Rheumatoid Arthritis

Steroids and hydroxychloroquine remain the most widely prescribed treatment options for pregnant women with rheumatologic diseases, according to a study looking at prescribing patterns in a cohort of women diagnosed with systemic lupus erythematosus, rheumatoid arthritis, psoriatic arthritis, or ankylosing spondylitis.

Lead investigator Dr. Rishi J. Desai of Brigham and Women’s Hospital and Harvard Medical School, both in Boston, and his colleagues found that the use of biologic agents during pregnancy, though still low, rose for 2,645 women from all regions of the United States covered by private insurance or Medicaid between 2001 and 2012. The investigators evaluated prescription filling records for steroids, nonbiologic disease-modifying agents, and biologics. The women in the study all had live births. Dr. Desai and his colleagues looked at scripts for individual agents filled in the 3-month period prior to each woman’s pregnancy and during her pregnancy (Arthritis Rheumatol. 2015 Nov 25. doi: 10.1002/art.39521).

©monkeybusinessimages/thinkstock.com

Nearly two-thirds of women with psoriatic arthritis or ankylosing spondylitis stopped filling immunomodulatory prescriptions during their pregnancies, while only 26% of lupus and 34.5% of rheumatoid arthritis patients did so. In the cohort as a whole, steroids and hydroxychloroquine were the most frequently used agents in pregnancy (48.4% and 27.1%, respectively). Steroid use during pregnancy dropped over time, from 54.4 per 100 deliveries to 42.4 between 2001 and 2012, while rates for biologics increased from 5.1 per 100 to 16.6 (P less than .001 for both trends).

“More comparative research on the safety of steroids as well as disease-modifying agents used during pregnancy will be critical for providing the necessary evidence to guide treatment decisions in future,” Dr. Desai and his colleagues wrote in their analysis.

The findings also suggest, the investigators wrote, “that with availability of some reassuring data indicating absence of a major fetal adverse event after biologic use in pregnancy, physicians have become more comfortable with continuing treatment with these agents.”

Use of agents potentially harmful to a developing fetus, including methotrexate, mycophenolate mofetil, and leflunomide, was very low in the study. However, the investigators noted, because their study enrolled only women with successful pregnancies, it could have underestimated the use of some of these agents, as women using them may have chosen to terminate their pregnancies.

The study received no outside funding. Two coauthors reported financial relationships with AstraZeneca, and one of them also reported funding from Pfizer and Eli Lilly.

Steroids and hydroxychloroquine remain the most widely prescribed treatment options for pregnant women with rheumatologic diseases, according to a study looking at prescribing patterns in a cohort of women diagnosed with systemic lupus erythematosus, rheumatoid arthritis, psoriatic arthritis, or ankylosing spondylitis.

Lead investigator Dr. Rishi J. Desai of Brigham and Women’s Hospital and Harvard Medical School, both in Boston, and his colleagues found that the use of biologic agents during pregnancy, though still low, rose for 2,645 women from all regions of the United States covered by private insurance or Medicaid between 2001 and 2012. The investigators evaluated prescription filling records for steroids, nonbiologic disease-modifying agents, and biologics. The women in the study all had live births. Dr. Desai and his colleagues looked at scripts for individual agents filled in the 3-month period prior to each woman’s pregnancy and during her pregnancy (Arthritis Rheumatol. 2015 Nov 25. doi: 10.1002/art.39521).

©monkeybusinessimages/thinkstock.com

Nearly two-thirds of women with psoriatic arthritis or ankylosing spondylitis stopped filling immunomodulatory prescriptions during their pregnancies, while only 26% of lupus and 34.5% of rheumatoid arthritis patients did so. In the cohort as a whole, steroids and hydroxychloroquine were the most frequently used agents in pregnancy (48.4% and 27.1%, respectively). Steroid use during pregnancy dropped over time, from 54.4 per 100 deliveries to 42.4 between 2001 and 2012, while rates for biologics increased from 5.1 per 100 to 16.6 (P less than .001 for both trends).

“More comparative research on the safety of steroids as well as disease-modifying agents used during pregnancy will be critical for providing the necessary evidence to guide treatment decisions in future,” Dr. Desai and his colleagues wrote in their analysis.

The findings also suggest, the investigators wrote, “that with availability of some reassuring data indicating absence of a major fetal adverse event after biologic use in pregnancy, physicians have become more comfortable with continuing treatment with these agents.”

Use of agents potentially harmful to a developing fetus, including methotrexate, mycophenolate mofetil, and leflunomide, was very low in the study. However, the investigators noted, because their study enrolled only women with successful pregnancies, it could have underestimated the use of some of these agents, as women using them may have chosen to terminate their pregnancies.

The study received no outside funding. Two coauthors reported financial relationships with AstraZeneca, and one of them also reported funding from Pfizer and Eli Lilly.

Steroids and hydroxychloroquine remain the most widely prescribed treatment options for pregnant women with rheumatologic diseases, according to a study looking at prescribing patterns in a cohort of women diagnosed with systemic lupus erythematosus, rheumatoid arthritis, psoriatic arthritis, or ankylosing spondylitis.

Lead investigator Dr. Rishi J. Desai of Brigham and Women’s Hospital and Harvard Medical School, both in Boston, and his colleagues found that the use of biologic agents during pregnancy, though still low, rose for 2,645 women from all regions of the United States covered by private insurance or Medicaid between 2001 and 2012. The investigators evaluated prescription filling records for steroids, nonbiologic disease-modifying agents, and biologics. The women in the study all had live births. Dr. Desai and his colleagues looked at scripts for individual agents filled in the 3-month period prior to each woman’s pregnancy and during her pregnancy (Arthritis Rheumatol. 2015 Nov 25. doi: 10.1002/art.39521).

©monkeybusinessimages/thinkstock.com

Nearly two-thirds of women with psoriatic arthritis or ankylosing spondylitis stopped filling immunomodulatory prescriptions during their pregnancies, while only 26% of lupus and 34.5% of rheumatoid arthritis patients did so. In the cohort as a whole, steroids and hydroxychloroquine were the most frequently used agents in pregnancy (48.4% and 27.1%, respectively). Steroid use during pregnancy dropped over time, from 54.4 per 100 deliveries to 42.4 between 2001 and 2012, while rates for biologics increased from 5.1 per 100 to 16.6 (P less than .001 for both trends).

“More comparative research on the safety of steroids as well as disease-modifying agents used during pregnancy will be critical for providing the necessary evidence to guide treatment decisions in future,” Dr. Desai and his colleagues wrote in their analysis.

The findings also suggest, the investigators wrote, “that with availability of some reassuring data indicating absence of a major fetal adverse event after biologic use in pregnancy, physicians have become more comfortable with continuing treatment with these agents.”

Use of agents potentially harmful to a developing fetus, including methotrexate, mycophenolate mofetil, and leflunomide, was very low in the study. However, the investigators noted, because their study enrolled only women with successful pregnancies, it could have underestimated the use of some of these agents, as women using them may have chosen to terminate their pregnancies.

The study received no outside funding. Two coauthors reported financial relationships with AstraZeneca, and one of them also reported funding from Pfizer and Eli Lilly.

SAN FRANCISCO – Patients with rheumatoid arthritis were five to nine times more likely to develop lower intestinal perforation on tocilizumab, compared with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), tumor necrosis factor inhibitors, abatacept, or rituximab, according to a large observational registry study.

“The increased risk could not be explained by glucocorticoid use or the age of the patients, which was similar to other patients treated with biologics,” said Dr. Anja Strangfeld of the German Rheumatism Research Center in Berlin. The findings reinforce previous smaller analyses of clinical trial data, and also localize the risk of perforation exclusively to the lower gastrointestinal tract, she added. “Overall, the mortality with lower intestinal perforation was high, and even higher with tocilizumab,” she said. “Tocilizumab patients with lower intestinal perforation present atypically, and patients starting treatment should be advised that symptoms might be mild, but the event is severe.”

Amy Karon/Frontline Medical News

Lower intestinal perforation is fairly rare, with a population-level incidence of about .04 cases for every 1,000 person-years. The risk in patients with rheumatoid arthritis (RA) is higher – anywhere from 0.15 to 1.3 cases per 1,000 person-years, Dr. Strangfeld noted. And the reported risk for tocilizumab is higher still, approaching two cases per 1,000 person-years, according to an analysis of 18 cases reported from clinical trials.

To better evaluate that risk, Dr. Strangfeld and her colleagues analyzed observational data collected between 2001 and 2015 for 15,000 patients with RA who were included in the German biologics registry, RABBIT. Patients were followed for 5-10 years, with Disease Activity Score in 28 joints (DAS28), treatment, and adverse events tracked every 6 months. Patients had been on RA therapies for about 7-14 years; tocilizumab patients had received the monoclonal antibody for an average of 10.6 years.

Medical record reviews confirmed 36 cases of lower intestinal perforation, 11 each on tocilizumab and csDMARDs, 12 on tumor necrosis factor (TNF) inhibitors, and one each on abatacept and rituximab. Notably, the incidence rate for lower intestinal perforation on tocilizumab was three cases per 1,000 person-years, compared with 0.5-0.6 cases per 1,000 person-years for csDMARDs, abatacept, and TNF inhibitors; and 0.2 cases per 1,000 person-years for rituximab, Dr. Strangfeld said at the annual meeting of the American College of Rheumatology.

Furthermore, four of the 11 patients who developed a perforation on tocilizumab only had late-onset abdominal pain, whereas more than 90% of those on csDMARDs had early, acute abdominal pain, Dr. Strangfeld said. That might have explained why 66% of the tocilizumab patients died, compared with 18%-25% of patients who perforated while on csDMARDs or TNF inhibitors. The tocilizumab patients also tended to report diffuse rather than localized pain and nausea or lack of appetite, but were rarely febrile. Their C-reactive protein levels were not elevated, in contrast to levels of 200-380 mg/L for cases involving csDMARDs or TNF inhibitors.

Patients who had a perforation while on tocilizumab or TNF inhibitors were receiving about two-thirds more prednisolone a day, compared with the average dose of about 5-6 mg for the entire cohort, Dr. Strangfeld reported. The risk of lower intestinal perforation rose by 130% with every 5-mg increase in prednisolone per day, and by 150% with every 10-year increase in age, she said. There was no difference in risk by sex, DAS28 score, body mass index, or number of previous biologics. Lower intestinal perforations occurred most often among patients with diverticulitis, as has been previously reported (Clin Rheumatol. 2011;30:1471-4). But “none of the patients with lower intestinal perforation had a history of diverticulitis known to the treating rheumatologist,” Dr. Strangfeld emphasized. “Most often, diverticulitis was diagnosed simultaneously with lower intestinal perforation.”

Dr. Strangfeld reported receiving unconditional research grants from AbbVie, Celltrion, Hospira, Bristol-Myers Squibb, Merck, Pfizer, Roche, and UCB Pharma.

SAN FRANCISCO – Patients with rheumatoid arthritis were five to nine times more likely to develop lower intestinal perforation on tocilizumab, compared with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), tumor necrosis factor inhibitors, abatacept, or rituximab, according to a large observational registry study.

“The increased risk could not be explained by glucocorticoid use or the age of the patients, which was similar to other patients treated with biologics,” said Dr. Anja Strangfeld of the German Rheumatism Research Center in Berlin. The findings reinforce previous smaller analyses of clinical trial data, and also localize the risk of perforation exclusively to the lower gastrointestinal tract, she added. “Overall, the mortality with lower intestinal perforation was high, and even higher with tocilizumab,” she said. “Tocilizumab patients with lower intestinal perforation present atypically, and patients starting treatment should be advised that symptoms might be mild, but the event is severe.”

