Rheumatoid Arthritis Treatment - Synthetics
1262 Leflunomide Increases the Risk for Incident Peripheral Neuropathies in Patients with RA
Authors:
Strangfeld, Kekow, Krause, Blussmann, Hierse, Listing, Zink; Berlin, Germany
Anecdotal cases of peripheral neuropathy have been reported with the use of leflunomide in RA; however, no systematic evaluation has been performed. Strangfeld and colleagues explored cases of peripheral neuropathy in patients enrolled in the German biologics register, RABBIT.
Methods:
The RABBIT registry was queried for RA patients without peripheral neuropathy (PN) at baseline with subsequent follow-up for whom a definite explanation of the cause of the PN was not known. Incident PN was compared for those reporting leflunomide use the month before PN vs. those with no exposure.
Results:
Among the 5,017 patients without PN at baseline, 22 developed incident definite PN and 53 additional patients had symptoms suggestive of PN. Univariate associations with definite PN included older age, longer disease duration, and Sjogren’s syndrome. Disease activity scores and CRP were not associated with PN. Among therapies, 27% of enrolled subjects were taking leflunomide either as monotherapy or in combination. Among those with definite PN, 64% had received leflunomide in the month prior to incidence, yielding incidence rates of 5.2, 1.4, and 0.9 per 10,000 for those receiving leflunomide, methotrexate, and TNF inhibitors, respectively. In multivariable Cox regression models, incidence rate ratios (IRRs) for PN were increased for males vs. females (IRR 2.63; p=0.03); each 5 year increase in disease duration (IRR 1.28; p=0.003); leflunomide use (IRR 4.27; p=0.002); and presence of Sjogren’s (IRR 6.77; p=0.012).
Among the 22 with definite PN, 11 stopped leflunomide. Among these, 7 (64%) resolved or significantly improved, 1 was unchanged, 2 unknown, and the remaining patient died. Re-challenge occurred in three patients, one of whom had a relapse after 9 months. The remaining two withdrew leflunomide within 4 months for reasons other than PN. Overall, the median time on leflunomide to a definite PN event was 9.6 months.
Conclusions:
Leflunomide use, but not other DMARDs, was associated with incident PN. Most cases improved with withdrawal of the drug, but re-challenge may be associated with recurrent disease.
Editorial Comment:
Large numbers of well-characterized patients are required to detect rare outcomes associated with pharmaceuticals. The risk of PN identified here would not have been detected in clinical trials and requires pharmacoepidemiologic investigation, such as this one, to quantify risk. Even though the risk of PN associated with leflunomide observed here is quite low, PN can be associated with significant morbidity in many patients. Recognizing leflunomide as a possible cause, and the potential for improvement with withdrawal, are the major advances of this study. Whether cholestyramine wash-out should be used in cases of leflunomide PN was not addressed in this study.
