Rheumatoid Arthritis

BERLIN – Treated patients in remission from rheumatoid arthritis who are rheumatoid factor–positive and have a high level of joint synovitis visible on MRI have an increased risk for progressive joint damage, according to a review of 287 patients from six international registry cohorts.

The presence of joint synovitis during remission signaled an especially poor prognosis in rheumatoid factor (RF)-positive patients, who accounted for slightly more than half of the group studied. Among rheumatoid arthritis (RA) patients in remission who were RF-positive and had an RA MRI score (RAMRIS) of 6 or more, 42% subsequently had progressive joint erosions, Dr. Espen A. Haavardsholm said at the annual European Congress of Rheumatology.

In contrast, among RF-positive patients in remission with a RAMRIS of 5 or less, 12% had radiographic progression. Among all RF-negative patients, the rate of radiographic progression was less than 20% regardless of their RAMRIS.

What this means is that when RA patients are in remission on treatment, if they are RF-negative their risk of radiographic progression is low and MRI examinations aren’t needed. But if they are RF-positive and if they score 6 or more for synovitis on MRI, their risk for progression is high, and they need close monitoring and no change in their treatment. Patients with a score of 5 or less, as well as those who are RF-negative, are candidates for less rigorous follow-up and a possible step-down in their treatment, said Dr. Haavardsholm, a rheumatologist at Diakohnjemmet Hospital in Oslo.

"When patients are in remission, do you keep them on their current treatment or step down? We suggest you take an MRI and decide based on that," he said in an interview. Although ideally a prospective study should be done to test this approach, "I would manage patients this way right now," Dr. Haavardsholm said. "If a patient [in remission] is RF-positive, they are a good candidate for MRI; that’s the implication of our study."

Dr. Haavardsholm and his associates from the OMERACT (Outcome Measures in Rheumatology) MRI in RA Task Force used data collected on 287 RA patients in remission or with low disease activity on treatment who were in registries in Oslo; Paris; Sydney; Leeds, England; and two different cohorts in Copenhagen. The patients ranged from 43 to 63 years old, and their average RA duration was about 2 years. Virtually all patients were on treatment with a disease-modifying antirheumatic drug, 15% were also on treatment with a biologic agent, and a quarter were on an oral corticosteroid. Nearly three-quarters were in remission, with the rest having low disease activity. The researchers had baseline MRI results for all patients.

A multivariate stepwise regression analysis and calculation of a receiver-operator curve for various cutoffs of the RAMRIS for synovitis showed that best dichotomous separation occurred when a RAMRIS of 0-5 was considered low and a score of 6 or more was considered high. Using this cutoff, the researchers found that among RF-positive patients, those with a score of at least 6 had a 4.4-fold increased risk for progressive joint disease compared with patients with a baseline score of 5 or less, a statistically significant difference, Dr. Haavardsholm reported. Among patients who were RF-negative, a RAMRIS of 6 or more boosted the risk for joint progression by 9% compared with patients with a score of 5 or less, a difference that was not statistically significant.

Dr. Haavardsholm said that he had no disclosures.

BERLIN – Treated patients in remission from rheumatoid arthritis who are rheumatoid factor–positive and have a high level of joint synovitis visible on MRI have an increased risk for progressive joint damage, according to a review of 287 patients from six international registry cohorts.

The presence of joint synovitis during remission signaled an especially poor prognosis in rheumatoid factor (RF)-positive patients, who accounted for slightly more than half of the group studied. Among rheumatoid arthritis (RA) patients in remission who were RF-positive and had an RA MRI score (RAMRIS) of 6 or more, 42% subsequently had progressive joint erosions, Dr. Espen A. Haavardsholm said at the annual European Congress of Rheumatology.

In contrast, among RF-positive patients in remission with a RAMRIS of 5 or less, 12% had radiographic progression. Among all RF-negative patients, the rate of radiographic progression was less than 20% regardless of their RAMRIS.

What this means is that when RA patients are in remission on treatment, if they are RF-negative their risk of radiographic progression is low and MRI examinations aren’t needed. But if they are RF-positive and if they score 6 or more for synovitis on MRI, their risk for progression is high, and they need close monitoring and no change in their treatment. Patients with a score of 5 or less, as well as those who are RF-negative, are candidates for less rigorous follow-up and a possible step-down in their treatment, said Dr. Haavardsholm, a rheumatologist at Diakohnjemmet Hospital in Oslo.

"When patients are in remission, do you keep them on their current treatment or step down? We suggest you take an MRI and decide based on that," he said in an interview. Although ideally a prospective study should be done to test this approach, "I would manage patients this way right now," Dr. Haavardsholm said. "If a patient [in remission] is RF-positive, they are a good candidate for MRI; that’s the implication of our study."

Dr. Haavardsholm and his associates from the OMERACT (Outcome Measures in Rheumatology) MRI in RA Task Force used data collected on 287 RA patients in remission or with low disease activity on treatment who were in registries in Oslo; Paris; Sydney; Leeds, England; and two different cohorts in Copenhagen. The patients ranged from 43 to 63 years old, and their average RA duration was about 2 years. Virtually all patients were on treatment with a disease-modifying antirheumatic drug, 15% were also on treatment with a biologic agent, and a quarter were on an oral corticosteroid. Nearly three-quarters were in remission, with the rest having low disease activity. The researchers had baseline MRI results for all patients.

A multivariate stepwise regression analysis and calculation of a receiver-operator curve for various cutoffs of the RAMRIS for synovitis showed that best dichotomous separation occurred when a RAMRIS of 0-5 was considered low and a score of 6 or more was considered high. Using this cutoff, the researchers found that among RF-positive patients, those with a score of at least 6 had a 4.4-fold increased risk for progressive joint disease compared with patients with a baseline score of 5 or less, a statistically significant difference, Dr. Haavardsholm reported. Among patients who were RF-negative, a RAMRIS of 6 or more boosted the risk for joint progression by 9% compared with patients with a score of 5 or less, a difference that was not statistically significant.

Dr. Haavardsholm said that he had no disclosures.

BERLIN – Treated patients in remission from rheumatoid arthritis who are rheumatoid factor–positive and have a high level of joint synovitis visible on MRI have an increased risk for progressive joint damage, according to a review of 287 patients from six international registry cohorts.

The presence of joint synovitis during remission signaled an especially poor prognosis in rheumatoid factor (RF)-positive patients, who accounted for slightly more than half of the group studied. Among rheumatoid arthritis (RA) patients in remission who were RF-positive and had an RA MRI score (RAMRIS) of 6 or more, 42% subsequently had progressive joint erosions, Dr. Espen A. Haavardsholm said at the annual European Congress of Rheumatology.

In contrast, among RF-positive patients in remission with a RAMRIS of 5 or less, 12% had radiographic progression. Among all RF-negative patients, the rate of radiographic progression was less than 20% regardless of their RAMRIS.

What this means is that when RA patients are in remission on treatment, if they are RF-negative their risk of radiographic progression is low and MRI examinations aren’t needed. But if they are RF-positive and if they score 6 or more for synovitis on MRI, their risk for progression is high, and they need close monitoring and no change in their treatment. Patients with a score of 5 or less, as well as those who are RF-negative, are candidates for less rigorous follow-up and a possible step-down in their treatment, said Dr. Haavardsholm, a rheumatologist at Diakohnjemmet Hospital in Oslo.

"When patients are in remission, do you keep them on their current treatment or step down? We suggest you take an MRI and decide based on that," he said in an interview. Although ideally a prospective study should be done to test this approach, "I would manage patients this way right now," Dr. Haavardsholm said. "If a patient [in remission] is RF-positive, they are a good candidate for MRI; that’s the implication of our study."

Dr. Haavardsholm and his associates from the OMERACT (Outcome Measures in Rheumatology) MRI in RA Task Force used data collected on 287 RA patients in remission or with low disease activity on treatment who were in registries in Oslo; Paris; Sydney; Leeds, England; and two different cohorts in Copenhagen. The patients ranged from 43 to 63 years old, and their average RA duration was about 2 years. Virtually all patients were on treatment with a disease-modifying antirheumatic drug, 15% were also on treatment with a biologic agent, and a quarter were on an oral corticosteroid. Nearly three-quarters were in remission, with the rest having low disease activity. The researchers had baseline MRI results for all patients.

A multivariate stepwise regression analysis and calculation of a receiver-operator curve for various cutoffs of the RAMRIS for synovitis showed that best dichotomous separation occurred when a RAMRIS of 0-5 was considered low and a score of 6 or more was considered high. Using this cutoff, the researchers found that among RF-positive patients, those with a score of at least 6 had a 4.4-fold increased risk for progressive joint disease compared with patients with a baseline score of 5 or less, a statistically significant difference, Dr. Haavardsholm reported. Among patients who were RF-negative, a RAMRIS of 6 or more boosted the risk for joint progression by 9% compared with patients with a score of 5 or less, a difference that was not statistically significant.

Dr. Haavardsholm said that he had no disclosures.

BERLIN – Two new Janus kinase inhibitor drugs have shown good safety and efficacy for clinical rheumatoid arthritis, following in the footsteps of the JAK inhibitor tofacitinib, researchers reported at the annual European Congress of Rheumatology.

Baricitinib showed safety and promising efficacy in a multicenter, phase 2 study with 301 rheumatoid arthritis (RA) patients, said Dr. Edward Keystone, professor of medicine at the University of Toronto. And in results from a second study, GLPG0634 showed good safety and efficacy in a placebo-controlled, early phase 2 study with 36 RA patients. In both cases the results should propel these drugs into wider clinical testing.

Mitchel Zoler/IMNG Medical Media

The results also hinted that different JAK inhibitors may produce somewhat different clinical effects depending on exactly which Janus kinases they inhibit. Tofacitinib blocks all four JAKs, but its effect seems strongest on JAK3. Baricitinib specifically inhibits JAK1 and JAK2, while GLPG0634 specifically inhibits only JAK1, said speakers at the meeting.

"JAK selectivity makes a difference," said Dr. Frédéric Vanhoutte, lead investigator of the GLPG0634 study and a staff member at Galapagos, the Belgium drug company developing the agent.

The baricitinib study randomized patients on methotrexate to any of four drug dosages, given as a single, daily oral treatment, or placebo and looked at safety and efficacy after 12 weeks on treatment. At 12 weeks 76% of patients treated with either of the two highest baricitinib dosages (4 mg or 8 mg daily) had an American College of Rheumatology (ACR) 20 response, compared with 41% of the placebo patients, a statistically significant difference for the study’s primary end point, reported Dr. Keystone, who also directs the center for arthritis and autoimmune disease at Mount Sinai Hospital in Toronto. The incidence of remission at 12 weeks, based on a simple disease activity index (SDAI) score of 3.3 or less, occurred in 18% of patients on the 4-mg/day baricitinib plus methotrexate regimen compared with 1% of patients on methotrexate and placebo; 8% of patients who received 8 mg daily also achieved remission.

