) classification criteria of FM or the 2010 ACR or modified 2010 ACR diagnostic criteria, which were developed for research and classification purposes, the investigators diagnosed FM based on a score of 5 or 6 on the six-question, self-reported Fibromyalgia Rapid Screening Tool (FiRST), which has 90.5% sensitivity and 85.7% specificity for FM. Patients’ SpA diagnoses were made by their rheumatologists. Overall, 30% of the cohort was female and had a mean age of 43 years.

The overall FM prevalence in the cohort was 21.4% (42 of 196 patients) and did not differ significantly according to whether the patients met either the clinical or imaging ASAS (Assessment of Spondyloarthritis International Society) criteria (21.3% vs. 18.8%, respectively) or whether they did or did not fulfill the ASAS criteria (21.1% vs. 30.0%, respectively).

Previous studies have shown the prevalence of FM at 12.6%-15.0% in SpA patients. Classifying axial SpA based on the clinical arm criteria alone has been controversial, the investigators said, mainly because it does not require an objective sign of inflammation (abnormal C-reactive protein or presence of inflammatory lesions seen on MRI of the sacroiliac joint) or structural damage in the sacroiliac joint seen on pelvic radiographs. But at least in this study there was no difference in FM prevalence in regard to whether patients met either the imaging and clinical arms of the ASAS classification criteria for axial SpA or both.

The study, according to the best knowledge of the investigators, is the first “to evaluate the prevalence of FM in a population of patients with SpA with regard to the fulfillment of the ASAS classification criteria.”

FM patients had as expected a significantly higher rate of either history of depression, or use of psychotropic drugs or strong opioids, compared with patients without FM (67% vs. 35%; P less than .01). Rates of exposure to treatment with different drug types (nonsteroidal anti-inflammatory drugs or conventional antirheumatic disease-modifying drugs) did not differ between those with and without FM, but FM patients switched significantly more often from their first TNFi (15.2% vs. 4.0%) and used it for a significantly shorter mean duration (1.7 vs. 3.5 years). The percentage of patients still taking their first TNFi after 2 years also was significantly lower among FM patients (28.1% vs. 41.7%).

Within the entire cohort, FM patients more often had enthesitis (59.5% vs. 39.0%, P  =  .01), a higher total Bath Ankylosing Spondylitis Disease Activity Index (4.7 vs. 2.6; P less than .01), higher global visual analog scale (5.9 vs. 3.0; P less than .01), and higher Bath Ankylosing Spondylitis Functional Index (4.8 vs. 2.0; P less than .01).

The authors suggested that FM patients’ higher rates of peripheral symptoms and enthesitis may warrant the use of the FiRST questionnaire in clinical practice before starting a TNFi in SpA patients to detect potentially coexisting FM.

The authors had no conflicts of interest to declare.

[email protected]

A biosimilar agent to Remicade, the brand-name and reference form of infliximab, stayed on track to become the second biosimilar drug to enter the U.S. market when the Arthritis Advisory Committee of the Food and Drug Administration voted overwhelmingly in favor of licensure of the biosimilar at a meeting on Feb. 9.

The vote was 21 in favor and 3 against, with no abstentions.

Because of the way the FDA staff worded the question that the Advisory Committee voted on, the panel not only was in favor of approving biosimilar licensure but also recommended that license for six of the seven diverse indications that Remicade currently has: treatment of rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, plaque psoriasis, adult and pediatric Crohn’s disease, and adult ulcerative colitis. The panel did not vote on licensing the biosimilar for treatment of pediatric ulcerative colitis because that specific indication for Remicade remains on patent for a few more years.

The broad range of indications for which the Committee recommended approval was notable because the formulation of biosimilar infliximab under review, manufactured by Celltrion and known in the United States as CT-P13, had been clinically studied only in patients with rheumatoid arthritis or ankylosing spondylitis. The other four recommended indications represented extrapolations, based on the totality of biosimilar evidence presented at the meeting by both Celltrion staffers and consultants as well as analyses presented by FDA staff members.

The overall thrust of the extrapolation issue was that if biosimilarity to Remicade was proven by a range of preclinical and clinical testing, and if safety and efficacy similar to Remicade was shown in trials that enrolled only patients with rheumatoid arthritis or ankylosing spondylitis, then the safety and efficacy previously proven for Remicade for the other indications could be reasonably extrapolated to apply to CT-P13 also, even though CT-P13 was never tested on patients with those conditions. This turned out to often be the key issue that panel members grappled with as they decided whether to vote in favor of the question the FDA asked them to address.

“Many of us are uncomfortable with this new pathway” of extrapolation, said panel member Dr. Beth L. Jonas, a rheumatologist at the University of North Carolina at Chapel Hill.

“I feel we’re taking a risk” with the extrapolations, said Dr. Mary E. Maloney, professor of medicine and chief of dermatology at the University of Massachusetts in Worcester. “We have a responsibility to take a risk to provide biosimilars to patients and to reduce their cost” for needed treatments, she said during the Committee’s discussion of their votes.