Amy Karon/Frontline Medical News

Lower intestinal perforation is fairly rare, with a population-level incidence of about .04 cases for every 1,000 person-years. The risk in patients with rheumatoid arthritis (RA) is higher – anywhere from 0.15 to 1.3 cases per 1,000 person-years, Dr. Strangfeld noted. And the reported risk for tocilizumab is higher still, approaching two cases per 1,000 person-years, according to an analysis of 18 cases reported from clinical trials.

To better evaluate that risk, Dr. Strangfeld and her colleagues analyzed observational data collected between 2001 and 2015 for 15,000 patients with RA who were included in the German biologics registry, RABBIT. Patients were followed for 5-10 years, with Disease Activity Score in 28 joints (DAS28), treatment, and adverse events tracked every 6 months. Patients had been on RA therapies for about 7-14 years; tocilizumab patients had received the monoclonal antibody for an average of 10.6 years.

Medical record reviews confirmed 36 cases of lower intestinal perforation, 11 each on tocilizumab and csDMARDs, 12 on tumor necrosis factor (TNF) inhibitors, and one each on abatacept and rituximab. Notably, the incidence rate for lower intestinal perforation on tocilizumab was three cases per 1,000 person-years, compared with 0.5-0.6 cases per 1,000 person-years for csDMARDs, abatacept, and TNF inhibitors; and 0.2 cases per 1,000 person-years for rituximab, Dr. Strangfeld said at the annual meeting of the American College of Rheumatology.

Furthermore, four of the 11 patients who developed a perforation on tocilizumab only had late-onset abdominal pain, whereas more than 90% of those on csDMARDs had early, acute abdominal pain, Dr. Strangfeld said. That might have explained why 66% of the tocilizumab patients died, compared with 18%-25% of patients who perforated while on csDMARDs or TNF inhibitors. The tocilizumab patients also tended to report diffuse rather than localized pain and nausea or lack of appetite, but were rarely febrile. Their C-reactive protein levels were not elevated, in contrast to levels of 200-380 mg/L for cases involving csDMARDs or TNF inhibitors.

Patients who had a perforation while on tocilizumab or TNF inhibitors were receiving about two-thirds more prednisolone a day, compared with the average dose of about 5-6 mg for the entire cohort, Dr. Strangfeld reported. The risk of lower intestinal perforation rose by 130% with every 5-mg increase in prednisolone per day, and by 150% with every 10-year increase in age, she said. There was no difference in risk by sex, DAS28 score, body mass index, or number of previous biologics. Lower intestinal perforations occurred most often among patients with diverticulitis, as has been previously reported (Clin Rheumatol. 2011;30:1471-4). But “none of the patients with lower intestinal perforation had a history of diverticulitis known to the treating rheumatologist,” Dr. Strangfeld emphasized. “Most often, diverticulitis was diagnosed simultaneously with lower intestinal perforation.”

Dr. Strangfeld reported receiving unconditional research grants from AbbVie, Celltrion, Hospira, Bristol-Myers Squibb, Merck, Pfizer, Roche, and UCB Pharma.

SAN FRANCISCO – Patients with rheumatoid arthritis were five to nine times more likely to develop lower intestinal perforation on tocilizumab, compared with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), tumor necrosis factor inhibitors, abatacept, or rituximab, according to a large observational registry study.

“The increased risk could not be explained by glucocorticoid use or the age of the patients, which was similar to other patients treated with biologics,” said Dr. Anja Strangfeld of the German Rheumatism Research Center in Berlin. The findings reinforce previous smaller analyses of clinical trial data, and also localize the risk of perforation exclusively to the lower gastrointestinal tract, she added. “Overall, the mortality with lower intestinal perforation was high, and even higher with tocilizumab,” she said. “Tocilizumab patients with lower intestinal perforation present atypically, and patients starting treatment should be advised that symptoms might be mild, but the event is severe.”

Amy Karon/Frontline Medical News

Lower intestinal perforation is fairly rare, with a population-level incidence of about .04 cases for every 1,000 person-years. The risk in patients with rheumatoid arthritis (RA) is higher – anywhere from 0.15 to 1.3 cases per 1,000 person-years, Dr. Strangfeld noted. And the reported risk for tocilizumab is higher still, approaching two cases per 1,000 person-years, according to an analysis of 18 cases reported from clinical trials.

To better evaluate that risk, Dr. Strangfeld and her colleagues analyzed observational data collected between 2001 and 2015 for 15,000 patients with RA who were included in the German biologics registry, RABBIT. Patients were followed for 5-10 years, with Disease Activity Score in 28 joints (DAS28), treatment, and adverse events tracked every 6 months. Patients had been on RA therapies for about 7-14 years; tocilizumab patients had received the monoclonal antibody for an average of 10.6 years.

Medical record reviews confirmed 36 cases of lower intestinal perforation, 11 each on tocilizumab and csDMARDs, 12 on tumor necrosis factor (TNF) inhibitors, and one each on abatacept and rituximab. Notably, the incidence rate for lower intestinal perforation on tocilizumab was three cases per 1,000 person-years, compared with 0.5-0.6 cases per 1,000 person-years for csDMARDs, abatacept, and TNF inhibitors; and 0.2 cases per 1,000 person-years for rituximab, Dr. Strangfeld said at the annual meeting of the American College of Rheumatology.

Furthermore, four of the 11 patients who developed a perforation on tocilizumab only had late-onset abdominal pain, whereas more than 90% of those on csDMARDs had early, acute abdominal pain, Dr. Strangfeld said. That might have explained why 66% of the tocilizumab patients died, compared with 18%-25% of patients who perforated while on csDMARDs or TNF inhibitors. The tocilizumab patients also tended to report diffuse rather than localized pain and nausea or lack of appetite, but were rarely febrile. Their C-reactive protein levels were not elevated, in contrast to levels of 200-380 mg/L for cases involving csDMARDs or TNF inhibitors.

Patients who had a perforation while on tocilizumab or TNF inhibitors were receiving about two-thirds more prednisolone a day, compared with the average dose of about 5-6 mg for the entire cohort, Dr. Strangfeld reported. The risk of lower intestinal perforation rose by 130% with every 5-mg increase in prednisolone per day, and by 150% with every 10-year increase in age, she said. There was no difference in risk by sex, DAS28 score, body mass index, or number of previous biologics. Lower intestinal perforations occurred most often among patients with diverticulitis, as has been previously reported (Clin Rheumatol. 2011;30:1471-4). But “none of the patients with lower intestinal perforation had a history of diverticulitis known to the treating rheumatologist,” Dr. Strangfeld emphasized. “Most often, diverticulitis was diagnosed simultaneously with lower intestinal perforation.”

Dr. Strangfeld reported receiving unconditional research grants from AbbVie, Celltrion, Hospira, Bristol-Myers Squibb, Merck, Pfizer, Roche, and UCB Pharma.

SAN FRANCISCO – Autoantibodies in patients with rheumatoid arthritis target both the native and citrullinated forms of the RA33 autoantigen, challenging the idea that protein citrullination underlies loss of tolerance in this disease, Dr. Maximilian Konig said at the annual meeting of the American College of Rheumatology.

“I think the important thing is that this makes us rethink how RA actually starts,” Dr. Konig said in an interview. “We identified three different antibody groups that clinically behave very differently. We identified a group of patients that has cross-reactive antibodies against RA33, and they seem to be the ones with the highest and the most rapid disease progression. Maybe identifying these patients early and targeting them more would help bring a subset of patients with the most advanced and aggressive disease under better control.”

Amy Karon/Frontline Medical News

Signs and symptoms are often inconclusive early in the course of RA, leading to the search for reliable biomarkers that can hasten diagnosis and treatment. Anti-citrullinated protein antibodies (ACPAs) are one hallmark of RA, and protein citrullination has been seen as central to autoimmunity in its pathogenesis, said Dr. Konig, a postdoctoral fellow in rheumatology at Johns Hopkins University, Baltimore. But patients also have autoantibodies against native or unmodified proteins, including calpastatin, Fc-gamma, peptidylarginine deiminase type 4, and heterogeneous nuclear ribonucleoprotein A2/B1 (also known as RA33), which has been correlated with clinical disease activity, radiographic evidence of bone resorption, C-reactive protein levels, and erythrocyte sedimentation rate in a few previous studies (Pediatr Int. 2009 Apr;51[2]:188-92 and J Immunol Res. 2014;2014:516593).

Dr. Konig and his coinvestigators contended that current models of RA do not adequately account for autoimmunity against native proteins. To explore that idea, they tested sera from 196 patients from the ESCAPE RA (Evaluation of Subclinical Cardiovascular Disease and Predictors of Events in Rheumatoid Arthritis) cohort study and from 56 healthy controls. They used quantitative ELISA to identify autoantibodies, and performed immunoblotting and immunoprecipitation to test antibody specificity. They also used immunoblotting and mass spectrometry to study synovial fluid from the patients.

The assays identified citrullinated RA33 in the joints of RA patients, and revealed distinct autoantibodies that targeted native and citrullinated RA33. Furthermore, this single antibody system seemed to change with disease duration, Dr. Konig said. Autoantibody against native RA33 was almost exclusively found in samples from patients in early-stage disease, whereas patients with long-established RA had much higher levels of anti-citrullinated RA33 antibodies. The switch from a predominance of anti-RA33 to anti-citrullinated RA33 autoantibodies seemed to happen about a decade into the disease course, Dr. Konig added. “These data suggest that citrullination may not be required to break tolerance to RA33, and support a model in which RA autoantigens are initially targeted as a native protein, and only later become targets of a citrulline-specific response,” he said.

Notably, immunoprecipitation, immunoblotting, and competitive assays all confirmed a third type of autoantibody that cross-reacted against both RA33 and citrullinated RA33. The “RA33 [protein] is targeted by patient sera in three ways: only as a native protein, both as a native and as a citrullinated protein, and only as a citrullinated protein,” Dr. Konig concluded. He and his associates are exploring the clinical implications of the finding, particularly because patients with the cross-reactive anti-RA33 autoantibodies seem to have the most rapidly progressive and severe disease, he added. The presence of these antibodies might one day help identify a patient who needs especially aggressive monitoring and treatment, he concluded.

Dr. Konig had no disclosures.*

*This story was updated 12/3/2015.

SAN FRANCISCO – Autoantibodies in patients with rheumatoid arthritis target both the native and citrullinated forms of the RA33 autoantigen, challenging the idea that protein citrullination underlies loss of tolerance in this disease, Dr. Maximilian Konig said at the annual meeting of the American College of Rheumatology.

“I think the important thing is that this makes us rethink how RA actually starts,” Dr. Konig said in an interview. “We identified three different antibody groups that clinically behave very differently. We identified a group of patients that has cross-reactive antibodies against RA33, and they seem to be the ones with the highest and the most rapid disease progression. Maybe identifying these patients early and targeting them more would help bring a subset of patients with the most advanced and aggressive disease under better control.”

Amy Karon/Frontline Medical News

Signs and symptoms are often inconclusive early in the course of RA, leading to the search for reliable biomarkers that can hasten diagnosis and treatment. Anti-citrullinated protein antibodies (ACPAs) are one hallmark of RA, and protein citrullination has been seen as central to autoimmunity in its pathogenesis, said Dr. Konig, a postdoctoral fellow in rheumatology at Johns Hopkins University, Baltimore. But patients also have autoantibodies against native or unmodified proteins, including calpastatin, Fc-gamma, peptidylarginine deiminase type 4, and heterogeneous nuclear ribonucleoprotein A2/B1 (also known as RA33), which has been correlated with clinical disease activity, radiographic evidence of bone resorption, C-reactive protein levels, and erythrocyte sedimentation rate in a few previous studies (Pediatr Int. 2009 Apr;51[2]:188-92 and J Immunol Res. 2014;2014:516593).