For safety, baricitinib appeared well tolerated, with an adverse event profile similar to the placebo arm. The results showed dose-dependent reductions in hemoglobin and neutrophils, and an increased level of low density lipoprotein cholesterol, but effects that surpassed the placebo arm primarily occurred in patients who received 8 mg of the drug daily. "The reductions in hemoglobin and neutrophils were of the same order of magnitude as with tofacitinib," Dr. Keystone said in an interview. "Some had thought that baricitinib might be more inhibitory to the hematologic system than tofacitinib, but it wasn’t very."

The study of 36 RA patients on methotrexate who received either of two dosages of the oral JAK 1 inhibitor GLPG0634 or placebo ran for 4 weeks at one center in Europe. The 100-mg b.i.d. dosage led to 92% of patients meeting ACR 20 criteria after 4 weeks, compared with 75% of patients who received 200 mg once daily and 33% among placebo patients, reported Dr. Vanhoutte. Treatment with the JAK1 inhibitor also led to higher remission rates and drops in C-reactive protein.

For safety, the JAK1 inhibitor actually boosted hemoglobin levels, led to no rise in LDL cholesterol or liver enzymes, and produced a "modest" reduction in neutrophils and platelets. Dr. Vanhoutte called the overall safety results "very encouraging."

The baricitinib trial was sponsored by Lilly, the company developing the drug. Dr. Keystone said that he has received research support from Lilly, and that he has received research support and has served as a consultant for several other drug companies. The GLPG0634 study was sponsored by Galapagos. Dr. Vanhoutte said that he is an employee of Galapagos.

BERLIN – Two new Janus kinase inhibitor drugs have shown good safety and efficacy for clinical rheumatoid arthritis, following in the footsteps of the JAK inhibitor tofacitinib, researchers reported at the annual European Congress of Rheumatology.

Baricitinib showed safety and promising efficacy in a multicenter, phase 2 study with 301 rheumatoid arthritis (RA) patients, said Dr. Edward Keystone, professor of medicine at the University of Toronto. And in results from a second study, GLPG0634 showed good safety and efficacy in a placebo-controlled, early phase 2 study with 36 RA patients. In both cases the results should propel these drugs into wider clinical testing.

Mitchel Zoler/IMNG Medical Media

The results also hinted that different JAK inhibitors may produce somewhat different clinical effects depending on exactly which Janus kinases they inhibit. Tofacitinib blocks all four JAKs, but its effect seems strongest on JAK3. Baricitinib specifically inhibits JAK1 and JAK2, while GLPG0634 specifically inhibits only JAK1, said speakers at the meeting.

"JAK selectivity makes a difference," said Dr. Frédéric Vanhoutte, lead investigator of the GLPG0634 study and a staff member at Galapagos, the Belgium drug company developing the agent.

The baricitinib study randomized patients on methotrexate to any of four drug dosages, given as a single, daily oral treatment, or placebo and looked at safety and efficacy after 12 weeks on treatment. At 12 weeks 76% of patients treated with either of the two highest baricitinib dosages (4 mg or 8 mg daily) had an American College of Rheumatology (ACR) 20 response, compared with 41% of the placebo patients, a statistically significant difference for the study’s primary end point, reported Dr. Keystone, who also directs the center for arthritis and autoimmune disease at Mount Sinai Hospital in Toronto. The incidence of remission at 12 weeks, based on a simple disease activity index (SDAI) score of 3.3 or less, occurred in 18% of patients on the 4-mg/day baricitinib plus methotrexate regimen compared with 1% of patients on methotrexate and placebo; 8% of patients who received 8 mg daily also achieved remission.

For safety, baricitinib appeared well tolerated, with an adverse event profile similar to the placebo arm. The results showed dose-dependent reductions in hemoglobin and neutrophils, and an increased level of low density lipoprotein cholesterol, but effects that surpassed the placebo arm primarily occurred in patients who received 8 mg of the drug daily. "The reductions in hemoglobin and neutrophils were of the same order of magnitude as with tofacitinib," Dr. Keystone said in an interview. "Some had thought that baricitinib might be more inhibitory to the hematologic system than tofacitinib, but it wasn’t very."

The study of 36 RA patients on methotrexate who received either of two dosages of the oral JAK 1 inhibitor GLPG0634 or placebo ran for 4 weeks at one center in Europe. The 100-mg b.i.d. dosage led to 92% of patients meeting ACR 20 criteria after 4 weeks, compared with 75% of patients who received 200 mg once daily and 33% among placebo patients, reported Dr. Vanhoutte. Treatment with the JAK1 inhibitor also led to higher remission rates and drops in C-reactive protein.

For safety, the JAK1 inhibitor actually boosted hemoglobin levels, led to no rise in LDL cholesterol or liver enzymes, and produced a "modest" reduction in neutrophils and platelets. Dr. Vanhoutte called the overall safety results "very encouraging."

The baricitinib trial was sponsored by Lilly, the company developing the drug. Dr. Keystone said that he has received research support from Lilly, and that he has received research support and has served as a consultant for several other drug companies. The GLPG0634 study was sponsored by Galapagos. Dr. Vanhoutte said that he is an employee of Galapagos.

BERLIN – Two new Janus kinase inhibitor drugs have shown good safety and efficacy for clinical rheumatoid arthritis, following in the footsteps of the JAK inhibitor tofacitinib, researchers reported at the annual European Congress of Rheumatology.

Baricitinib showed safety and promising efficacy in a multicenter, phase 2 study with 301 rheumatoid arthritis (RA) patients, said Dr. Edward Keystone, professor of medicine at the University of Toronto. And in results from a second study, GLPG0634 showed good safety and efficacy in a placebo-controlled, early phase 2 study with 36 RA patients. In both cases the results should propel these drugs into wider clinical testing.

Mitchel Zoler/IMNG Medical Media

The results also hinted that different JAK inhibitors may produce somewhat different clinical effects depending on exactly which Janus kinases they inhibit. Tofacitinib blocks all four JAKs, but its effect seems strongest on JAK3. Baricitinib specifically inhibits JAK1 and JAK2, while GLPG0634 specifically inhibits only JAK1, said speakers at the meeting.

"JAK selectivity makes a difference," said Dr. Frédéric Vanhoutte, lead investigator of the GLPG0634 study and a staff member at Galapagos, the Belgium drug company developing the agent.

The baricitinib study randomized patients on methotrexate to any of four drug dosages, given as a single, daily oral treatment, or placebo and looked at safety and efficacy after 12 weeks on treatment. At 12 weeks 76% of patients treated with either of the two highest baricitinib dosages (4 mg or 8 mg daily) had an American College of Rheumatology (ACR) 20 response, compared with 41% of the placebo patients, a statistically significant difference for the study’s primary end point, reported Dr. Keystone, who also directs the center for arthritis and autoimmune disease at Mount Sinai Hospital in Toronto. The incidence of remission at 12 weeks, based on a simple disease activity index (SDAI) score of 3.3 or less, occurred in 18% of patients on the 4-mg/day baricitinib plus methotrexate regimen compared with 1% of patients on methotrexate and placebo; 8% of patients who received 8 mg daily also achieved remission.

For safety, baricitinib appeared well tolerated, with an adverse event profile similar to the placebo arm. The results showed dose-dependent reductions in hemoglobin and neutrophils, and an increased level of low density lipoprotein cholesterol, but effects that surpassed the placebo arm primarily occurred in patients who received 8 mg of the drug daily. "The reductions in hemoglobin and neutrophils were of the same order of magnitude as with tofacitinib," Dr. Keystone said in an interview. "Some had thought that baricitinib might be more inhibitory to the hematologic system than tofacitinib, but it wasn’t very."

The study of 36 RA patients on methotrexate who received either of two dosages of the oral JAK 1 inhibitor GLPG0634 or placebo ran for 4 weeks at one center in Europe. The 100-mg b.i.d. dosage led to 92% of patients meeting ACR 20 criteria after 4 weeks, compared with 75% of patients who received 200 mg once daily and 33% among placebo patients, reported Dr. Vanhoutte. Treatment with the JAK1 inhibitor also led to higher remission rates and drops in C-reactive protein.

For safety, the JAK1 inhibitor actually boosted hemoglobin levels, led to no rise in LDL cholesterol or liver enzymes, and produced a "modest" reduction in neutrophils and platelets. Dr. Vanhoutte called the overall safety results "very encouraging."

The baricitinib trial was sponsored by Lilly, the company developing the drug. Dr. Keystone said that he has received research support from Lilly, and that he has received research support and has served as a consultant for several other drug companies. The GLPG0634 study was sponsored by Galapagos. Dr. Vanhoutte said that he is an employee of Galapagos.

BERLIN – Most patients with long-standing rheumatoid arthritis or other rheumatic diseases and in remission while on an anti–tumor necrosis factor drug could successfully undergo dose reduction and stay in remission, based on experience with 90 patients at one U.K. center.

In addition to maintaining a majority of patients on a reduced biologic regimen, a step that pleased patients, the program produced substantial cost savings, cutting drug costs in the unit by more than $400,000 during the course of 1 year, Dr. Jane Gibson said at the annual meeting of the European Congress of Rheumatology.

Out of 90 patients with rheumatoid arthritis (RA) or another rheumatic disease and in remission for more than a year and on a stable, standard regimen with etanercept or adalimumab, 68 (76%) successfully underwent a dosage reduction and remained in remission, said Dr. Gibson, head of the Fife Rheumatic Diseases Unit, part of the U.K. National Health Service serving the county of Fife in Scotland.

The sixteen patients who failed to stay in remission while on a reduced dosage of an anti–tumor necrosis factor (anti-TNF) drug were all successfully put back into remission with a corticosteroid injection and reinstitution of their prior treatment. Another six patients stopped their anti-TNF regimen for unrelated reasons during the period of the study, December 2010 to December 2011.

"These were patients with very long-standing disease, with some patients having RA for more than 40 years. The patients loved it; they felt it was a positive step. That was a big surprise because I thought that I’d have to persuade patients, but they thought it was great," Dr. Gibson said in an interview.

A regression analysis identified several factors significantly linked with an increased likelihood of patients’ successfully undergoing a dose reduction and remaining in remission. The strongest link was for concomitant treatment with methotrexate, according to Dr. Gibson and her associates. Patients who received methotrexate along with the anti-TNF drug had a substantially better rate of continued remission once the anti-TNF dosage dropped. Other statistically significant factors linked with successful dose reduction were concomitant treatment with any disease modifying anti-rheumatic drug (DMARD), and treatment with adalimumab (compared with treatment with etanercept). In addition, smoking history showed a strong trend toward a better rate of remission among never smokers or former smokers, but this did not reach statistical significance.

Dr. Gibson cautioned that any difference in the durability of remission on adalimumab compared with etanercept might result from the substantially shorter clinical half-lives of the two drugs. Etanercept has a half-life of 3-4 days, so cutting the dosage from the standard 50 mg subcutaneously once per week to 50 mg once every 2 weeks meant that patients scaled back to roughly four times the drug’s half-life. Thirteen of the 16 failed remissions occurred among patients switched to 50 mg etanercept every 2 weeks; among four patients scaled back to 50 mg etanercept administered every 10 days, none fell out of remission, Dr. Gibson said.