“Biosimilar is a new concept, but it’s the future of how we will look at drugs,” explained panel member Dr. Wilma Bergfeld, professor of dermatology at the Cleveland Clinic.

CT-P13 is currently marketed in many other countries worldwide under the brand names Remsima or Inflectra.

The FDA’s staff was clearly behind this application. After summarizing the agency’s internal analysis of the data submitted by Celltrion, Dr. Nikolay Nikolov, clinical team leader for the FDA’s Division of Pulmonary, Allergy and Rheumatology Products, concluded that “the totality of evidence provided by the applicant supports a conclusion that CT-P13 is biosimilar to U.S.-licensed Remicade,” and that “scientific justification for extrapolating the clinical data supports a finding of biosimilarity for all indications for which U.S.-licensed Remicade is licensed.” The FDA’s position makes it seem very likely that the agency will accept the Advisory Committee’s vote and grant CT-P13 license for U.S. marketing in the near future.

CT-P13 also received support during the public comment period of the Committee’s deliberations. At that time, Dr. Gideon P. Smith, a dermatologist at Massachusetts General Hospital in Boston spoke on behalf of the American Academy of Dermatology Association. “Biologics are some of the most important recent developments in treating plaque psoriasis, but cost is an important issue. We hope that biosimilars will decrease the cost of this treatment,” Dr. Smith said. “Infliximab is a complex molecule with a complex production process. We are concerned about the safety and efficacy of treatment. The AADA supports approval based on reducing cost and improving patient access. However, we strongly recommend caution through long-term postmarketing surveillance and using registry data to identify issues of immunogenicity, efficacy, and safety that were not seen in the clinical trials.”

The drug also received support from Dr. Angus B. Worthing, who represented the American College of Rheumatology. “Biosimilars may be the only tool to keep prices of biologics within reason,” said Dr. Worthing, a rheumatologist in Washington. But he also stressed that “extrapolation should be done with caution and not routinely granted.”

CT-P13 has the potential to make a fairly widely used biologic significantly more affordable. In countries where it has come onto the market, it’s been priced at roughly 30% below the prevailing cost of Remicade prior to this competition.

“Infliximab is an extremely important tool in our armamentarium for treatment of both ulcerative colitis and Crohn’s disease,” commented Dr. Stephen B. Hanauer, professor of gastroenterology and hepatology at Northwestern University in Chicago. “Biologic therapies account for an increasing proportion of health care costs for chronic diseases such as inflammatory bowel disease and reducing these costs will be important as increasing numbers of patients are benefiting from long-term biologic therapies. Having reviewed the extensive preclinical and clinical data with CT-P13, I am comfortable with potential substitution or switching as long as physicians are aware of the change and can track any potential reactions to the administered product,” he said in an interview.

“Infliximab is currently used by U.S. rheumatologists to treat certain patients with rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis. It is not the most-widely used tumor necrosis factor inhibitor, which is adalimumab, but it is often used. After FDA approval, biosimilar infliximab is anticipated to be priced lower than Remicade and that would likely increase use of infliximab for rheumatologic conditions,” said Dr. Jonathan Kay, a rheumatologist and professor of medicine at the University of Massachusetts in Worcester. “The clinical experience with CT-P13 in trials and in routine use in other countries show no significant loss of efficacy or any other major problem when changing patients from Remicade to CT-P13. All the data suggest that CT-P13 is highly similar to the reference product. It’s almost akin to comparing one lot of Remicade to another lot of Remicade. I personally would not have a problem initiating a patient on CT-P13 if infliximab was the appropriate drug to use,” Dr. Kay said in an interview.

Dr. Hanauer has been a consultant to Celltrion. Dr. Kay has been a consultant to several drug companies.

[email protected]

On Twitter @mitchelzoler

A biosimilar agent to Remicade, the brand-name and reference form of infliximab, stayed on track to become the second biosimilar drug to enter the U.S. market when the Arthritis Advisory Committee of the Food and Drug Administration voted overwhelmingly in favor of licensure of the biosimilar at a meeting on Feb. 9.

The vote was 21 in favor and 3 against, with no abstentions.

Because of the way the FDA staff worded the question that the Advisory Committee voted on, the panel not only was in favor of approving biosimilar licensure but also recommended that license for six of the seven diverse indications that Remicade currently has: treatment of rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, plaque psoriasis, adult and pediatric Crohn’s disease, and adult ulcerative colitis. The panel did not vote on licensing the biosimilar for treatment of pediatric ulcerative colitis because that specific indication for Remicade remains on patent for a few more years.

The broad range of indications for which the Committee recommended approval was notable because the formulation of biosimilar infliximab under review, manufactured by Celltrion and known in the United States as CT-P13, had been clinically studied only in patients with rheumatoid arthritis or ankylosing spondylitis. The other four recommended indications represented extrapolations, based on the totality of biosimilar evidence presented at the meeting by both Celltrion staffers and consultants as well as analyses presented by FDA staff members.