Dr. Konig and his coinvestigators contended that current models of RA do not adequately account for autoimmunity against native proteins. To explore that idea, they tested sera from 196 patients from the ESCAPE RA (Evaluation of Subclinical Cardiovascular Disease and Predictors of Events in Rheumatoid Arthritis) cohort study and from 56 healthy controls. They used quantitative ELISA to identify autoantibodies, and performed immunoblotting and immunoprecipitation to test antibody specificity. They also used immunoblotting and mass spectrometry to study synovial fluid from the patients.

The assays identified citrullinated RA33 in the joints of RA patients, and revealed distinct autoantibodies that targeted native and citrullinated RA33. Furthermore, this single antibody system seemed to change with disease duration, Dr. Konig said. Autoantibody against native RA33 was almost exclusively found in samples from patients in early-stage disease, whereas patients with long-established RA had much higher levels of anti-citrullinated RA33 antibodies. The switch from a predominance of anti-RA33 to anti-citrullinated RA33 autoantibodies seemed to happen about a decade into the disease course, Dr. Konig added. “These data suggest that citrullination may not be required to break tolerance to RA33, and support a model in which RA autoantigens are initially targeted as a native protein, and only later become targets of a citrulline-specific response,” he said.

Notably, immunoprecipitation, immunoblotting, and competitive assays all confirmed a third type of autoantibody that cross-reacted against both RA33 and citrullinated RA33. The “RA33 [protein] is targeted by patient sera in three ways: only as a native protein, both as a native and as a citrullinated protein, and only as a citrullinated protein,” Dr. Konig concluded. He and his associates are exploring the clinical implications of the finding, particularly because patients with the cross-reactive anti-RA33 autoantibodies seem to have the most rapidly progressive and severe disease, he added. The presence of these antibodies might one day help identify a patient who needs especially aggressive monitoring and treatment, he concluded.

Dr. Konig had no disclosures.*

*This story was updated 12/3/2015.

SAN FRANCISCO – Autoantibodies in patients with rheumatoid arthritis target both the native and citrullinated forms of the RA33 autoantigen, challenging the idea that protein citrullination underlies loss of tolerance in this disease, Dr. Maximilian Konig said at the annual meeting of the American College of Rheumatology.

“I think the important thing is that this makes us rethink how RA actually starts,” Dr. Konig said in an interview. “We identified three different antibody groups that clinically behave very differently. We identified a group of patients that has cross-reactive antibodies against RA33, and they seem to be the ones with the highest and the most rapid disease progression. Maybe identifying these patients early and targeting them more would help bring a subset of patients with the most advanced and aggressive disease under better control.”

Amy Karon/Frontline Medical News

Signs and symptoms are often inconclusive early in the course of RA, leading to the search for reliable biomarkers that can hasten diagnosis and treatment. Anti-citrullinated protein antibodies (ACPAs) are one hallmark of RA, and protein citrullination has been seen as central to autoimmunity in its pathogenesis, said Dr. Konig, a postdoctoral fellow in rheumatology at Johns Hopkins University, Baltimore. But patients also have autoantibodies against native or unmodified proteins, including calpastatin, Fc-gamma, peptidylarginine deiminase type 4, and heterogeneous nuclear ribonucleoprotein A2/B1 (also known as RA33), which has been correlated with clinical disease activity, radiographic evidence of bone resorption, C-reactive protein levels, and erythrocyte sedimentation rate in a few previous studies (Pediatr Int. 2009 Apr;51[2]:188-92 and J Immunol Res. 2014;2014:516593).

Dr. Konig and his coinvestigators contended that current models of RA do not adequately account for autoimmunity against native proteins. To explore that idea, they tested sera from 196 patients from the ESCAPE RA (Evaluation of Subclinical Cardiovascular Disease and Predictors of Events in Rheumatoid Arthritis) cohort study and from 56 healthy controls. They used quantitative ELISA to identify autoantibodies, and performed immunoblotting and immunoprecipitation to test antibody specificity. They also used immunoblotting and mass spectrometry to study synovial fluid from the patients.

The assays identified citrullinated RA33 in the joints of RA patients, and revealed distinct autoantibodies that targeted native and citrullinated RA33. Furthermore, this single antibody system seemed to change with disease duration, Dr. Konig said. Autoantibody against native RA33 was almost exclusively found in samples from patients in early-stage disease, whereas patients with long-established RA had much higher levels of anti-citrullinated RA33 antibodies. The switch from a predominance of anti-RA33 to anti-citrullinated RA33 autoantibodies seemed to happen about a decade into the disease course, Dr. Konig added. “These data suggest that citrullination may not be required to break tolerance to RA33, and support a model in which RA autoantigens are initially targeted as a native protein, and only later become targets of a citrulline-specific response,” he said.

Notably, immunoprecipitation, immunoblotting, and competitive assays all confirmed a third type of autoantibody that cross-reacted against both RA33 and citrullinated RA33. The “RA33 [protein] is targeted by patient sera in three ways: only as a native protein, both as a native and as a citrullinated protein, and only as a citrullinated protein,” Dr. Konig concluded. He and his associates are exploring the clinical implications of the finding, particularly because patients with the cross-reactive anti-RA33 autoantibodies seem to have the most rapidly progressive and severe disease, he added. The presence of these antibodies might one day help identify a patient who needs especially aggressive monitoring and treatment, he concluded.

Dr. Konig had no disclosures.*

*This story was updated 12/3/2015.

SAN FRANCISCO – Filgotinib monotherapy yielded a 72% week 12 ACR 20 response for patients with rheumatoid arthritis and a 79% response when combined with methotrexate, according to two phase IIb dose-finding studies reported at the annual meeting of the American College of Rheumatology.

The Janus 1 kinase (JAK1) inhibitor caused dose-dependent increases in hemoglobin levels in both trials, and a few patients also had “substantial increases in creatinine, with some indication of a dose response,” said Dr. Arthur Kavanaugh, professor of clinical medicine and director of the Center for Innovative Therapy at the University of California, San Diego. But the overall safety profile for filgotinib was “attractive. We can see that this is an effective therapy,” he added.

Filgotinib, the first selective JAK1 inhibitor in development for rheumatoid arthritis, entered double-blind phase IIb trials in 2013. The DARWIN 1 trial compared filgotinib and a stable methotrexate dose with methotrexate and placebo in 594 patients with rheumatoid arthritis. The DARWIN 2 study compared filgotinib monotherapy with placebo in 283 patients who had not responded adequately to methotrexate. Patients in both trials were usually in their mid-fifties, had been diagnosed 7-10 years earlier, and had baseline 28-joint Disease Activity Score using C-reactive protein (DAS28-CRP) scores ranging from 6.0 to 6.2. The primary endpoint in both studies was the proportion of patients who achieved an ACR 20 response by week 12, said Dr. Rene R. Westhovens of KU Leuven (Belgium). He reported the results of DARWIN 1.

©kgtoh/thinkstockphotos.com

The combination regimen statistically outperformed methotrexate plus placebo at filgotinib doses of 100 mg once per day (week 12 ACR 20, 64% vs. 44%; P =.044), 200 mg once per day (69%; P less than .01), and 100 mg twice per day (79%; P less than .0001), Dr. Westhovens said. Filgotinib monotherapy also significantly outperformed placebo in terms of week 12 ACR 20, at all three doses tested – 50 mg once a day (67% vs. 29% for placebo), 100 mg once a day (66%), and 200 mg once a day (72%; all P less than .0001), according to Dr. Kavanaugh. “You might take away that perhaps the higher dose group got there faster. That should be the focus of future studies,” he said.

All three doses of filgotinib, given alone, also significantly outperformed placebo on several other endpoints, including ACR 50, ACR-N, DAS28-CRP, the Clinical Disease Activity Index, and the Simple Disease Activity Index, Dr. Kavanaugh added. By week 12, 24%-45% of patients who received filgotinib achieved low disease activity (DAS28-CRP of 3.2 or less), compared with 14% of the placebo group. Furthermore, after just 1 week of 100 mg or 200 mg of filgotinib per day, patients significantly improved on the ACR-N and the DAS28-CRP, compared with the placebo group.

Rates of serious adverse events were similar for the filgotinib and comparison groups in both trials, Dr. Kavanaugh and Dr. Westhovens reported. Notably, filgotinib was not associated with declines in natural killer cells or other forms of lymphopenia. Neutrophil counts declined slightly, compared with placebo, through 24 weeks, but did not seem to increase the risk of serious infections, although there was one case of cutaneous herpes zoster, Dr. Kavanaugh said. Likewise, rises in creatinine were usually mild and clinically insignificant, he added. “The reason for the rise in creatinine is unclear. It might be mechanistic, but whether we will see differences among the different [JAK] compounds remains to be elucidated,” he said.

Both DARWIN 1 and DARWIN 2 also reported dose-dependent rises in hemoglobin levels. Patients tended to have “small” increases in blood lipid levels, but the effects on HDL cholesterol were greater than for LDL cholesterol, Dr. Westhovens said.

For DARWIN 1, Dr. Westhovens reported financial support from Galapagos, the maker of filgotinib, and from Roche, Bristol-Myers Squibb, and Janssen. His senior author and three coauthors also reported financial relationships with Galapagos, and the other five coauthors had no disclosures. For DARWIN 2, Dr. Kavanaugh, his senior author, and three coauthors reported financial support from Galapagos, and five coauthors had no disclosures.

SAN FRANCISCO – Filgotinib monotherapy yielded a 72% week 12 ACR 20 response for patients with rheumatoid arthritis and a 79% response when combined with methotrexate, according to two phase IIb dose-finding studies reported at the annual meeting of the American College of Rheumatology.

The Janus 1 kinase (JAK1) inhibitor caused dose-dependent increases in hemoglobin levels in both trials, and a few patients also had “substantial increases in creatinine, with some indication of a dose response,” said Dr. Arthur Kavanaugh, professor of clinical medicine and director of the Center for Innovative Therapy at the University of California, San Diego. But the overall safety profile for filgotinib was “attractive. We can see that this is an effective therapy,” he added.

Filgotinib, the first selective JAK1 inhibitor in development for rheumatoid arthritis, entered double-blind phase IIb trials in 2013. The DARWIN 1 trial compared filgotinib and a stable methotrexate dose with methotrexate and placebo in 594 patients with rheumatoid arthritis. The DARWIN 2 study compared filgotinib monotherapy with placebo in 283 patients who had not responded adequately to methotrexate. Patients in both trials were usually in their mid-fifties, had been diagnosed 7-10 years earlier, and had baseline 28-joint Disease Activity Score using C-reactive protein (DAS28-CRP) scores ranging from 6.0 to 6.2. The primary endpoint in both studies was the proportion of patients who achieved an ACR 20 response by week 12, said Dr. Rene R. Westhovens of KU Leuven (Belgium). He reported the results of DARWIN 1.

