Ankylosing spondylitis

BOSTON – Secukinumab showed enduring efficacy in ankylosing spondylitis after 52 weeks of treatment, based on data reported at the annual meeting of the American College of Rheumatology.

The monoclonal antibody, which targets interleukin-17A, is the first drug with demonstrated efficacy against ankylosing spondylitis since the introduction of tumor necrosis factor inhibitors.

In our exclusive video interview, Dr. Dominique Baeten, professor of clinical immunology and rheumatology at the Academic Medical Center of the University of Amsterdam, outlines results from the phase III trial in 371 U.S. and European patients, describes how targeting the IL-17A pathway is uniquely beneficial in AS, and discusses new data from other secukinumab trials in psoriatic arthritis patients.

Secukinumab’s maker, Novartis, sponsored the study. Dr. Baeten has received research grants from Novartis and other drug companies.

[email protected]

BOSTON – Secukinumab showed enduring efficacy in ankylosing spondylitis after 52 weeks of treatment, based on data reported at the annual meeting of the American College of Rheumatology.

The monoclonal antibody, which targets interleukin-17A, is the first drug with demonstrated efficacy against ankylosing spondylitis since the introduction of tumor necrosis factor inhibitors.

In our exclusive video interview, Dr. Dominique Baeten, professor of clinical immunology and rheumatology at the Academic Medical Center of the University of Amsterdam, outlines results from the phase III trial in 371 U.S. and European patients, describes how targeting the IL-17A pathway is uniquely beneficial in AS, and discusses new data from other secukinumab trials in psoriatic arthritis patients.

Secukinumab’s maker, Novartis, sponsored the study. Dr. Baeten has received research grants from Novartis and other drug companies.

[email protected]

BOSTON – Secukinumab showed enduring efficacy in ankylosing spondylitis after 52 weeks of treatment, based on data reported at the annual meeting of the American College of Rheumatology.

The monoclonal antibody, which targets interleukin-17A, is the first drug with demonstrated efficacy against ankylosing spondylitis since the introduction of tumor necrosis factor inhibitors.

In our exclusive video interview, Dr. Dominique Baeten, professor of clinical immunology and rheumatology at the Academic Medical Center of the University of Amsterdam, outlines results from the phase III trial in 371 U.S. and European patients, describes how targeting the IL-17A pathway is uniquely beneficial in AS, and discusses new data from other secukinumab trials in psoriatic arthritis patients.

Secukinumab’s maker, Novartis, sponsored the study. Dr. Baeten has received research grants from Novartis and other drug companies.

[email protected]

Current use of cyclooxygenase-2 inhibitors was associated with an increase in 30-day mortality after ischemic stroke in a population-based cohort study published Nov. 5 in Neurology.

Since the association between COX-2 inhibitors and ischemic stroke mortality was associated only with current use and not former use, the researchers, led by Dr. Morten Schmidt of Aarhus (Denmark) University Hospital, believe that alternative treatment options – such as nonselective NSAIDs, which did not have an impact on overall mortality after ischemic stroke – may be more suitable for treating potential ischemic stroke patients, such as those with atrial fibrillation and a high CHA₂DS₂-VASc score.

Denise Fulton/Frontline Medical News

If the association is truly causal, it constitutes a strong argument for increasing the efforts to ensure that patients with a high predicted risk of arterial thromboembolism are not prescribed COX-2 inhibitors when alternative treatment options are available,” Dr. Schmidt and his associates wrote.

In order to determine whether COX-2 inhibitors influenced 30-day mortality at the time of hospitalization for stroke, the researchers examined records of 100,243 people hospitalized for a first-time stroke in Denmark during 2004-2012 and deaths within 1 month after the stroke (Neurology 2014 Nov. 5 [doi:10.1212/WNL.0000000000001024]).

The hazard ratio for ischemic stroke was 1.19 (95% confidence interval, 1.02-1.38) for current users of COX-2 inhibitors, while current users of nonselective NSAIDs had an HR of 1.00 (95% CI, 0.87-1.15), compared with nonusers.

The COX-2 inhibitors in the study included diclofenac, etodolac, nabumeton, and meloxicam, as well as coxibs including celecoxib and rofecoxib. The nonselective NSAIDs in the study were ibuprofen, naproxen, ketoprofen, dexibuprofen, piroxicam, tolfenamic acid, and indomethacin.

Though the researchers acknowledged more studies are needed to truly examine the effects of COX-2 inhibitors on stroke mortality, they hypothesized that the increased mortality rate may be caused by COX-2 inhibition interfering with the pathophysiologic response to a stroke, or unwanted effects from the thromboembolic properties of COX-2 inhibitors.

“Our study adds to the increasing body of evidence concerning the vascular risk and prognostic impact associated with use of COX-2 inhibitors,” Dr. Schmidt and his associates wrote.

The study was funded by several Danish research foundations and the Program for Clinical Research Infrastructure, which was established by the Lundbeck Foundation and the Novo Nordisk Foundation. The authors reported no relevant disclosures.

[email protected]

Current use of cyclooxygenase-2 inhibitors was associated with an increase in 30-day mortality after ischemic stroke in a population-based cohort study published Nov. 5 in Neurology.

Since the association between COX-2 inhibitors and ischemic stroke mortality was associated only with current use and not former use, the researchers, led by Dr. Morten Schmidt of Aarhus (Denmark) University Hospital, believe that alternative treatment options – such as nonselective NSAIDs, which did not have an impact on overall mortality after ischemic stroke – may be more suitable for treating potential ischemic stroke patients, such as those with atrial fibrillation and a high CHA₂DS₂-VASc score.

Denise Fulton/Frontline Medical News

If the association is truly causal, it constitutes a strong argument for increasing the efforts to ensure that patients with a high predicted risk of arterial thromboembolism are not prescribed COX-2 inhibitors when alternative treatment options are available,” Dr. Schmidt and his associates wrote.

In order to determine whether COX-2 inhibitors influenced 30-day mortality at the time of hospitalization for stroke, the researchers examined records of 100,243 people hospitalized for a first-time stroke in Denmark during 2004-2012 and deaths within 1 month after the stroke (Neurology 2014 Nov. 5 [doi:10.1212/WNL.0000000000001024]).

The hazard ratio for ischemic stroke was 1.19 (95% confidence interval, 1.02-1.38) for current users of COX-2 inhibitors, while current users of nonselective NSAIDs had an HR of 1.00 (95% CI, 0.87-1.15), compared with nonusers.

The COX-2 inhibitors in the study included diclofenac, etodolac, nabumeton, and meloxicam, as well as coxibs including celecoxib and rofecoxib. The nonselective NSAIDs in the study were ibuprofen, naproxen, ketoprofen, dexibuprofen, piroxicam, tolfenamic acid, and indomethacin.

Though the researchers acknowledged more studies are needed to truly examine the effects of COX-2 inhibitors on stroke mortality, they hypothesized that the increased mortality rate may be caused by COX-2 inhibition interfering with the pathophysiologic response to a stroke, or unwanted effects from the thromboembolic properties of COX-2 inhibitors.

“Our study adds to the increasing body of evidence concerning the vascular risk and prognostic impact associated with use of COX-2 inhibitors,” Dr. Schmidt and his associates wrote.

The study was funded by several Danish research foundations and the Program for Clinical Research Infrastructure, which was established by the Lundbeck Foundation and the Novo Nordisk Foundation. The authors reported no relevant disclosures.

[email protected]

Current use of cyclooxygenase-2 inhibitors was associated with an increase in 30-day mortality after ischemic stroke in a population-based cohort study published Nov. 5 in Neurology.

Since the association between COX-2 inhibitors and ischemic stroke mortality was associated only with current use and not former use, the researchers, led by Dr. Morten Schmidt of Aarhus (Denmark) University Hospital, believe that alternative treatment options – such as nonselective NSAIDs, which did not have an impact on overall mortality after ischemic stroke – may be more suitable for treating potential ischemic stroke patients, such as those with atrial fibrillation and a high CHA₂DS₂-VASc score.

Denise Fulton/Frontline Medical News

If the association is truly causal, it constitutes a strong argument for increasing the efforts to ensure that patients with a high predicted risk of arterial thromboembolism are not prescribed COX-2 inhibitors when alternative treatment options are available,” Dr. Schmidt and his associates wrote.

In order to determine whether COX-2 inhibitors influenced 30-day mortality at the time of hospitalization for stroke, the researchers examined records of 100,243 people hospitalized for a first-time stroke in Denmark during 2004-2012 and deaths within 1 month after the stroke (Neurology 2014 Nov. 5 [doi:10.1212/WNL.0000000000001024]).

The hazard ratio for ischemic stroke was 1.19 (95% confidence interval, 1.02-1.38) for current users of COX-2 inhibitors, while current users of nonselective NSAIDs had an HR of 1.00 (95% CI, 0.87-1.15), compared with nonusers.

The COX-2 inhibitors in the study included diclofenac, etodolac, nabumeton, and meloxicam, as well as coxibs including celecoxib and rofecoxib. The nonselective NSAIDs in the study were ibuprofen, naproxen, ketoprofen, dexibuprofen, piroxicam, tolfenamic acid, and indomethacin.

Though the researchers acknowledged more studies are needed to truly examine the effects of COX-2 inhibitors on stroke mortality, they hypothesized that the increased mortality rate may be caused by COX-2 inhibition interfering with the pathophysiologic response to a stroke, or unwanted effects from the thromboembolic properties of COX-2 inhibitors.

“Our study adds to the increasing body of evidence concerning the vascular risk and prognostic impact associated with use of COX-2 inhibitors,” Dr. Schmidt and his associates wrote.

The study was funded by several Danish research foundations and the Program for Clinical Research Infrastructure, which was established by the Lundbeck Foundation and the Novo Nordisk Foundation. The authors reported no relevant disclosures.

[email protected]

The biosimilar age for rheumatology has arrived, and experts expect wider use of previously expensive biologic drugs as biosimilar competition drives prices down and makes biologics more affordable.

An infliximab biosimilar became the first such agent to arrive onto the European market in the second half of 2013, and by the start of 2014, it was already having an impact by, for example, dropping the cost of infliximab by a third in Norway. Norway may have received the biggest biosimilar effect so far because it runs an annual auction for the best prices on competing drugs from manufacturers and then mandates Norwegian clinicians to prescribe the lowest-price option when starting a new therapy.

A U.S. version of this scenario may soon follow. In August 2014, Celltrion and Hospira, the two companies jointly producing and marketing biosimilar forms of infliximab under the names Remsima and Inflectra (in parts of eastern Europe and elsewhere), announced they had submitted a marketing application to the Food and Drug Administration. In the announcement, Celltrion officials said they expected Food and Drug Administration approval within a year. If that were to happen, and if Celltrion mounts a successful patent challenge, the Remsima form of infliximab could become one of the first biosimilars on the U.S. market. (In July, Sandoz – a subsidiary of Novartis – announced it submitted an FDA application for Zarzio, a biosimilar version of filgrastim that until now has been only available as Neupogen, a granulocyte colony–stimulating factor. Biosimilar filgrastim seems like the only contender that could edge out Remsima as the first biosimilar on the U.S. market.)

At least two more biosimilars – a third form of infliximab, and a new form of etanercept – may come next, although rheumatologists following the field caution that additional studies are needed on top of what was reported for these two biosimilars last June at the annual European Congress of Rheumatology.

Lower cost broadens use

With one rheumatology biosimilar already on several global formularies and others nearing that status, the next challenge is convincing clinicians that cut-rate biologics are safe and effective and patients can switch from the brand-name form to a biosimilar without adverse effects. Meanwhile, payers and patients are pressing for biosimilars to cut the high cost of biologic treatment. By making biologic drugs more affordable for more patients, introduction of biosimilars will change patient care, experts said.

“A decrease in price will change how biologics are used in U.S. patients. In the United States today, about half of rheumatoid arthritis (RA) patients receive a biologic,” a rate substantially below where it should be, said Dr. Vibeke Strand, a biopharmaceutical consultant and rheumatologist at Stanford (Calif.) University. “Biosimilars will have a very big impact,” she predicted.

“Clinicians are under a lot of pressure from pharmacies, hospitals, and managed-care organization to avoid expensive medications when possible. Starting a biologic will become easier,” when prices start falling. And adherence may also improve. “Part of why patients don’t take their biologics for more than 1-2 years is they can’t afford the copay. That may change” if prices drop, Dr. Strand said in an interview.

Before biosimilars became available, “countries with low GDPs [gross domestic products] had less access to biologics and more restrictions; richer countries had better access,” noted Dr. Tore K. Kvien, a rheumatologist and professor of rheumatology at the University of Oslo.

Greater affordability and access to biologics is the sole factor driving the biosimilar movement. “Cost is the only reason why you have biosimilars,” noted Dr. Bruce N. Cronstein, a rheumatologist and professor of medicine, pathology, and pharmacology at New York University. Aside from cost, there are, by definition, no meaningful differences between a biosimilar and the reference brand-name formulation.