The overall thrust of the extrapolation issue was that if biosimilarity to Remicade was proven by a range of preclinical and clinical testing, and if safety and efficacy similar to Remicade was shown in trials that enrolled only patients with rheumatoid arthritis or ankylosing spondylitis, then the safety and efficacy previously proven for Remicade for the other indications could be reasonably extrapolated to apply to CT-P13 also, even though CT-P13 was never tested on patients with those conditions. This turned out to often be the key issue that panel members grappled with as they decided whether to vote in favor of the question the FDA asked them to address.

“Many of us are uncomfortable with this new pathway” of extrapolation, said panel member Dr. Beth L. Jonas, a rheumatologist at the University of North Carolina at Chapel Hill.

“I feel we’re taking a risk” with the extrapolations, said Dr. Mary E. Maloney, professor of medicine and chief of dermatology at the University of Massachusetts in Worcester. “We have a responsibility to take a risk to provide biosimilars to patients and to reduce their cost” for needed treatments, she said during the Committee’s discussion of their votes.

“Biosimilar is a new concept, but it’s the future of how we will look at drugs,” explained panel member Dr. Wilma Bergfeld, professor of dermatology at the Cleveland Clinic.

CT-P13 is currently marketed in many other countries worldwide under the brand names Remsima or Inflectra.

The FDA’s staff was clearly behind this application. After summarizing the agency’s internal analysis of the data submitted by Celltrion, Dr. Nikolay Nikolov, clinical team leader for the FDA’s Division of Pulmonary, Allergy and Rheumatology Products, concluded that “the totality of evidence provided by the applicant supports a conclusion that CT-P13 is biosimilar to U.S.-licensed Remicade,” and that “scientific justification for extrapolating the clinical data supports a finding of biosimilarity for all indications for which U.S.-licensed Remicade is licensed.” The FDA’s position makes it seem very likely that the agency will accept the Advisory Committee’s vote and grant CT-P13 license for U.S. marketing in the near future.

CT-P13 also received support during the public comment period of the Committee’s deliberations. At that time, Dr. Gideon P. Smith, a dermatologist at Massachusetts General Hospital in Boston spoke on behalf of the American Academy of Dermatology Association. “Biologics are some of the most important recent developments in treating plaque psoriasis, but cost is an important issue. We hope that biosimilars will decrease the cost of this treatment,” Dr. Smith said. “Infliximab is a complex molecule with a complex production process. We are concerned about the safety and efficacy of treatment. The AADA supports approval based on reducing cost and improving patient access. However, we strongly recommend caution through long-term postmarketing surveillance and using registry data to identify issues of immunogenicity, efficacy, and safety that were not seen in the clinical trials.”

The drug also received support from Dr. Angus B. Worthing, who represented the American College of Rheumatology. “Biosimilars may be the only tool to keep prices of biologics within reason,” said Dr. Worthing, a rheumatologist in Washington. But he also stressed that “extrapolation should be done with caution and not routinely granted.”

CT-P13 has the potential to make a fairly widely used biologic significantly more affordable. In countries where it has come onto the market, it’s been priced at roughly 30% below the prevailing cost of Remicade prior to this competition.

“Infliximab is an extremely important tool in our armamentarium for treatment of both ulcerative colitis and Crohn’s disease,” commented Dr. Stephen B. Hanauer, professor of gastroenterology and hepatology at Northwestern University in Chicago. “Biologic therapies account for an increasing proportion of health care costs for chronic diseases such as inflammatory bowel disease and reducing these costs will be important as increasing numbers of patients are benefiting from long-term biologic therapies. Having reviewed the extensive preclinical and clinical data with CT-P13, I am comfortable with potential substitution or switching as long as physicians are aware of the change and can track any potential reactions to the administered product,” he said in an interview.

“Infliximab is currently used by U.S. rheumatologists to treat certain patients with rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis. It is not the most-widely used tumor necrosis factor inhibitor, which is adalimumab, but it is often used. After FDA approval, biosimilar infliximab is anticipated to be priced lower than Remicade and that would likely increase use of infliximab for rheumatologic conditions,” said Dr. Jonathan Kay, a rheumatologist and professor of medicine at the University of Massachusetts in Worcester. “The clinical experience with CT-P13 in trials and in routine use in other countries show no significant loss of efficacy or any other major problem when changing patients from Remicade to CT-P13. All the data suggest that CT-P13 is highly similar to the reference product. It’s almost akin to comparing one lot of Remicade to another lot of Remicade. I personally would not have a problem initiating a patient on CT-P13 if infliximab was the appropriate drug to use,” Dr. Kay said in an interview.

Dr. Hanauer has been a consultant to Celltrion. Dr. Kay has been a consultant to several drug companies.

[email protected]

On Twitter @mitchelzoler

A biosimilar agent to Remicade, the brand-name and reference form of infliximab, stayed on track to become the second biosimilar drug to enter the U.S. market when the Arthritis Advisory Committee of the Food and Drug Administration voted overwhelmingly in favor of licensure of the biosimilar at a meeting on Feb. 9.