©kgtoh/thinkstockphotos.com

The combination regimen statistically outperformed methotrexate plus placebo at filgotinib doses of 100 mg once per day (week 12 ACR 20, 64% vs. 44%; P =.044), 200 mg once per day (69%; P less than .01), and 100 mg twice per day (79%; P less than .0001), Dr. Westhovens said. Filgotinib monotherapy also significantly outperformed placebo in terms of week 12 ACR 20, at all three doses tested – 50 mg once a day (67% vs. 29% for placebo), 100 mg once a day (66%), and 200 mg once a day (72%; all P less than .0001), according to Dr. Kavanaugh. “You might take away that perhaps the higher dose group got there faster. That should be the focus of future studies,” he said.

All three doses of filgotinib, given alone, also significantly outperformed placebo on several other endpoints, including ACR 50, ACR-N, DAS28-CRP, the Clinical Disease Activity Index, and the Simple Disease Activity Index, Dr. Kavanaugh added. By week 12, 24%-45% of patients who received filgotinib achieved low disease activity (DAS28-CRP of 3.2 or less), compared with 14% of the placebo group. Furthermore, after just 1 week of 100 mg or 200 mg of filgotinib per day, patients significantly improved on the ACR-N and the DAS28-CRP, compared with the placebo group.

Rates of serious adverse events were similar for the filgotinib and comparison groups in both trials, Dr. Kavanaugh and Dr. Westhovens reported. Notably, filgotinib was not associated with declines in natural killer cells or other forms of lymphopenia. Neutrophil counts declined slightly, compared with placebo, through 24 weeks, but did not seem to increase the risk of serious infections, although there was one case of cutaneous herpes zoster, Dr. Kavanaugh said. Likewise, rises in creatinine were usually mild and clinically insignificant, he added. “The reason for the rise in creatinine is unclear. It might be mechanistic, but whether we will see differences among the different [JAK] compounds remains to be elucidated,” he said.

Both DARWIN 1 and DARWIN 2 also reported dose-dependent rises in hemoglobin levels. Patients tended to have “small” increases in blood lipid levels, but the effects on HDL cholesterol were greater than for LDL cholesterol, Dr. Westhovens said.

For DARWIN 1, Dr. Westhovens reported financial support from Galapagos, the maker of filgotinib, and from Roche, Bristol-Myers Squibb, and Janssen. His senior author and three coauthors also reported financial relationships with Galapagos, and the other five coauthors had no disclosures. For DARWIN 2, Dr. Kavanaugh, his senior author, and three coauthors reported financial support from Galapagos, and five coauthors had no disclosures.

SAN FRANCISCO – Filgotinib monotherapy yielded a 72% week 12 ACR 20 response for patients with rheumatoid arthritis and a 79% response when combined with methotrexate, according to two phase IIb dose-finding studies reported at the annual meeting of the American College of Rheumatology.

The Janus 1 kinase (JAK1) inhibitor caused dose-dependent increases in hemoglobin levels in both trials, and a few patients also had “substantial increases in creatinine, with some indication of a dose response,” said Dr. Arthur Kavanaugh, professor of clinical medicine and director of the Center for Innovative Therapy at the University of California, San Diego. But the overall safety profile for filgotinib was “attractive. We can see that this is an effective therapy,” he added.

Filgotinib, the first selective JAK1 inhibitor in development for rheumatoid arthritis, entered double-blind phase IIb trials in 2013. The DARWIN 1 trial compared filgotinib and a stable methotrexate dose with methotrexate and placebo in 594 patients with rheumatoid arthritis. The DARWIN 2 study compared filgotinib monotherapy with placebo in 283 patients who had not responded adequately to methotrexate. Patients in both trials were usually in their mid-fifties, had been diagnosed 7-10 years earlier, and had baseline 28-joint Disease Activity Score using C-reactive protein (DAS28-CRP) scores ranging from 6.0 to 6.2. The primary endpoint in both studies was the proportion of patients who achieved an ACR 20 response by week 12, said Dr. Rene R. Westhovens of KU Leuven (Belgium). He reported the results of DARWIN 1.

©kgtoh/thinkstockphotos.com

The combination regimen statistically outperformed methotrexate plus placebo at filgotinib doses of 100 mg once per day (week 12 ACR 20, 64% vs. 44%; P =.044), 200 mg once per day (69%; P less than .01), and 100 mg twice per day (79%; P less than .0001), Dr. Westhovens said. Filgotinib monotherapy also significantly outperformed placebo in terms of week 12 ACR 20, at all three doses tested – 50 mg once a day (67% vs. 29% for placebo), 100 mg once a day (66%), and 200 mg once a day (72%; all P less than .0001), according to Dr. Kavanaugh. “You might take away that perhaps the higher dose group got there faster. That should be the focus of future studies,” he said.

All three doses of filgotinib, given alone, also significantly outperformed placebo on several other endpoints, including ACR 50, ACR-N, DAS28-CRP, the Clinical Disease Activity Index, and the Simple Disease Activity Index, Dr. Kavanaugh added. By week 12, 24%-45% of patients who received filgotinib achieved low disease activity (DAS28-CRP of 3.2 or less), compared with 14% of the placebo group. Furthermore, after just 1 week of 100 mg or 200 mg of filgotinib per day, patients significantly improved on the ACR-N and the DAS28-CRP, compared with the placebo group.

Rates of serious adverse events were similar for the filgotinib and comparison groups in both trials, Dr. Kavanaugh and Dr. Westhovens reported. Notably, filgotinib was not associated with declines in natural killer cells or other forms of lymphopenia. Neutrophil counts declined slightly, compared with placebo, through 24 weeks, but did not seem to increase the risk of serious infections, although there was one case of cutaneous herpes zoster, Dr. Kavanaugh said. Likewise, rises in creatinine were usually mild and clinically insignificant, he added. “The reason for the rise in creatinine is unclear. It might be mechanistic, but whether we will see differences among the different [JAK] compounds remains to be elucidated,” he said.

Both DARWIN 1 and DARWIN 2 also reported dose-dependent rises in hemoglobin levels. Patients tended to have “small” increases in blood lipid levels, but the effects on HDL cholesterol were greater than for LDL cholesterol, Dr. Westhovens said.

For DARWIN 1, Dr. Westhovens reported financial support from Galapagos, the maker of filgotinib, and from Roche, Bristol-Myers Squibb, and Janssen. His senior author and three coauthors also reported financial relationships with Galapagos, and the other five coauthors had no disclosures. For DARWIN 2, Dr. Kavanaugh, his senior author, and three coauthors reported financial support from Galapagos, and five coauthors had no disclosures.

SAN FRANCISCO – It might be best to keep women with rheumatoid arthritis on their tumor necrosis factor blockers during pregnancy, according to German investigators.

They found that women are likely to flare without them and need more prednisolone, which is associated with preterm birth and other problems, while an increasing body of evidence suggests that tumor necrosis factor inhibitors (TNFis) are relatively safe during pregnancy.

“We should” rethink discontinuing TNFis during pregnancy, as recommended in some quarters. “We do not want women to flare during pregnancy,” said investigator Dr. Rebecca Fischer-Betz of the department of rheumatology at Heinrich Heine University in Düsseldorf.

She and her colleagues compared birth outcomes in 18 rheumatoid arthritis (RA) patients who discontinued TNFi treatment shortly after they got pregnant against those of 24 women with RA who were never exposed to a TNFi because, in general, they had less severe disease.

Twelve of the women (75%) in the TNFi group flared, versus four women (17%) in the control group. Although patients in both groups started with a mean 28-joint Disease Activity Score using C-reactive protein (DAS28-CRP) below 3.0, women in the TNFi group had a rise in activity to a mean of about 3.5 in the second trimester, while disease activity in control patients remained stable.

Compared with controls, women who stopped TNFis were also far more likely to flare (odds ratio, 10.0; 95% confidence interval, 2.3-42.8; P = .002), even after adjusting for age, DAS28-CRP at conception, rheumatoid factor and cyclic citrullinated peptide status, and other potential confounders. They also relied more heavily on prednisolone, taking, for example, a mean dose of 13 mg in the second trimester versus 8 mg in the control group. Perhaps not surprisingly, the mean duration of pregnancy was 37 weeks in the TNFi group, with six women (33%) delivering at or before 37 weeks; women in the control group delivered, on average, at 39 weeks, with four (17%) delivering at or before week 37.

The investigators found that the risk of preterm birth increased with every cumulative milligram of prednisolone (OR, 1.08; 95% CI, 1.02-1.15; P less than .01).

“Women with RA who discontinue TNFis at conception face a high risk for flares during pregnancy, independently of known risk factors like seropositivity. Flares are usually treated with prednisolone. We found a dose-dependent, significant increased risk for preterm birth associated with prednisolone. In this era of treat-to-target management of RA, our paradigm for RA pregnancy management may need adjusting. By controlling RA activity with medications considered relatively safe in pregnancy, we may be able to improve both the pregnancy experience and pregnancy outcomes,” the investigators concluded.

The women were 33 years old on average, and all had live births; four early miscarriages were excluded from analysis. All the pregnancies were planned, with methotrexate discontinued at least 3 months before conception. There was no statistical difference in the rate of seropositivity between the groups, “which is interesting because we know seropositivity is a risk factor for staying active during pregnancy,” Dr. Fischer-Betz said.

Two boys born to women who took TNFis had minor malformations, one with nasal bone aplasia, retrognathia, and hydronephrosis, and the other with hypospadias. Both of their mothers had taken etanercept (Enbrel) in the first trimester. There was one malformation in the control group, a girl born with hydronephrosis.

There was no outside funding for the work, and the investigators have no disclosures.

aotto@frontlinemedcom.com

SAN FRANCISCO – It might be best to keep women with rheumatoid arthritis on their tumor necrosis factor blockers during pregnancy, according to German investigators.

They found that women are likely to flare without them and need more prednisolone, which is associated with preterm birth and other problems, while an increasing body of evidence suggests that tumor necrosis factor inhibitors (TNFis) are relatively safe during pregnancy.

“We should” rethink discontinuing TNFis during pregnancy, as recommended in some quarters. “We do not want women to flare during pregnancy,” said investigator Dr. Rebecca Fischer-Betz of the department of rheumatology at Heinrich Heine University in Düsseldorf.

She and her colleagues compared birth outcomes in 18 rheumatoid arthritis (RA) patients who discontinued TNFi treatment shortly after they got pregnant against those of 24 women with RA who were never exposed to a TNFi because, in general, they had less severe disease.

Twelve of the women (75%) in the TNFi group flared, versus four women (17%) in the control group. Although patients in both groups started with a mean 28-joint Disease Activity Score using C-reactive protein (DAS28-CRP) below 3.0, women in the TNFi group had a rise in activity to a mean of about 3.5 in the second trimester, while disease activity in control patients remained stable.

Compared with controls, women who stopped TNFis were also far more likely to flare (odds ratio, 10.0; 95% confidence interval, 2.3-42.8; P = .002), even after adjusting for age, DAS28-CRP at conception, rheumatoid factor and cyclic citrullinated peptide status, and other potential confounders. They also relied more heavily on prednisolone, taking, for example, a mean dose of 13 mg in the second trimester versus 8 mg in the control group. Perhaps not surprisingly, the mean duration of pregnancy was 37 weeks in the TNFi group, with six women (33%) delivering at or before 37 weeks; women in the control group delivered, on average, at 39 weeks, with four (17%) delivering at or before week 37.

The investigators found that the risk of preterm birth increased with every cumulative milligram of prednisolone (OR, 1.08; 95% CI, 1.02-1.15; P less than .01).

“Women with RA who discontinue TNFis at conception face a high risk for flares during pregnancy, independently of known risk factors like seropositivity. Flares are usually treated with prednisolone. We found a dose-dependent, significant increased risk for preterm birth associated with prednisolone. In this era of treat-to-target management of RA, our paradigm for RA pregnancy management may need adjusting. By controlling RA activity with medications considered relatively safe in pregnancy, we may be able to improve both the pregnancy experience and pregnancy outcomes,” the investigators concluded.