Biosimilars, Dr. Cronstein said, “will be cheaper, but it won’t be like the difference with generic and brand-name statins. You won’t see a 90% price drop. Maybe we’ll see a 30% or 40% price cut, which is considerable. The biologics are all very expensive drugs. But biosimilars will not lead to anything like the savings with small generic molecules.”

While Dr. Cronstein noted that there are no guarantees regarding the timing of price changes, the extent of price cuts, or how competition might affect pricing of the brand-name alternative, the experience in Norway showed a quick, one-third price cut when Remsima became an option, Dr. Kvien said in an interview. For years, Norway has negotiated 1-year contracts for setting drug costs with manufacturers. Norwegian officials invite competitors to submit bids in an annual auction. Celltrion won the auction to make Remsima the infliximab of choice in Norway during 2014 for all six European Medicines Agency (EMA)-approved infliximab indications: rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis, Crohn’s disease, and ulcerative colitis.

“My colleagues tell me that the one-third reduction in price [compared with Remicade's price in 2014] was larger than they expected,” Dr. Kvien said. A year of treatment for an RA patient receiving Remsima averages about 6,000 euro now, down from the roughly 9,000 euro current annual cost for Remicade.

Dr. Strand maintained that economic pressures play a role in how easily biosimilars gain regulatory approval. For example, EMA received pressure from Eastern European countries where biologics have been relatively unavailable because of their price, she said. In the United States, pressure on the FDA comes from payers and patients because biologic copays are so high. But despite pressure, Dr. Strand and others believe that EMA and the FDA have set reasonable approval standards for biosimilars that clinicians can rely on.

“I think for all intents and purposes if EMA decides something is a biosimilar then I definitely think it is,” Dr. Strand said. “There may be subtle differences, but nothing big.” In some cases reference, brand-name biologics themselves have undergone substantial changes from what they originally had been, as happened with Enbrel and Rituxan, she noted. “The FDA will not entertain even a small change in an amino acid sequence, and requires two immunogenicity studies.”

Concerns about safety

But biosimilars may be a special case, where even the regulatory stamp of approval may not fully convince some clinicians.

“There is still quite a bit of skepticism,” Dr. Strand said. “I think there will be less skepticism once more data show that biosimilars are safe. The biggest concern seems to be that if the FDA decides something is not just biosimilar but also equivalent then there might be substitutions by a pharmacist without knowledge of the health care provider. I think there is concern because people are still not sure what biosimilar means. It will take more data to convince some people.”

“I think that physicians will be convinced by the data showing these compounds act in a similar way. What physicians worry about is that while these drugs may look good in a trial there might be some subtle difference that increases drug resistance or anaphylaxis,” said Dr. Cronstein. “I think clinicians will accept biosimilars and use them, but worry that a safety signal may not be seen in clinical trials. I think the FDA is trying to figure out how to be sure that switching from one drug to another does not cause an adverse effect. That is the major potential downside people see.”

The safety of switching to a biosimilar was an important enough issue for the Norwegian government to sponsor a 2.5 million euro trial to address the question. The 500-patient study, slated to start in the fall of 2014, will randomize patients on stable Remicade treatment to either remain on Remicade or switch to Remsima. The NOR-SWITCH trial will include patients with any of the six indications for which Remsima received EMA approval.

Until trial results are available, anticipated to be in 2016, Norway does not sanction switching patients on a stable Remicade regimen to Remsima even though Remsima is the infliximab of choice for patients starting infliximab for the first time. Despite this, some Norwegian departments have already made the switch in some patients, said Dr. Kvien, who is lead investigator for NOR-SWITCH. “They say the scientific data available now are sufficient to show switching is safe, but I do not agree.” The willingness of some Norwegian clinicians to switch their patients now from infliximab to the biosimilar shows how eager they and patients in Norway are to save money with Remsima.

While biosimilars face challenges entering and gaining traction in the European and American markets, they also seem driven by an overwhelming inevitability.

“Biosimilars will absolutely be routine in 10-20 years. They will be accepted, but it will take time,” Dr. Cronstein predicted.

“Biosimilars are here, they are not going away, and as patents run out we’ll see more and more of them,” predicted Dr. Paul Emery, professor of rheumatology at Leeds (England) University, while speaking at the annual European Congress of Rheumatology last June in Paris.

“I expect biosimilars will be important. My hope is that their lower cost will improve access to these treatments and this will mean better treatment for more patients around the world,” Dr. Kvien said.

Dr. Strand has been a consultant to Hospira, Celltrion, Amgen, Pfizer, Epirus, Baxter, and Merck Serono. Dr. Kvien has been a consultant to AbbVie, Bristol-Myers Squibb, Hospira, Celltrion, Pfizer/Wyeth, Merck Serono, Merck Sharp & Dohme, Roche, UCB, Orion, and Takeda. Dr. Cronstein has been a consultant to Pfizer and Merck Serono. Dr. Emery has been a consultant to AbbVie, Bristol-Myers Squibb, Merck, Pfizer, Roche, and Takeda.

[email protected]

On Twitter @mitchelzoler

The biosimilar age for rheumatology has arrived, and experts expect wider use of previously expensive biologic drugs as biosimilar competition drives prices down and makes biologics more affordable.

An infliximab biosimilar became the first such agent to arrive onto the European market in the second half of 2013, and by the start of 2014, it was already having an impact by, for example, dropping the cost of infliximab by a third in Norway. Norway may have received the biggest biosimilar effect so far because it runs an annual auction for the best prices on competing drugs from manufacturers and then mandates Norwegian clinicians to prescribe the lowest-price option when starting a new therapy.

A U.S. version of this scenario may soon follow. In August 2014, Celltrion and Hospira, the two companies jointly producing and marketing biosimilar forms of infliximab under the names Remsima and Inflectra (in parts of eastern Europe and elsewhere), announced they had submitted a marketing application to the Food and Drug Administration. In the announcement, Celltrion officials said they expected Food and Drug Administration approval within a year. If that were to happen, and if Celltrion mounts a successful patent challenge, the Remsima form of infliximab could become one of the first biosimilars on the U.S. market. (In July, Sandoz – a subsidiary of Novartis – announced it submitted an FDA application for Zarzio, a biosimilar version of filgrastim that until now has been only available as Neupogen, a granulocyte colony–stimulating factor. Biosimilar filgrastim seems like the only contender that could edge out Remsima as the first biosimilar on the U.S. market.)

At least two more biosimilars – a third form of infliximab, and a new form of etanercept – may come next, although rheumatologists following the field caution that additional studies are needed on top of what was reported for these two biosimilars last June at the annual European Congress of Rheumatology.

Lower cost broadens use

With one rheumatology biosimilar already on several global formularies and others nearing that status, the next challenge is convincing clinicians that cut-rate biologics are safe and effective and patients can switch from the brand-name form to a biosimilar without adverse effects. Meanwhile, payers and patients are pressing for biosimilars to cut the high cost of biologic treatment. By making biologic drugs more affordable for more patients, introduction of biosimilars will change patient care, experts said.

“A decrease in price will change how biologics are used in U.S. patients. In the United States today, about half of rheumatoid arthritis (RA) patients receive a biologic,” a rate substantially below where it should be, said Dr. Vibeke Strand, a biopharmaceutical consultant and rheumatologist at Stanford (Calif.) University. “Biosimilars will have a very big impact,” she predicted.

“Clinicians are under a lot of pressure from pharmacies, hospitals, and managed-care organization to avoid expensive medications when possible. Starting a biologic will become easier,” when prices start falling. And adherence may also improve. “Part of why patients don’t take their biologics for more than 1-2 years is they can’t afford the copay. That may change” if prices drop, Dr. Strand said in an interview.

Before biosimilars became available, “countries with low GDPs [gross domestic products] had less access to biologics and more restrictions; richer countries had better access,” noted Dr. Tore K. Kvien, a rheumatologist and professor of rheumatology at the University of Oslo.

Greater affordability and access to biologics is the sole factor driving the biosimilar movement. “Cost is the only reason why you have biosimilars,” noted Dr. Bruce N. Cronstein, a rheumatologist and professor of medicine, pathology, and pharmacology at New York University. Aside from cost, there are, by definition, no meaningful differences between a biosimilar and the reference brand-name formulation.

Biosimilars, Dr. Cronstein said, “will be cheaper, but it won’t be like the difference with generic and brand-name statins. You won’t see a 90% price drop. Maybe we’ll see a 30% or 40% price cut, which is considerable. The biologics are all very expensive drugs. But biosimilars will not lead to anything like the savings with small generic molecules.”

While Dr. Cronstein noted that there are no guarantees regarding the timing of price changes, the extent of price cuts, or how competition might affect pricing of the brand-name alternative, the experience in Norway showed a quick, one-third price cut when Remsima became an option, Dr. Kvien said in an interview. For years, Norway has negotiated 1-year contracts for setting drug costs with manufacturers. Norwegian officials invite competitors to submit bids in an annual auction. Celltrion won the auction to make Remsima the infliximab of choice in Norway during 2014 for all six European Medicines Agency (EMA)-approved infliximab indications: rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis, Crohn’s disease, and ulcerative colitis.

“My colleagues tell me that the one-third reduction in price [compared with Remicade's price in 2014] was larger than they expected,” Dr. Kvien said. A year of treatment for an RA patient receiving Remsima averages about 6,000 euro now, down from the roughly 9,000 euro current annual cost for Remicade.

Dr. Strand maintained that economic pressures play a role in how easily biosimilars gain regulatory approval. For example, EMA received pressure from Eastern European countries where biologics have been relatively unavailable because of their price, she said. In the United States, pressure on the FDA comes from payers and patients because biologic copays are so high. But despite pressure, Dr. Strand and others believe that EMA and the FDA have set reasonable approval standards for biosimilars that clinicians can rely on.

“I think for all intents and purposes if EMA decides something is a biosimilar then I definitely think it is,” Dr. Strand said. “There may be subtle differences, but nothing big.” In some cases reference, brand-name biologics themselves have undergone substantial changes from what they originally had been, as happened with Enbrel and Rituxan, she noted. “The FDA will not entertain even a small change in an amino acid sequence, and requires two immunogenicity studies.”

Concerns about safety

But biosimilars may be a special case, where even the regulatory stamp of approval may not fully convince some clinicians.

“There is still quite a bit of skepticism,” Dr. Strand said. “I think there will be less skepticism once more data show that biosimilars are safe. The biggest concern seems to be that if the FDA decides something is not just biosimilar but also equivalent then there might be substitutions by a pharmacist without knowledge of the health care provider. I think there is concern because people are still not sure what biosimilar means. It will take more data to convince some people.”

“I think that physicians will be convinced by the data showing these compounds act in a similar way. What physicians worry about is that while these drugs may look good in a trial there might be some subtle difference that increases drug resistance or anaphylaxis,” said Dr. Cronstein. “I think clinicians will accept biosimilars and use them, but worry that a safety signal may not be seen in clinical trials. I think the FDA is trying to figure out how to be sure that switching from one drug to another does not cause an adverse effect. That is the major potential downside people see.”

The safety of switching to a biosimilar was an important enough issue for the Norwegian government to sponsor a 2.5 million euro trial to address the question. The 500-patient study, slated to start in the fall of 2014, will randomize patients on stable Remicade treatment to either remain on Remicade or switch to Remsima. The NOR-SWITCH trial will include patients with any of the six indications for which Remsima received EMA approval.

Until trial results are available, anticipated to be in 2016, Norway does not sanction switching patients on a stable Remicade regimen to Remsima even though Remsima is the infliximab of choice for patients starting infliximab for the first time. Despite this, some Norwegian departments have already made the switch in some patients, said Dr. Kvien, who is lead investigator for NOR-SWITCH. “They say the scientific data available now are sufficient to show switching is safe, but I do not agree.” The willingness of some Norwegian clinicians to switch their patients now from infliximab to the biosimilar shows how eager they and patients in Norway are to save money with Remsima.

While biosimilars face challenges entering and gaining traction in the European and American markets, they also seem driven by an overwhelming inevitability.

“Biosimilars will absolutely be routine in 10-20 years. They will be accepted, but it will take time,” Dr. Cronstein predicted.

“Biosimilars are here, they are not going away, and as patents run out we’ll see more and more of them,” predicted Dr. Paul Emery, professor of rheumatology at Leeds (England) University, while speaking at the annual European Congress of Rheumatology last June in Paris.

“I expect biosimilars will be important. My hope is that their lower cost will improve access to these treatments and this will mean better treatment for more patients around the world,” Dr. Kvien said.