The vote was 21 in favor and 3 against, with no abstentions.

Because of the way the FDA staff worded the question that the Advisory Committee voted on, the panel not only was in favor of approving biosimilar licensure but also recommended that license for six of the seven diverse indications that Remicade currently has: treatment of rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, plaque psoriasis, adult and pediatric Crohn’s disease, and adult ulcerative colitis. The panel did not vote on licensing the biosimilar for treatment of pediatric ulcerative colitis because that specific indication for Remicade remains on patent for a few more years.

The broad range of indications for which the Committee recommended approval was notable because the formulation of biosimilar infliximab under review, manufactured by Celltrion and known in the United States as CT-P13, had been clinically studied only in patients with rheumatoid arthritis or ankylosing spondylitis. The other four recommended indications represented extrapolations, based on the totality of biosimilar evidence presented at the meeting by both Celltrion staffers and consultants as well as analyses presented by FDA staff members.

The overall thrust of the extrapolation issue was that if biosimilarity to Remicade was proven by a range of preclinical and clinical testing, and if safety and efficacy similar to Remicade was shown in trials that enrolled only patients with rheumatoid arthritis or ankylosing spondylitis, then the safety and efficacy previously proven for Remicade for the other indications could be reasonably extrapolated to apply to CT-P13 also, even though CT-P13 was never tested on patients with those conditions. This turned out to often be the key issue that panel members grappled with as they decided whether to vote in favor of the question the FDA asked them to address.

“Many of us are uncomfortable with this new pathway” of extrapolation, said panel member Dr. Beth L. Jonas, a rheumatologist at the University of North Carolina at Chapel Hill.

“I feel we’re taking a risk” with the extrapolations, said Dr. Mary E. Maloney, professor of medicine and chief of dermatology at the University of Massachusetts in Worcester. “We have a responsibility to take a risk to provide biosimilars to patients and to reduce their cost” for needed treatments, she said during the Committee’s discussion of their votes.

“Biosimilar is a new concept, but it’s the future of how we will look at drugs,” explained panel member Dr. Wilma Bergfeld, professor of dermatology at the Cleveland Clinic.

CT-P13 is currently marketed in many other countries worldwide under the brand names Remsima or Inflectra.

The FDA’s staff was clearly behind this application. After summarizing the agency’s internal analysis of the data submitted by Celltrion, Dr. Nikolay Nikolov, clinical team leader for the FDA’s Division of Pulmonary, Allergy and Rheumatology Products, concluded that “the totality of evidence provided by the applicant supports a conclusion that CT-P13 is biosimilar to U.S.-licensed Remicade,” and that “scientific justification for extrapolating the clinical data supports a finding of biosimilarity for all indications for which U.S.-licensed Remicade is licensed.” The FDA’s position makes it seem very likely that the agency will accept the Advisory Committee’s vote and grant CT-P13 license for U.S. marketing in the near future.

CT-P13 also received support during the public comment period of the Committee’s deliberations. At that time, Dr. Gideon P. Smith, a dermatologist at Massachusetts General Hospital in Boston spoke on behalf of the American Academy of Dermatology Association. “Biologics are some of the most important recent developments in treating plaque psoriasis, but cost is an important issue. We hope that biosimilars will decrease the cost of this treatment,” Dr. Smith said. “Infliximab is a complex molecule with a complex production process. We are concerned about the safety and efficacy of treatment. The AADA supports approval based on reducing cost and improving patient access. However, we strongly recommend caution through long-term postmarketing surveillance and using registry data to identify issues of immunogenicity, efficacy, and safety that were not seen in the clinical trials.”

The drug also received support from Dr. Angus B. Worthing, who represented the American College of Rheumatology. “Biosimilars may be the only tool to keep prices of biologics within reason,” said Dr. Worthing, a rheumatologist in Washington. But he also stressed that “extrapolation should be done with caution and not routinely granted.”

CT-P13 has the potential to make a fairly widely used biologic significantly more affordable. In countries where it has come onto the market, it’s been priced at roughly 30% below the prevailing cost of Remicade prior to this competition.

“Infliximab is an extremely important tool in our armamentarium for treatment of both ulcerative colitis and Crohn’s disease,” commented Dr. Stephen B. Hanauer, professor of gastroenterology and hepatology at Northwestern University in Chicago. “Biologic therapies account for an increasing proportion of health care costs for chronic diseases such as inflammatory bowel disease and reducing these costs will be important as increasing numbers of patients are benefiting from long-term biologic therapies. Having reviewed the extensive preclinical and clinical data with CT-P13, I am comfortable with potential substitution or switching as long as physicians are aware of the change and can track any potential reactions to the administered product,” he said in an interview.