The women were 33 years old on average, and all had live births; four early miscarriages were excluded from analysis. All the pregnancies were planned, with methotrexate discontinued at least 3 months before conception. There was no statistical difference in the rate of seropositivity between the groups, “which is interesting because we know seropositivity is a risk factor for staying active during pregnancy,” Dr. Fischer-Betz said.

Two boys born to women who took TNFis had minor malformations, one with nasal bone aplasia, retrognathia, and hydronephrosis, and the other with hypospadias. Both of their mothers had taken etanercept (Enbrel) in the first trimester. There was one malformation in the control group, a girl born with hydronephrosis.

There was no outside funding for the work, and the investigators have no disclosures.

aotto@frontlinemedcom.com

SAN FRANCISCO – It might be best to keep women with rheumatoid arthritis on their tumor necrosis factor blockers during pregnancy, according to German investigators.

They found that women are likely to flare without them and need more prednisolone, which is associated with preterm birth and other problems, while an increasing body of evidence suggests that tumor necrosis factor inhibitors (TNFis) are relatively safe during pregnancy.

“We should” rethink discontinuing TNFis during pregnancy, as recommended in some quarters. “We do not want women to flare during pregnancy,” said investigator Dr. Rebecca Fischer-Betz of the department of rheumatology at Heinrich Heine University in Düsseldorf.

She and her colleagues compared birth outcomes in 18 rheumatoid arthritis (RA) patients who discontinued TNFi treatment shortly after they got pregnant against those of 24 women with RA who were never exposed to a TNFi because, in general, they had less severe disease.

Twelve of the women (75%) in the TNFi group flared, versus four women (17%) in the control group. Although patients in both groups started with a mean 28-joint Disease Activity Score using C-reactive protein (DAS28-CRP) below 3.0, women in the TNFi group had a rise in activity to a mean of about 3.5 in the second trimester, while disease activity in control patients remained stable.

Compared with controls, women who stopped TNFis were also far more likely to flare (odds ratio, 10.0; 95% confidence interval, 2.3-42.8; P = .002), even after adjusting for age, DAS28-CRP at conception, rheumatoid factor and cyclic citrullinated peptide status, and other potential confounders. They also relied more heavily on prednisolone, taking, for example, a mean dose of 13 mg in the second trimester versus 8 mg in the control group. Perhaps not surprisingly, the mean duration of pregnancy was 37 weeks in the TNFi group, with six women (33%) delivering at or before 37 weeks; women in the control group delivered, on average, at 39 weeks, with four (17%) delivering at or before week 37.

The investigators found that the risk of preterm birth increased with every cumulative milligram of prednisolone (OR, 1.08; 95% CI, 1.02-1.15; P less than .01).

“Women with RA who discontinue TNFis at conception face a high risk for flares during pregnancy, independently of known risk factors like seropositivity. Flares are usually treated with prednisolone. We found a dose-dependent, significant increased risk for preterm birth associated with prednisolone. In this era of treat-to-target management of RA, our paradigm for RA pregnancy management may need adjusting. By controlling RA activity with medications considered relatively safe in pregnancy, we may be able to improve both the pregnancy experience and pregnancy outcomes,” the investigators concluded.

The women were 33 years old on average, and all had live births; four early miscarriages were excluded from analysis. All the pregnancies were planned, with methotrexate discontinued at least 3 months before conception. There was no statistical difference in the rate of seropositivity between the groups, “which is interesting because we know seropositivity is a risk factor for staying active during pregnancy,” Dr. Fischer-Betz said.

Two boys born to women who took TNFis had minor malformations, one with nasal bone aplasia, retrognathia, and hydronephrosis, and the other with hypospadias. Both of their mothers had taken etanercept (Enbrel) in the first trimester. There was one malformation in the control group, a girl born with hydronephrosis.

There was no outside funding for the work, and the investigators have no disclosures.

aotto@frontlinemedcom.com

SAN FRANCISCO – Oral methotrexate is frequently underdosed, given for an inadequate length of time, and rarely switched to subcutaneous formulations before rheumatologists move on to biologics, according to an analysis of claims data from 35,640 rheumatoid arthritis patients.

“There’re some major concerns here. Methotrexate is the anchor drug for rheumatoid arthritis, the best drug we have. More appropriate [use] could lead to better control” and “produce significant cost savings,” said investigator Dr. James O’Dell, chief of the division of rheumatology at the University of Nebraska Medical Center, Omaha.

When patients don’t fully respond to lower doses, the ground rules for oral methotrexate include escalation up to 25 mg or a switch to subcutaneous formulations, which have better bioavailability. Those moves should be considered before turning to biologics, Dr. O’Dell explained at the American College of Rheumatology annual meeting.

Rheumatologists, by and large, aren’t playing by those rules, according to the analysis. “We need to own these data because the majority of patients, over three-quarters, were treated by rheumatologists. We are not doing a great job,” Dr. ODell said.

The claims data came from Symphony Health Solutions, which captures about 92% of prescriptions written in the United States. The 35,640 rheumatoid arthritis patients in the study were started on methotrexate in 2009 and followed through 2014; 15,599 (43.8%) didn’t need anything else and stayed on oral methotrexate alone throughout the study period.

Prescribers, however, gave up on oral methotrexate at a mean dose of 15.3 mg and moved 17,528 patients (49%) straight to a biologic without giving subcutaneous methotrexate a shot. They did that after a median of less than 6 months, and within 3 months in more than 40% of patients.

Just 2,513 patients (7%) moved on to subcutaneous methotrexate when their oral formulation wasn’t enough. That’s all most of them needed; 1,802 (72%) remained on subcutaneous methotrexate alone for the remainder of the study period. The rest moved on to a biologic, but after a median of almost a year, not a few months. When their time on oral and subcutaneous methotrexate was included, their median time to a biologic was more than 2 years.

The investigators checked to see if things improved for patients who started on oral methotrexate in 2012. “The answer was no. We didn’t do better,” Dr. O’Dell said.

He didn’t speculate on why methotrexate is underused in the United States.

Claims data can’t address why patients were switched from methotrexate and other issues, but such nuances “don’t even begin to explain the doses and the timing of switch that we saw here,” he said.

Dr. O’Dell is an adviser for AbbVie, Lilly, Coherus, Bristol-Myers Squibb, Antares, and Medac. Other investigators disclosed relationships with those or other companies.

aotto@frontlinemedcom.com

SAN FRANCISCO – Oral methotrexate is frequently underdosed, given for an inadequate length of time, and rarely switched to subcutaneous formulations before rheumatologists move on to biologics, according to an analysis of claims data from 35,640 rheumatoid arthritis patients.

“There’re some major concerns here. Methotrexate is the anchor drug for rheumatoid arthritis, the best drug we have. More appropriate [use] could lead to better control” and “produce significant cost savings,” said investigator Dr. James O’Dell, chief of the division of rheumatology at the University of Nebraska Medical Center, Omaha.

When patients don’t fully respond to lower doses, the ground rules for oral methotrexate include escalation up to 25 mg or a switch to subcutaneous formulations, which have better bioavailability. Those moves should be considered before turning to biologics, Dr. O’Dell explained at the American College of Rheumatology annual meeting.

Rheumatologists, by and large, aren’t playing by those rules, according to the analysis. “We need to own these data because the majority of patients, over three-quarters, were treated by rheumatologists. We are not doing a great job,” Dr. ODell said.

The claims data came from Symphony Health Solutions, which captures about 92% of prescriptions written in the United States. The 35,640 rheumatoid arthritis patients in the study were started on methotrexate in 2009 and followed through 2014; 15,599 (43.8%) didn’t need anything else and stayed on oral methotrexate alone throughout the study period.

Prescribers, however, gave up on oral methotrexate at a mean dose of 15.3 mg and moved 17,528 patients (49%) straight to a biologic without giving subcutaneous methotrexate a shot. They did that after a median of less than 6 months, and within 3 months in more than 40% of patients.

Just 2,513 patients (7%) moved on to subcutaneous methotrexate when their oral formulation wasn’t enough. That’s all most of them needed; 1,802 (72%) remained on subcutaneous methotrexate alone for the remainder of the study period. The rest moved on to a biologic, but after a median of almost a year, not a few months. When their time on oral and subcutaneous methotrexate was included, their median time to a biologic was more than 2 years.

The investigators checked to see if things improved for patients who started on oral methotrexate in 2012. “The answer was no. We didn’t do better,” Dr. O’Dell said.

He didn’t speculate on why methotrexate is underused in the United States.

Claims data can’t address why patients were switched from methotrexate and other issues, but such nuances “don’t even begin to explain the doses and the timing of switch that we saw here,” he said.

Dr. O’Dell is an adviser for AbbVie, Lilly, Coherus, Bristol-Myers Squibb, Antares, and Medac. Other investigators disclosed relationships with those or other companies.

aotto@frontlinemedcom.com

SAN FRANCISCO – Oral methotrexate is frequently underdosed, given for an inadequate length of time, and rarely switched to subcutaneous formulations before rheumatologists move on to biologics, according to an analysis of claims data from 35,640 rheumatoid arthritis patients.

“There’re some major concerns here. Methotrexate is the anchor drug for rheumatoid arthritis, the best drug we have. More appropriate [use] could lead to better control” and “produce significant cost savings,” said investigator Dr. James O’Dell, chief of the division of rheumatology at the University of Nebraska Medical Center, Omaha.

When patients don’t fully respond to lower doses, the ground rules for oral methotrexate include escalation up to 25 mg or a switch to subcutaneous formulations, which have better bioavailability. Those moves should be considered before turning to biologics, Dr. O’Dell explained at the American College of Rheumatology annual meeting.

Rheumatologists, by and large, aren’t playing by those rules, according to the analysis. “We need to own these data because the majority of patients, over three-quarters, were treated by rheumatologists. We are not doing a great job,” Dr. ODell said.

The claims data came from Symphony Health Solutions, which captures about 92% of prescriptions written in the United States. The 35,640 rheumatoid arthritis patients in the study were started on methotrexate in 2009 and followed through 2014; 15,599 (43.8%) didn’t need anything else and stayed on oral methotrexate alone throughout the study period.

Prescribers, however, gave up on oral methotrexate at a mean dose of 15.3 mg and moved 17,528 patients (49%) straight to a biologic without giving subcutaneous methotrexate a shot. They did that after a median of less than 6 months, and within 3 months in more than 40% of patients.

Just 2,513 patients (7%) moved on to subcutaneous methotrexate when their oral formulation wasn’t enough. That’s all most of them needed; 1,802 (72%) remained on subcutaneous methotrexate alone for the remainder of the study period. The rest moved on to a biologic, but after a median of almost a year, not a few months. When their time on oral and subcutaneous methotrexate was included, their median time to a biologic was more than 2 years.

The investigators checked to see if things improved for patients who started on oral methotrexate in 2012. “The answer was no. We didn’t do better,” Dr. O’Dell said.

He didn’t speculate on why methotrexate is underused in the United States.

Claims data can’t address why patients were switched from methotrexate and other issues, but such nuances “don’t even begin to explain the doses and the timing of switch that we saw here,” he said.

