Peripheral neuropathy in patients on leflunomide

A. Bharadwaj and N. Haroon

Department of Immunology–Rheumatology, Kasturba Medical College, Manipal, India

Correspondence to: A. Bharadwaj, Department of Immunology-Rheumatology, Charaka Express, Kasturba Medical College, Manipal, Udupi District, Karnataka, India 576 104. E-mail: Anurag_Bharadwaj{at}hotmail.com

SIR, Much progress has been made in understanding the pathogenesis of rheumatoid arthritis. This has resulted in the development of novel therapeutic strategies. Leflunomide is a disease-modifying anti-rheumatic drug (DMARD) which is in vogue all over the world. The active metabolite of leflunomide, A77 1726, reversibly inhibits dihydroorotate dehydrogenase (DHODH), the rate-limiting step in the de novo synthesis of pyrimidines [1]. The side-effects so far reported in trials are gastrointestinal intolerance, elevation of liver enzymes, mild allergic reactions, reversible alopecia and hypertension [2]. Peripheral neuropathy has not been reported so far in these studies with leflunomide.

Our immunology–rheumatology clinic is part of a tertiary care centre in southern India. One hundred and fifty patients with rheumatoid arthritis (ACR criteria) attending our clinic between October 2000 and March 2003 formed the study cohort. All patients were given single or combination DMARDs. Patients who were already on DMARDs and those with confounding factors for neuropathy were excluded from the study. Patients were followed up at 1 month and then 2-monthly. A thorough clinical examination was done for any side-effects, and haemogram, liver function and renal function tests were obtained at each visit.

Fifty patients received leflunomide with or without methotrexate while 100 patients were on other medications (methotrexate, hydroxychloroquine and sulphasalazine alone or in combination). Leflunomide was given in a loading dose of 100 mg for 3 days and then 20 mg per day as single DMARD or 10 mg/day with methotrexate. Standard recommended dosage was used for the other DMARDs. The median follow-up period was 22 months (interquartile range 16, 28).

There was a significantly (P = 0.02, {chi}2 test) higher incidence of peripheral neuropathy in patients on leflunomide (5/50) compared with those on methotrexate (2/100). Among those who were on leflunomide, four were on a single drug while one also received methotrexate. Both patients in the other group were on methotrexate and hydroxychloroquine. The onset of neuropathy was on an average 3 months (range 45 days to 120 days) after the initiation of leflunomide. Peripheral neuropathy was suspected clinically and proved by nerve conduction studies. All patients had paraesthesiae. Three of these patients on leflunomide reported sleep disturbance due to this. One had a reduction (50%) in sensation of touch over the dorsum of both feet. None of the patients had loss of ankle reflex. Nerve conduction velocity (NCV) tests showed a motor axonal type of neuropathy in all seven patients.

A diligent search for the cause of neuropathy was made in all the patients, including blood sugar, thyroid function test, venereal disease research laboratory test, serum B12 levels, HIV, ELISA, ANA, serum proteins and myeloma screening. All tests failed to reveal a cause for the neuropathy. There were no confounding factors such as alcoholism or simultaneous intake of any neurotoxic drugs in any of the patients. Nerve biopsy was done in three patients with neuropathy in the leflunomide group. The other patients declined consent for this. Nerve biopsy showed epineural perivascular inflammation around small and medium-sized arterioles. There was prominent neovascularization and K-pal staining showed patchy loss of large and small myelinated fibres indicating a predominant axonopathic process and vasculitis in all three. On stopping leflunomide, all five patients reported significant improvement and were asymptomatic by the end of 3 months. This was, however, not confirmed by repeat NCV.

There was a strong temporal association to the onset of neuropathy and the introduction of leflunomide. The reversal of symptoms on discontinuing the drug also supports a relation between the two. Carulli and Davies [3] suggested the possibility of leflunomide-induced vasculitis leading to such a complication. At a time when leflunomide use is increasing widely, why patients on the drug are developing this hitherto rare complication needs to be investigated. In the meantime, physicians should be on the lookout for reversible motor axonal neuropathy in patients on leflunomide.

Informed consent was obtained from all patients. The article has full approval from the ethical committee of the hospital.

The authors have declared no conflicts of interest.

References

  1. Schiff MH, Strand V,d Oed C, Loew-Friedrich I. Leflunomide: efficacy and safety in clinical trials for the treatment of rheumatoid arthritis. Drugs Today 2000;36:383–94.[ISI]
  2. Osiri M, Shea B, Robinson V et al. Leflunomide for the treatment of rheumatoid arthritis: a systematic review and metaanalysis. J Rheumatol 2003;30:1182–90.[ISI][Medline]
  3. Carulli MT, Davies UM. Peripheral neuropathy: an unwanted effect of leflunomide? Rheumatology 2002;41:952–3.[Free Full Text]
Accepted 12 March 2004





This Article
Full Text (PDF)
Alert me when this article is cited
Alert me if a correction is posted
Services
Email this article to a friend
Similar articles in this journal
Similar articles in PubMed
Alert me to new issues of the journal
Add to My Personal Archive
Download to citation manager
Search for citing articles in:
ISI Web of Science (3)
Disclaimer
Request Permissions
Google Scholar
Articles by Bharadwaj, A.
Articles by Haroon, N.
PubMed
PubMed Citation
Articles by Bharadwaj, A.
Articles by Haroon, N.
Related Collections
Rheumatoid Arthritis