“Infliximab is currently used by U.S. rheumatologists to treat certain patients with rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis. It is not the most-widely used tumor necrosis factor inhibitor, which is adalimumab, but it is often used. After FDA approval, biosimilar infliximab is anticipated to be priced lower than Remicade and that would likely increase use of infliximab for rheumatologic conditions,” said Dr. Jonathan Kay, a rheumatologist and professor of medicine at the University of Massachusetts in Worcester. “The clinical experience with CT-P13 in trials and in routine use in other countries show no significant loss of efficacy or any other major problem when changing patients from Remicade to CT-P13. All the data suggest that CT-P13 is highly similar to the reference product. It’s almost akin to comparing one lot of Remicade to another lot of Remicade. I personally would not have a problem initiating a patient on CT-P13 if infliximab was the appropriate drug to use,” Dr. Kay said in an interview.

Dr. Hanauer has been a consultant to Celltrion. Dr. Kay has been a consultant to several drug companies.

[email protected]

On Twitter @mitchelzoler

People under the age of 45 with chronic back pain for more than 3 months can be reliably identified as having axial spondyloarthritis (axSpA) if they have one or more of three SpA disease features, researchers report in Arthritis & Rheumatology.

The research team, led by rheumatologist Dr. Atul Deodhar from Oregon Health & Science University in Portland, noted that results of the German MASTER study indicated that among undiagnosed patients with chronic back pain starting before the age of 45 the presence of inflammatory back pain, human leukocyte antigen B27 (HLA-B27), and/or sacroiliitis on imaging was a reliable screening method for axSpA.

However, the authors said, there is limited information on the epidemiology of axSpA, which encompasses ankylosing spondylitis (AS) and nonradiographic axSpA (nr-axSpA), in the United States. Both AS and nr-axSpA typically go undiagnosed for many years, but AS is more easily identified by the presence of sacroiliitis on radiographs.

In order to determine if the German research finding applied to the U.S. population, the researchers conducted the Prevalence of Axial SpA (PROSpA) trial, involving 751 patients from 68 rheumatology centers who were either existing patients in rheumatology practices, new referrals, or were self-referred.

Participants were required to have chronic back pain for 3 or more months beginning at less than 45 years of age and have one or more of three SpA features: 1. positive HLA-B27; 2. current inflammatory back pain; and 3. MRI/x-ray evidence of sacroiliitis, and no prior SpA diagnosis.

Medical history/physical exam, pelvic x-ray, MRI of sacroiliac joints, C-reactive protein, and HLA-B27 were collected and rheumatologists were asked if a clinical diagnosis of axSpA could be made based upon results. 

Results showed that out of a total of 697 patients, 319 (46%) were given a clinical diagnosis of axSpA by the rheumatologist (Arthritis Rheumatol. 2016 Jan 27. doi: 10.1002/art.39612).

Of 744 patients, 348 (47%) fulfilled Assessment of SpondyloArthritis International Society (ASAS) criteria. Of these, 238 were classified as nr-axSpA, and 108 were classified as having AS based on fulfillment of the modified New York criteria. (Two patients had missing data.)

Additionally, 238 (32%) patients were categorized as having nr-axSpA, and 396 patients did not fulfill ASAS criteria or the modified New York criteria for AS.

The specificity and sensitivity of the ASAS criteria are reported at 84% and 83%. About 80% of the patients who received a clinical diagnosis of axSpA also fulfilled the ASAS axSpA criteria. The specificity and sensitivity of the criteria in this study were 79% (95% confidence interval, 75%-83%) and 81% (95% CI, 77%-85%), respectively.

The researchers noted that the majority of patients who received a diagnosis from a rheumatologist fulfilled the imaging arm of the ASAS criteria, whereas those who did not receive a diagnosis fulfilled the clinical arm.

“This observation highlights the need for accurate interpretation of MRI images in clinical practice given the importance of MRI imaging for evaluation of patients for axial SpA,” they wrote.

Overall, the findings emphasized the need to improve the identification and diagnosis of both AS and nr-axSpA among patients already receiving care in rheumatology practices and those newly referred to rheumatologists, the researchers said.

“These patients experience similar burden of disease and can remain undiagnosed, and therefore, untreated, for many years,” they wrote.

Indeed, the data indicated that some of the patients included in the study had symptoms for an average of 14 years, they said.

People under the age of 45 with chronic back pain for more than 3 months can be reliably identified as having axial spondyloarthritis (axSpA) if they have one or more of three SpA disease features, researchers report in Arthritis & Rheumatology.

The research team, led by rheumatologist Dr. Atul Deodhar from Oregon Health & Science University in Portland, noted that results of the German MASTER study indicated that among undiagnosed patients with chronic back pain starting before the age of 45 the presence of inflammatory back pain, human leukocyte antigen B27 (HLA-B27), and/or sacroiliitis on imaging was a reliable screening method for axSpA.

However, the authors said, there is limited information on the epidemiology of axSpA, which encompasses ankylosing spondylitis (AS) and nonradiographic axSpA (nr-axSpA), in the United States. Both AS and nr-axSpA typically go undiagnosed for many years, but AS is more easily identified by the presence of sacroiliitis on radiographs.

