Background Methotrexate (MTX) is the most widely used DMARD in JIA. MTX is regarded to be a safe drug, effective in around 70% of JIA cases. Due to the frequent reoccurrence of disease after discontinuing drug therapy, MTX is often prescribed to patients over an extended period of time. However, little is known about its tolerability in long-term use in JIA.
Objectives To determine the frequency of adverse events in JIA patients on MTX and the frequency of drug discontinuation due to MTX intolerance.
Methods Patients treated with MTX and prospectively followed in the JIA biologic registers BiKeR and JuMBO were considered for this analysis. Adverse events (AEs) were categorized on the basis of MedDRA. Exposure-adjusted rates for AEs were calculated. MTX intolerance comprised defined preferred terms, representing well-known MTX-induced symptoms, such as nausea, vomiting, and abdominal pain, and direct reports of adverse drug reactions or refusal of MTX. Only events reported by physicians to have at least a possible causal relationship were considered as MTX-related.
Results Out of 848 JIA patients followed into adulthood, 725 patients were treated with MTX during the mean observation period of 7.3 years (6,188 patient-years of observation). During this period, patients had been exposed to MTX for a total of 2,762 years (exposure-years [EY]). At enrollment into the register, 687 patients were on MTX (61% of these in combination with a biologic), while at the last follow-up at which patients had a mean age of 21.7 years, only 296 patients were still on MTX (62% in combination with a biologic DMARD). Reasons for MTX discontinuation were provided for 323 cases. MTX was discontinued most frequently because of an AE (39%). Remission was the second most common reason (37%), followed by request from the patient in 22%, inefficacy was the least common reason in 9%. One in three patients received more than one course of MTX, with the first course being the longest with a median treatment duration of 2.6 years (second and third course 1.2 and 1.1 years, respectively).
During MTX exposure, 435 AEs (17.7/100 EY) and 50 serious AEs (1.8/100 EY) were considered by the physicians as causally related to MTX. Among these, intolerance dominated with 204 events (7.39/100 EY), followed by infections (n=68, 2.46/100 EY) and hepatotoxicity (n=29, 1.05/100 EY). The frequency of intolerance did not decrease, if patients received further courses of MTX; the exposure-adjusted intolerance rate was 4.3/100 EY during the first MTX course, 11.2, 5.6 and 14.3 during the second, third and fourth course of MTX, respectively.
Conclusions These results reflect the major problem of MTX intolerance in the long-term care of JIA patients. Intolerance is the leading cause of MTX discontinuation. Assuming that the request from the patient to stop MTX is related to symptoms experienced during drug exposure, about half of the cases discontinue MTX after almost 3 years due to intolerance. Re-exposure to the drug seems to further increase the intolerance rate of MTX.
Acknowledgements BiKeR and JuMBO are funded by unconditional grants from Abbvie, Pfizer, Roche.
Disclosure of Interest K. Minden Grant/research support from: Pfizer, Abbvie, Consultant for: Pfizer, Chugai, J. Klotsche: None declared, M. Niewerth: None declared, A. Zink Grant/research support from: AbbVie, BMS, GKS, Medac, MSD, Mundipharma, Roche, Sanofi, Pfizer, UCB, E. Seipelt: None declared, J.-P. Haas Grant/research support from: Pfizer, Novartis, G. Ganser: None declared, G. Horneff Grant/research support from: Pfizer, Abbvie, Roche/Chugai, Consultant for: Pfizer, Chugai