Dr. Strand has been a consultant to Hospira, Celltrion, Amgen, Pfizer, Epirus, Baxter, and Merck Serono. Dr. Kvien has been a consultant to AbbVie, Bristol-Myers Squibb, Hospira, Celltrion, Pfizer/Wyeth, Merck Serono, Merck Sharp & Dohme, Roche, UCB, Orion, and Takeda. Dr. Cronstein has been a consultant to Pfizer and Merck Serono. Dr. Emery has been a consultant to AbbVie, Bristol-Myers Squibb, Merck, Pfizer, Roche, and Takeda.

[email protected]

On Twitter @mitchelzoler

The biosimilar age for rheumatology has arrived, and experts expect wider use of previously expensive biologic drugs as biosimilar competition drives prices down and makes biologics more affordable.

An infliximab biosimilar became the first such agent to arrive onto the European market in the second half of 2013, and by the start of 2014, it was already having an impact by, for example, dropping the cost of infliximab by a third in Norway. Norway may have received the biggest biosimilar effect so far because it runs an annual auction for the best prices on competing drugs from manufacturers and then mandates Norwegian clinicians to prescribe the lowest-price option when starting a new therapy.

A U.S. version of this scenario may soon follow. In August 2014, Celltrion and Hospira, the two companies jointly producing and marketing biosimilar forms of infliximab under the names Remsima and Inflectra (in parts of eastern Europe and elsewhere), announced they had submitted a marketing application to the Food and Drug Administration. In the announcement, Celltrion officials said they expected Food and Drug Administration approval within a year. If that were to happen, and if Celltrion mounts a successful patent challenge, the Remsima form of infliximab could become one of the first biosimilars on the U.S. market. (In July, Sandoz – a subsidiary of Novartis – announced it submitted an FDA application for Zarzio, a biosimilar version of filgrastim that until now has been only available as Neupogen, a granulocyte colony–stimulating factor. Biosimilar filgrastim seems like the only contender that could edge out Remsima as the first biosimilar on the U.S. market.)

At least two more biosimilars – a third form of infliximab, and a new form of etanercept – may come next, although rheumatologists following the field caution that additional studies are needed on top of what was reported for these two biosimilars last June at the annual European Congress of Rheumatology.

Lower cost broadens use

With one rheumatology biosimilar already on several global formularies and others nearing that status, the next challenge is convincing clinicians that cut-rate biologics are safe and effective and patients can switch from the brand-name form to a biosimilar without adverse effects. Meanwhile, payers and patients are pressing for biosimilars to cut the high cost of biologic treatment. By making biologic drugs more affordable for more patients, introduction of biosimilars will change patient care, experts said.

“A decrease in price will change how biologics are used in U.S. patients. In the United States today, about half of rheumatoid arthritis (RA) patients receive a biologic,” a rate substantially below where it should be, said Dr. Vibeke Strand, a biopharmaceutical consultant and rheumatologist at Stanford (Calif.) University. “Biosimilars will have a very big impact,” she predicted.

“Clinicians are under a lot of pressure from pharmacies, hospitals, and managed-care organization to avoid expensive medications when possible. Starting a biologic will become easier,” when prices start falling. And adherence may also improve. “Part of why patients don’t take their biologics for more than 1-2 years is they can’t afford the copay. That may change” if prices drop, Dr. Strand said in an interview.

Before biosimilars became available, “countries with low GDPs [gross domestic products] had less access to biologics and more restrictions; richer countries had better access,” noted Dr. Tore K. Kvien, a rheumatologist and professor of rheumatology at the University of Oslo.

Greater affordability and access to biologics is the sole factor driving the biosimilar movement. “Cost is the only reason why you have biosimilars,” noted Dr. Bruce N. Cronstein, a rheumatologist and professor of medicine, pathology, and pharmacology at New York University. Aside from cost, there are, by definition, no meaningful differences between a biosimilar and the reference brand-name formulation.

Biosimilars, Dr. Cronstein said, “will be cheaper, but it won’t be like the difference with generic and brand-name statins. You won’t see a 90% price drop. Maybe we’ll see a 30% or 40% price cut, which is considerable. The biologics are all very expensive drugs. But biosimilars will not lead to anything like the savings with small generic molecules.”

While Dr. Cronstein noted that there are no guarantees regarding the timing of price changes, the extent of price cuts, or how competition might affect pricing of the brand-name alternative, the experience in Norway showed a quick, one-third price cut when Remsima became an option, Dr. Kvien said in an interview. For years, Norway has negotiated 1-year contracts for setting drug costs with manufacturers. Norwegian officials invite competitors to submit bids in an annual auction. Celltrion won the auction to make Remsima the infliximab of choice in Norway during 2014 for all six European Medicines Agency (EMA)-approved infliximab indications: rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis, Crohn’s disease, and ulcerative colitis.

“My colleagues tell me that the one-third reduction in price [compared with Remicade's price in 2014] was larger than they expected,” Dr. Kvien said. A year of treatment for an RA patient receiving Remsima averages about 6,000 euro now, down from the roughly 9,000 euro current annual cost for Remicade.

Dr. Strand maintained that economic pressures play a role in how easily biosimilars gain regulatory approval. For example, EMA received pressure from Eastern European countries where biologics have been relatively unavailable because of their price, she said. In the United States, pressure on the FDA comes from payers and patients because biologic copays are so high. But despite pressure, Dr. Strand and others believe that EMA and the FDA have set reasonable approval standards for biosimilars that clinicians can rely on.

“I think for all intents and purposes if EMA decides something is a biosimilar then I definitely think it is,” Dr. Strand said. “There may be subtle differences, but nothing big.” In some cases reference, brand-name biologics themselves have undergone substantial changes from what they originally had been, as happened with Enbrel and Rituxan, she noted. “The FDA will not entertain even a small change in an amino acid sequence, and requires two immunogenicity studies.”

Concerns about safety

But biosimilars may be a special case, where even the regulatory stamp of approval may not fully convince some clinicians.

“There is still quite a bit of skepticism,” Dr. Strand said. “I think there will be less skepticism once more data show that biosimilars are safe. The biggest concern seems to be that if the FDA decides something is not just biosimilar but also equivalent then there might be substitutions by a pharmacist without knowledge of the health care provider. I think there is concern because people are still not sure what biosimilar means. It will take more data to convince some people.”

“I think that physicians will be convinced by the data showing these compounds act in a similar way. What physicians worry about is that while these drugs may look good in a trial there might be some subtle difference that increases drug resistance or anaphylaxis,” said Dr. Cronstein. “I think clinicians will accept biosimilars and use them, but worry that a safety signal may not be seen in clinical trials. I think the FDA is trying to figure out how to be sure that switching from one drug to another does not cause an adverse effect. That is the major potential downside people see.”

The safety of switching to a biosimilar was an important enough issue for the Norwegian government to sponsor a 2.5 million euro trial to address the question. The 500-patient study, slated to start in the fall of 2014, will randomize patients on stable Remicade treatment to either remain on Remicade or switch to Remsima. The NOR-SWITCH trial will include patients with any of the six indications for which Remsima received EMA approval.

Until trial results are available, anticipated to be in 2016, Norway does not sanction switching patients on a stable Remicade regimen to Remsima even though Remsima is the infliximab of choice for patients starting infliximab for the first time. Despite this, some Norwegian departments have already made the switch in some patients, said Dr. Kvien, who is lead investigator for NOR-SWITCH. “They say the scientific data available now are sufficient to show switching is safe, but I do not agree.” The willingness of some Norwegian clinicians to switch their patients now from infliximab to the biosimilar shows how eager they and patients in Norway are to save money with Remsima.

While biosimilars face challenges entering and gaining traction in the European and American markets, they also seem driven by an overwhelming inevitability.

“Biosimilars will absolutely be routine in 10-20 years. They will be accepted, but it will take time,” Dr. Cronstein predicted.

“Biosimilars are here, they are not going away, and as patents run out we’ll see more and more of them,” predicted Dr. Paul Emery, professor of rheumatology at Leeds (England) University, while speaking at the annual European Congress of Rheumatology last June in Paris.

“I expect biosimilars will be important. My hope is that their lower cost will improve access to these treatments and this will mean better treatment for more patients around the world,” Dr. Kvien said.

Dr. Strand has been a consultant to Hospira, Celltrion, Amgen, Pfizer, Epirus, Baxter, and Merck Serono. Dr. Kvien has been a consultant to AbbVie, Bristol-Myers Squibb, Hospira, Celltrion, Pfizer/Wyeth, Merck Serono, Merck Sharp & Dohme, Roche, UCB, Orion, and Takeda. Dr. Cronstein has been a consultant to Pfizer and Merck Serono. Dr. Emery has been a consultant to AbbVie, Bristol-Myers Squibb, Merck, Pfizer, Roche, and Takeda.

[email protected]

On Twitter @mitchelzoler

BELLEVUE, WASH. – Women with autoimmune diseases who take corticosteroids and disease-modifying antirheumatic drugs later in pregnancy have an increased risk of preterm birth, but this association is largely explained by confounding with sociodemographic and clinical factors and disease severity, a study showed.

Researchers prospectively studied 678 pregnant women from the MotherToBaby database who had rheumatoid arthritis, psoriasis or psoriatic arthritis, ankylosing spondylitis, or Crohn’s disease. They focused on steroid use and disease-modifying antirheumatic drug (DMARD) use in the 16 weeks before delivery.

The results presented at the annual meeting of the Teratology Society showed that the incidence of preterm birth (birth before 37 weeks of gestation) was 19.2% among women using only steroids, 11.9% among those using only DMARDs, and 25.0% among those using both, compared with 11.2% among women who used neither throughout pregnancy.

In unadjusted analyses, women taking both steroids and DMARDs had significantly higher odds of preterm birth relative to peers who took neither (relative risk, 2.23), reported lead author Kristin Palmsten, Sc.D., of the University of California, San Diego.

But this risk was attenuated and no longer significant after adjustment for sociodemographic and clinical factors, such as age, race/ethnicity, parity, prior preterm birth, twin pregnancy, prepregnancy hypertension, depression, and use of nonsteroidal anti-inflammatory drugs.

It was attenuated further still after additional adjustment for the severity of autoimmune disease earlier in pregnancy, as assessed with the Health Assessment Questionnaire Disability Index (HAQ-DI) in analyses that excluded patients with Crohn’s disease (because they were not asked about disease severity).

The use of steroids alone and the use of DMARDs alone were not associated with a significantly elevated risk of preterm birth in either unadjusted or adjusted analyses.

The findings showed that confounders at least partially explain the heightened risk of preterm birth associated with autoimmune therapy, according to Dr. Palmsten.

A major study strength was exposure ascertainment, as the women were directly asked about their medication use several times during pregnancy, she noted. A limitation was the potential lack of generalizability, as the women studied were predominantly white and had higher socioeconomic status and lower disease severity.

In ongoing analyses, the investigators are looking at the proportions of preterm births that were spontaneous and medically indicated, and at the specific gestational age of the preterm births.

"I’d like to confirm the results in a different population; I’d like to look at this association in the Medicaid population, which is a low-income population," Dr. Palmsten added. "And I think preterm birth subtypes should be considered in further investigation. I’d also like to explore the timing of exposure and dose as well."

Session attendee Dr. Jan M. Friedman of the University of British Columbia in Vancouver noted the wide confidence intervals seen in analyses. "Obviously, that’s partially a function of the fact that the groups are fairly small. Is this an ongoing study? Will you have more data, more patients to look at in a year or something?" he asked.

"It is ongoing," Dr. Palmsten replied. "I don’t think that we’ll have 500 women exposed even after a year. But I do hope to address that with the Medicaid data because that would have a very large population."

Dr. Palmsten disclosed no relevant conflicts of interest. The MotherToBaby Pregnancy Study is sponsored by AbbVie, Amgen, Sanofi-Aventis, Apotex, Barr, Par Pharmaceutical, Sandoz, Teva, Bristol-Myers Squibb, Roche/Genentech, UCB Pharma, Pfizer, and Janssen.

BELLEVUE, WASH. – Women with autoimmune diseases who take corticosteroids and disease-modifying antirheumatic drugs later in pregnancy have an increased risk of preterm birth, but this association is largely explained by confounding with sociodemographic and clinical factors and disease severity, a study showed.

Researchers prospectively studied 678 pregnant women from the MotherToBaby database who had rheumatoid arthritis, psoriasis or psoriatic arthritis, ankylosing spondylitis, or Crohn’s disease. They focused on steroid use and disease-modifying antirheumatic drug (DMARD) use in the 16 weeks before delivery.

The results presented at the annual meeting of the Teratology Society showed that the incidence of preterm birth (birth before 37 weeks of gestation) was 19.2% among women using only steroids, 11.9% among those using only DMARDs, and 25.0% among those using both, compared with 11.2% among women who used neither throughout pregnancy.

In unadjusted analyses, women taking both steroids and DMARDs had significantly higher odds of preterm birth relative to peers who took neither (relative risk, 2.23), reported lead author Kristin Palmsten, Sc.D., of the University of California, San Diego.