In contrast, adalimumab’s clinical half-life is about 14 days, so scaling back from the standard dosage of 40 mg subcutaneously every 2 weeks to the same amount given every 4 weeks meant that patients received the drug at intervals twice as long as the half-life. None of the 14 patients who received adalimumab every 4 weeks fell out of remission, and just two of 16 patients came out of remission when scaled back to a dosage of 40 mg adalimumab every 3 weeks.

Although concomitant methotrexate was the strongest predictor of success with scaled back dosing, only about half the patients in the Fife series were on methotrexate, and nearly a third were not on any concomitant DMARD, and so Dr. Gibson said she was unsure about any ironclad need to get patients on methotrexate or another DMARD before attempting to scale back the frequency of use of an anti-TNF agent. She said that she would attempt a small cut in anti-TNF dosage – to etanercept every 10 days or adalimumab every 3 weeks – even in patients not on a DMARD, especially if they were not current smokers, she said, although she would also frequently review these patients to watch for signs of a flare.

The premise of the approach is: "Why keep patients at the same dose? Why not see if we can adjust it?" she said.

The 84 rheumatic-disease patients who underwent an anti-TNF dose-adjustment included three-quarters with RA, with most other patients having psoriatic arthritis or ankylosing spondylitis. The average age was 57 years. Mean disease duration was more than 15 years. Their average time in continued remission at a reduced anti-TNF dosage was 11 months, with one patient followed for almost 3 years. Patients who fell out of remission tended to do so quickly, after an average of less than 4 months, and with only one patient taking longer than 5 months to fail.

Dr. Gibson said that she had no disclosures.

BERLIN – Most patients with long-standing rheumatoid arthritis or other rheumatic diseases and in remission while on an anti–tumor necrosis factor drug could successfully undergo dose reduction and stay in remission, based on experience with 90 patients at one U.K. center.

In addition to maintaining a majority of patients on a reduced biologic regimen, a step that pleased patients, the program produced substantial cost savings, cutting drug costs in the unit by more than $400,000 during the course of 1 year, Dr. Jane Gibson said at the annual meeting of the European Congress of Rheumatology.

Out of 90 patients with rheumatoid arthritis (RA) or another rheumatic disease and in remission for more than a year and on a stable, standard regimen with etanercept or adalimumab, 68 (76%) successfully underwent a dosage reduction and remained in remission, said Dr. Gibson, head of the Fife Rheumatic Diseases Unit, part of the U.K. National Health Service serving the county of Fife in Scotland.

The sixteen patients who failed to stay in remission while on a reduced dosage of an anti–tumor necrosis factor (anti-TNF) drug were all successfully put back into remission with a corticosteroid injection and reinstitution of their prior treatment. Another six patients stopped their anti-TNF regimen for unrelated reasons during the period of the study, December 2010 to December 2011.

"These were patients with very long-standing disease, with some patients having RA for more than 40 years. The patients loved it; they felt it was a positive step. That was a big surprise because I thought that I’d have to persuade patients, but they thought it was great," Dr. Gibson said in an interview.

A regression analysis identified several factors significantly linked with an increased likelihood of patients’ successfully undergoing a dose reduction and remaining in remission. The strongest link was for concomitant treatment with methotrexate, according to Dr. Gibson and her associates. Patients who received methotrexate along with the anti-TNF drug had a substantially better rate of continued remission once the anti-TNF dosage dropped. Other statistically significant factors linked with successful dose reduction were concomitant treatment with any disease modifying anti-rheumatic drug (DMARD), and treatment with adalimumab (compared with treatment with etanercept). In addition, smoking history showed a strong trend toward a better rate of remission among never smokers or former smokers, but this did not reach statistical significance.

Dr. Gibson cautioned that any difference in the durability of remission on adalimumab compared with etanercept might result from the substantially shorter clinical half-lives of the two drugs. Etanercept has a half-life of 3-4 days, so cutting the dosage from the standard 50 mg subcutaneously once per week to 50 mg once every 2 weeks meant that patients scaled back to roughly four times the drug’s half-life. Thirteen of the 16 failed remissions occurred among patients switched to 50 mg etanercept every 2 weeks; among four patients scaled back to 50 mg etanercept administered every 10 days, none fell out of remission, Dr. Gibson said.

In contrast, adalimumab’s clinical half-life is about 14 days, so scaling back from the standard dosage of 40 mg subcutaneously every 2 weeks to the same amount given every 4 weeks meant that patients received the drug at intervals twice as long as the half-life. None of the 14 patients who received adalimumab every 4 weeks fell out of remission, and just two of 16 patients came out of remission when scaled back to a dosage of 40 mg adalimumab every 3 weeks.

Although concomitant methotrexate was the strongest predictor of success with scaled back dosing, only about half the patients in the Fife series were on methotrexate, and nearly a third were not on any concomitant DMARD, and so Dr. Gibson said she was unsure about any ironclad need to get patients on methotrexate or another DMARD before attempting to scale back the frequency of use of an anti-TNF agent. She said that she would attempt a small cut in anti-TNF dosage – to etanercept every 10 days or adalimumab every 3 weeks – even in patients not on a DMARD, especially if they were not current smokers, she said, although she would also frequently review these patients to watch for signs of a flare.

The premise of the approach is: "Why keep patients at the same dose? Why not see if we can adjust it?" she said.

The 84 rheumatic-disease patients who underwent an anti-TNF dose-adjustment included three-quarters with RA, with most other patients having psoriatic arthritis or ankylosing spondylitis. The average age was 57 years. Mean disease duration was more than 15 years. Their average time in continued remission at a reduced anti-TNF dosage was 11 months, with one patient followed for almost 3 years. Patients who fell out of remission tended to do so quickly, after an average of less than 4 months, and with only one patient taking longer than 5 months to fail.

Dr. Gibson said that she had no disclosures.

BERLIN – Most patients with long-standing rheumatoid arthritis or other rheumatic diseases and in remission while on an anti–tumor necrosis factor drug could successfully undergo dose reduction and stay in remission, based on experience with 90 patients at one U.K. center.

In addition to maintaining a majority of patients on a reduced biologic regimen, a step that pleased patients, the program produced substantial cost savings, cutting drug costs in the unit by more than $400,000 during the course of 1 year, Dr. Jane Gibson said at the annual meeting of the European Congress of Rheumatology.

Out of 90 patients with rheumatoid arthritis (RA) or another rheumatic disease and in remission for more than a year and on a stable, standard regimen with etanercept or adalimumab, 68 (76%) successfully underwent a dosage reduction and remained in remission, said Dr. Gibson, head of the Fife Rheumatic Diseases Unit, part of the U.K. National Health Service serving the county of Fife in Scotland.

The sixteen patients who failed to stay in remission while on a reduced dosage of an anti–tumor necrosis factor (anti-TNF) drug were all successfully put back into remission with a corticosteroid injection and reinstitution of their prior treatment. Another six patients stopped their anti-TNF regimen for unrelated reasons during the period of the study, December 2010 to December 2011.

"These were patients with very long-standing disease, with some patients having RA for more than 40 years. The patients loved it; they felt it was a positive step. That was a big surprise because I thought that I’d have to persuade patients, but they thought it was great," Dr. Gibson said in an interview.

A regression analysis identified several factors significantly linked with an increased likelihood of patients’ successfully undergoing a dose reduction and remaining in remission. The strongest link was for concomitant treatment with methotrexate, according to Dr. Gibson and her associates. Patients who received methotrexate along with the anti-TNF drug had a substantially better rate of continued remission once the anti-TNF dosage dropped. Other statistically significant factors linked with successful dose reduction were concomitant treatment with any disease modifying anti-rheumatic drug (DMARD), and treatment with adalimumab (compared with treatment with etanercept). In addition, smoking history showed a strong trend toward a better rate of remission among never smokers or former smokers, but this did not reach statistical significance.

Dr. Gibson cautioned that any difference in the durability of remission on adalimumab compared with etanercept might result from the substantially shorter clinical half-lives of the two drugs. Etanercept has a half-life of 3-4 days, so cutting the dosage from the standard 50 mg subcutaneously once per week to 50 mg once every 2 weeks meant that patients scaled back to roughly four times the drug’s half-life. Thirteen of the 16 failed remissions occurred among patients switched to 50 mg etanercept every 2 weeks; among four patients scaled back to 50 mg etanercept administered every 10 days, none fell out of remission, Dr. Gibson said.

In contrast, adalimumab’s clinical half-life is about 14 days, so scaling back from the standard dosage of 40 mg subcutaneously every 2 weeks to the same amount given every 4 weeks meant that patients received the drug at intervals twice as long as the half-life. None of the 14 patients who received adalimumab every 4 weeks fell out of remission, and just two of 16 patients came out of remission when scaled back to a dosage of 40 mg adalimumab every 3 weeks.

Although concomitant methotrexate was the strongest predictor of success with scaled back dosing, only about half the patients in the Fife series were on methotrexate, and nearly a third were not on any concomitant DMARD, and so Dr. Gibson said she was unsure about any ironclad need to get patients on methotrexate or another DMARD before attempting to scale back the frequency of use of an anti-TNF agent. She said that she would attempt a small cut in anti-TNF dosage – to etanercept every 10 days or adalimumab every 3 weeks – even in patients not on a DMARD, especially if they were not current smokers, she said, although she would also frequently review these patients to watch for signs of a flare.

The premise of the approach is: "Why keep patients at the same dose? Why not see if we can adjust it?" she said.

The 84 rheumatic-disease patients who underwent an anti-TNF dose-adjustment included three-quarters with RA, with most other patients having psoriatic arthritis or ankylosing spondylitis. The average age was 57 years. Mean disease duration was more than 15 years. Their average time in continued remission at a reduced anti-TNF dosage was 11 months, with one patient followed for almost 3 years. Patients who fell out of remission tended to do so quickly, after an average of less than 4 months, and with only one patient taking longer than 5 months to fail.

Dr. Gibson said that she had no disclosures.

BERLIN – The notion of a tocilizumab-based treatment strategy without the use of methotrexate in rheumatoid arthritis patients having an inadequate response to methotrexate monotherapy has lost some of its allure in light of 52-week data from the phase IIIb ACT-RAY trial.

Preliminary results of the randomized, double-blind study reported at last fall’s annual meeting of the American College of Rheumatology showed similar clinical improvement in patients with a prior inadequate response to methotrexate alone regardless of whether they received 24 weeks of methotrexate plus tocilizumab (Actemra) or tocilizumab plus placebo. But by the 52-week mark, things had changed, Dr. Maxime Dougados reported at the annual European Congress of Rheumatology.