Dr. O’Dell is an adviser for AbbVie, Lilly, Coherus, Bristol-Myers Squibb, Antares, and Medac. Other investigators disclosed relationships with those or other companies.

aotto@frontlinemedcom.com

SAN FRANCISCO – Biologics do not pose an increased risk of infection in patients with elderly-onset rheumatoid arthritis over the age of 60 years because their time to first infection and time to multiple infections were not different from people of the same age who developed the disease at a younger age in a large, prospective, longitudinal, observational study .

The data also suggest that noncytotoxic disease-modifying antirheumatic drugs (DMARDs) and non-TNF biologics may have a protective effect against infection in elderly patients with RA regardless of time of disease onset when compared with methotrexate monotherapy.

“Elderly-onset RA [EORA] patients are less likely to be treated with biologics than [are] patients with younger-onset RA [YORA]. This difference may be related to concerns about the risk of serious infections in elderly patients versus younger ones. There are only two papers on this subject in the literature, and now our study shows no increased risk. These findings support providing similar treatment for elderly versus younger-onset RA patients,” lead author Sofia Pedro of the National Data Bank for Rheumatic Diseases, Wichita, Kan., said at the annual meeting of the American College of Rheumatology.

The study was based on people with RA included in the National Data Bank for Rheumatic Diseases followed from 1998 through 2014. Patients filled out questionnaires on demographics, clinical factors, medications, and infections. A total of 1,865 EORA patients (onset older than 60 years) were matched 1:3 with 5,595 YORA patients (onset younger than 60 years) based on age, sex, and year of study entry.

At baseline, all patients were older than 60 years. The median age was between 65 and 70 years.

Serious infections were those that required hospitalization or intravenous antibiotics or caused death. Serious infectious were validated from hospital, physician, and death records. Overall, a total of 1,196 serious infections were reported during the study: 204 (11%) in the EORA group and 992 (18%) in YORA patients. Pneumonia, skin, and sepsis were the most common infections in both groups. Pneumonia was reported in 55% of EORA patients and 66% of the YORA group; skin infections, in 22% vs. 14%, respectively; and sepsis in 16% vs. 17%, respectively. The rate of self-reported prior infections was 4% in EORA patients and 7% in YORA patients (P less than .01). Overall, EORA patients were no quicker to have a first infection or multiple infections than were YORA patients after adjustments for Comorbidity Index, Health Assessment Questionnaire (HAQ), headache, pain, education, ethnicity, prednisone use, and urban versus rural setting.

Treatments were grouped according to noncytotoxic DMARDS; cytotoxic DMARDs; anti-TNF biologics; and non-TNF biologics. Methotrexate monotherapy was the referent. The hazard ratios for time to first infection and time to multiple infections were 0.72 and 0.82, respectively, for non-cytotoxic DMARDs and 0.43 and 0.48, respectively, for non-TNF biologics, all of which were statistically significant after adjustment for confounders.

EORA patients, compared with YORA patients, had greater exposure to prednisone and fewer prior serious infections, shorter disease duration (4.4 years vs. 20.9 years, respectively), lower Comorbidity Index, and more favorable disease markers. YORA patients had greater exposure to TNF biologics.

YORA patients had slightly higher incidence rates across all age groups, except between the ages of 60-70 years, when more infections were reported in EORA patients. The risk for multiple infections was greater in patients aged 80 years and older, but Ms. Pedro noted that covariates, such as HAQ, Comorbidity Index, prior serious infection, and exposure to prednisone, were associated with increased risk.

Ms. Pedro had no financial disclosures.

SAN FRANCISCO – Biologics do not pose an increased risk of infection in patients with elderly-onset rheumatoid arthritis over the age of 60 years because their time to first infection and time to multiple infections were not different from people of the same age who developed the disease at a younger age in a large, prospective, longitudinal, observational study .

The data also suggest that noncytotoxic disease-modifying antirheumatic drugs (DMARDs) and non-TNF biologics may have a protective effect against infection in elderly patients with RA regardless of time of disease onset when compared with methotrexate monotherapy.

“Elderly-onset RA [EORA] patients are less likely to be treated with biologics than [are] patients with younger-onset RA [YORA]. This difference may be related to concerns about the risk of serious infections in elderly patients versus younger ones. There are only two papers on this subject in the literature, and now our study shows no increased risk. These findings support providing similar treatment for elderly versus younger-onset RA patients,” lead author Sofia Pedro of the National Data Bank for Rheumatic Diseases, Wichita, Kan., said at the annual meeting of the American College of Rheumatology.

The study was based on people with RA included in the National Data Bank for Rheumatic Diseases followed from 1998 through 2014. Patients filled out questionnaires on demographics, clinical factors, medications, and infections. A total of 1,865 EORA patients (onset older than 60 years) were matched 1:3 with 5,595 YORA patients (onset younger than 60 years) based on age, sex, and year of study entry.

At baseline, all patients were older than 60 years. The median age was between 65 and 70 years.

Serious infections were those that required hospitalization or intravenous antibiotics or caused death. Serious infectious were validated from hospital, physician, and death records. Overall, a total of 1,196 serious infections were reported during the study: 204 (11%) in the EORA group and 992 (18%) in YORA patients. Pneumonia, skin, and sepsis were the most common infections in both groups. Pneumonia was reported in 55% of EORA patients and 66% of the YORA group; skin infections, in 22% vs. 14%, respectively; and sepsis in 16% vs. 17%, respectively. The rate of self-reported prior infections was 4% in EORA patients and 7% in YORA patients (P less than .01). Overall, EORA patients were no quicker to have a first infection or multiple infections than were YORA patients after adjustments for Comorbidity Index, Health Assessment Questionnaire (HAQ), headache, pain, education, ethnicity, prednisone use, and urban versus rural setting.

Treatments were grouped according to noncytotoxic DMARDS; cytotoxic DMARDs; anti-TNF biologics; and non-TNF biologics. Methotrexate monotherapy was the referent. The hazard ratios for time to first infection and time to multiple infections were 0.72 and 0.82, respectively, for non-cytotoxic DMARDs and 0.43 and 0.48, respectively, for non-TNF biologics, all of which were statistically significant after adjustment for confounders.

EORA patients, compared with YORA patients, had greater exposure to prednisone and fewer prior serious infections, shorter disease duration (4.4 years vs. 20.9 years, respectively), lower Comorbidity Index, and more favorable disease markers. YORA patients had greater exposure to TNF biologics.

YORA patients had slightly higher incidence rates across all age groups, except between the ages of 60-70 years, when more infections were reported in EORA patients. The risk for multiple infections was greater in patients aged 80 years and older, but Ms. Pedro noted that covariates, such as HAQ, Comorbidity Index, prior serious infection, and exposure to prednisone, were associated with increased risk.

Ms. Pedro had no financial disclosures.

SAN FRANCISCO – Biologics do not pose an increased risk of infection in patients with elderly-onset rheumatoid arthritis over the age of 60 years because their time to first infection and time to multiple infections were not different from people of the same age who developed the disease at a younger age in a large, prospective, longitudinal, observational study .

The data also suggest that noncytotoxic disease-modifying antirheumatic drugs (DMARDs) and non-TNF biologics may have a protective effect against infection in elderly patients with RA regardless of time of disease onset when compared with methotrexate monotherapy.

“Elderly-onset RA [EORA] patients are less likely to be treated with biologics than [are] patients with younger-onset RA [YORA]. This difference may be related to concerns about the risk of serious infections in elderly patients versus younger ones. There are only two papers on this subject in the literature, and now our study shows no increased risk. These findings support providing similar treatment for elderly versus younger-onset RA patients,” lead author Sofia Pedro of the National Data Bank for Rheumatic Diseases, Wichita, Kan., said at the annual meeting of the American College of Rheumatology.

The study was based on people with RA included in the National Data Bank for Rheumatic Diseases followed from 1998 through 2014. Patients filled out questionnaires on demographics, clinical factors, medications, and infections. A total of 1,865 EORA patients (onset older than 60 years) were matched 1:3 with 5,595 YORA patients (onset younger than 60 years) based on age, sex, and year of study entry.

At baseline, all patients were older than 60 years. The median age was between 65 and 70 years.

Serious infections were those that required hospitalization or intravenous antibiotics or caused death. Serious infectious were validated from hospital, physician, and death records. Overall, a total of 1,196 serious infections were reported during the study: 204 (11%) in the EORA group and 992 (18%) in YORA patients. Pneumonia, skin, and sepsis were the most common infections in both groups. Pneumonia was reported in 55% of EORA patients and 66% of the YORA group; skin infections, in 22% vs. 14%, respectively; and sepsis in 16% vs. 17%, respectively. The rate of self-reported prior infections was 4% in EORA patients and 7% in YORA patients (P less than .01). Overall, EORA patients were no quicker to have a first infection or multiple infections than were YORA patients after adjustments for Comorbidity Index, Health Assessment Questionnaire (HAQ), headache, pain, education, ethnicity, prednisone use, and urban versus rural setting.

Treatments were grouped according to noncytotoxic DMARDS; cytotoxic DMARDs; anti-TNF biologics; and non-TNF biologics. Methotrexate monotherapy was the referent. The hazard ratios for time to first infection and time to multiple infections were 0.72 and 0.82, respectively, for non-cytotoxic DMARDs and 0.43 and 0.48, respectively, for non-TNF biologics, all of which were statistically significant after adjustment for confounders.

EORA patients, compared with YORA patients, had greater exposure to prednisone and fewer prior serious infections, shorter disease duration (4.4 years vs. 20.9 years, respectively), lower Comorbidity Index, and more favorable disease markers. YORA patients had greater exposure to TNF biologics.

YORA patients had slightly higher incidence rates across all age groups, except between the ages of 60-70 years, when more infections were reported in EORA patients. The risk for multiple infections was greater in patients aged 80 years and older, but Ms. Pedro noted that covariates, such as HAQ, Comorbidity Index, prior serious infection, and exposure to prednisone, were associated with increased risk.

Ms. Pedro had no financial disclosures.

SAN FRANCISCO – A growing number of states are passing laws that set the parameters for how originator biologics may be replaced with biosimilars, and not all of them are helpful to physicians trying to maintain some knowledge and control over how prescriptions for biologics are dispensed, according to speakers at the annual meeting of the American College of Rheumatology.

These laws – now passed by a total of 19 states and Puerto Rico, including 12 in 2015 – address a requirement built into the Biologics Price Competition and Innovation Act of 2009 (part of the Affordable Care Act) that introduced the term “interchangeability” into the biosimilars approval pathway, stating that an approved biosimilar “may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product.” The law also gives 1 year of exclusive marketing rights to the first biosimilar approved as being interchangeable with the reference product.

Although regulations on how the Food and Drug Administration will deem a biosimilar to be interchangeable have yet to be drafted, it’s important for physicians to play an active role in shaping the laws that address interchangeability, said Dr. J. Eugene Huffstutter, a rheumatologist in private practice in Hixson, Tenn., and clinical assistant professor of medicine at the University of Tennessee, Chattanooga.

Dr. Huffstutter encouraged rheumatologists and other physicians to work with their local state medical associations to contact their state legislators to explain to them the need for strict laws on how biosimilars can be dispensed. He suggested that good state legislation on biosimilars should contain provisions stating that:

• Only FDA-approved interchangeable biosimilars can be substituted.

• No substitution can be made with “dispense as written” prescription.

• The prescribing physician must be notified of substitution within 1-5 days by electronic record or fax.

• The pharmacy must maintain a record of the dispensed drug.

Organizations including the ACR, the Coalition of State Rheumatology Organizations, patient groups, electronic prescribers, state medical societies, and pharmaceutical companies (for the most part) support strong state laws on biosimilars, while the pharmacy lobby and insurance companies have opposed them, Dr. Huffstutter said.