But this risk was attenuated and no longer significant after adjustment for sociodemographic and clinical factors, such as age, race/ethnicity, parity, prior preterm birth, twin pregnancy, prepregnancy hypertension, depression, and use of nonsteroidal anti-inflammatory drugs.

It was attenuated further still after additional adjustment for the severity of autoimmune disease earlier in pregnancy, as assessed with the Health Assessment Questionnaire Disability Index (HAQ-DI) in analyses that excluded patients with Crohn’s disease (because they were not asked about disease severity).

The use of steroids alone and the use of DMARDs alone were not associated with a significantly elevated risk of preterm birth in either unadjusted or adjusted analyses.

The findings showed that confounders at least partially explain the heightened risk of preterm birth associated with autoimmune therapy, according to Dr. Palmsten.

A major study strength was exposure ascertainment, as the women were directly asked about their medication use several times during pregnancy, she noted. A limitation was the potential lack of generalizability, as the women studied were predominantly white and had higher socioeconomic status and lower disease severity.

In ongoing analyses, the investigators are looking at the proportions of preterm births that were spontaneous and medically indicated, and at the specific gestational age of the preterm births.

"I’d like to confirm the results in a different population; I’d like to look at this association in the Medicaid population, which is a low-income population," Dr. Palmsten added. "And I think preterm birth subtypes should be considered in further investigation. I’d also like to explore the timing of exposure and dose as well."

Session attendee Dr. Jan M. Friedman of the University of British Columbia in Vancouver noted the wide confidence intervals seen in analyses. "Obviously, that’s partially a function of the fact that the groups are fairly small. Is this an ongoing study? Will you have more data, more patients to look at in a year or something?" he asked.

"It is ongoing," Dr. Palmsten replied. "I don’t think that we’ll have 500 women exposed even after a year. But I do hope to address that with the Medicaid data because that would have a very large population."

Dr. Palmsten disclosed no relevant conflicts of interest. The MotherToBaby Pregnancy Study is sponsored by AbbVie, Amgen, Sanofi-Aventis, Apotex, Barr, Par Pharmaceutical, Sandoz, Teva, Bristol-Myers Squibb, Roche/Genentech, UCB Pharma, Pfizer, and Janssen.

BELLEVUE, WASH. – Women with autoimmune diseases who take corticosteroids and disease-modifying antirheumatic drugs later in pregnancy have an increased risk of preterm birth, but this association is largely explained by confounding with sociodemographic and clinical factors and disease severity, a study showed.

Researchers prospectively studied 678 pregnant women from the MotherToBaby database who had rheumatoid arthritis, psoriasis or psoriatic arthritis, ankylosing spondylitis, or Crohn’s disease. They focused on steroid use and disease-modifying antirheumatic drug (DMARD) use in the 16 weeks before delivery.

The results presented at the annual meeting of the Teratology Society showed that the incidence of preterm birth (birth before 37 weeks of gestation) was 19.2% among women using only steroids, 11.9% among those using only DMARDs, and 25.0% among those using both, compared with 11.2% among women who used neither throughout pregnancy.

In unadjusted analyses, women taking both steroids and DMARDs had significantly higher odds of preterm birth relative to peers who took neither (relative risk, 2.23), reported lead author Kristin Palmsten, Sc.D., of the University of California, San Diego.

But this risk was attenuated and no longer significant after adjustment for sociodemographic and clinical factors, such as age, race/ethnicity, parity, prior preterm birth, twin pregnancy, prepregnancy hypertension, depression, and use of nonsteroidal anti-inflammatory drugs.

It was attenuated further still after additional adjustment for the severity of autoimmune disease earlier in pregnancy, as assessed with the Health Assessment Questionnaire Disability Index (HAQ-DI) in analyses that excluded patients with Crohn’s disease (because they were not asked about disease severity).

The use of steroids alone and the use of DMARDs alone were not associated with a significantly elevated risk of preterm birth in either unadjusted or adjusted analyses.

The findings showed that confounders at least partially explain the heightened risk of preterm birth associated with autoimmune therapy, according to Dr. Palmsten.

A major study strength was exposure ascertainment, as the women were directly asked about their medication use several times during pregnancy, she noted. A limitation was the potential lack of generalizability, as the women studied were predominantly white and had higher socioeconomic status and lower disease severity.

In ongoing analyses, the investigators are looking at the proportions of preterm births that were spontaneous and medically indicated, and at the specific gestational age of the preterm births.

"I’d like to confirm the results in a different population; I’d like to look at this association in the Medicaid population, which is a low-income population," Dr. Palmsten added. "And I think preterm birth subtypes should be considered in further investigation. I’d also like to explore the timing of exposure and dose as well."

Session attendee Dr. Jan M. Friedman of the University of British Columbia in Vancouver noted the wide confidence intervals seen in analyses. "Obviously, that’s partially a function of the fact that the groups are fairly small. Is this an ongoing study? Will you have more data, more patients to look at in a year or something?" he asked.

"It is ongoing," Dr. Palmsten replied. "I don’t think that we’ll have 500 women exposed even after a year. But I do hope to address that with the Medicaid data because that would have a very large population."

Dr. Palmsten disclosed no relevant conflicts of interest. The MotherToBaby Pregnancy Study is sponsored by AbbVie, Amgen, Sanofi-Aventis, Apotex, Barr, Par Pharmaceutical, Sandoz, Teva, Bristol-Myers Squibb, Roche/Genentech, UCB Pharma, Pfizer, and Janssen.

NEW YORK – Axial spondyloarthritis is not being seen by U.S. rheumatologists at a rate commensurate with prevalence, according to an expert providing the rationale for a major educational initiative.

In the United States, several studies, including the most recent, suggest that the prevalence of axSpA is at least as great as that of rheumatoid arthritis even though most rheumatologists see a much lower proportion of axSpA patients, according to Dr. Atul Deodhar, medical director of the rheumatology clinics at Oregon Health & Science University, Portland.

The reasons for this disparity are not fully understood, but it has prompted a major educational initiative by the Spondyloarthritis Research & Treatment Network (SPARTAN), according to Dr. Deodhar, who spoke at the joint meetings of SPARTAN and the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis. The goal of the initiative is to reduce the delay to diagnosis and to funnel these patients more efficiently to experts in inflammatory joint diseases.

The most recent U.S. prevalence estimate for axSpA is 0.7%, reported Dr. Deodhar, citing a study that employed Assessment of Spondyloarthritis International Society (ASAS) criteria (Arthritis Care Res. 2013;65:1299-306). Other studies have generated prevalence rates as high as 1.4%, but even this lower recent estimate exceeds the typically cited 0.6% estimated prevalence rate for RA, he said.

"One wonders where these patients are going," said Dr. Deodhar, emphasizing the relative infrequency with which axSpA is managed by U.S. rheumatologists.

Some of these patients are likely to be seen by orthopedists, chiropractors, internists, or other health care providers, but one concern is that many are not being seen at all or at least not until the disease has advanced. Dr. Deodhar cited evidence that the average delay to diagnosis of axSpA in the United States is 6-8 years, which is likely to worsen outcome.

"Several studies suggest that partial remission is about double when patients are caught early and treated appropriately," Dr. Deodhar said. However, although rheumatologists are in the best position to help axSpA patients, they might be part of the problem, he said.

"Rheumatologists have traditionally shied away from seeing patients with back pain, because 95% of these patients have mechanical pain for which rheumatologists do not have much to offer," Dr. Deodhar said.

Yet for those with an inflammatory etiology, rheumatologists can play an essential role in treatment that slows or halts progression. A SPARTAN initiative has been specifically planned to educate those health care providers likely to hear initial complaints of lower back pain as well as to increase attention to axSpA by rheumatologists.

For referral physicians, the initiatives are being focused on increasing awareness of inflammatory back pain and providing simple criteria for referral, according to Dr. Deodhar. The ASAS diagnostic criteria for axSpA are considered sensitive and specific, but simplified referral strategies may accelerate the time to a specialist consultation.

Several referral strategies are effective. Dr. Deodhar cited one study that tested two. In one strategy, a referral was made in patients younger than 45, with chronic back pain of at least 3 months, who met two of three screening criteria: inflammatory back pain, HLA-B27 positivity, or sacroiliitis on imaging. In the other, the same criteria were employed and patients had to have a positive family history of ankylosing spondylitis or a good treatment response to NSAIDs (J. Rheumatol. 2011;38:2452-60).

With the first strategy, "nearly 42% [41.8%] had definite axSpA," according to Dr. Deodhar. The slightly lower sensitivity of the other was not inferior statistically, but the first strategy was preferred for simplicity.

These types of referral strategies will be included in the SPARTAN educational initiatives being developed to improve early recognition of axSpA and to bring patients to the specialists most suited to offering effective management.

Dr. Deodhar reported financial relationships with Amgen, Abbott, Genentech, and Janssen.

NEW YORK – Axial spondyloarthritis is not being seen by U.S. rheumatologists at a rate commensurate with prevalence, according to an expert providing the rationale for a major educational initiative.

In the United States, several studies, including the most recent, suggest that the prevalence of axSpA is at least as great as that of rheumatoid arthritis even though most rheumatologists see a much lower proportion of axSpA patients, according to Dr. Atul Deodhar, medical director of the rheumatology clinics at Oregon Health & Science University, Portland.

The reasons for this disparity are not fully understood, but it has prompted a major educational initiative by the Spondyloarthritis Research & Treatment Network (SPARTAN), according to Dr. Deodhar, who spoke at the joint meetings of SPARTAN and the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis. The goal of the initiative is to reduce the delay to diagnosis and to funnel these patients more efficiently to experts in inflammatory joint diseases.

The most recent U.S. prevalence estimate for axSpA is 0.7%, reported Dr. Deodhar, citing a study that employed Assessment of Spondyloarthritis International Society (ASAS) criteria (Arthritis Care Res. 2013;65:1299-306). Other studies have generated prevalence rates as high as 1.4%, but even this lower recent estimate exceeds the typically cited 0.6% estimated prevalence rate for RA, he said.

"One wonders where these patients are going," said Dr. Deodhar, emphasizing the relative infrequency with which axSpA is managed by U.S. rheumatologists.

Some of these patients are likely to be seen by orthopedists, chiropractors, internists, or other health care providers, but one concern is that many are not being seen at all or at least not until the disease has advanced. Dr. Deodhar cited evidence that the average delay to diagnosis of axSpA in the United States is 6-8 years, which is likely to worsen outcome.

"Several studies suggest that partial remission is about double when patients are caught early and treated appropriately," Dr. Deodhar said. However, although rheumatologists are in the best position to help axSpA patients, they might be part of the problem, he said.

"Rheumatologists have traditionally shied away from seeing patients with back pain, because 95% of these patients have mechanical pain for which rheumatologists do not have much to offer," Dr. Deodhar said.

Yet for those with an inflammatory etiology, rheumatologists can play an essential role in treatment that slows or halts progression. A SPARTAN initiative has been specifically planned to educate those health care providers likely to hear initial complaints of lower back pain as well as to increase attention to axSpA by rheumatologists.

For referral physicians, the initiatives are being focused on increasing awareness of inflammatory back pain and providing simple criteria for referral, according to Dr. Deodhar. The ASAS diagnostic criteria for axSpA are considered sensitive and specific, but simplified referral strategies may accelerate the time to a specialist consultation.

Several referral strategies are effective. Dr. Deodhar cited one study that tested two. In one strategy, a referral was made in patients younger than 45, with chronic back pain of at least 3 months, who met two of three screening criteria: inflammatory back pain, HLA-B27 positivity, or sacroiliitis on imaging. In the other, the same criteria were employed and patients had to have a positive family history of ankylosing spondylitis or a good treatment response to NSAIDs (J. Rheumatol. 2011;38:2452-60).

With the first strategy, "nearly 42% [41.8%] had definite axSpA," according to Dr. Deodhar. The slightly lower sensitivity of the other was not inferior statistically, but the first strategy was preferred for simplicity.

These types of referral strategies will be included in the SPARTAN educational initiatives being developed to improve early recognition of axSpA and to bring patients to the specialists most suited to offering effective management.

Dr. Deodhar reported financial relationships with Amgen, Abbott, Genentech, and Janssen.

NEW YORK – Axial spondyloarthritis is not being seen by U.S. rheumatologists at a rate commensurate with prevalence, according to an expert providing the rationale for a major educational initiative.

In the United States, several studies, including the most recent, suggest that the prevalence of axSpA is at least as great as that of rheumatoid arthritis even though most rheumatologists see a much lower proportion of axSpA patients, according to Dr. Atul Deodhar, medical director of the rheumatology clinics at Oregon Health & Science University, Portland.