At 52 weeks in the 556-patient trial, the DAS28 remission rate, defined as a DAS28 score below 2.6, had been achieved by 45.5% of patients assigned to methotrexate plus tocilizumab at 8 mg/kg given intravenously every 4 weeks, a significantly better outcome than the 36.6% rate in patients on the interleukin-6 inhibitor plus an oral placebo in lieu of methotrexate.

Moreover, while 92.4% of patients assigned to tocilizumab/methotrexate combination therapy were free of radiographic disease progression at 1 year, that was true for only 85.5% of those on tocilizumab plus placebo (P = .007).

This doesn’t mean the end for a tocilizumab-based, methotrexate-free treatment strategy in RA. But it does suggest such a strategy will likely find a niche that’s restricted to patients with contraindications or intolerance to methotrexate, rather than a broader role in patients who are able to take methotrexate but don’t show adequate benefit without an add-on biologic, according to Dr. Dougados, professor of rheumatology at Cochin Hospital and René Descartes University, Paris.

The ACT-RAY trial introduced a more convoluted treatment protocol beginning at week 24. If at that point a patient had a DAS28 score in excess of 3.2, an open-label conventional disease-modifying antirheumatic drug other than methotrexate was added – for example, azathioprine, sulfasalazine, or hydroxychloroquine. This occurred in 29% of patients on the tocilizumab/methotrexate combination and in a similar 33% of those on tocilizumab/placebo.

Of note, the 52-week ACR 20, 50, 70, and 90 rates in the two study arms were similar. Nor were there significant differences between the two groups in terms of immunogenicity as reflected in rates of antidrug antibodies or neutralizing antidrug antibodies. And the incidence of elevated liver enzymes greater than three times the upper limit of normal was significantly lower in the methotrexate-free study arm.

"Despite some signals in favor of the add-on strategy – the percentage of patients in remission at week 52 and the structural data – this analysis suggests that tocilizumab monotherapy might be an acceptable therapeutic strategy in patients with a contraindication for or intolerance to methotrexate," he concluded.

Dr. Dougados reported serving as a consultant to Roche, which funds the ACT-RAY study.

BERLIN – The notion of a tocilizumab-based treatment strategy without the use of methotrexate in rheumatoid arthritis patients having an inadequate response to methotrexate monotherapy has lost some of its allure in light of 52-week data from the phase IIIb ACT-RAY trial.

Preliminary results of the randomized, double-blind study reported at last fall’s annual meeting of the American College of Rheumatology showed similar clinical improvement in patients with a prior inadequate response to methotrexate alone regardless of whether they received 24 weeks of methotrexate plus tocilizumab (Actemra) or tocilizumab plus placebo. But by the 52-week mark, things had changed, Dr. Maxime Dougados reported at the annual European Congress of Rheumatology.

At 52 weeks in the 556-patient trial, the DAS28 remission rate, defined as a DAS28 score below 2.6, had been achieved by 45.5% of patients assigned to methotrexate plus tocilizumab at 8 mg/kg given intravenously every 4 weeks, a significantly better outcome than the 36.6% rate in patients on the interleukin-6 inhibitor plus an oral placebo in lieu of methotrexate.

Moreover, while 92.4% of patients assigned to tocilizumab/methotrexate combination therapy were free of radiographic disease progression at 1 year, that was true for only 85.5% of those on tocilizumab plus placebo (P = .007).

This doesn’t mean the end for a tocilizumab-based, methotrexate-free treatment strategy in RA. But it does suggest such a strategy will likely find a niche that’s restricted to patients with contraindications or intolerance to methotrexate, rather than a broader role in patients who are able to take methotrexate but don’t show adequate benefit without an add-on biologic, according to Dr. Dougados, professor of rheumatology at Cochin Hospital and René Descartes University, Paris.

The ACT-RAY trial introduced a more convoluted treatment protocol beginning at week 24. If at that point a patient had a DAS28 score in excess of 3.2, an open-label conventional disease-modifying antirheumatic drug other than methotrexate was added – for example, azathioprine, sulfasalazine, or hydroxychloroquine. This occurred in 29% of patients on the tocilizumab/methotrexate combination and in a similar 33% of those on tocilizumab/placebo.

Of note, the 52-week ACR 20, 50, 70, and 90 rates in the two study arms were similar. Nor were there significant differences between the two groups in terms of immunogenicity as reflected in rates of antidrug antibodies or neutralizing antidrug antibodies. And the incidence of elevated liver enzymes greater than three times the upper limit of normal was significantly lower in the methotrexate-free study arm.

"Despite some signals in favor of the add-on strategy – the percentage of patients in remission at week 52 and the structural data – this analysis suggests that tocilizumab monotherapy might be an acceptable therapeutic strategy in patients with a contraindication for or intolerance to methotrexate," he concluded.

Dr. Dougados reported serving as a consultant to Roche, which funds the ACT-RAY study.

BERLIN – The notion of a tocilizumab-based treatment strategy without the use of methotrexate in rheumatoid arthritis patients having an inadequate response to methotrexate monotherapy has lost some of its allure in light of 52-week data from the phase IIIb ACT-RAY trial.

Preliminary results of the randomized, double-blind study reported at last fall’s annual meeting of the American College of Rheumatology showed similar clinical improvement in patients with a prior inadequate response to methotrexate alone regardless of whether they received 24 weeks of methotrexate plus tocilizumab (Actemra) or tocilizumab plus placebo. But by the 52-week mark, things had changed, Dr. Maxime Dougados reported at the annual European Congress of Rheumatology.

At 52 weeks in the 556-patient trial, the DAS28 remission rate, defined as a DAS28 score below 2.6, had been achieved by 45.5% of patients assigned to methotrexate plus tocilizumab at 8 mg/kg given intravenously every 4 weeks, a significantly better outcome than the 36.6% rate in patients on the interleukin-6 inhibitor plus an oral placebo in lieu of methotrexate.

Moreover, while 92.4% of patients assigned to tocilizumab/methotrexate combination therapy were free of radiographic disease progression at 1 year, that was true for only 85.5% of those on tocilizumab plus placebo (P = .007).

This doesn’t mean the end for a tocilizumab-based, methotrexate-free treatment strategy in RA. But it does suggest such a strategy will likely find a niche that’s restricted to patients with contraindications or intolerance to methotrexate, rather than a broader role in patients who are able to take methotrexate but don’t show adequate benefit without an add-on biologic, according to Dr. Dougados, professor of rheumatology at Cochin Hospital and René Descartes University, Paris.

The ACT-RAY trial introduced a more convoluted treatment protocol beginning at week 24. If at that point a patient had a DAS28 score in excess of 3.2, an open-label conventional disease-modifying antirheumatic drug other than methotrexate was added – for example, azathioprine, sulfasalazine, or hydroxychloroquine. This occurred in 29% of patients on the tocilizumab/methotrexate combination and in a similar 33% of those on tocilizumab/placebo.

Of note, the 52-week ACR 20, 50, 70, and 90 rates in the two study arms were similar. Nor were there significant differences between the two groups in terms of immunogenicity as reflected in rates of antidrug antibodies or neutralizing antidrug antibodies. And the incidence of elevated liver enzymes greater than three times the upper limit of normal was significantly lower in the methotrexate-free study arm.

"Despite some signals in favor of the add-on strategy – the percentage of patients in remission at week 52 and the structural data – this analysis suggests that tocilizumab monotherapy might be an acceptable therapeutic strategy in patients with a contraindication for or intolerance to methotrexate," he concluded.

Dr. Dougados reported serving as a consultant to Roche, which funds the ACT-RAY study.

BERLIN – The interleukin-17 blocker ixekizumab demonstrated significant clinical benefit and noteworthy rapid onset of efficacy in a phase II clinical trial in rheumatoid arthritis patients.

The anti-IL-17 monoclonal antibody proved effective both in patients naive to biologic therapy and in prior inadequate responders to tumor necrosis factor (TNF) inhibitors, reported Dr. Mark Genovese, who is professor of medicine at Stanford (Calif.) University.

"We saw ACR 20 responses and DAS28 and C-reactive protein values decrease within 3 days," he observed.

The randomized, double-blind study included 260 biologic-naive subjects and 188 others with an inadequate response to one or more TNF inhibitors. The biologic-naive patients were randomized to subcutaneous ixekizumab at 3, 10, 30, 80, or 180 mg at weeks 0, 1, 2, and every 2 weeks thereafter or to placebo. The TNF inhibitor–refractory patients received ixekizumab at 80 or 180 mg or placebo on the same dosing schedule. Everyone also received methotrexate or another nonbiologic disease-modifying antirheumatic drug.

The prespecified primary end point required by the Food and Drug Administration was the ACR 20 response at week 12. Although all patients in the biologic-naive group had higher ACR 20 response rates than did the placebo-treated controls, there was no clear dose-response effect. Only in subjects on ixekizumab at 30 mg did the difference from placebo attain statistical significance; their ACR 20 rate of 70% was twice than in controls.

In patients with prior inadequate response to anti-TNF agents, both the 80- and 180-mg doses of the anti-IL-17 biologic resulted in ACR 20 response rates of about 40%, roughly twice the rate with placebo.

For the secondary end points of Disease Activity Score based on 28-joint counts (DAS28), Clinical Disease Activity Index, and C-reactive protein titers, moderate to good responses were seen at multiple doses. For example, mean CRP levels remained essentially unchanged over time in the placebo group but dropped by 10.2-11.0 mg/L from a baseline of about 20 mg/L in biologic-naive patients on 30, 80, or 180 mg of ixekizumab. Mean CRP dropped by 5.7 and 8.1 mg/L, respectively, in patients with prior inadequate response to anti-TNF therapy who were assigned to ixekizumab at 80 and 180 mg.

Asked later about the somewhat muddy ACR 20 findings, Dr. Genovese replied, "This isn’t the only trial to date that’s been able to show a much nicer dose-response curve with DAS28 as opposed to ACR 20. While it’s only my personal opinion, it appears to me that the DAS scoring system seems to be a more robust and clinically applicable scoring system for use in outcomes in a dose-response study."

Ixekizumab’s safety profile in the phase II study was "comparable to other biologic therapies," the rheumatologist continued. Attrition was low, with only three treatment discontinuations because of adverse events in the active-treatment arm. Serious treatment-emergent adverse events occurred in 1.7% of controls and 4% of patients on the IL-17 inhibitor. Upper respiratory and urinary tract infections were slightly more frequent in ixekizumab-treated patients; however, no mycobacterial or systemic fungal infections occurred. Neutrophil counts were modestly lower in the ixekizumab group but were unrelated to infection risk.

Dr. Genovese reported receiving research grants from and serving as a consultant to Eli Lilly, which is developing ixekizumab for treatment of rheumatoid arthritis and psoriasis.

BERLIN – The interleukin-17 blocker ixekizumab demonstrated significant clinical benefit and noteworthy rapid onset of efficacy in a phase II clinical trial in rheumatoid arthritis patients.

The anti-IL-17 monoclonal antibody proved effective both in patients naive to biologic therapy and in prior inadequate responders to tumor necrosis factor (TNF) inhibitors, reported Dr. Mark Genovese, who is professor of medicine at Stanford (Calif.) University.