The 19 states with biosimilars laws include California, Colorado, Delaware, Florida, Georgia, Idaho, Illinois, Indiana, Louisiana, Massachusetts, New Jersey, North Carolina, North Dakota, Oregon, Tennessee, Texas, Utah, Virginia, and Washington, along with Puerto Rico. However, the laws in Oregon and Virginia will sunset in 2016. Another seven states have 2015 or current session legislation on biosimilar substitution: Hawaii, Maryland, Michigan, Mississippi, Oklahoma, Pennsylvania, and Vermont. States with bills that failed or were not acted upon at adjournment include Arizona, Arkansas, Nevada, and Rhode Island, according to information provided to Dr. Huffstutter by the Coalition.

State laws may differ on substitution notification, he noted. In Tennessee, the law (H.B. 572) states that notification should occur in “a reasonable period of time” instead of a defined period. “What may be reasonable for one person may not be reasonable for another. I really think 5 days is the outside time, or 5 business days, because if you’re thinking about some of the biosimilars that are coming down the pike, they’ll be given on a weekly basis, so you’ll at least know before [patients] get their second shot what they’re receiving,” Dr. Huffstutter noted.

Idaho is unique in that it impaneled a board of pharmacy regulation on biosimilar substitution rather than a separate law. It states that “A pharmacist may substitute an interchangeable biosimilar product for a prescribed biological product if the biosimilar has been determined by the FDA to be interchangeable and published in the Purple Book; the prescriber does not indicate by any means that the prescribed biological product must be dispensed; and the name of the drug and the manufacturer or the NDC [National Drug Code] number is documented in the patient medical record.”

The situation may become trickier as more biosimilars are approved, noted Dr. Huffstutter, who is a member of the ACR’s Government Affairs Committee and is a liaison to the Committee on Rheumatologic Care. It could potentially be a problem when a patient is taking a biosimilar for a particular originator biologic and then other biosimilars for that originator join the marketplace. A patient could potentially be switched from one biosimilar to another when a prescription is filled if the company marketing the second biosimilar happens to win a competitive bid with an insurance company, he said.

The filgrastim biosimilar called Zarxio is the only biosimilar currently approved in the United States, but the FDA has received two applications for biosimilars for inflammatory diseases: one from Celltrion for infliximab biosimilar Remsima (August 2014) and one from Sandoz for an etanercept biosimilar (October 2015). In addition to two infliximab biosimilars that have been approved in other countries, one etanercept biosimilar that has been approved in South Korea, and one adalimumab biosimilar approved in India, there are many others in development to treat inflammatory diseases as of July 2015, including 12 for adalimumab, 9 for etanercept, 5 for infliximab, 2 for tocilizumab, and 7 for rituximab, according to Dr. Jonathan Kay, professor of medicine and director of clinical research in the division of rheumatology at the University of Massachusetts, Worcester.

Unresolved regulatory concerns

In separate presentations at the meeting, Dr. Kay described many of the nuances that define biosimilars, which go by different terminology in other countries, such as “follow-on biologic” in Japan, “subsequent-entry biological” in Canada, and “similar biological medicinal product” in the European Union. They are defined as a legitimate copy of an off-patent biopharmaceutical that has undergone rigorous analytical comparison and clinical assessment, in comparison to its reference product, and are approved by a regulatory agency according to a specific pathway for biosimilar evaluation. These differ from biomimetics, which are developed as a replica of a biopharmaceutical but have not been developed, assessed, or approved according to regulatory guidelines for biosimilars.

The FDA takes a “totality of the evidence” approach to establish biosimilarity. The biosimilar pathway for approval is different from the originator pathway by relying more on analytical and preclinical studies and less on the clinical pharmacology and clinical trial data to support biosimilarity.

However, the agency has not yet published final guidance for all steps in demonstrating biosimilarity, particularly for clinical pharmacology data. Draft guidance says the biosimilar must be analyzed and assigned to an assessment grade: not similar, similar, highly similar, and highly similar with fingerprintlike similarity.

During production, both originator and biosimilar biopharmaceuticals can have protein-folding variants, misfolding, aggregation, enzymatic cleavage, and degradation that can lead to inactivation of the protein or increased immunogenicity. Even so, most biosimilars are not identical to the originator because of post-translational modifications, but they do not matter as long as they are not clinically meaningful. Even originator products can drift over time because small changes in manufacturing processes can lead to gradual changes in the molecule, Dr. Kay said.

Extrapolation of indications from the originator to a biosimilar is another area of concern, Dr. Kay said. The FDA will consider the extrapolation of data from a clinical trial of a biosimilar conducted in one disease to support approval for additional indications for which the originator product is already licensed, but not across indications with different mechanisms of action, such as between rheumatoid arthritis and non-Hodgkin’s lymphoma for rituximab. But for which inflammatory diseases should a biosimilar be studied to provide adequate information for extrapolation of indications? Dr. Kay asked. This situation brings about questions of whether dermatologists would be comfortable using a biosimilar that has been studied for rheumatoid arthritis to treat psoriasis or gastroenterologists using a drug with data only from psoriatic arthritis to treat Crohn’s disease or ulcerative colitis.

Both the Coalition of State Rheumatology Organizations and the ACR oppose extrapolation of indications from the clinical trial data of a biosimilar in one disease to support approval of additional indications for which the originator product is already licensed, but Dr. Kay thought that “extrapolation of indications makes perfect sense” because it won’t be possible to review a biosimilar for indications not already approved for the originator and it’s natural to extrapolate to already approved indications once the protein is shown to function nearly identically to the originator.

Ideally, the nomenclature system for biosimilars should clearly identify each product to improve pharmacovigilance and to differentiate between products that have not been determined to be interchangeable, Dr. Kay said. In August, the FDA announced draft guidance proposing that all biopharmaceutical products (originator and biosimilars) would have a nonproprietary name that includes a suffix of four lowercase letters that is devoid of meaning. For example, all products that share a core name such as replicamab would be named replicamab-cznm, replicamab-hixf, and so on, Dr. Kay said. Some people have voiced concern that it would be better for names to have some meaning, such as using an abbreviated name for the developing company along with the nonproprietary name of the originator product, but others noted that method could be problematic when companies merge or are acquired by others.

Dr. Huffstutter disclosed relationships with Janssen, UCB, Lilly, Pfizer, Genentech, Bristol-Myers Squibb, and Celgene. Dr. Kay has received grant and research support from many pharmaceutical companies and has served as a consultant or on an advisory board for many pharmaceutical companies, including those developing biosimilars.

jevans@frontlinemedcom.com

SAN FRANCISCO – A growing number of states are passing laws that set the parameters for how originator biologics may be replaced with biosimilars, and not all of them are helpful to physicians trying to maintain some knowledge and control over how prescriptions for biologics are dispensed, according to speakers at the annual meeting of the American College of Rheumatology.

These laws – now passed by a total of 19 states and Puerto Rico, including 12 in 2015 – address a requirement built into the Biologics Price Competition and Innovation Act of 2009 (part of the Affordable Care Act) that introduced the term “interchangeability” into the biosimilars approval pathway, stating that an approved biosimilar “may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product.” The law also gives 1 year of exclusive marketing rights to the first biosimilar approved as being interchangeable with the reference product.

Although regulations on how the Food and Drug Administration will deem a biosimilar to be interchangeable have yet to be drafted, it’s important for physicians to play an active role in shaping the laws that address interchangeability, said Dr. J. Eugene Huffstutter, a rheumatologist in private practice in Hixson, Tenn., and clinical assistant professor of medicine at the University of Tennessee, Chattanooga.

Dr. Huffstutter encouraged rheumatologists and other physicians to work with their local state medical associations to contact their state legislators to explain to them the need for strict laws on how biosimilars can be dispensed. He suggested that good state legislation on biosimilars should contain provisions stating that:

• Only FDA-approved interchangeable biosimilars can be substituted.

• No substitution can be made with “dispense as written” prescription.

• The prescribing physician must be notified of substitution within 1-5 days by electronic record or fax.

• The pharmacy must maintain a record of the dispensed drug.

Organizations including the ACR, the Coalition of State Rheumatology Organizations, patient groups, electronic prescribers, state medical societies, and pharmaceutical companies (for the most part) support strong state laws on biosimilars, while the pharmacy lobby and insurance companies have opposed them, Dr. Huffstutter said.

The 19 states with biosimilars laws include California, Colorado, Delaware, Florida, Georgia, Idaho, Illinois, Indiana, Louisiana, Massachusetts, New Jersey, North Carolina, North Dakota, Oregon, Tennessee, Texas, Utah, Virginia, and Washington, along with Puerto Rico. However, the laws in Oregon and Virginia will sunset in 2016. Another seven states have 2015 or current session legislation on biosimilar substitution: Hawaii, Maryland, Michigan, Mississippi, Oklahoma, Pennsylvania, and Vermont. States with bills that failed or were not acted upon at adjournment include Arizona, Arkansas, Nevada, and Rhode Island, according to information provided to Dr. Huffstutter by the Coalition.

State laws may differ on substitution notification, he noted. In Tennessee, the law (H.B. 572) states that notification should occur in “a reasonable period of time” instead of a defined period. “What may be reasonable for one person may not be reasonable for another. I really think 5 days is the outside time, or 5 business days, because if you’re thinking about some of the biosimilars that are coming down the pike, they’ll be given on a weekly basis, so you’ll at least know before [patients] get their second shot what they’re receiving,” Dr. Huffstutter noted.

Idaho is unique in that it impaneled a board of pharmacy regulation on biosimilar substitution rather than a separate law. It states that “A pharmacist may substitute an interchangeable biosimilar product for a prescribed biological product if the biosimilar has been determined by the FDA to be interchangeable and published in the Purple Book; the prescriber does not indicate by any means that the prescribed biological product must be dispensed; and the name of the drug and the manufacturer or the NDC [National Drug Code] number is documented in the patient medical record.”

The situation may become trickier as more biosimilars are approved, noted Dr. Huffstutter, who is a member of the ACR’s Government Affairs Committee and is a liaison to the Committee on Rheumatologic Care. It could potentially be a problem when a patient is taking a biosimilar for a particular originator biologic and then other biosimilars for that originator join the marketplace. A patient could potentially be switched from one biosimilar to another when a prescription is filled if the company marketing the second biosimilar happens to win a competitive bid with an insurance company, he said.

The filgrastim biosimilar called Zarxio is the only biosimilar currently approved in the United States, but the FDA has received two applications for biosimilars for inflammatory diseases: one from Celltrion for infliximab biosimilar Remsima (August 2014) and one from Sandoz for an etanercept biosimilar (October 2015). In addition to two infliximab biosimilars that have been approved in other countries, one etanercept biosimilar that has been approved in South Korea, and one adalimumab biosimilar approved in India, there are many others in development to treat inflammatory diseases as of July 2015, including 12 for adalimumab, 9 for etanercept, 5 for infliximab, 2 for tocilizumab, and 7 for rituximab, according to Dr. Jonathan Kay, professor of medicine and director of clinical research in the division of rheumatology at the University of Massachusetts, Worcester.

Unresolved regulatory concerns

In separate presentations at the meeting, Dr. Kay described many of the nuances that define biosimilars, which go by different terminology in other countries, such as “follow-on biologic” in Japan, “subsequent-entry biological” in Canada, and “similar biological medicinal product” in the European Union. They are defined as a legitimate copy of an off-patent biopharmaceutical that has undergone rigorous analytical comparison and clinical assessment, in comparison to its reference product, and are approved by a regulatory agency according to a specific pathway for biosimilar evaluation. These differ from biomimetics, which are developed as a replica of a biopharmaceutical but have not been developed, assessed, or approved according to regulatory guidelines for biosimilars.