The reasons for this disparity are not fully understood, but it has prompted a major educational initiative by the Spondyloarthritis Research & Treatment Network (SPARTAN), according to Dr. Deodhar, who spoke at the joint meetings of SPARTAN and the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis. The goal of the initiative is to reduce the delay to diagnosis and to funnel these patients more efficiently to experts in inflammatory joint diseases.

The most recent U.S. prevalence estimate for axSpA is 0.7%, reported Dr. Deodhar, citing a study that employed Assessment of Spondyloarthritis International Society (ASAS) criteria (Arthritis Care Res. 2013;65:1299-306). Other studies have generated prevalence rates as high as 1.4%, but even this lower recent estimate exceeds the typically cited 0.6% estimated prevalence rate for RA, he said.

"One wonders where these patients are going," said Dr. Deodhar, emphasizing the relative infrequency with which axSpA is managed by U.S. rheumatologists.

Some of these patients are likely to be seen by orthopedists, chiropractors, internists, or other health care providers, but one concern is that many are not being seen at all or at least not until the disease has advanced. Dr. Deodhar cited evidence that the average delay to diagnosis of axSpA in the United States is 6-8 years, which is likely to worsen outcome.

"Several studies suggest that partial remission is about double when patients are caught early and treated appropriately," Dr. Deodhar said. However, although rheumatologists are in the best position to help axSpA patients, they might be part of the problem, he said.

"Rheumatologists have traditionally shied away from seeing patients with back pain, because 95% of these patients have mechanical pain for which rheumatologists do not have much to offer," Dr. Deodhar said.

Yet for those with an inflammatory etiology, rheumatologists can play an essential role in treatment that slows or halts progression. A SPARTAN initiative has been specifically planned to educate those health care providers likely to hear initial complaints of lower back pain as well as to increase attention to axSpA by rheumatologists.

For referral physicians, the initiatives are being focused on increasing awareness of inflammatory back pain and providing simple criteria for referral, according to Dr. Deodhar. The ASAS diagnostic criteria for axSpA are considered sensitive and specific, but simplified referral strategies may accelerate the time to a specialist consultation.

Several referral strategies are effective. Dr. Deodhar cited one study that tested two. In one strategy, a referral was made in patients younger than 45, with chronic back pain of at least 3 months, who met two of three screening criteria: inflammatory back pain, HLA-B27 positivity, or sacroiliitis on imaging. In the other, the same criteria were employed and patients had to have a positive family history of ankylosing spondylitis or a good treatment response to NSAIDs (J. Rheumatol. 2011;38:2452-60).

With the first strategy, "nearly 42% [41.8%] had definite axSpA," according to Dr. Deodhar. The slightly lower sensitivity of the other was not inferior statistically, but the first strategy was preferred for simplicity.

These types of referral strategies will be included in the SPARTAN educational initiatives being developed to improve early recognition of axSpA and to bring patients to the specialists most suited to offering effective management.

Dr. Deodhar reported financial relationships with Amgen, Abbott, Genentech, and Janssen.

NEW YORK – Patients with ankylosing spondylitis who used opiate analgesics were five times more likely to report depression than were those who did not, in a retrospective case-control study of 611 patients.

The relationship between opiate usage and depression was significant even though those who took antidepressants or anxiolytics were significantly less likely to use opiates, according to Dr. Jonathan D. Dau of the department of rheumatology at the University of Texas, Houston.

In the study, there were several highly significant distinctions between those who used opiate analgesics and those who did not, but none could be connected to inflammatory activity, Dr. Dau said.

"None of the objective measures of AS [ankylosing spondylitis] disease activity or progression were found to be associated with opiate usage. This adds confirmation to the hypothesis that pain associated with AS may develop from sources other than spinal inflammation alone," he said.

In data presented at the joint meetings of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis and the Spondyloarthritis Research & Treatment Network, a large variety of parameters were compared between the 87 patients who took opiate analgesics intermittently (91%) or continuously (9%) and the remaining 524 who never took opiate analgesics over a follow-up period of up to 4 years. Three centers in addition to the University of Texas contributed AS patients to the analysis. The mean disease duration was 17.6 years.

Although there were no significant differences between users and nonusers of opiates for radiographic severity, as measured with the modified Stoke Ankylosing Spondylitis Spinal Score, or inflammation, as measured with C-reactive protein levels or erythrocyte sedimentation rate, opiate users scored high on subjective measures. Specifically, the odds ratio for a Bath AS Disease Activity Index score of 4 or greater was 5.460 (P less than .0001). The OR for a high patient global pain assessment was 4.240 (P less than .0001).

As for depression, the OR for opiate users relative to nonopiate users was 5.907 (P less than .0001) by self-report and 3.071 (P less than .0001) by the Center for Epidemiologic Study Depression scale. The authors also reported an OR for smoking among opiate users of 2.125 (P = .0018).

Conversely, an analysis of concomitant medication use found that antidepressants correlated with a 63% reduction (OR, 0.371; P = .0004) in the likelihood of opiate use. Anxiolytics correlated with a nearly 90% reduction (OR, 0.124; P less than .0001). There was no significant association with opiate use and use of either NSAIDs or tumor necrosis factor inhibitors.

However, the study found that opiate users were almost three times more likely to be taking prednisone (OR, 2.996; P = .0073) and more than eight times more likely to be taking muscle relaxants (OR, 8.458; P less than .0001). Dr. Dau observed that muscle relaxants on top of opiates "may provide a greater magnitude of pain relief taken together than when taken alone."

Because of the concerns about use of opiates, particularly their propensity to induce dependence, Dr. Dau suggested that it is important to further explore why some patients take these agents in addition to treatments targeted at disease activity. While standard medications such as NSAIDs and TNF inhibitors have been shown to relieve pain, they do not control somatic pain for all patients.

"This is especially true when the pain stems from processes other than inflammation," reported Dr. Dau. More data are needed to determine whether control of depression through antidepressants is a factor for reducing opiate use, he said.

Dr. Dau reported no relevant financial disclosures.

NEW YORK – Patients with ankylosing spondylitis who used opiate analgesics were five times more likely to report depression than were those who did not, in a retrospective case-control study of 611 patients.

The relationship between opiate usage and depression was significant even though those who took antidepressants or anxiolytics were significantly less likely to use opiates, according to Dr. Jonathan D. Dau of the department of rheumatology at the University of Texas, Houston.

In the study, there were several highly significant distinctions between those who used opiate analgesics and those who did not, but none could be connected to inflammatory activity, Dr. Dau said.

"None of the objective measures of AS [ankylosing spondylitis] disease activity or progression were found to be associated with opiate usage. This adds confirmation to the hypothesis that pain associated with AS may develop from sources other than spinal inflammation alone," he said.

In data presented at the joint meetings of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis and the Spondyloarthritis Research & Treatment Network, a large variety of parameters were compared between the 87 patients who took opiate analgesics intermittently (91%) or continuously (9%) and the remaining 524 who never took opiate analgesics over a follow-up period of up to 4 years. Three centers in addition to the University of Texas contributed AS patients to the analysis. The mean disease duration was 17.6 years.

Although there were no significant differences between users and nonusers of opiates for radiographic severity, as measured with the modified Stoke Ankylosing Spondylitis Spinal Score, or inflammation, as measured with C-reactive protein levels or erythrocyte sedimentation rate, opiate users scored high on subjective measures. Specifically, the odds ratio for a Bath AS Disease Activity Index score of 4 or greater was 5.460 (P less than .0001). The OR for a high patient global pain assessment was 4.240 (P less than .0001).

As for depression, the OR for opiate users relative to nonopiate users was 5.907 (P less than .0001) by self-report and 3.071 (P less than .0001) by the Center for Epidemiologic Study Depression scale. The authors also reported an OR for smoking among opiate users of 2.125 (P = .0018).

Conversely, an analysis of concomitant medication use found that antidepressants correlated with a 63% reduction (OR, 0.371; P = .0004) in the likelihood of opiate use. Anxiolytics correlated with a nearly 90% reduction (OR, 0.124; P less than .0001). There was no significant association with opiate use and use of either NSAIDs or tumor necrosis factor inhibitors.

However, the study found that opiate users were almost three times more likely to be taking prednisone (OR, 2.996; P = .0073) and more than eight times more likely to be taking muscle relaxants (OR, 8.458; P less than .0001). Dr. Dau observed that muscle relaxants on top of opiates "may provide a greater magnitude of pain relief taken together than when taken alone."

Because of the concerns about use of opiates, particularly their propensity to induce dependence, Dr. Dau suggested that it is important to further explore why some patients take these agents in addition to treatments targeted at disease activity. While standard medications such as NSAIDs and TNF inhibitors have been shown to relieve pain, they do not control somatic pain for all patients.

"This is especially true when the pain stems from processes other than inflammation," reported Dr. Dau. More data are needed to determine whether control of depression through antidepressants is a factor for reducing opiate use, he said.

Dr. Dau reported no relevant financial disclosures.

NEW YORK – Patients with ankylosing spondylitis who used opiate analgesics were five times more likely to report depression than were those who did not, in a retrospective case-control study of 611 patients.

The relationship between opiate usage and depression was significant even though those who took antidepressants or anxiolytics were significantly less likely to use opiates, according to Dr. Jonathan D. Dau of the department of rheumatology at the University of Texas, Houston.

In the study, there were several highly significant distinctions between those who used opiate analgesics and those who did not, but none could be connected to inflammatory activity, Dr. Dau said.

"None of the objective measures of AS [ankylosing spondylitis] disease activity or progression were found to be associated with opiate usage. This adds confirmation to the hypothesis that pain associated with AS may develop from sources other than spinal inflammation alone," he said.

In data presented at the joint meetings of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis and the Spondyloarthritis Research & Treatment Network, a large variety of parameters were compared between the 87 patients who took opiate analgesics intermittently (91%) or continuously (9%) and the remaining 524 who never took opiate analgesics over a follow-up period of up to 4 years. Three centers in addition to the University of Texas contributed AS patients to the analysis. The mean disease duration was 17.6 years.

Although there were no significant differences between users and nonusers of opiates for radiographic severity, as measured with the modified Stoke Ankylosing Spondylitis Spinal Score, or inflammation, as measured with C-reactive protein levels or erythrocyte sedimentation rate, opiate users scored high on subjective measures. Specifically, the odds ratio for a Bath AS Disease Activity Index score of 4 or greater was 5.460 (P less than .0001). The OR for a high patient global pain assessment was 4.240 (P less than .0001).

As for depression, the OR for opiate users relative to nonopiate users was 5.907 (P less than .0001) by self-report and 3.071 (P less than .0001) by the Center for Epidemiologic Study Depression scale. The authors also reported an OR for smoking among opiate users of 2.125 (P = .0018).

Conversely, an analysis of concomitant medication use found that antidepressants correlated with a 63% reduction (OR, 0.371; P = .0004) in the likelihood of opiate use. Anxiolytics correlated with a nearly 90% reduction (OR, 0.124; P less than .0001). There was no significant association with opiate use and use of either NSAIDs or tumor necrosis factor inhibitors.

However, the study found that opiate users were almost three times more likely to be taking prednisone (OR, 2.996; P = .0073) and more than eight times more likely to be taking muscle relaxants (OR, 8.458; P less than .0001). Dr. Dau observed that muscle relaxants on top of opiates "may provide a greater magnitude of pain relief taken together than when taken alone."

Because of the concerns about use of opiates, particularly their propensity to induce dependence, Dr. Dau suggested that it is important to further explore why some patients take these agents in addition to treatments targeted at disease activity. While standard medications such as NSAIDs and TNF inhibitors have been shown to relieve pain, they do not control somatic pain for all patients.

"This is especially true when the pain stems from processes other than inflammation," reported Dr. Dau. More data are needed to determine whether control of depression through antidepressants is a factor for reducing opiate use, he said.

Dr. Dau reported no relevant financial disclosures.

NEW YORK – Consistent evidence for a substantial increase in cardiovascular events remains elusive for patients with ankylosing spondylitis who have a broad range of CV risk factors.

"We can all agree that the risk factors for cardiovascular disease are higher in patients with AS [ankylosing spondylitis], but I think it is more controversial whether every AS patient faces a higher risk of events," observed Dr. Lianne Gensler, director of the ankylosing spondylitis clinic at the University of California, San Francisco.

Although this statement was made in reference to ischemic heart disease, the analysis presented by Dr. Gensler at the joint meetings of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis and the Spondyloarthritis Research & Treatment Network appears to be relevant to valvular disease, arrhythmias, and left ventricular dysfunction. Other CV risk factors associated with AS include hypertension, aortic insufficiency, and conduction disorders.

Inconsistencies in studies of CV

The obstacle for drawing conclusions is the lack of consistency in the published studies that relate specifically to AS but are independent of other inflammatory joint diseases, such as rheumatoid arthritis. In a review, Dr. Gensler cited one meta-analysis of 17 studies published in 2011 that did not associate AS with increased CV events (Arthritis Care Res. 2011;63:557-63). Although several studies published subsequently did associate AS with an increased rate of events, there were others that did not.