"We saw ACR 20 responses and DAS28 and C-reactive protein values decrease within 3 days," he observed.

The randomized, double-blind study included 260 biologic-naive subjects and 188 others with an inadequate response to one or more TNF inhibitors. The biologic-naive patients were randomized to subcutaneous ixekizumab at 3, 10, 30, 80, or 180 mg at weeks 0, 1, 2, and every 2 weeks thereafter or to placebo. The TNF inhibitor–refractory patients received ixekizumab at 80 or 180 mg or placebo on the same dosing schedule. Everyone also received methotrexate or another nonbiologic disease-modifying antirheumatic drug.

The prespecified primary end point required by the Food and Drug Administration was the ACR 20 response at week 12. Although all patients in the biologic-naive group had higher ACR 20 response rates than did the placebo-treated controls, there was no clear dose-response effect. Only in subjects on ixekizumab at 30 mg did the difference from placebo attain statistical significance; their ACR 20 rate of 70% was twice than in controls.

In patients with prior inadequate response to anti-TNF agents, both the 80- and 180-mg doses of the anti-IL-17 biologic resulted in ACR 20 response rates of about 40%, roughly twice the rate with placebo.

For the secondary end points of Disease Activity Score based on 28-joint counts (DAS28), Clinical Disease Activity Index, and C-reactive protein titers, moderate to good responses were seen at multiple doses. For example, mean CRP levels remained essentially unchanged over time in the placebo group but dropped by 10.2-11.0 mg/L from a baseline of about 20 mg/L in biologic-naive patients on 30, 80, or 180 mg of ixekizumab. Mean CRP dropped by 5.7 and 8.1 mg/L, respectively, in patients with prior inadequate response to anti-TNF therapy who were assigned to ixekizumab at 80 and 180 mg.

Asked later about the somewhat muddy ACR 20 findings, Dr. Genovese replied, "This isn’t the only trial to date that’s been able to show a much nicer dose-response curve with DAS28 as opposed to ACR 20. While it’s only my personal opinion, it appears to me that the DAS scoring system seems to be a more robust and clinically applicable scoring system for use in outcomes in a dose-response study."

Ixekizumab’s safety profile in the phase II study was "comparable to other biologic therapies," the rheumatologist continued. Attrition was low, with only three treatment discontinuations because of adverse events in the active-treatment arm. Serious treatment-emergent adverse events occurred in 1.7% of controls and 4% of patients on the IL-17 inhibitor. Upper respiratory and urinary tract infections were slightly more frequent in ixekizumab-treated patients; however, no mycobacterial or systemic fungal infections occurred. Neutrophil counts were modestly lower in the ixekizumab group but were unrelated to infection risk.

Dr. Genovese reported receiving research grants from and serving as a consultant to Eli Lilly, which is developing ixekizumab for treatment of rheumatoid arthritis and psoriasis.

BERLIN – The interleukin-17 blocker ixekizumab demonstrated significant clinical benefit and noteworthy rapid onset of efficacy in a phase II clinical trial in rheumatoid arthritis patients.

The anti-IL-17 monoclonal antibody proved effective both in patients naive to biologic therapy and in prior inadequate responders to tumor necrosis factor (TNF) inhibitors, reported Dr. Mark Genovese, who is professor of medicine at Stanford (Calif.) University.

"We saw ACR 20 responses and DAS28 and C-reactive protein values decrease within 3 days," he observed.

The randomized, double-blind study included 260 biologic-naive subjects and 188 others with an inadequate response to one or more TNF inhibitors. The biologic-naive patients were randomized to subcutaneous ixekizumab at 3, 10, 30, 80, or 180 mg at weeks 0, 1, 2, and every 2 weeks thereafter or to placebo. The TNF inhibitor–refractory patients received ixekizumab at 80 or 180 mg or placebo on the same dosing schedule. Everyone also received methotrexate or another nonbiologic disease-modifying antirheumatic drug.

The prespecified primary end point required by the Food and Drug Administration was the ACR 20 response at week 12. Although all patients in the biologic-naive group had higher ACR 20 response rates than did the placebo-treated controls, there was no clear dose-response effect. Only in subjects on ixekizumab at 30 mg did the difference from placebo attain statistical significance; their ACR 20 rate of 70% was twice than in controls.

In patients with prior inadequate response to anti-TNF agents, both the 80- and 180-mg doses of the anti-IL-17 biologic resulted in ACR 20 response rates of about 40%, roughly twice the rate with placebo.

For the secondary end points of Disease Activity Score based on 28-joint counts (DAS28), Clinical Disease Activity Index, and C-reactive protein titers, moderate to good responses were seen at multiple doses. For example, mean CRP levels remained essentially unchanged over time in the placebo group but dropped by 10.2-11.0 mg/L from a baseline of about 20 mg/L in biologic-naive patients on 30, 80, or 180 mg of ixekizumab. Mean CRP dropped by 5.7 and 8.1 mg/L, respectively, in patients with prior inadequate response to anti-TNF therapy who were assigned to ixekizumab at 80 and 180 mg.

Asked later about the somewhat muddy ACR 20 findings, Dr. Genovese replied, "This isn’t the only trial to date that’s been able to show a much nicer dose-response curve with DAS28 as opposed to ACR 20. While it’s only my personal opinion, it appears to me that the DAS scoring system seems to be a more robust and clinically applicable scoring system for use in outcomes in a dose-response study."

Ixekizumab’s safety profile in the phase II study was "comparable to other biologic therapies," the rheumatologist continued. Attrition was low, with only three treatment discontinuations because of adverse events in the active-treatment arm. Serious treatment-emergent adverse events occurred in 1.7% of controls and 4% of patients on the IL-17 inhibitor. Upper respiratory and urinary tract infections were slightly more frequent in ixekizumab-treated patients; however, no mycobacterial or systemic fungal infections occurred. Neutrophil counts were modestly lower in the ixekizumab group but were unrelated to infection risk.

Dr. Genovese reported receiving research grants from and serving as a consultant to Eli Lilly, which is developing ixekizumab for treatment of rheumatoid arthritis and psoriasis.

BERLIN – If at first you don’t succeed in getting satisfactory results when prescribing a tumor necrosis factor inhibitor in ankylosing spondylitis, don’t hesitate to switch to another. And, if need be, switch again. And again.

"Irrespective of the reason for discontinuation of the first [tumor necrosis factor (TNF)] inhibitor, switching to another TNF inhibitor should be considered," said Dr. Bente Glintborg of Gentofte University Hospital, Copenhagen, at the annual European Congress of Rheumatology.

That’s her key message gleaned from DANBIO, the Danish national registry of patients on biologic agents for rheumatic diseases. DANBIO is a comprehensive registry reflecting real-world clinical practice. Physician reporting to the registry is mandatory, with no informed consent requirement.

Dr. Glintborg reported on 1,436 ankylosing spondylitis (AS) patients followed for a median of 2.4 years after going on their first TNF inhibitor and enrolling in DANBIO.

The first key lesson from DANBIO is that switching anti-TNF biologics in patients with AS is common. Of DANBIO participants, 30% switched to a different TNF inhibitor. Changes made due to lack of efficacy outnumbered those due to adverse events by 2 to 1.

A total of 137 patients, or 10% of the original cohort, switched again to a third TNF inhibitor. This time around, changes made because of lack of efficacy outpaced those due to adverse events by 3 to 1. Thirty-nine patients went on to switch to a fourth TNF inhibitor.

Switchers were disproportionately female, and had an average disease duration several years less briefer than that of nonswitchers. They also had greater baseline disease activity by a variety of measures.

Each successive switch to a different TNF inhibitor brought a yet-lower favorable clinical response rate. Nevertheless, 2 years after embarking on anti-TNF therapy, 52% of switchers enjoyed a good clinical response as defined by at least a 50% decrease from baseline in the Bath Ankylosing Spondylitis Functional Index (BASFI), as did 63% of nonswitchers. The number needed to treat in order to obtain a good clinical response was 1.6 among nonswitchers and 1.9 for switchers.

The favorable clinical response rate after 6 months on a TNF inhibitor was 59% during the first treatment course, 41% during the second, and 32% with the third. The number needed to treat was 1.7, 2.4, and 3.0, respectively, she reported.

The median duration on first-line anti-TNF therapy was 3.1 years, falling to 1.6 years for a second course and 1.8 years with a third.

Male gender and a low baseline BASFI were significant predictors of longer adherence to the second TNF inhibitor prescribed. Among the many factors that proved unrelated to adherence were the specific anti-TNF agent, baseline C-reactive protein level, presence or absence of concomitant methotrexate, and the reason for stopping the first TNF inhibitor.

Infliximab (Remicade) was the most frequently prescribed first-line agent among Danish AS patients. A total of 45% of patients received it. The next most popular first-line TNF inhibitors were adalimumab (Humira), given to 37%, and etanercept (Enbrel), at 16%. Adalimumab was the second-line agent selected in 46% of first-time switchers, followed by etanercept in 40% and infliximab in 10%.

Session cochair Dr. Martin Rudwaleit expressed appreciation for the Danish effort to shed light on the sequential use of TNF inhibitors in AS, a heretofore understudied subject.

"I think it’s very good news to hear that switching can be quite effective, as you have shown in this open registry, particularly in light of not having any other compounds available at the moment to give to these patients," commented Dr. Rudwaleit of Charité University Hospital, Berlin.

Dr. Glintborg reported having no financial conflicts.

BERLIN – If at first you don’t succeed in getting satisfactory results when prescribing a tumor necrosis factor inhibitor in ankylosing spondylitis, don’t hesitate to switch to another. And, if need be, switch again. And again.

"Irrespective of the reason for discontinuation of the first [tumor necrosis factor (TNF)] inhibitor, switching to another TNF inhibitor should be considered," said Dr. Bente Glintborg of Gentofte University Hospital, Copenhagen, at the annual European Congress of Rheumatology.

That’s her key message gleaned from DANBIO, the Danish national registry of patients on biologic agents for rheumatic diseases. DANBIO is a comprehensive registry reflecting real-world clinical practice. Physician reporting to the registry is mandatory, with no informed consent requirement.

Dr. Glintborg reported on 1,436 ankylosing spondylitis (AS) patients followed for a median of 2.4 years after going on their first TNF inhibitor and enrolling in DANBIO.

The first key lesson from DANBIO is that switching anti-TNF biologics in patients with AS is common. Of DANBIO participants, 30% switched to a different TNF inhibitor. Changes made due to lack of efficacy outnumbered those due to adverse events by 2 to 1.

A total of 137 patients, or 10% of the original cohort, switched again to a third TNF inhibitor. This time around, changes made because of lack of efficacy outpaced those due to adverse events by 3 to 1. Thirty-nine patients went on to switch to a fourth TNF inhibitor.

Switchers were disproportionately female, and had an average disease duration several years less briefer than that of nonswitchers. They also had greater baseline disease activity by a variety of measures.

