ROME – Biologic drug use in combination with methotrexate appears to carry the greatest risk for serious adverse events in patients with juvenile idiopathic arthritis when different biologics are tried sequentially, according to findings from a study of nearly 6,000 patients in the Pharmachild registry.
The results from the registry, the largest international pharmacovigilance juvenile idiopathic arthritis (JIA) database in the world, showed that patients who had used more than one biologic while on methotrexate had nearly twice the rate of adverse events as did those on methotrexate alone and more than three times the rate of serious adverse events, Dr. Joost F. Swart reported at the European Congress of Rheumatology.
The timing of “when to switch to a biological or even to a second one should not only be based on the activity of the joints as it is recommended nowadays, but should also take into account the different risk profiles of the drugs,” Dr. Swart, a pediatric rheumatologist/immunologist in the department of pediatric immunology and rheumatology in the Wilhelmina Children’s Hospital at University Medical Center Utrecht (the Netherlands), said in an interview. He received a clinical research abstract award for the research at the congress.
The study involved 5,862 JIA patients in the registry who continued methotrexate and either stayed on it alone (1,674) or also added one (3,025) or more biologics over time (1,163). The registry includes 93 centers of the Paediatric Rheumatology International Trials Organization (PRINTO) from more than 30 countries.
Most of the patients who had been treated with one biologic in addition to methotrexate had taken etanercept (66%), followed by adalimumab (19%), infliximab/tocilizumab (about 5% each), and other biologic agents (5%). Treatment experience with multiple biologics was most often with etanercept (30%), adalimumab (27%), infliximab (14%), tocilizumab (9%), abatacept (7%), anakinra (4%), golimumab (4%), and other biologic agents (5%). A total of 40% of children also were treated with corticosteroids (82% of those with systemic JIA); another 20% received other disease-modifying antirheumatic drugs. The patients’ JIA subtypes included systemic (10%), persistent oligoarticular (20%), polyarticular rheumatoid factor positive or negative (50%), and other JIA categories (20%).
Dr. Swart and his coauthors determined that the overall adverse event incidence rate per 100 patient-years was lowest in JIA patients who took methotrexate alone (10.7), intermediate in those who took methotrexate plus one biologic (13.9), and highest among patients who took methotrexate in combination with more than one biologic in sequence over time (19.5). Similar trends were observed for serious adverse events with methotrexate alone (3.0), with one biologic (4.7), and with more than one biologic (9.2).
Although the infection rate was higher for patients who took one biologic (4.6) in comparison with methotrexate alone (2.9), the rate did not increase significantly with more than one biologic (4.8). The same trend applied for serious infections (0.7, 1.4, and 2.0, respectively).
The median disease duration increased from methotrexate-only users (3.6 years) to those who used one biologic with methotrexate (5.4 years) and those who used more than one biologic (7.6 years). The investigators tracked more patient-years of use of one biologic (about 9,000) than two (about 2,800). The number of patient-years on methotrexate for those who took a biologic were not counted in the study.
The proportion of patients who discontinued treatment because of an adverse event or drug intolerance rose along with exposure to greater numbers of drugs, from 4% of methotrexate-only users to 16% of those exposed to a single biologic and 18% of those who took more than one biologic.
The group treated with more than one biologic had higher incidence rates for injury, poisoning and procedural complications, blood and lymphatic system disorders, and eye disorders than did the other groups, whereas methotrexate-only users had a higher incidence of hepatobiliary disorders.
“In due time, we will be able to predict which patients [age, sex, subcategory of JIA, disease activity score, which drugs/drug-combinations, etc.] have the highest risk for certain adverse events and make prediction rules for that. In that way, you might be able to prevent adverse events by specifically avoiding some drugs or drug combinations in certain patient categories or by taking precautionary measures” such as vaccination and antibiotic prophylaxis, Dr. Swart said in an interview.
Analyses are in progress for determining the relationships between individual biologics and adverse events and for differences in adverse events according to geographic area, he said.
Dr. Swart had no conflicts of interest to disclose, but many of his 28 coauthors disclosed relationships with companies that market the drugs used by patients in the registry.