In an analysis that was performed at her institution based on AS patient data from the Healthcare Cost and Utilization Project National Inpatient Sample, no difference could be found in in-hospital mortality due to CV events when AS patients were compared with non-AS patients stratified by age.

In regard to CV structural disease related to AS, there is substantial evidence that several abnormalities are more common in AS, but there is far less to document that these lead to an increased risk of events. For example, Dr. Gensler cited one study in which the prevalence of aortic insufficiency climbed from 2% in patients with 10 years’ AS duration to 12% in those with 30 years. In another, inflammation of the septum, a potential risk for conduction disorders, climbed from 3% to 90% in AS patients followed long-term.

Asymptomatic conduction disorders

Conduction disorders in general – and QRS disturbances in particular – have been commonly reported in AS patients, but typically in the absence of symptoms, according to Dr. Gensler. She cited one electrocardiogram study in which 30% of AS patients had QRS prolongation, but all were asymptomatic. In another study of 200 AS patients, conduction disorders were found in 33%, of which atrioventricular block was the most common. In this study, increased markers of inflammation did not correlate with conduction disorders in a multivariate analysis.

"Whether we should be doing anything to look for these [conduction disorders] when they do not have symptoms is a question that I will put out to the audience," Dr. Gensler said.

Effect of treatment on CV events

The effect of AS therapies, particularly tumor necrosis factor (TNF) inhibitors, on CV risk also remains incompletely understood. In one study cited by Dr. Gensler, improved endothelial function was observed in AS patients treated with a TNF inhibitor, suggesting a potential protective effect, but, again, no difference in event rates in AS patients has ever been documented between those on TNF inhibitors and those not on TNF inhibitors.

Overall, more data are needed to determine the effect of AS on the risk of CV events, but one risk factor deserves attention even if there is no specific evidence that it affects CV events, according to Dr. Gensler.

In AS, "we know that smoking is a risk for early-onset disease, more inflammation, more damage, and more progression, so I think this [smoking cessation] is one guideline we can take to heart and take home to our patients," she said.

Dr. Gensler reported financial relationships with UCB and AbbVie.

NEW YORK – Consistent evidence for a substantial increase in cardiovascular events remains elusive for patients with ankylosing spondylitis who have a broad range of CV risk factors.

"We can all agree that the risk factors for cardiovascular disease are higher in patients with AS [ankylosing spondylitis], but I think it is more controversial whether every AS patient faces a higher risk of events," observed Dr. Lianne Gensler, director of the ankylosing spondylitis clinic at the University of California, San Francisco.

Although this statement was made in reference to ischemic heart disease, the analysis presented by Dr. Gensler at the joint meetings of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis and the Spondyloarthritis Research & Treatment Network appears to be relevant to valvular disease, arrhythmias, and left ventricular dysfunction. Other CV risk factors associated with AS include hypertension, aortic insufficiency, and conduction disorders.

Inconsistencies in studies of CV

The obstacle for drawing conclusions is the lack of consistency in the published studies that relate specifically to AS but are independent of other inflammatory joint diseases, such as rheumatoid arthritis. In a review, Dr. Gensler cited one meta-analysis of 17 studies published in 2011 that did not associate AS with increased CV events (Arthritis Care Res. 2011;63:557-63). Although several studies published subsequently did associate AS with an increased rate of events, there were others that did not.

In an analysis that was performed at her institution based on AS patient data from the Healthcare Cost and Utilization Project National Inpatient Sample, no difference could be found in in-hospital mortality due to CV events when AS patients were compared with non-AS patients stratified by age.

In regard to CV structural disease related to AS, there is substantial evidence that several abnormalities are more common in AS, but there is far less to document that these lead to an increased risk of events. For example, Dr. Gensler cited one study in which the prevalence of aortic insufficiency climbed from 2% in patients with 10 years’ AS duration to 12% in those with 30 years. In another, inflammation of the septum, a potential risk for conduction disorders, climbed from 3% to 90% in AS patients followed long-term.

Asymptomatic conduction disorders

Conduction disorders in general – and QRS disturbances in particular – have been commonly reported in AS patients, but typically in the absence of symptoms, according to Dr. Gensler. She cited one electrocardiogram study in which 30% of AS patients had QRS prolongation, but all were asymptomatic. In another study of 200 AS patients, conduction disorders were found in 33%, of which atrioventricular block was the most common. In this study, increased markers of inflammation did not correlate with conduction disorders in a multivariate analysis.

"Whether we should be doing anything to look for these [conduction disorders] when they do not have symptoms is a question that I will put out to the audience," Dr. Gensler said.

Effect of treatment on CV events

The effect of AS therapies, particularly tumor necrosis factor (TNF) inhibitors, on CV risk also remains incompletely understood. In one study cited by Dr. Gensler, improved endothelial function was observed in AS patients treated with a TNF inhibitor, suggesting a potential protective effect, but, again, no difference in event rates in AS patients has ever been documented between those on TNF inhibitors and those not on TNF inhibitors.

Overall, more data are needed to determine the effect of AS on the risk of CV events, but one risk factor deserves attention even if there is no specific evidence that it affects CV events, according to Dr. Gensler.

In AS, "we know that smoking is a risk for early-onset disease, more inflammation, more damage, and more progression, so I think this [smoking cessation] is one guideline we can take to heart and take home to our patients," she said.

Dr. Gensler reported financial relationships with UCB and AbbVie.

NEW YORK – Consistent evidence for a substantial increase in cardiovascular events remains elusive for patients with ankylosing spondylitis who have a broad range of CV risk factors.

"We can all agree that the risk factors for cardiovascular disease are higher in patients with AS [ankylosing spondylitis], but I think it is more controversial whether every AS patient faces a higher risk of events," observed Dr. Lianne Gensler, director of the ankylosing spondylitis clinic at the University of California, San Francisco.

Although this statement was made in reference to ischemic heart disease, the analysis presented by Dr. Gensler at the joint meetings of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis and the Spondyloarthritis Research & Treatment Network appears to be relevant to valvular disease, arrhythmias, and left ventricular dysfunction. Other CV risk factors associated with AS include hypertension, aortic insufficiency, and conduction disorders.

Inconsistencies in studies of CV

The obstacle for drawing conclusions is the lack of consistency in the published studies that relate specifically to AS but are independent of other inflammatory joint diseases, such as rheumatoid arthritis. In a review, Dr. Gensler cited one meta-analysis of 17 studies published in 2011 that did not associate AS with increased CV events (Arthritis Care Res. 2011;63:557-63). Although several studies published subsequently did associate AS with an increased rate of events, there were others that did not.

In an analysis that was performed at her institution based on AS patient data from the Healthcare Cost and Utilization Project National Inpatient Sample, no difference could be found in in-hospital mortality due to CV events when AS patients were compared with non-AS patients stratified by age.

In regard to CV structural disease related to AS, there is substantial evidence that several abnormalities are more common in AS, but there is far less to document that these lead to an increased risk of events. For example, Dr. Gensler cited one study in which the prevalence of aortic insufficiency climbed from 2% in patients with 10 years’ AS duration to 12% in those with 30 years. In another, inflammation of the septum, a potential risk for conduction disorders, climbed from 3% to 90% in AS patients followed long-term.

Asymptomatic conduction disorders

Conduction disorders in general – and QRS disturbances in particular – have been commonly reported in AS patients, but typically in the absence of symptoms, according to Dr. Gensler. She cited one electrocardiogram study in which 30% of AS patients had QRS prolongation, but all were asymptomatic. In another study of 200 AS patients, conduction disorders were found in 33%, of which atrioventricular block was the most common. In this study, increased markers of inflammation did not correlate with conduction disorders in a multivariate analysis.

"Whether we should be doing anything to look for these [conduction disorders] when they do not have symptoms is a question that I will put out to the audience," Dr. Gensler said.

Effect of treatment on CV events

The effect of AS therapies, particularly tumor necrosis factor (TNF) inhibitors, on CV risk also remains incompletely understood. In one study cited by Dr. Gensler, improved endothelial function was observed in AS patients treated with a TNF inhibitor, suggesting a potential protective effect, but, again, no difference in event rates in AS patients has ever been documented between those on TNF inhibitors and those not on TNF inhibitors.

Overall, more data are needed to determine the effect of AS on the risk of CV events, but one risk factor deserves attention even if there is no specific evidence that it affects CV events, according to Dr. Gensler.

In AS, "we know that smoking is a risk for early-onset disease, more inflammation, more damage, and more progression, so I think this [smoking cessation] is one guideline we can take to heart and take home to our patients," she said.

Dr. Gensler reported financial relationships with UCB and AbbVie.

NEW YORK – Late initiation of tumor necrosis factor inhibitors in patients with ankylosing spondylitis more than doubles their risk of radiographic worsening, according to a prospective study that provides insight into the natural history of this disease.

"We are probably looking at a window of opportunity. If we capture patients with more acute lesions, we may be able to inhibit the processes that drive progression that cannot be reversed once the lesions are more mature," reported Dr. Nigil Haroon of the division of rheumatology at the University of Toronto.

The data presented by Dr. Haroon were characterized as the first to show a clear association between reduced ankylosing spondylitis (AS) damage and tumor necrosis factor (TNF) overall and early initiation of TNF inhibitors specifically. According to Dr. Haroon, earlier studies have not shown this association because of inadequate follow-up.

"AS is slowly progressive. Two years is not enough to see an effect," said Dr. Haroon, who noted that most TNF inhibitor trials have not exceeded this period. He believes at least 4 years of follow-up are needed.

Long follow-up is particularly relevant for showing benefit from anti-inflammatory therapy if, as described by Dr. Haroon, sustained inflammation is required to induce vertebral fat infiltration and if, in turn, this infiltration promotes formation of syndesmophytes. However, from the clinical perspective, there is now at least some evidence that early is better than late initiation of TNF inhibitors in AS patients at risk for progressive disease.

The clinical evidence is drawn from a five-center study with 334 patients published late last year and updated by Dr. Haroon at the joint meetings of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis and the Spondyloarthritis Research & Treatment Network (Arthritis Rheum. 2013;65:2645-54). However, Dr. Haroon primarily focused on the significance of these data as they relate to the natural history of AS.

In the study, the goal was to evaluate the impact of TNF inhibitors on spinal damage in AS. Overall, TNF inhibitors, vs. no TNF inhibitors, were associated with a 48% reduction in the odds of radiographic progression (P = .02), but the timing of TNF inhibitors was an independent predictor of benefit. In those who initiated TNF inhibitors 10 or more years after disease onset, the odds of progression was increased 2.4-fold (P = .03) relative to an earlier start. Duration of TNF inhibitor therapy was also inversely correlated with progression.

These findings are highly consistent with an independent series of studies conducted by Dr. Haroon and others who have linked sustained inflammation with vertebral fat infiltration. Visible on MRI, fat infiltration at the vertebral corners has been linked to metaplasia and the de novo syndesmophyte formation that characterizes radiographic progression.

"We are not 100% sure that inflammation and new bone formation are linked, but the evidence is accumulating," Dr. Haroon reported. The theory supported by the clinical study is that early control of inflammation aborts the pathologic process that leads first to vertebral fat infiltration and then to syndesmophyte formation.

Not all AS patients may benefit equally from TNF inhibitors from the perspective of disease progression. In the five-center study data presented by Dr. Haroon, only 30.5% of the patients experienced progression, defined by having at least a one unit per year increase in the mSASSS (modified Stokes AS Spine Score). Elevated baseline inflammatory markers, such as C-reactive protein, and smoking, for which there was a dose effect, were associated with progression after researchers controlled for baseline mSASSS totals. Other factors, particularly genetics, have also been strongly linked to risk of progression in AS.

Dr. Haroon reported no relevant financial relationships.

NEW YORK – Late initiation of tumor necrosis factor inhibitors in patients with ankylosing spondylitis more than doubles their risk of radiographic worsening, according to a prospective study that provides insight into the natural history of this disease.

"We are probably looking at a window of opportunity. If we capture patients with more acute lesions, we may be able to inhibit the processes that drive progression that cannot be reversed once the lesions are more mature," reported Dr. Nigil Haroon of the division of rheumatology at the University of Toronto.

The data presented by Dr. Haroon were characterized as the first to show a clear association between reduced ankylosing spondylitis (AS) damage and tumor necrosis factor (TNF) overall and early initiation of TNF inhibitors specifically. According to Dr. Haroon, earlier studies have not shown this association because of inadequate follow-up.

"AS is slowly progressive. Two years is not enough to see an effect," said Dr. Haroon, who noted that most TNF inhibitor trials have not exceeded this period. He believes at least 4 years of follow-up are needed.