Each successive switch to a different TNF inhibitor brought a yet-lower favorable clinical response rate. Nevertheless, 2 years after embarking on anti-TNF therapy, 52% of switchers enjoyed a good clinical response as defined by at least a 50% decrease from baseline in the Bath Ankylosing Spondylitis Functional Index (BASFI), as did 63% of nonswitchers. The number needed to treat in order to obtain a good clinical response was 1.6 among nonswitchers and 1.9 for switchers.

The favorable clinical response rate after 6 months on a TNF inhibitor was 59% during the first treatment course, 41% during the second, and 32% with the third. The number needed to treat was 1.7, 2.4, and 3.0, respectively, she reported.

The median duration on first-line anti-TNF therapy was 3.1 years, falling to 1.6 years for a second course and 1.8 years with a third.

Male gender and a low baseline BASFI were significant predictors of longer adherence to the second TNF inhibitor prescribed. Among the many factors that proved unrelated to adherence were the specific anti-TNF agent, baseline C-reactive protein level, presence or absence of concomitant methotrexate, and the reason for stopping the first TNF inhibitor.

Infliximab (Remicade) was the most frequently prescribed first-line agent among Danish AS patients. A total of 45% of patients received it. The next most popular first-line TNF inhibitors were adalimumab (Humira), given to 37%, and etanercept (Enbrel), at 16%. Adalimumab was the second-line agent selected in 46% of first-time switchers, followed by etanercept in 40% and infliximab in 10%.

Session cochair Dr. Martin Rudwaleit expressed appreciation for the Danish effort to shed light on the sequential use of TNF inhibitors in AS, a heretofore understudied subject.

"I think it’s very good news to hear that switching can be quite effective, as you have shown in this open registry, particularly in light of not having any other compounds available at the moment to give to these patients," commented Dr. Rudwaleit of Charité University Hospital, Berlin.

Dr. Glintborg reported having no financial conflicts.

BERLIN – If at first you don’t succeed in getting satisfactory results when prescribing a tumor necrosis factor inhibitor in ankylosing spondylitis, don’t hesitate to switch to another. And, if need be, switch again. And again.

"Irrespective of the reason for discontinuation of the first [tumor necrosis factor (TNF)] inhibitor, switching to another TNF inhibitor should be considered," said Dr. Bente Glintborg of Gentofte University Hospital, Copenhagen, at the annual European Congress of Rheumatology.

That’s her key message gleaned from DANBIO, the Danish national registry of patients on biologic agents for rheumatic diseases. DANBIO is a comprehensive registry reflecting real-world clinical practice. Physician reporting to the registry is mandatory, with no informed consent requirement.

Dr. Glintborg reported on 1,436 ankylosing spondylitis (AS) patients followed for a median of 2.4 years after going on their first TNF inhibitor and enrolling in DANBIO.

The first key lesson from DANBIO is that switching anti-TNF biologics in patients with AS is common. Of DANBIO participants, 30% switched to a different TNF inhibitor. Changes made due to lack of efficacy outnumbered those due to adverse events by 2 to 1.

A total of 137 patients, or 10% of the original cohort, switched again to a third TNF inhibitor. This time around, changes made because of lack of efficacy outpaced those due to adverse events by 3 to 1. Thirty-nine patients went on to switch to a fourth TNF inhibitor.

Switchers were disproportionately female, and had an average disease duration several years less briefer than that of nonswitchers. They also had greater baseline disease activity by a variety of measures.

Each successive switch to a different TNF inhibitor brought a yet-lower favorable clinical response rate. Nevertheless, 2 years after embarking on anti-TNF therapy, 52% of switchers enjoyed a good clinical response as defined by at least a 50% decrease from baseline in the Bath Ankylosing Spondylitis Functional Index (BASFI), as did 63% of nonswitchers. The number needed to treat in order to obtain a good clinical response was 1.6 among nonswitchers and 1.9 for switchers.

The favorable clinical response rate after 6 months on a TNF inhibitor was 59% during the first treatment course, 41% during the second, and 32% with the third. The number needed to treat was 1.7, 2.4, and 3.0, respectively, she reported.

The median duration on first-line anti-TNF therapy was 3.1 years, falling to 1.6 years for a second course and 1.8 years with a third.

Male gender and a low baseline BASFI were significant predictors of longer adherence to the second TNF inhibitor prescribed. Among the many factors that proved unrelated to adherence were the specific anti-TNF agent, baseline C-reactive protein level, presence or absence of concomitant methotrexate, and the reason for stopping the first TNF inhibitor.

Infliximab (Remicade) was the most frequently prescribed first-line agent among Danish AS patients. A total of 45% of patients received it. The next most popular first-line TNF inhibitors were adalimumab (Humira), given to 37%, and etanercept (Enbrel), at 16%. Adalimumab was the second-line agent selected in 46% of first-time switchers, followed by etanercept in 40% and infliximab in 10%.

Session cochair Dr. Martin Rudwaleit expressed appreciation for the Danish effort to shed light on the sequential use of TNF inhibitors in AS, a heretofore understudied subject.

"I think it’s very good news to hear that switching can be quite effective, as you have shown in this open registry, particularly in light of not having any other compounds available at the moment to give to these patients," commented Dr. Rudwaleit of Charité University Hospital, Berlin.

Dr. Glintborg reported having no financial conflicts.

BERLIN – Ankylosing spondylitis patients are at sharply increased risk of various forms of acute and chronic renal comorbidity, according to the first population-based study to examine the issue.

The explanation for this elevated renal risk is likely twofold: the well-documented nephrotoxic effects of long-term therapy with nonsteroidal anti-inflammatory drugs (NSAIDs), the first-line treatment mainstay in ankylosing spondylitis (AS); and extra-articular manifestations of the disease process itself, according to Adrian R. Levy, Ph.D., of the research firm Oxford Outcomes in Vancouver, B.C.

He presented a retrospective cohort study utilizing Quebec’s administrative physician-billing database. He identified 8,616 individuals with AS in the Canadian province during 1996-2006, and determined their rate of diagnosed renal comorbidities. Then he compared the AS group to a randomly generated sample of 1% of the general Quebec population without AS.

Overall, diagnosed renal complications were present in 3.4% of men and 2.1% of women with AS, compared with 2% and 1.6%, respectively, in the general population. Age- and gender-adjusted prevalence ratios demonstrated significantly excess risks of various forms of renal disease in the AS population, Dr. Levy said at the annual European Congress of Rheumatology.

The magnitude of the increased risk was greatest in younger patients with AS. For example, the prevalence ratio for any of the renal conditions under study was 2.4-fold greater among 20- to 39-year-old men with AS than controls, but only 1.5-fold greater in AS patients over age 60.

The clinical implications are clear, Dr. Levy emphasized: Close and careful monitoring for renal complications is de rigueur in individuals with AS, especially if they are on long-term, full-dose, continuous NSAID therapy.

The study was funded by Abbott.

BERLIN – Ankylosing spondylitis patients are at sharply increased risk of various forms of acute and chronic renal comorbidity, according to the first population-based study to examine the issue.

The explanation for this elevated renal risk is likely twofold: the well-documented nephrotoxic effects of long-term therapy with nonsteroidal anti-inflammatory drugs (NSAIDs), the first-line treatment mainstay in ankylosing spondylitis (AS); and extra-articular manifestations of the disease process itself, according to Adrian R. Levy, Ph.D., of the research firm Oxford Outcomes in Vancouver, B.C.

He presented a retrospective cohort study utilizing Quebec’s administrative physician-billing database. He identified 8,616 individuals with AS in the Canadian province during 1996-2006, and determined their rate of diagnosed renal comorbidities. Then he compared the AS group to a randomly generated sample of 1% of the general Quebec population without AS.

Overall, diagnosed renal complications were present in 3.4% of men and 2.1% of women with AS, compared with 2% and 1.6%, respectively, in the general population. Age- and gender-adjusted prevalence ratios demonstrated significantly excess risks of various forms of renal disease in the AS population, Dr. Levy said at the annual European Congress of Rheumatology.

The magnitude of the increased risk was greatest in younger patients with AS. For example, the prevalence ratio for any of the renal conditions under study was 2.4-fold greater among 20- to 39-year-old men with AS than controls, but only 1.5-fold greater in AS patients over age 60.

The clinical implications are clear, Dr. Levy emphasized: Close and careful monitoring for renal complications is de rigueur in individuals with AS, especially if they are on long-term, full-dose, continuous NSAID therapy.

The study was funded by Abbott.

BERLIN – Ankylosing spondylitis patients are at sharply increased risk of various forms of acute and chronic renal comorbidity, according to the first population-based study to examine the issue.

The explanation for this elevated renal risk is likely twofold: the well-documented nephrotoxic effects of long-term therapy with nonsteroidal anti-inflammatory drugs (NSAIDs), the first-line treatment mainstay in ankylosing spondylitis (AS); and extra-articular manifestations of the disease process itself, according to Adrian R. Levy, Ph.D., of the research firm Oxford Outcomes in Vancouver, B.C.

He presented a retrospective cohort study utilizing Quebec’s administrative physician-billing database. He identified 8,616 individuals with AS in the Canadian province during 1996-2006, and determined their rate of diagnosed renal comorbidities. Then he compared the AS group to a randomly generated sample of 1% of the general Quebec population without AS.

Overall, diagnosed renal complications were present in 3.4% of men and 2.1% of women with AS, compared with 2% and 1.6%, respectively, in the general population. Age- and gender-adjusted prevalence ratios demonstrated significantly excess risks of various forms of renal disease in the AS population, Dr. Levy said at the annual European Congress of Rheumatology.

The magnitude of the increased risk was greatest in younger patients with AS. For example, the prevalence ratio for any of the renal conditions under study was 2.4-fold greater among 20- to 39-year-old men with AS than controls, but only 1.5-fold greater in AS patients over age 60.

The clinical implications are clear, Dr. Levy emphasized: Close and careful monitoring for renal complications is de rigueur in individuals with AS, especially if they are on long-term, full-dose, continuous NSAID therapy.

The study was funded by Abbott.

UPDATED: 06/21/2012

BERLIN – If the Food and Drug Administration follows the advice of its Arthritis Advisory Committee and approves tofacitinib as a new drug for treating rheumatoid arthritis later this summer, the oral, small-molecule drug may start to muscle in on the treatment turf now occupied by antitumor necrosis factor drugs, some experts predicted at the Annual European Congress of Rheumatology.

The attraction would be the good efficacy tofacitinib has shown in five phase III trials, a decent safety profile that looks on par with antitumor necrosis factor (TNF) drugs, and delivery as a twice-daily oral pill, a property that will give tofacitinib an edge over the anti-TNFs and other biologics that require injection or infusion.

"The fact that [tofacitinib] is oral is something of an advantage, so there will be a role for it, and it makes sense therapeutically," Dr. Joel M. Kremer said at the meeting. "But we will need to be smart" on using tofacitinib and other new drugs from the same class to treat patients with rheumatoid arthritis (RA), and their use relative to methotrexate and the biologics, said Dr. Kremer, a rheumatologist and professor of medicine at Albany (N.Y.) Medical College.