The FDA takes a “totality of the evidence” approach to establish biosimilarity. The biosimilar pathway for approval is different from the originator pathway by relying more on analytical and preclinical studies and less on the clinical pharmacology and clinical trial data to support biosimilarity.

However, the agency has not yet published final guidance for all steps in demonstrating biosimilarity, particularly for clinical pharmacology data. Draft guidance says the biosimilar must be analyzed and assigned to an assessment grade: not similar, similar, highly similar, and highly similar with fingerprintlike similarity.

During production, both originator and biosimilar biopharmaceuticals can have protein-folding variants, misfolding, aggregation, enzymatic cleavage, and degradation that can lead to inactivation of the protein or increased immunogenicity. Even so, most biosimilars are not identical to the originator because of post-translational modifications, but they do not matter as long as they are not clinically meaningful. Even originator products can drift over time because small changes in manufacturing processes can lead to gradual changes in the molecule, Dr. Kay said.

Extrapolation of indications from the originator to a biosimilar is another area of concern, Dr. Kay said. The FDA will consider the extrapolation of data from a clinical trial of a biosimilar conducted in one disease to support approval for additional indications for which the originator product is already licensed, but not across indications with different mechanisms of action, such as between rheumatoid arthritis and non-Hodgkin’s lymphoma for rituximab. But for which inflammatory diseases should a biosimilar be studied to provide adequate information for extrapolation of indications? Dr. Kay asked. This situation brings about questions of whether dermatologists would be comfortable using a biosimilar that has been studied for rheumatoid arthritis to treat psoriasis or gastroenterologists using a drug with data only from psoriatic arthritis to treat Crohn’s disease or ulcerative colitis.

Both the Coalition of State Rheumatology Organizations and the ACR oppose extrapolation of indications from the clinical trial data of a biosimilar in one disease to support approval of additional indications for which the originator product is already licensed, but Dr. Kay thought that “extrapolation of indications makes perfect sense” because it won’t be possible to review a biosimilar for indications not already approved for the originator and it’s natural to extrapolate to already approved indications once the protein is shown to function nearly identically to the originator.

Ideally, the nomenclature system for biosimilars should clearly identify each product to improve pharmacovigilance and to differentiate between products that have not been determined to be interchangeable, Dr. Kay said. In August, the FDA announced draft guidance proposing that all biopharmaceutical products (originator and biosimilars) would have a nonproprietary name that includes a suffix of four lowercase letters that is devoid of meaning. For example, all products that share a core name such as replicamab would be named replicamab-cznm, replicamab-hixf, and so on, Dr. Kay said. Some people have voiced concern that it would be better for names to have some meaning, such as using an abbreviated name for the developing company along with the nonproprietary name of the originator product, but others noted that method could be problematic when companies merge or are acquired by others.

Dr. Huffstutter disclosed relationships with Janssen, UCB, Lilly, Pfizer, Genentech, Bristol-Myers Squibb, and Celgene. Dr. Kay has received grant and research support from many pharmaceutical companies and has served as a consultant or on an advisory board for many pharmaceutical companies, including those developing biosimilars.

jevans@frontlinemedcom.com

SAN FRANCISCO – A growing number of states are passing laws that set the parameters for how originator biologics may be replaced with biosimilars, and not all of them are helpful to physicians trying to maintain some knowledge and control over how prescriptions for biologics are dispensed, according to speakers at the annual meeting of the American College of Rheumatology.

These laws – now passed by a total of 19 states and Puerto Rico, including 12 in 2015 – address a requirement built into the Biologics Price Competition and Innovation Act of 2009 (part of the Affordable Care Act) that introduced the term “interchangeability” into the biosimilars approval pathway, stating that an approved biosimilar “may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product.” The law also gives 1 year of exclusive marketing rights to the first biosimilar approved as being interchangeable with the reference product.

Although regulations on how the Food and Drug Administration will deem a biosimilar to be interchangeable have yet to be drafted, it’s important for physicians to play an active role in shaping the laws that address interchangeability, said Dr. J. Eugene Huffstutter, a rheumatologist in private practice in Hixson, Tenn., and clinical assistant professor of medicine at the University of Tennessee, Chattanooga.

Dr. Huffstutter encouraged rheumatologists and other physicians to work with their local state medical associations to contact their state legislators to explain to them the need for strict laws on how biosimilars can be dispensed. He suggested that good state legislation on biosimilars should contain provisions stating that:

• Only FDA-approved interchangeable biosimilars can be substituted.

• No substitution can be made with “dispense as written” prescription.

• The prescribing physician must be notified of substitution within 1-5 days by electronic record or fax.

• The pharmacy must maintain a record of the dispensed drug.

Organizations including the ACR, the Coalition of State Rheumatology Organizations, patient groups, electronic prescribers, state medical societies, and pharmaceutical companies (for the most part) support strong state laws on biosimilars, while the pharmacy lobby and insurance companies have opposed them, Dr. Huffstutter said.

The 19 states with biosimilars laws include California, Colorado, Delaware, Florida, Georgia, Idaho, Illinois, Indiana, Louisiana, Massachusetts, New Jersey, North Carolina, North Dakota, Oregon, Tennessee, Texas, Utah, Virginia, and Washington, along with Puerto Rico. However, the laws in Oregon and Virginia will sunset in 2016. Another seven states have 2015 or current session legislation on biosimilar substitution: Hawaii, Maryland, Michigan, Mississippi, Oklahoma, Pennsylvania, and Vermont. States with bills that failed or were not acted upon at adjournment include Arizona, Arkansas, Nevada, and Rhode Island, according to information provided to Dr. Huffstutter by the Coalition.

State laws may differ on substitution notification, he noted. In Tennessee, the law (H.B. 572) states that notification should occur in “a reasonable period of time” instead of a defined period. “What may be reasonable for one person may not be reasonable for another. I really think 5 days is the outside time, or 5 business days, because if you’re thinking about some of the biosimilars that are coming down the pike, they’ll be given on a weekly basis, so you’ll at least know before [patients] get their second shot what they’re receiving,” Dr. Huffstutter noted.

Idaho is unique in that it impaneled a board of pharmacy regulation on biosimilar substitution rather than a separate law. It states that “A pharmacist may substitute an interchangeable biosimilar product for a prescribed biological product if the biosimilar has been determined by the FDA to be interchangeable and published in the Purple Book; the prescriber does not indicate by any means that the prescribed biological product must be dispensed; and the name of the drug and the manufacturer or the NDC [National Drug Code] number is documented in the patient medical record.”

The situation may become trickier as more biosimilars are approved, noted Dr. Huffstutter, who is a member of the ACR’s Government Affairs Committee and is a liaison to the Committee on Rheumatologic Care. It could potentially be a problem when a patient is taking a biosimilar for a particular originator biologic and then other biosimilars for that originator join the marketplace. A patient could potentially be switched from one biosimilar to another when a prescription is filled if the company marketing the second biosimilar happens to win a competitive bid with an insurance company, he said.

The filgrastim biosimilar called Zarxio is the only biosimilar currently approved in the United States, but the FDA has received two applications for biosimilars for inflammatory diseases: one from Celltrion for infliximab biosimilar Remsima (August 2014) and one from Sandoz for an etanercept biosimilar (October 2015). In addition to two infliximab biosimilars that have been approved in other countries, one etanercept biosimilar that has been approved in South Korea, and one adalimumab biosimilar approved in India, there are many others in development to treat inflammatory diseases as of July 2015, including 12 for adalimumab, 9 for etanercept, 5 for infliximab, 2 for tocilizumab, and 7 for rituximab, according to Dr. Jonathan Kay, professor of medicine and director of clinical research in the division of rheumatology at the University of Massachusetts, Worcester.

Unresolved regulatory concerns

In separate presentations at the meeting, Dr. Kay described many of the nuances that define biosimilars, which go by different terminology in other countries, such as “follow-on biologic” in Japan, “subsequent-entry biological” in Canada, and “similar biological medicinal product” in the European Union. They are defined as a legitimate copy of an off-patent biopharmaceutical that has undergone rigorous analytical comparison and clinical assessment, in comparison to its reference product, and are approved by a regulatory agency according to a specific pathway for biosimilar evaluation. These differ from biomimetics, which are developed as a replica of a biopharmaceutical but have not been developed, assessed, or approved according to regulatory guidelines for biosimilars.

The FDA takes a “totality of the evidence” approach to establish biosimilarity. The biosimilar pathway for approval is different from the originator pathway by relying more on analytical and preclinical studies and less on the clinical pharmacology and clinical trial data to support biosimilarity.

However, the agency has not yet published final guidance for all steps in demonstrating biosimilarity, particularly for clinical pharmacology data. Draft guidance says the biosimilar must be analyzed and assigned to an assessment grade: not similar, similar, highly similar, and highly similar with fingerprintlike similarity.

During production, both originator and biosimilar biopharmaceuticals can have protein-folding variants, misfolding, aggregation, enzymatic cleavage, and degradation that can lead to inactivation of the protein or increased immunogenicity. Even so, most biosimilars are not identical to the originator because of post-translational modifications, but they do not matter as long as they are not clinically meaningful. Even originator products can drift over time because small changes in manufacturing processes can lead to gradual changes in the molecule, Dr. Kay said.

Extrapolation of indications from the originator to a biosimilar is another area of concern, Dr. Kay said. The FDA will consider the extrapolation of data from a clinical trial of a biosimilar conducted in one disease to support approval for additional indications for which the originator product is already licensed, but not across indications with different mechanisms of action, such as between rheumatoid arthritis and non-Hodgkin’s lymphoma for rituximab. But for which inflammatory diseases should a biosimilar be studied to provide adequate information for extrapolation of indications? Dr. Kay asked. This situation brings about questions of whether dermatologists would be comfortable using a biosimilar that has been studied for rheumatoid arthritis to treat psoriasis or gastroenterologists using a drug with data only from psoriatic arthritis to treat Crohn’s disease or ulcerative colitis.

Both the Coalition of State Rheumatology Organizations and the ACR oppose extrapolation of indications from the clinical trial data of a biosimilar in one disease to support approval of additional indications for which the originator product is already licensed, but Dr. Kay thought that “extrapolation of indications makes perfect sense” because it won’t be possible to review a biosimilar for indications not already approved for the originator and it’s natural to extrapolate to already approved indications once the protein is shown to function nearly identically to the originator.

Ideally, the nomenclature system for biosimilars should clearly identify each product to improve pharmacovigilance and to differentiate between products that have not been determined to be interchangeable, Dr. Kay said. In August, the FDA announced draft guidance proposing that all biopharmaceutical products (originator and biosimilars) would have a nonproprietary name that includes a suffix of four lowercase letters that is devoid of meaning. For example, all products that share a core name such as replicamab would be named replicamab-cznm, replicamab-hixf, and so on, Dr. Kay said. Some people have voiced concern that it would be better for names to have some meaning, such as using an abbreviated name for the developing company along with the nonproprietary name of the originator product, but others noted that method could be problematic when companies merge or are acquired by others.

Dr. Huffstutter disclosed relationships with Janssen, UCB, Lilly, Pfizer, Genentech, Bristol-Myers Squibb, and Celgene. Dr. Kay has received grant and research support from many pharmaceutical companies and has served as a consultant or on an advisory board for many pharmaceutical companies, including those developing biosimilars.

jevans@frontlinemedcom.com