Long follow-up is particularly relevant for showing benefit from anti-inflammatory therapy if, as described by Dr. Haroon, sustained inflammation is required to induce vertebral fat infiltration and if, in turn, this infiltration promotes formation of syndesmophytes. However, from the clinical perspective, there is now at least some evidence that early is better than late initiation of TNF inhibitors in AS patients at risk for progressive disease.

The clinical evidence is drawn from a five-center study with 334 patients published late last year and updated by Dr. Haroon at the joint meetings of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis and the Spondyloarthritis Research & Treatment Network (Arthritis Rheum. 2013;65:2645-54). However, Dr. Haroon primarily focused on the significance of these data as they relate to the natural history of AS.

In the study, the goal was to evaluate the impact of TNF inhibitors on spinal damage in AS. Overall, TNF inhibitors, vs. no TNF inhibitors, were associated with a 48% reduction in the odds of radiographic progression (P = .02), but the timing of TNF inhibitors was an independent predictor of benefit. In those who initiated TNF inhibitors 10 or more years after disease onset, the odds of progression was increased 2.4-fold (P = .03) relative to an earlier start. Duration of TNF inhibitor therapy was also inversely correlated with progression.

These findings are highly consistent with an independent series of studies conducted by Dr. Haroon and others who have linked sustained inflammation with vertebral fat infiltration. Visible on MRI, fat infiltration at the vertebral corners has been linked to metaplasia and the de novo syndesmophyte formation that characterizes radiographic progression.

"We are not 100% sure that inflammation and new bone formation are linked, but the evidence is accumulating," Dr. Haroon reported. The theory supported by the clinical study is that early control of inflammation aborts the pathologic process that leads first to vertebral fat infiltration and then to syndesmophyte formation.

Not all AS patients may benefit equally from TNF inhibitors from the perspective of disease progression. In the five-center study data presented by Dr. Haroon, only 30.5% of the patients experienced progression, defined by having at least a one unit per year increase in the mSASSS (modified Stokes AS Spine Score). Elevated baseline inflammatory markers, such as C-reactive protein, and smoking, for which there was a dose effect, were associated with progression after researchers controlled for baseline mSASSS totals. Other factors, particularly genetics, have also been strongly linked to risk of progression in AS.

Dr. Haroon reported no relevant financial relationships.

NEW YORK – Late initiation of tumor necrosis factor inhibitors in patients with ankylosing spondylitis more than doubles their risk of radiographic worsening, according to a prospective study that provides insight into the natural history of this disease.

"We are probably looking at a window of opportunity. If we capture patients with more acute lesions, we may be able to inhibit the processes that drive progression that cannot be reversed once the lesions are more mature," reported Dr. Nigil Haroon of the division of rheumatology at the University of Toronto.

The data presented by Dr. Haroon were characterized as the first to show a clear association between reduced ankylosing spondylitis (AS) damage and tumor necrosis factor (TNF) overall and early initiation of TNF inhibitors specifically. According to Dr. Haroon, earlier studies have not shown this association because of inadequate follow-up.

"AS is slowly progressive. Two years is not enough to see an effect," said Dr. Haroon, who noted that most TNF inhibitor trials have not exceeded this period. He believes at least 4 years of follow-up are needed.

Long follow-up is particularly relevant for showing benefit from anti-inflammatory therapy if, as described by Dr. Haroon, sustained inflammation is required to induce vertebral fat infiltration and if, in turn, this infiltration promotes formation of syndesmophytes. However, from the clinical perspective, there is now at least some evidence that early is better than late initiation of TNF inhibitors in AS patients at risk for progressive disease.

The clinical evidence is drawn from a five-center study with 334 patients published late last year and updated by Dr. Haroon at the joint meetings of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis and the Spondyloarthritis Research & Treatment Network (Arthritis Rheum. 2013;65:2645-54). However, Dr. Haroon primarily focused on the significance of these data as they relate to the natural history of AS.

In the study, the goal was to evaluate the impact of TNF inhibitors on spinal damage in AS. Overall, TNF inhibitors, vs. no TNF inhibitors, were associated with a 48% reduction in the odds of radiographic progression (P = .02), but the timing of TNF inhibitors was an independent predictor of benefit. In those who initiated TNF inhibitors 10 or more years after disease onset, the odds of progression was increased 2.4-fold (P = .03) relative to an earlier start. Duration of TNF inhibitor therapy was also inversely correlated with progression.

These findings are highly consistent with an independent series of studies conducted by Dr. Haroon and others who have linked sustained inflammation with vertebral fat infiltration. Visible on MRI, fat infiltration at the vertebral corners has been linked to metaplasia and the de novo syndesmophyte formation that characterizes radiographic progression.

"We are not 100% sure that inflammation and new bone formation are linked, but the evidence is accumulating," Dr. Haroon reported. The theory supported by the clinical study is that early control of inflammation aborts the pathologic process that leads first to vertebral fat infiltration and then to syndesmophyte formation.

Not all AS patients may benefit equally from TNF inhibitors from the perspective of disease progression. In the five-center study data presented by Dr. Haroon, only 30.5% of the patients experienced progression, defined by having at least a one unit per year increase in the mSASSS (modified Stokes AS Spine Score). Elevated baseline inflammatory markers, such as C-reactive protein, and smoking, for which there was a dose effect, were associated with progression after researchers controlled for baseline mSASSS totals. Other factors, particularly genetics, have also been strongly linked to risk of progression in AS.

Dr. Haroon reported no relevant financial relationships.

NEW YORK – There appears to be progress in the effort to convince the Food and Drug Administration that nonradiologic axial spondyloarthritis is a viable disease entity that deserves to be the target of therapeutic trials, according to an account of recent deliberations.

"We are happy that the FDA [now] agrees with the axSpA [axial spondyloarthritis] concept, the burden of disease, and the need to treat such patients," reported Dr. Atul Deodhar, professor of medicine and medical director of the rheumatology clinics at Oregon Health and Science University, Portland.

However, this is a process. The FDA "remains very concerned about the specificity of the ASAS [Assessment of Spondyloarthritis International Society] classification criteria," Dr. Deodhar said at the joint meetings of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis and the Spondyloarthritis Research & Treatment Network (SPARTAN).

Treatment trials for nonradiologic axSpA (nr-axSpA) followed the development of diagnostic criteria by ASAS in 2009 (Ann. Rheum. Dis. 2009;68:777-83). On the basis of randomized controlled trials in nr-axSpA patients with adalimumab (ABILITY-1) and both nr-axSpA and axSpA patients with certolizumab pegol (AS001), both drugs were approved by the European Medicines Agency for the treatment nr-axSpA. The same evidence, reviewed by an FDA advisory committee in July 2013, produced rejections the following October.

The major problem, according to Dr. Deodhar’s account, was that the FDA found the ASAS diagnostic criteria "overly broad," creating a potential for some low-risk patients to be prescribed therapies in which a favorable benefit-to-risk ratio could not be ensured. But the decision also denied these biologics to patients who could benefit.

"Rheumatologists were put in a difficult position, inducing some to label these patients as having ankylosing spondylitis to obtain third-party approval for therapies they needed," Dr. Deodhar observed. Concerned that patients with significant disability were being denied effective therapies, leaders of both SPARTAN and ASAS are attempting to work with the FDA to define more acceptable criteria.

In a joint letter from SPARTAN and ASAS to the FDA in early 2014 requesting a meeting, the key issues outlined for discussion included the need to recognize axSpA in general and nr-axSpA specifically as pathologies associated with significant morbidity and for which there is an unmet need for therapies.

At the meeting, held in June, both of these points and several others regarding the clinical importance of nr-axSpA and axSpA were conceded by the FDA officials, according to Dr. Deodhar. He recounted that some rheumatologists on staff at the FDA continue to see patients and were empathetic about the unmet need for therapies even while expressing concern about overuse of biologics.

The solution, in the opinion of FDA regulators, as described by Dr. Deodhar, is a better set of sensitive and specific diagnostic criteria for nr-axSpA that can reliably define those patients who benefit from biologics or other therapies when compared with the current standard of care. This is a goal now being pursued by SPARTAN in collaboration with ASAS. The American College of Rheumatology (ACR) and the European League Against Rheumatism may also be invited to participate.

The acknowledgment by the FDA that nr-axSpA is a disease entity that is poorly treated with current options is an important first step in a process that Dr. Deodhar and others believe will eventually lead to approval of tumor necrosis factor inhibitors.

Asked for a comment, Dr. David Borenstein, clinical professor of rheumatology at George Washington University Medical Center, Washington, said he is confident that diagnostic criteria acceptable to professional rheumatology organizations and the FDA will eventually be created.

"There has been some dissension about the reproducibility of the current axSpA criteria and how they might be used effectively by nonspecialists," agreed Dr. Borenstein, who is a past president of the ACR. "We need to tighten the criteria to make sure we are all talking about the same problem."

Dr. Deodhar reported financial relationships with Amgen, Abbott, Genentech, and Janssen.

NEW YORK – There appears to be progress in the effort to convince the Food and Drug Administration that nonradiologic axial spondyloarthritis is a viable disease entity that deserves to be the target of therapeutic trials, according to an account of recent deliberations.

"We are happy that the FDA [now] agrees with the axSpA [axial spondyloarthritis] concept, the burden of disease, and the need to treat such patients," reported Dr. Atul Deodhar, professor of medicine and medical director of the rheumatology clinics at Oregon Health and Science University, Portland.

However, this is a process. The FDA "remains very concerned about the specificity of the ASAS [Assessment of Spondyloarthritis International Society] classification criteria," Dr. Deodhar said at the joint meetings of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis and the Spondyloarthritis Research & Treatment Network (SPARTAN).

Treatment trials for nonradiologic axSpA (nr-axSpA) followed the development of diagnostic criteria by ASAS in 2009 (Ann. Rheum. Dis. 2009;68:777-83). On the basis of randomized controlled trials in nr-axSpA patients with adalimumab (ABILITY-1) and both nr-axSpA and axSpA patients with certolizumab pegol (AS001), both drugs were approved by the European Medicines Agency for the treatment nr-axSpA. The same evidence, reviewed by an FDA advisory committee in July 2013, produced rejections the following October.

The major problem, according to Dr. Deodhar’s account, was that the FDA found the ASAS diagnostic criteria "overly broad," creating a potential for some low-risk patients to be prescribed therapies in which a favorable benefit-to-risk ratio could not be ensured. But the decision also denied these biologics to patients who could benefit.

"Rheumatologists were put in a difficult position, inducing some to label these patients as having ankylosing spondylitis to obtain third-party approval for therapies they needed," Dr. Deodhar observed. Concerned that patients with significant disability were being denied effective therapies, leaders of both SPARTAN and ASAS are attempting to work with the FDA to define more acceptable criteria.

In a joint letter from SPARTAN and ASAS to the FDA in early 2014 requesting a meeting, the key issues outlined for discussion included the need to recognize axSpA in general and nr-axSpA specifically as pathologies associated with significant morbidity and for which there is an unmet need for therapies.

At the meeting, held in June, both of these points and several others regarding the clinical importance of nr-axSpA and axSpA were conceded by the FDA officials, according to Dr. Deodhar. He recounted that some rheumatologists on staff at the FDA continue to see patients and were empathetic about the unmet need for therapies even while expressing concern about overuse of biologics.

The solution, in the opinion of FDA regulators, as described by Dr. Deodhar, is a better set of sensitive and specific diagnostic criteria for nr-axSpA that can reliably define those patients who benefit from biologics or other therapies when compared with the current standard of care. This is a goal now being pursued by SPARTAN in collaboration with ASAS. The American College of Rheumatology (ACR) and the European League Against Rheumatism may also be invited to participate.

The acknowledgment by the FDA that nr-axSpA is a disease entity that is poorly treated with current options is an important first step in a process that Dr. Deodhar and others believe will eventually lead to approval of tumor necrosis factor inhibitors.

Asked for a comment, Dr. David Borenstein, clinical professor of rheumatology at George Washington University Medical Center, Washington, said he is confident that diagnostic criteria acceptable to professional rheumatology organizations and the FDA will eventually be created.

"There has been some dissension about the reproducibility of the current axSpA criteria and how they might be used effectively by nonspecialists," agreed Dr. Borenstein, who is a past president of the ACR. "We need to tighten the criteria to make sure we are all talking about the same problem."

Dr. Deodhar reported financial relationships with Amgen, Abbott, Genentech, and Janssen.

NEW YORK – There appears to be progress in the effort to convince the Food and Drug Administration that nonradiologic axial spondyloarthritis is a viable disease entity that deserves to be the target of therapeutic trials, according to an account of recent deliberations.

"We are happy that the FDA [now] agrees with the axSpA [axial spondyloarthritis] concept, the burden of disease, and the need to treat such patients," reported Dr. Atul Deodhar, professor of medicine and medical director of the rheumatology clinics at Oregon Health and Science University, Portland.