Another view was that tofacitinib will need to prove its value in larger numbers of patients, and though it will be a welcome new option – first to market from the class of Janus kinase (JAK) inhibitors – it will take its initial place post approval behind the anti-TNFs, which have more than a decade’s track record, said Dr. Iain B. McInnes in a separate talk at the meeting. Many rheumatologists "feel they will kick in after a first biologic treatment," which itself comes after first-line methotrexate, said Dr. McInnes, a rheumatologist and professor and Muirhead Chair of Medicine at the University of Glasgow, Scotland.

"The efficacy we’ve seen [from tofacitinib and other JAK inhibitors] is very encouraging, but safety will be a major driver of clinical decisions and [will] influence the order of choice. If a patient does not get an adequate response from methotrexate after 3-6 months, I would add a biologic drug, especially an anti-TNF. Inevitably, there will be less safety assurance with the new drugs. The current role for JAK inhibitors is closer to the options like abatacept, rituximab, and tocilizumab, but I think that may change" once JAK inhibitors enter routine practice, Dr. McInnes said in his talk.

"I have a lot of experience with tofacitinib, and I’m very comfortable with it; if a patient wanted this drug, I would use it," said Dr. Roy Fleischmann, who led phase II and phase III trials with tofacitinib and is codirector of rheumatology at Texas Health Presbyterian Medical Center in Dallas.

"What will practicing rheumatologists with no experience with the drug do? We’ll see what the FDA says. They might use it after methotrexate, because the data are strong. It will be up to patients: an oral drug or an injected one."

Pfizer, the company developing tofacitinib, reported data from five phase III trials and safety experience in about 4,800 patients to the FDA Advisory Committee in May. And four of the five trials examined use of the drug in RA patients as monotherapy; in combination with methotrexate; in combination with background methotrexate in patients who failed to respond to an anti-TNF drug; and in combination with a background disease modifying antirheumatic drug. The fifth study, a 2-year trial that so far has reported results from an interim, 1-year analysis only, examined tofacitinib’s ability when used in combination with methotrexate to stop radiographic progression of joint damage, compared with methotrexate alone.

Results from across the studies showed consistent efficacy, including inhibition of radiographic progression that significantly surpassed placebo patients, and a "consistent side effect profile," Dr. Kremer said. "I consider it on the same shelf for potential infections and adverse events as the [already approved] biologics," he said in an interview. He said he would shy away from prescribing tofacitinib, or any biologic, to patients who get frequent pneumonia, cellulitis, or other infections.

Perceived safety will likely be the major driver – or impediment – for use of tofacitinib during the first year or 2 after its approval, predicted Madhuri Borde, Ph.D., director of the immune and inflammatory disorders group of Decision Resources, a pharmaceutical-market consulting company in Burlington, Mass. In mid-May, Dr. Borde presented 52 U.S. rheumatologists with active RA practices the same tofacitinib data that the FDA Advisory Committee saw and she asked the rheumatologists what they thought of the drug and how they might use it soon after it hit the U.S. market.*

The results showed that rheumatologists were impressed by the efficacy results, saw safety as being similar to anti-TNF drugs, and mostly saw tofacitinib currently as a drug they would use when RA patients don’t respond to an anti-TNF agent. "For physicians, it boils down to their comfort with the safety profile," she said in an interview, and they think safety is still a little uncertain.

Although Dr. Borde conceded that "patients are wary of injections" and that oral dosing is an attractive option for many patients, physician uncertainty about safety will generally trump that. "I think safety concerns will drive caution in using tofacitinib," at least during the first couple of years on the market, until a higher comfort level is reached. It’s likely that in an effort to stimulate interest in the drug, Pfizer will price it aggressively, at a small but significant discount to anti-TNF drugs. But even a cost savings probably won’t be enough early on to knock the anti-TNFs from their established RA perch, she said.

Dr. Kremer said that he has received research support from and has been a consultant to Pfizer and several other drugs companies. Dr. McInnes said that he has received research support from and has been a consultant to and speaker for Pfizer and several other drug companies. Dr. Fleischmann said that he has received research support from and has been a consultant to Pfizer and several other drug companies. Dr. Borde said that she had no disclosures.

*New information about Dr. Borde's title has been added to this story.

UPDATED: 06/21/2012

BERLIN – If the Food and Drug Administration follows the advice of its Arthritis Advisory Committee and approves tofacitinib as a new drug for treating rheumatoid arthritis later this summer, the oral, small-molecule drug may start to muscle in on the treatment turf now occupied by antitumor necrosis factor drugs, some experts predicted at the Annual European Congress of Rheumatology.

The attraction would be the good efficacy tofacitinib has shown in five phase III trials, a decent safety profile that looks on par with antitumor necrosis factor (TNF) drugs, and delivery as a twice-daily oral pill, a property that will give tofacitinib an edge over the anti-TNFs and other biologics that require injection or infusion.

"The fact that [tofacitinib] is oral is something of an advantage, so there will be a role for it, and it makes sense therapeutically," Dr. Joel M. Kremer said at the meeting. "But we will need to be smart" on using tofacitinib and other new drugs from the same class to treat patients with rheumatoid arthritis (RA), and their use relative to methotrexate and the biologics, said Dr. Kremer, a rheumatologist and professor of medicine at Albany (N.Y.) Medical College.

Another view was that tofacitinib will need to prove its value in larger numbers of patients, and though it will be a welcome new option – first to market from the class of Janus kinase (JAK) inhibitors – it will take its initial place post approval behind the anti-TNFs, which have more than a decade’s track record, said Dr. Iain B. McInnes in a separate talk at the meeting. Many rheumatologists "feel they will kick in after a first biologic treatment," which itself comes after first-line methotrexate, said Dr. McInnes, a rheumatologist and professor and Muirhead Chair of Medicine at the University of Glasgow, Scotland.

"The efficacy we’ve seen [from tofacitinib and other JAK inhibitors] is very encouraging, but safety will be a major driver of clinical decisions and [will] influence the order of choice. If a patient does not get an adequate response from methotrexate after 3-6 months, I would add a biologic drug, especially an anti-TNF. Inevitably, there will be less safety assurance with the new drugs. The current role for JAK inhibitors is closer to the options like abatacept, rituximab, and tocilizumab, but I think that may change" once JAK inhibitors enter routine practice, Dr. McInnes said in his talk.

"I have a lot of experience with tofacitinib, and I’m very comfortable with it; if a patient wanted this drug, I would use it," said Dr. Roy Fleischmann, who led phase II and phase III trials with tofacitinib and is codirector of rheumatology at Texas Health Presbyterian Medical Center in Dallas.

"What will practicing rheumatologists with no experience with the drug do? We’ll see what the FDA says. They might use it after methotrexate, because the data are strong. It will be up to patients: an oral drug or an injected one."

Pfizer, the company developing tofacitinib, reported data from five phase III trials and safety experience in about 4,800 patients to the FDA Advisory Committee in May. And four of the five trials examined use of the drug in RA patients as monotherapy; in combination with methotrexate; in combination with background methotrexate in patients who failed to respond to an anti-TNF drug; and in combination with a background disease modifying antirheumatic drug. The fifth study, a 2-year trial that so far has reported results from an interim, 1-year analysis only, examined tofacitinib’s ability when used in combination with methotrexate to stop radiographic progression of joint damage, compared with methotrexate alone.

Results from across the studies showed consistent efficacy, including inhibition of radiographic progression that significantly surpassed placebo patients, and a "consistent side effect profile," Dr. Kremer said. "I consider it on the same shelf for potential infections and adverse events as the [already approved] biologics," he said in an interview. He said he would shy away from prescribing tofacitinib, or any biologic, to patients who get frequent pneumonia, cellulitis, or other infections.

Perceived safety will likely be the major driver – or impediment – for use of tofacitinib during the first year or 2 after its approval, predicted Madhuri Borde, Ph.D., director of the immune and inflammatory disorders group of Decision Resources, a pharmaceutical-market consulting company in Burlington, Mass. In mid-May, Dr. Borde presented 52 U.S. rheumatologists with active RA practices the same tofacitinib data that the FDA Advisory Committee saw and she asked the rheumatologists what they thought of the drug and how they might use it soon after it hit the U.S. market.*

The results showed that rheumatologists were impressed by the efficacy results, saw safety as being similar to anti-TNF drugs, and mostly saw tofacitinib currently as a drug they would use when RA patients don’t respond to an anti-TNF agent. "For physicians, it boils down to their comfort with the safety profile," she said in an interview, and they think safety is still a little uncertain.

Although Dr. Borde conceded that "patients are wary of injections" and that oral dosing is an attractive option for many patients, physician uncertainty about safety will generally trump that. "I think safety concerns will drive caution in using tofacitinib," at least during the first couple of years on the market, until a higher comfort level is reached. It’s likely that in an effort to stimulate interest in the drug, Pfizer will price it aggressively, at a small but significant discount to anti-TNF drugs. But even a cost savings probably won’t be enough early on to knock the anti-TNFs from their established RA perch, she said.

Dr. Kremer said that he has received research support from and has been a consultant to Pfizer and several other drugs companies. Dr. McInnes said that he has received research support from and has been a consultant to and speaker for Pfizer and several other drug companies. Dr. Fleischmann said that he has received research support from and has been a consultant to Pfizer and several other drug companies. Dr. Borde said that she had no disclosures.

*New information about Dr. Borde's title has been added to this story.

UPDATED: 06/21/2012

BERLIN – If the Food and Drug Administration follows the advice of its Arthritis Advisory Committee and approves tofacitinib as a new drug for treating rheumatoid arthritis later this summer, the oral, small-molecule drug may start to muscle in on the treatment turf now occupied by antitumor necrosis factor drugs, some experts predicted at the Annual European Congress of Rheumatology.

The attraction would be the good efficacy tofacitinib has shown in five phase III trials, a decent safety profile that looks on par with antitumor necrosis factor (TNF) drugs, and delivery as a twice-daily oral pill, a property that will give tofacitinib an edge over the anti-TNFs and other biologics that require injection or infusion.

"The fact that [tofacitinib] is oral is something of an advantage, so there will be a role for it, and it makes sense therapeutically," Dr. Joel M. Kremer said at the meeting. "But we will need to be smart" on using tofacitinib and other new drugs from the same class to treat patients with rheumatoid arthritis (RA), and their use relative to methotrexate and the biologics, said Dr. Kremer, a rheumatologist and professor of medicine at Albany (N.Y.) Medical College.

Another view was that tofacitinib will need to prove its value in larger numbers of patients, and though it will be a welcome new option – first to market from the class of Janus kinase (JAK) inhibitors – it will take its initial place post approval behind the anti-TNFs, which have more than a decade’s track record, said Dr. Iain B. McInnes in a separate talk at the meeting. Many rheumatologists "feel they will kick in after a first biologic treatment," which itself comes after first-line methotrexate, said Dr. McInnes, a rheumatologist and professor and Muirhead Chair of Medicine at the University of Glasgow, Scotland.