In order to determine if the German research finding applied to the U.S. population, the researchers conducted the Prevalence of Axial SpA (PROSpA) trial, involving 751 patients from 68 rheumatology centers who were either existing patients in rheumatology practices, new referrals, or were self-referred.

Participants were required to have chronic back pain for 3 or more months beginning at less than 45 years of age and have one or more of three SpA features: 1. positive HLA-B27; 2. current inflammatory back pain; and 3. MRI/x-ray evidence of sacroiliitis, and no prior SpA diagnosis.

Medical history/physical exam, pelvic x-ray, MRI of sacroiliac joints, C-reactive protein, and HLA-B27 were collected and rheumatologists were asked if a clinical diagnosis of axSpA could be made based upon results. 

Results showed that out of a total of 697 patients, 319 (46%) were given a clinical diagnosis of axSpA by the rheumatologist (Arthritis Rheumatol. 2016 Jan 27. doi: 10.1002/art.39612).

Of 744 patients, 348 (47%) fulfilled Assessment of SpondyloArthritis International Society (ASAS) criteria. Of these, 238 were classified as nr-axSpA, and 108 were classified as having AS based on fulfillment of the modified New York criteria. (Two patients had missing data.)

Additionally, 238 (32%) patients were categorized as having nr-axSpA, and 396 patients did not fulfill ASAS criteria or the modified New York criteria for AS.

The specificity and sensitivity of the ASAS criteria are reported at 84% and 83%. About 80% of the patients who received a clinical diagnosis of axSpA also fulfilled the ASAS axSpA criteria. The specificity and sensitivity of the criteria in this study were 79% (95% confidence interval, 75%-83%) and 81% (95% CI, 77%-85%), respectively.

The researchers noted that the majority of patients who received a diagnosis from a rheumatologist fulfilled the imaging arm of the ASAS criteria, whereas those who did not receive a diagnosis fulfilled the clinical arm.

“This observation highlights the need for accurate interpretation of MRI images in clinical practice given the importance of MRI imaging for evaluation of patients for axial SpA,” they wrote.

Overall, the findings emphasized the need to improve the identification and diagnosis of both AS and nr-axSpA among patients already receiving care in rheumatology practices and those newly referred to rheumatologists, the researchers said.

“These patients experience similar burden of disease and can remain undiagnosed, and therefore, untreated, for many years,” they wrote.

Indeed, the data indicated that some of the patients included in the study had symptoms for an average of 14 years, they said.

People under the age of 45 with chronic back pain for more than 3 months can be reliably identified as having axial spondyloarthritis (axSpA) if they have one or more of three SpA disease features, researchers report in Arthritis & Rheumatology.

The research team, led by rheumatologist Dr. Atul Deodhar from Oregon Health & Science University in Portland, noted that results of the German MASTER study indicated that among undiagnosed patients with chronic back pain starting before the age of 45 the presence of inflammatory back pain, human leukocyte antigen B27 (HLA-B27), and/or sacroiliitis on imaging was a reliable screening method for axSpA.

However, the authors said, there is limited information on the epidemiology of axSpA, which encompasses ankylosing spondylitis (AS) and nonradiographic axSpA (nr-axSpA), in the United States. Both AS and nr-axSpA typically go undiagnosed for many years, but AS is more easily identified by the presence of sacroiliitis on radiographs.

In order to determine if the German research finding applied to the U.S. population, the researchers conducted the Prevalence of Axial SpA (PROSpA) trial, involving 751 patients from 68 rheumatology centers who were either existing patients in rheumatology practices, new referrals, or were self-referred.

Participants were required to have chronic back pain for 3 or more months beginning at less than 45 years of age and have one or more of three SpA features: 1. positive HLA-B27; 2. current inflammatory back pain; and 3. MRI/x-ray evidence of sacroiliitis, and no prior SpA diagnosis.

Medical history/physical exam, pelvic x-ray, MRI of sacroiliac joints, C-reactive protein, and HLA-B27 were collected and rheumatologists were asked if a clinical diagnosis of axSpA could be made based upon results. 

Results showed that out of a total of 697 patients, 319 (46%) were given a clinical diagnosis of axSpA by the rheumatologist (Arthritis Rheumatol. 2016 Jan 27. doi: 10.1002/art.39612).

Of 744 patients, 348 (47%) fulfilled Assessment of SpondyloArthritis International Society (ASAS) criteria. Of these, 238 were classified as nr-axSpA, and 108 were classified as having AS based on fulfillment of the modified New York criteria. (Two patients had missing data.)

Additionally, 238 (32%) patients were categorized as having nr-axSpA, and 396 patients did not fulfill ASAS criteria or the modified New York criteria for AS.

The specificity and sensitivity of the ASAS criteria are reported at 84% and 83%. About 80% of the patients who received a clinical diagnosis of axSpA also fulfilled the ASAS axSpA criteria. The specificity and sensitivity of the criteria in this study were 79% (95% confidence interval, 75%-83%) and 81% (95% CI, 77%-85%), respectively.

