Ann Rehabil Med.  2012 Apr;36(2):207-212. 10.5535/arm.2012.36.2.207.

The Effect of Leflunomide on Cold and Vibratory Sensation in Patients with Rheumatoid Arthritis

• Kim HK
• Park SB
• Park JW
• Jang SH
• Kim TH
• Sung YK
• Jun JB

• KMID: 2266758
• DOI: http://doi.org/10.5535/arm.2012.36.2.207

Abstract

OBJECTIVE
To evaluate the prevalence and risk factors of peripheral neuropathy in patients with rheumatoid arthritis (RA) treated with leflunomide (LEF) by quantitative sensory testing (QST). METHOD: A total of 94 patients were enrolledin this study, out of which 47 patients received LEF. The other 47 patients received alternative disease-modifying antirheumatic drugs and served as the control group. The demographic characteristics, laboratory findings, concomitant diseases, and medication history were evaluated at the time of QST. The cooling (CDT) and vibratory detection threshold (VDT) as the representative components of QST were measured.
RESULTS
Age, gender, RA duration, ESR, and CRP did not show any significant differences between the two groups. VDT did not demonstrate any significant difference in both groups. However, CDT in LEF group was significantly higher than that of the control group (8.6+/-2.7 in LEF vs. 5.6+/-3.8 in control). The proportion of RA patients in the LEF group showing abnormally high CDT was over 2 times greater than that of the control group, but these findings were not statistically significant. Age, RA duration (or LEF medication in LEF group), ESR, and CRP did not show significant correlation with CDT in both groups. VDT significantly correlated with age in both groups.
CONCLUSION
LEF treatment in patients with RA may lead to abnormal CDT in QST. CDT value was not affected by age, RA duration, disease activity, or LEF duration. It remains to be determined whether QST may be a valuable non-invasive instrument to evaluate the early sensory changes in patients with RA taking LEF.

Keyword

Rheumatoid arthritis; Polyneuropathy; Leflunomide; Quantitative sensory testing

MeSH Terms

Antirheumatic Agents
Arthritis, Rheumatoid
Cold Temperature
Humans
Isoxazoles
Peripheral Nervous System Diseases
Polyneuropathies
Prevalence
Risk Factors
Sensation
Antirheumatic Agents
Isoxazoles

Reference

1. Breedveld FC, Dayer JM. Leflunomide: mode of action in the treatment of rheumatoid arthritis. Ann Rheum Dis. 2000; 59:841–849. PMID: 11053058.

2. Elkayam O, Yaron I, Shirazi I, Judovitch R, Caspi D, Yaron M. Active leflunomide metabolite inhibits interleukin 1beta, tumor necrosis factor alpha, nitric oxide and metalloproteinase-3 production in activated human synovial tissue cultures. Ann Rheum Dis. 2003; 62:440–443. PMID: 12695157.

3. Palmer G, Burger D, Mezein F, Magne D, Gabay C, Dayer JM, Guerne PA. The active metabolite of leflunomide, A77 1726, increases the production of IL-1 receptor antagonist in human synovial fibroblasts and articular chondrocytes. Arthritis Res Ther. 2004; 6:R181–R189. PMID: 15142263.

4. Saag KG, Teng GG, Patkar NM, Anuntiyo J, Finney C, Curtis JR, Paulus HE, Mudano A, Pisu M, Elkins-Melton M, et al. American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis. Arthritis Rheum. 2008; 59:762–784. PMID: 18512708.

5. Kremer JM, Cannon GW. Benefit/risk of leflunomide in rheumatoid arthritis. Clin Exp Rheumatol. 2004; 22(5 suppl 35):S95–S100. PMID: 15552521.

6. van Riel PL, Smolen JS, Emery P, Kalden JR, Dougados M, Strand CV, Breedveld FC. Leflunomide: a manageable safety profile. J Rheumatol Suppl. 2004; 71:21–24. PMID: 15170904.

7. van Roon EN, Jansen TL, Houtman NM, Spoelstra P, Brouwers JR. Leflunomide for the treatment of rheumatoid arthritis in clinical practice: incidence and severity of hepatotoxicity. Drug Saf. 2004; 27:345–352. PMID: 15061688.

8. Rozman B, Praprotnik S, Logar D, Tomsic M, Hojnik M, Kos-Golja M, Accetto R, Dolenc P. Leflunomide and hypertension. Ann Rheum Dis. 2002; 61:567–569. PMID: 12006342.

9. Ito S, Sumida T. Interstitial lung disease associated with leflunomide. Intern Med. 2004; 43:1103–1104. PMID: 15645640.

10. Metzler C, Arlt AC, Gross WL, Brandt J. Peripheral neuropathy in patients with systemic rheumatic diseases treated with leflunomide. Ann Rheum Dis. 2005; 64:1798–1800. PMID: 16284351.

11. Martin K, Bentaberry F, Dumoulin C, Longy-Boursier M, Lifermann F, Haramburu F, Dehais J, Schaeverbeke T, Begaud B, Moore N. Neuropathy associated with leflunomide: a case series. Ann Rheum Dis. 2005; 64:649–650. PMID: 15769926.

12. Kho LK, Kermode AG. Leflunomide-induced peripheral neuropathy. J Clin Neurosci. 2007; 14:179–181. PMID: 17107800.

13. Richards BL, Spies J, McGill N, Richards GW, Vaile J, Bleasel JF, Youssef PP. Effect of leflunomide on the peripheral nerves in rheumatoid arthritis. Intern Med J. 2007; 37:101–107. PMID: 17229252.

14. American Diabetes Association American Academy of Neurology. Consensus statement: Report and recommendations of the San Antonio Conference of Diabetic Neuropathy. Diabetes Care. 1988; 11:592–597. PMID: 3060328.

15. Dyck PJ, Bushek W, Spring EM, Karnes JL, Litchy WJ, O'Brien PC, Service FJ. Vibratory and cooling detection threshold compared with other tests in diagnosing and staging diabetic neuropathy. Diabetes Care. 1987; 10:432–444. PMID: 3622200.

16. Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, Healey LA, Kaplan SR, Liang MH, Luthra HS, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988; 31:315–324. PMID: 3358796.

17. Bonnel RA, Graham DJ. Peripheral neuropathy in patients treated with leflunomide. Clin Pharmacol Ther. 2004; 75:580–585. PMID: 15179412.

18. Lee SM, Kim BJ. Diagnostic usefulness of quantitative sensory test in diabetic polyneuropathy: comparison with nerve conduction study. J Korean Neurol Assoc. 1999; 17:106–111.

19. Carulli MT, Davies UM. Peripheral neuropathy: an unwanted effect of leflunomide? Rheumatology. 2002; 41:952–953. PMID: 12154221.

20. Kim HC, Jun JB, Lee KA, Kim D, Kim HS, Kim SH. A case of peripheral neuropathy in a patient with rheumatoid arthritis treated with leflunomide. J Korean Rheum Assoc. 2008; 15:273–276.

21. Martin K, Bentaberry F, Dumoulin C, Miremont-Salame G, Haramburu F, Dehais J, Schaeverbeke T. Peripheral neuropathy associated with leflunomide: is there a risk patient profile? Pharmacoepidemiol Drug Saf. 2007; 16:74–78. PMID: 16845649.

22. Fox RI, Herrmann ML, Frangou CG, Wahl GM, Morris RE, Strand V, Kirschbaum BJ. Mechanism of action for leflunomide in rheumatoid arthritis. Clin Immunol. 1999; 93:198–208. PMID: 10600330.