"The efficacy we’ve seen [from tofacitinib and other JAK inhibitors] is very encouraging, but safety will be a major driver of clinical decisions and [will] influence the order of choice. If a patient does not get an adequate response from methotrexate after 3-6 months, I would add a biologic drug, especially an anti-TNF. Inevitably, there will be less safety assurance with the new drugs. The current role for JAK inhibitors is closer to the options like abatacept, rituximab, and tocilizumab, but I think that may change" once JAK inhibitors enter routine practice, Dr. McInnes said in his talk.

"I have a lot of experience with tofacitinib, and I’m very comfortable with it; if a patient wanted this drug, I would use it," said Dr. Roy Fleischmann, who led phase II and phase III trials with tofacitinib and is codirector of rheumatology at Texas Health Presbyterian Medical Center in Dallas.

"What will practicing rheumatologists with no experience with the drug do? We’ll see what the FDA says. They might use it after methotrexate, because the data are strong. It will be up to patients: an oral drug or an injected one."

Pfizer, the company developing tofacitinib, reported data from five phase III trials and safety experience in about 4,800 patients to the FDA Advisory Committee in May. And four of the five trials examined use of the drug in RA patients as monotherapy; in combination with methotrexate; in combination with background methotrexate in patients who failed to respond to an anti-TNF drug; and in combination with a background disease modifying antirheumatic drug. The fifth study, a 2-year trial that so far has reported results from an interim, 1-year analysis only, examined tofacitinib’s ability when used in combination with methotrexate to stop radiographic progression of joint damage, compared with methotrexate alone.

Results from across the studies showed consistent efficacy, including inhibition of radiographic progression that significantly surpassed placebo patients, and a "consistent side effect profile," Dr. Kremer said. "I consider it on the same shelf for potential infections and adverse events as the [already approved] biologics," he said in an interview. He said he would shy away from prescribing tofacitinib, or any biologic, to patients who get frequent pneumonia, cellulitis, or other infections.

Perceived safety will likely be the major driver – or impediment – for use of tofacitinib during the first year or 2 after its approval, predicted Madhuri Borde, Ph.D., director of the immune and inflammatory disorders group of Decision Resources, a pharmaceutical-market consulting company in Burlington, Mass. In mid-May, Dr. Borde presented 52 U.S. rheumatologists with active RA practices the same tofacitinib data that the FDA Advisory Committee saw and she asked the rheumatologists what they thought of the drug and how they might use it soon after it hit the U.S. market.*

The results showed that rheumatologists were impressed by the efficacy results, saw safety as being similar to anti-TNF drugs, and mostly saw tofacitinib currently as a drug they would use when RA patients don’t respond to an anti-TNF agent. "For physicians, it boils down to their comfort with the safety profile," she said in an interview, and they think safety is still a little uncertain.

Although Dr. Borde conceded that "patients are wary of injections" and that oral dosing is an attractive option for many patients, physician uncertainty about safety will generally trump that. "I think safety concerns will drive caution in using tofacitinib," at least during the first couple of years on the market, until a higher comfort level is reached. It’s likely that in an effort to stimulate interest in the drug, Pfizer will price it aggressively, at a small but significant discount to anti-TNF drugs. But even a cost savings probably won’t be enough early on to knock the anti-TNFs from their established RA perch, she said.

Dr. Kremer said that he has received research support from and has been a consultant to Pfizer and several other drugs companies. Dr. McInnes said that he has received research support from and has been a consultant to and speaker for Pfizer and several other drug companies. Dr. Fleischmann said that he has received research support from and has been a consultant to Pfizer and several other drug companies. Dr. Borde said that she had no disclosures.

*New information about Dr. Borde's title has been added to this story.

BERLIN – Prescribing hydroxychloroquine for the treatment of rheumatoid arthritis may reduce a patient’s risk of developing type 2 diabetes by more than 40%.

That’s the provocative implication of a longitudinal prospective observational study of 10,583 American patients with rheumatologist-diagnosed rheumatoid arthritis (RA) followed from 2000 through 2010. It’s a clinically important observation in light of the impact of diabetes on cardiovascular risk, Dr. Marie Holmqvist said at the annual European Congress of Rheumatology.

Findings from other, smaller studies also have shown the potential benefit of hydroxychloroquine in lowering the risk of diabetes in RA patients, but none was as large as this one (J. Clin. Rheumatol. 2011;17:115-20; JAMA 2007;298:187-93). The association has led some investigators to dub hydroxychloroquine "a diabetes drug in disguise" (BMJ Case Rep. 2009;2009. pii: bcr08.2008.0654).

At baseline, the patients with RA had an average age of 60 years and a mean 13.6-year disease duration. One-quarter of them were on hydroxychloroquine as mono- or combination therapy, 30% were on methotrexate with or without a tumor necrosis factor (TNF) inhibitor, and 42% were on other or no disease-modifying antirheumatic drugs (DMARDs).

During follow-up, 6.4% of subjects were diagnosed with new-onset type 2 diabetes. The incidence was 1.34 cases per 100 person-years. In a multivariate analysis adjusted for RA duration, ethnicity, body mass index, employment status, income, age, gender, comorbidity, and Health Assessment Questionnaire score, hydroxychloroquine use was independently associated with a 41% reduction in the likelihood of developing diabetes compared with Centers for Disease Control and Prevention–generated figures for the matched U.S. population.

Methotrexate with or without a TNF inhibitor was associated with a 20% decrease in the risk of diabetes as long as a patient wasn’t also on prednisone. If the methotrexate regimen included prednisone, the protective effect was lost. In contrast, hydroxychloroquine with prednisone remained protective, with an associated 40% risk reduction.

Prednisone by itself was associated with a 30% increased risk of developing diabetes. Most strikingly, golimumab (Simponi) was associated with a 12.3-fold increased risk. None of the other medications prescribed for RA showed a significant relationship with diabetes risk, reported Dr. Holmqvist of Karolinska University, Stockholm.

Her study was funded by the Karolinska Institute and the U.S. National Data Bank for Rheumatic Diseases. Dr. Holmqvist reported having no financial conflicts.

BERLIN – Prescribing hydroxychloroquine for the treatment of rheumatoid arthritis may reduce a patient’s risk of developing type 2 diabetes by more than 40%.

That’s the provocative implication of a longitudinal prospective observational study of 10,583 American patients with rheumatologist-diagnosed rheumatoid arthritis (RA) followed from 2000 through 2010. It’s a clinically important observation in light of the impact of diabetes on cardiovascular risk, Dr. Marie Holmqvist said at the annual European Congress of Rheumatology.

Findings from other, smaller studies also have shown the potential benefit of hydroxychloroquine in lowering the risk of diabetes in RA patients, but none was as large as this one (J. Clin. Rheumatol. 2011;17:115-20; JAMA 2007;298:187-93). The association has led some investigators to dub hydroxychloroquine "a diabetes drug in disguise" (BMJ Case Rep. 2009;2009. pii: bcr08.2008.0654).

At baseline, the patients with RA had an average age of 60 years and a mean 13.6-year disease duration. One-quarter of them were on hydroxychloroquine as mono- or combination therapy, 30% were on methotrexate with or without a tumor necrosis factor (TNF) inhibitor, and 42% were on other or no disease-modifying antirheumatic drugs (DMARDs).

During follow-up, 6.4% of subjects were diagnosed with new-onset type 2 diabetes. The incidence was 1.34 cases per 100 person-years. In a multivariate analysis adjusted for RA duration, ethnicity, body mass index, employment status, income, age, gender, comorbidity, and Health Assessment Questionnaire score, hydroxychloroquine use was independently associated with a 41% reduction in the likelihood of developing diabetes compared with Centers for Disease Control and Prevention–generated figures for the matched U.S. population.

Methotrexate with or without a TNF inhibitor was associated with a 20% decrease in the risk of diabetes as long as a patient wasn’t also on prednisone. If the methotrexate regimen included prednisone, the protective effect was lost. In contrast, hydroxychloroquine with prednisone remained protective, with an associated 40% risk reduction.

Prednisone by itself was associated with a 30% increased risk of developing diabetes. Most strikingly, golimumab (Simponi) was associated with a 12.3-fold increased risk. None of the other medications prescribed for RA showed a significant relationship with diabetes risk, reported Dr. Holmqvist of Karolinska University, Stockholm.

Her study was funded by the Karolinska Institute and the U.S. National Data Bank for Rheumatic Diseases. Dr. Holmqvist reported having no financial conflicts.

BERLIN – Prescribing hydroxychloroquine for the treatment of rheumatoid arthritis may reduce a patient’s risk of developing type 2 diabetes by more than 40%.

That’s the provocative implication of a longitudinal prospective observational study of 10,583 American patients with rheumatologist-diagnosed rheumatoid arthritis (RA) followed from 2000 through 2010. It’s a clinically important observation in light of the impact of diabetes on cardiovascular risk, Dr. Marie Holmqvist said at the annual European Congress of Rheumatology.

Findings from other, smaller studies also have shown the potential benefit of hydroxychloroquine in lowering the risk of diabetes in RA patients, but none was as large as this one (J. Clin. Rheumatol. 2011;17:115-20; JAMA 2007;298:187-93). The association has led some investigators to dub hydroxychloroquine "a diabetes drug in disguise" (BMJ Case Rep. 2009;2009. pii: bcr08.2008.0654).

At baseline, the patients with RA had an average age of 60 years and a mean 13.6-year disease duration. One-quarter of them were on hydroxychloroquine as mono- or combination therapy, 30% were on methotrexate with or without a tumor necrosis factor (TNF) inhibitor, and 42% were on other or no disease-modifying antirheumatic drugs (DMARDs).

During follow-up, 6.4% of subjects were diagnosed with new-onset type 2 diabetes. The incidence was 1.34 cases per 100 person-years. In a multivariate analysis adjusted for RA duration, ethnicity, body mass index, employment status, income, age, gender, comorbidity, and Health Assessment Questionnaire score, hydroxychloroquine use was independently associated with a 41% reduction in the likelihood of developing diabetes compared with Centers for Disease Control and Prevention–generated figures for the matched U.S. population.

Methotrexate with or without a TNF inhibitor was associated with a 20% decrease in the risk of diabetes as long as a patient wasn’t also on prednisone. If the methotrexate regimen included prednisone, the protective effect was lost. In contrast, hydroxychloroquine with prednisone remained protective, with an associated 40% risk reduction.

Prednisone by itself was associated with a 30% increased risk of developing diabetes. Most strikingly, golimumab (Simponi) was associated with a 12.3-fold increased risk. None of the other medications prescribed for RA showed a significant relationship with diabetes risk, reported Dr. Holmqvist of Karolinska University, Stockholm.

Her study was funded by the Karolinska Institute and the U.S. National Data Bank for Rheumatic Diseases. Dr. Holmqvist reported having no financial conflicts.