The researchers noted that the majority of patients who received a diagnosis from a rheumatologist fulfilled the imaging arm of the ASAS criteria, whereas those who did not receive a diagnosis fulfilled the clinical arm.

“This observation highlights the need for accurate interpretation of MRI images in clinical practice given the importance of MRI imaging for evaluation of patients for axial SpA,” they wrote.

Overall, the findings emphasized the need to improve the identification and diagnosis of both AS and nr-axSpA among patients already receiving care in rheumatology practices and those newly referred to rheumatologists, the researchers said.

“These patients experience similar burden of disease and can remain undiagnosed, and therefore, untreated, for many years,” they wrote.

Indeed, the data indicated that some of the patients included in the study had symptoms for an average of 14 years, they said.

Current recommendations for identifying sacroiliitis on MRI to classify patients with nonradiographic axial spondyloarthritis should still depend on the presence of subchondral bone marrow edema, but additional evidence of structural lesions can be taken into account to define the presence of inflammatory lesions, according to a consensus review by experts from the Assessment in SpondyloArthritis International Society MRI working group.

The additional information provided by structural lesions, such as erosions, detected via MRI of the sacroiliac (SI) joint or spine is not necessary for the definition, but “may enhance confidence in the classification of axial SpA [spondyloarthritis],” said the panel of 16 rheumatologists, 4 radiologists, and 1 research fellow, who presented their summary and draft proposal at the January 2014 annual assembly of the Assessment in SpondyloArthritis International Society (ASAS), where members unanimously approved it (Ann Rheum Dis. 2016 Jan 14. doi: 10.1136/annrheumdis-2015-208642).

© parisvas/Thinkstockphotos.com

The group’s goal was to examine whether new data published on axial SpA in the 5 years following the 2009 publication of the ASAS recommendations were “sufficient to merit a change in the MRI definition of a positive MRI and clarify any misunderstanding of the existing definition.”

Overall, the working group determined that the addition of “structural damage changes of the SI joints and the addition of features on MRI of the spine for classification purposes is not yet clear and this continues to be an important research agenda.”

Adding any single lesion or combination of lesions to the current classification criteria for nonradiographic axial spondyloarthritis (nr-axSpA) did not increase the sensitivity of the MRI definition without losing specificity in one cohort, whereas there was an unclear benefit to adding SI erosion to the definition in another cohort. The evaluation of these lesions on MRI depended on the use of T1 weighting and fat-suppression techniques, as well as the contextual interpretation of MRI, which currently add too much complexity to the definition of a positive SI joint MRI to be useful in achieving a “consensus for definitions for each MRI structural damage lesion and the setting of thresholds for any defined lesion or combination of lesions,” the working group wrote.

The panelists found that there was no consistent beneficial effect of adding features of SpA on spine MRI to the definition. Spine MRI added incremental sensitivity in other analyses, but also increased false-positive SpA diagnoses.

In a commentary reviewing the controversy and evidence for classifying diseases within the spectrum of axial SpA, Dr. Atul Deodhar of Oregon Health and Science University, Portland, and his colleagues noted that “there is no need to differentiate between a diagnosis of nr-axSpA and that of [ankylosing spondylitis] in clinical practice, since the only purpose for having these two labels is classification.” They said the need for formal distinction between nr-axSpA and ankylosing spondylitis may require some exceptions, such as when it is necessary “to specify an approved indication for TNFi [tumor necrosis factor inhibitor] therapy, when off-label use of biologics must be avoided ... and to clarify the presence of structural changes that are required for patients to receive coverage from their insurance carrier to use a TNFi” (Ann. Rheum Dis. 2016 Jan 14. doi: 10.1136/annrheumdis-2015-208852).

The working panel and commentary authors declared having no competing interests.

[email protected]

Current recommendations for identifying sacroiliitis on MRI to classify patients with nonradiographic axial spondyloarthritis should still depend on the presence of subchondral bone marrow edema, but additional evidence of structural lesions can be taken into account to define the presence of inflammatory lesions, according to a consensus review by experts from the Assessment in SpondyloArthritis International Society MRI working group.

The additional information provided by structural lesions, such as erosions, detected via MRI of the sacroiliac (SI) joint or spine is not necessary for the definition, but “may enhance confidence in the classification of axial SpA [spondyloarthritis],” said the panel of 16 rheumatologists, 4 radiologists, and 1 research fellow, who presented their summary and draft proposal at the January 2014 annual assembly of the Assessment in SpondyloArthritis International Society (ASAS), where members unanimously approved it (Ann Rheum Dis. 2016 Jan 14. doi: 10.1136/annrheumdis-2015-208642).

© parisvas/Thinkstockphotos.com

The group’s goal was to examine whether new data published on axial SpA in the 5 years following the 2009 publication of the ASAS recommendations were “sufficient to merit a change in the MRI definition of a positive MRI and clarify any misunderstanding of the existing definition.”