However, this is a process. The FDA "remains very concerned about the specificity of the ASAS [Assessment of Spondyloarthritis International Society] classification criteria," Dr. Deodhar said at the joint meetings of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis and the Spondyloarthritis Research & Treatment Network (SPARTAN).

Treatment trials for nonradiologic axSpA (nr-axSpA) followed the development of diagnostic criteria by ASAS in 2009 (Ann. Rheum. Dis. 2009;68:777-83). On the basis of randomized controlled trials in nr-axSpA patients with adalimumab (ABILITY-1) and both nr-axSpA and axSpA patients with certolizumab pegol (AS001), both drugs were approved by the European Medicines Agency for the treatment nr-axSpA. The same evidence, reviewed by an FDA advisory committee in July 2013, produced rejections the following October.

The major problem, according to Dr. Deodhar’s account, was that the FDA found the ASAS diagnostic criteria "overly broad," creating a potential for some low-risk patients to be prescribed therapies in which a favorable benefit-to-risk ratio could not be ensured. But the decision also denied these biologics to patients who could benefit.

"Rheumatologists were put in a difficult position, inducing some to label these patients as having ankylosing spondylitis to obtain third-party approval for therapies they needed," Dr. Deodhar observed. Concerned that patients with significant disability were being denied effective therapies, leaders of both SPARTAN and ASAS are attempting to work with the FDA to define more acceptable criteria.

In a joint letter from SPARTAN and ASAS to the FDA in early 2014 requesting a meeting, the key issues outlined for discussion included the need to recognize axSpA in general and nr-axSpA specifically as pathologies associated with significant morbidity and for which there is an unmet need for therapies.

At the meeting, held in June, both of these points and several others regarding the clinical importance of nr-axSpA and axSpA were conceded by the FDA officials, according to Dr. Deodhar. He recounted that some rheumatologists on staff at the FDA continue to see patients and were empathetic about the unmet need for therapies even while expressing concern about overuse of biologics.

The solution, in the opinion of FDA regulators, as described by Dr. Deodhar, is a better set of sensitive and specific diagnostic criteria for nr-axSpA that can reliably define those patients who benefit from biologics or other therapies when compared with the current standard of care. This is a goal now being pursued by SPARTAN in collaboration with ASAS. The American College of Rheumatology (ACR) and the European League Against Rheumatism may also be invited to participate.

The acknowledgment by the FDA that nr-axSpA is a disease entity that is poorly treated with current options is an important first step in a process that Dr. Deodhar and others believe will eventually lead to approval of tumor necrosis factor inhibitors.

Asked for a comment, Dr. David Borenstein, clinical professor of rheumatology at George Washington University Medical Center, Washington, said he is confident that diagnostic criteria acceptable to professional rheumatology organizations and the FDA will eventually be created.

"There has been some dissension about the reproducibility of the current axSpA criteria and how they might be used effectively by nonspecialists," agreed Dr. Borenstein, who is a past president of the ACR. "We need to tighten the criteria to make sure we are all talking about the same problem."

Dr. Deodhar reported financial relationships with Amgen, Abbott, Genentech, and Janssen.

PARIS – Patients with ankylosing spondylitis who worked at more physically-demanding jobs showed greater radiographic progression than did patients who performed more sedentary jobs in a prospective cohort study with 136 patients.

The findings immediately raised questions about "our commonly given advice to patients with spondylarthritis to strenuously exercise. Should physically demanding labor be discouraged?" asked Dr. Sofia Ramiro at the annual European Congress of Rheumatology.

© CandyBoxImages/Thinkstock

Dr. Ramiro stressed that the finding needs confirmation from studies in other cohorts of patients with ankylosing spondylitis (AS), but it raises the possibility that certain stresses and loads on the spine, from work or exercise, can worsen disease severity.

"If we can confirm that mechanical stress has an impact on radiographic progression, then I think we would have to analyze further and identify the type of activity having this impact, and then recommend the activity not be done," said Dr. Ramiro, a researcher at the Amsterdam Rheumatology Center, University of Amsterdam.

"I’m not saying that we would stop recommending exercise and that patients with AS should stay quiet at home, but perhaps we will advise against certain types of exercise," Dr. Ramiro said in an interview.

Dr. Ramiro and her associates previously reported this year that disease activity contributed longitudinally to radiographic AS progression during up to 12 years of follow-up (Ann. Rheum. Dis. 2014 [doi:10.1136/annrheumdis-2014-205178]). They further evaluated patients in the same cohort, 184 AS patients enrolled in OASIS (the Outcome in AS International Study), for additional factors that might affect radiographic progression either directly or indirectly. In addition to documenting a link between disease activity and radiographic progression, the report earlier this year had identified sex and disease duration as modifiers of the impact of disease activity. This impact on radiographic progression was greater in men, and early during the course of AS.

The new analysis looked for possible effects from smoking, and for chronic activity patterns using the surrogate marker of job type. The 184 patients in OASIS were sorted by their type of regular work, which identified 65 people with physically demanding (blue collar) jobs and 71 with relatively sedentary (white collar) jobs. The other 48 patients had either missing employment data or jobs with less clear links to activity levels, such as students or homemakers.

The findings showed that neither smoking nor job type appeared to have a direct influence on radiographic progression, but that smoking and a physically demanding job each had significant indirect effects. A physically demanding job linked with a 1.19-U increase in a measure of radiographic progression (the modified Stoke AS Spine Score, or mSASSS) for every 1-U increase in a measure of disease activity (the AS disease activity score, or ASDAS) during 2 years of follow-up, Dr. Ramiro reported. In contrast, the impact of a sedentary job was a 0.20-U rise in mSASSS for each 1-U rise in ASDAS. Smoking produced a 1.95-U rise in the mSASSS for each 1-U rise in ASDAS, significantly more than the 0.35 rate among nonsmokers.

Personal income, family income, and education each showed no statistically significant link with radiographic progression.

When the investigators analyzed job activity in subgroups divided by sex, they found that the relationship between a more physically demanding job and increased radiographic progression remained statistically significant in men, but the relationship was no longer significant in women.

The researchers could not include leisure activity or sports participation in their analysis as these data were not available. In addition, analysis by leisure activity may pose problems because baseline data on leisure activity may not extrapolate long-term, and patients can also have recall bias when reporting leisure activity, Dr. Ramiro said.

Dr. Ramiro said that she had no disclosures.

[email protected]

On Twitter @mitchelzoler

PARIS – Patients with ankylosing spondylitis who worked at more physically-demanding jobs showed greater radiographic progression than did patients who performed more sedentary jobs in a prospective cohort study with 136 patients.

The findings immediately raised questions about "our commonly given advice to patients with spondylarthritis to strenuously exercise. Should physically demanding labor be discouraged?" asked Dr. Sofia Ramiro at the annual European Congress of Rheumatology.

© CandyBoxImages/Thinkstock

Dr. Ramiro stressed that the finding needs confirmation from studies in other cohorts of patients with ankylosing spondylitis (AS), but it raises the possibility that certain stresses and loads on the spine, from work or exercise, can worsen disease severity.

"If we can confirm that mechanical stress has an impact on radiographic progression, then I think we would have to analyze further and identify the type of activity having this impact, and then recommend the activity not be done," said Dr. Ramiro, a researcher at the Amsterdam Rheumatology Center, University of Amsterdam.

"I’m not saying that we would stop recommending exercise and that patients with AS should stay quiet at home, but perhaps we will advise against certain types of exercise," Dr. Ramiro said in an interview.

Dr. Ramiro and her associates previously reported this year that disease activity contributed longitudinally to radiographic AS progression during up to 12 years of follow-up (Ann. Rheum. Dis. 2014 [doi:10.1136/annrheumdis-2014-205178]). They further evaluated patients in the same cohort, 184 AS patients enrolled in OASIS (the Outcome in AS International Study), for additional factors that might affect radiographic progression either directly or indirectly. In addition to documenting a link between disease activity and radiographic progression, the report earlier this year had identified sex and disease duration as modifiers of the impact of disease activity. This impact on radiographic progression was greater in men, and early during the course of AS.

The new analysis looked for possible effects from smoking, and for chronic activity patterns using the surrogate marker of job type. The 184 patients in OASIS were sorted by their type of regular work, which identified 65 people with physically demanding (blue collar) jobs and 71 with relatively sedentary (white collar) jobs. The other 48 patients had either missing employment data or jobs with less clear links to activity levels, such as students or homemakers.

The findings showed that neither smoking nor job type appeared to have a direct influence on radiographic progression, but that smoking and a physically demanding job each had significant indirect effects. A physically demanding job linked with a 1.19-U increase in a measure of radiographic progression (the modified Stoke AS Spine Score, or mSASSS) for every 1-U increase in a measure of disease activity (the AS disease activity score, or ASDAS) during 2 years of follow-up, Dr. Ramiro reported. In contrast, the impact of a sedentary job was a 0.20-U rise in mSASSS for each 1-U rise in ASDAS. Smoking produced a 1.95-U rise in the mSASSS for each 1-U rise in ASDAS, significantly more than the 0.35 rate among nonsmokers.

Personal income, family income, and education each showed no statistically significant link with radiographic progression.

When the investigators analyzed job activity in subgroups divided by sex, they found that the relationship between a more physically demanding job and increased radiographic progression remained statistically significant in men, but the relationship was no longer significant in women.

The researchers could not include leisure activity or sports participation in their analysis as these data were not available. In addition, analysis by leisure activity may pose problems because baseline data on leisure activity may not extrapolate long-term, and patients can also have recall bias when reporting leisure activity, Dr. Ramiro said.

Dr. Ramiro said that she had no disclosures.

[email protected]

On Twitter @mitchelzoler

PARIS – Patients with ankylosing spondylitis who worked at more physically-demanding jobs showed greater radiographic progression than did patients who performed more sedentary jobs in a prospective cohort study with 136 patients.

The findings immediately raised questions about "our commonly given advice to patients with spondylarthritis to strenuously exercise. Should physically demanding labor be discouraged?" asked Dr. Sofia Ramiro at the annual European Congress of Rheumatology.

© CandyBoxImages/Thinkstock

Dr. Ramiro stressed that the finding needs confirmation from studies in other cohorts of patients with ankylosing spondylitis (AS), but it raises the possibility that certain stresses and loads on the spine, from work or exercise, can worsen disease severity.

"If we can confirm that mechanical stress has an impact on radiographic progression, then I think we would have to analyze further and identify the type of activity having this impact, and then recommend the activity not be done," said Dr. Ramiro, a researcher at the Amsterdam Rheumatology Center, University of Amsterdam.

"I’m not saying that we would stop recommending exercise and that patients with AS should stay quiet at home, but perhaps we will advise against certain types of exercise," Dr. Ramiro said in an interview.

Dr. Ramiro and her associates previously reported this year that disease activity contributed longitudinally to radiographic AS progression during up to 12 years of follow-up (Ann. Rheum. Dis. 2014 [doi:10.1136/annrheumdis-2014-205178]). They further evaluated patients in the same cohort, 184 AS patients enrolled in OASIS (the Outcome in AS International Study), for additional factors that might affect radiographic progression either directly or indirectly. In addition to documenting a link between disease activity and radiographic progression, the report earlier this year had identified sex and disease duration as modifiers of the impact of disease activity. This impact on radiographic progression was greater in men, and early during the course of AS.

The new analysis looked for possible effects from smoking, and for chronic activity patterns using the surrogate marker of job type. The 184 patients in OASIS were sorted by their type of regular work, which identified 65 people with physically demanding (blue collar) jobs and 71 with relatively sedentary (white collar) jobs. The other 48 patients had either missing employment data or jobs with less clear links to activity levels, such as students or homemakers.

The findings showed that neither smoking nor job type appeared to have a direct influence on radiographic progression, but that smoking and a physically demanding job each had significant indirect effects. A physically demanding job linked with a 1.19-U increase in a measure of radiographic progression (the modified Stoke AS Spine Score, or mSASSS) for every 1-U increase in a measure of disease activity (the AS disease activity score, or ASDAS) during 2 years of follow-up, Dr. Ramiro reported. In contrast, the impact of a sedentary job was a 0.20-U rise in mSASSS for each 1-U rise in ASDAS. Smoking produced a 1.95-U rise in the mSASSS for each 1-U rise in ASDAS, significantly more than the 0.35 rate among nonsmokers.

Personal income, family income, and education each showed no statistically significant link with radiographic progression.

When the investigators analyzed job activity in subgroups divided by sex, they found that the relationship between a more physically demanding job and increased radiographic progression remained statistically significant in men, but the relationship was no longer significant in women.

The researchers could not include leisure activity or sports participation in their analysis as these data were not available. In addition, analysis by leisure activity may pose problems because baseline data on leisure activity may not extrapolate long-term, and patients can also have recall bias when reporting leisure activity, Dr. Ramiro said.

Dr. Ramiro said that she had no disclosures.

[email protected]

On Twitter @mitchelzoler