Overall, the working group determined that the addition of “structural damage changes of the SI joints and the addition of features on MRI of the spine for classification purposes is not yet clear and this continues to be an important research agenda.”

Adding any single lesion or combination of lesions to the current classification criteria for nonradiographic axial spondyloarthritis (nr-axSpA) did not increase the sensitivity of the MRI definition without losing specificity in one cohort, whereas there was an unclear benefit to adding SI erosion to the definition in another cohort. The evaluation of these lesions on MRI depended on the use of T1 weighting and fat-suppression techniques, as well as the contextual interpretation of MRI, which currently add too much complexity to the definition of a positive SI joint MRI to be useful in achieving a “consensus for definitions for each MRI structural damage lesion and the setting of thresholds for any defined lesion or combination of lesions,” the working group wrote.

The panelists found that there was no consistent beneficial effect of adding features of SpA on spine MRI to the definition. Spine MRI added incremental sensitivity in other analyses, but also increased false-positive SpA diagnoses.

In a commentary reviewing the controversy and evidence for classifying diseases within the spectrum of axial SpA, Dr. Atul Deodhar of Oregon Health and Science University, Portland, and his colleagues noted that “there is no need to differentiate between a diagnosis of nr-axSpA and that of [ankylosing spondylitis] in clinical practice, since the only purpose for having these two labels is classification.” They said the need for formal distinction between nr-axSpA and ankylosing spondylitis may require some exceptions, such as when it is necessary “to specify an approved indication for TNFi [tumor necrosis factor inhibitor] therapy, when off-label use of biologics must be avoided ... and to clarify the presence of structural changes that are required for patients to receive coverage from their insurance carrier to use a TNFi” (Ann. Rheum Dis. 2016 Jan 14. doi: 10.1136/annrheumdis-2015-208852).

The working panel and commentary authors declared having no competing interests.

[email protected]

Current recommendations for identifying sacroiliitis on MRI to classify patients with nonradiographic axial spondyloarthritis should still depend on the presence of subchondral bone marrow edema, but additional evidence of structural lesions can be taken into account to define the presence of inflammatory lesions, according to a consensus review by experts from the Assessment in SpondyloArthritis International Society MRI working group.

The additional information provided by structural lesions, such as erosions, detected via MRI of the sacroiliac (SI) joint or spine is not necessary for the definition, but “may enhance confidence in the classification of axial SpA [spondyloarthritis],” said the panel of 16 rheumatologists, 4 radiologists, and 1 research fellow, who presented their summary and draft proposal at the January 2014 annual assembly of the Assessment in SpondyloArthritis International Society (ASAS), where members unanimously approved it (Ann Rheum Dis. 2016 Jan 14. doi: 10.1136/annrheumdis-2015-208642).

© parisvas/Thinkstockphotos.com

The group’s goal was to examine whether new data published on axial SpA in the 5 years following the 2009 publication of the ASAS recommendations were “sufficient to merit a change in the MRI definition of a positive MRI and clarify any misunderstanding of the existing definition.”

Overall, the working group determined that the addition of “structural damage changes of the SI joints and the addition of features on MRI of the spine for classification purposes is not yet clear and this continues to be an important research agenda.”

Adding any single lesion or combination of lesions to the current classification criteria for nonradiographic axial spondyloarthritis (nr-axSpA) did not increase the sensitivity of the MRI definition without losing specificity in one cohort, whereas there was an unclear benefit to adding SI erosion to the definition in another cohort. The evaluation of these lesions on MRI depended on the use of T1 weighting and fat-suppression techniques, as well as the contextual interpretation of MRI, which currently add too much complexity to the definition of a positive SI joint MRI to be useful in achieving a “consensus for definitions for each MRI structural damage lesion and the setting of thresholds for any defined lesion or combination of lesions,” the working group wrote.

The panelists found that there was no consistent beneficial effect of adding features of SpA on spine MRI to the definition. Spine MRI added incremental sensitivity in other analyses, but also increased false-positive SpA diagnoses.

In a commentary reviewing the controversy and evidence for classifying diseases within the spectrum of axial SpA, Dr. Atul Deodhar of Oregon Health and Science University, Portland, and his colleagues noted that “there is no need to differentiate between a diagnosis of nr-axSpA and that of [ankylosing spondylitis] in clinical practice, since the only purpose for having these two labels is classification.” They said the need for formal distinction between nr-axSpA and ankylosing spondylitis may require some exceptions, such as when it is necessary “to specify an approved indication for TNFi [tumor necrosis factor inhibitor] therapy, when off-label use of biologics must be avoided ... and to clarify the presence of structural changes that are required for patients to receive coverage from their insurance carrier to use a TNFi” (Ann. Rheum Dis. 2016 Jan 14. doi: 10.1136/annrheumdis-2015-208852).

The working panel and commentary authors declared having no competing interests.

[email protected]