Skip Navigation


Rheumatology Advance Access originally published online on November 30, 2005
Rheumatology 2006 45(2):228-229; doi:10.1093/rheumatology/kei173
This Article
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
45/2/228    most recent
kei173v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (6)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Hocevar, A.
Right arrow Articles by Tomsic, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Hocevar, A.
Right arrow Articles by Tomsic, M.
Related Collections
Right arrow Rheumatoid Arthritis
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author 2005. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

LETTER TO THE EDITOR

Leflunomide-associated tuberculosis?

A. Hocevar, B. Rozman, S. Praprotnik, B. Lestan, D. Erzen1, V. Petric2 and M. Tomsic

Department of Rheumatology, University Medical Centre, Ljubljana, 1 University Clinic of Respiratory and Allergic Diseases, Golnik and 2 Department of Internal Medicine, General Hospital, Murska Sobota, Slovenia

Correspondence to: M. Tomsic, Department of Rheumatology, University Medical Centre, Vodnikova 62, 1000 Ljubljana, Slovenia. E-mail: matija.tomsic{at}guest.arnes.si

SIR, Tuberculosis (TB) is still one of the world's most frequently occurring infectious diseases. The incidence of active TB in Slovenia is 14.7 patients per 105 inhabitants [1]. In Spain, the risk of TB infection in rheumatoid arthritis (RA) patients is increased fourfold compared with the general Spanish population [2], which is not the case in the USA, a country with a low incidence of TB [3]. The major risk factor for active disease seems to be immunosuppressive therapy. Following the introduction of TNF-{alpha}-blocking agents in order to control RA, a growing number of active TB cases have been reported, leading to renewed interest in this disease.

One of the widely used and efficacious disease-modifying antirheumatic drugs (DMARDs) is leflunomide. We used leflunomide from early 1990 as part of early phase II studies [3] and later in phase III clinical trials [4]. Among 2000 randomly selected RA patients in Slovenia (with a population of 1.5 million adults and a prevalence of RA of 1.2%), 13% have been treated with leflunomide.

Adverse effects associated with leflunomide have been closely followed and, as documented, are generally mild and only seldom life-threatening even in a 5-yr follow up study [6]. We present five cases of active pulmonary TB that developed during treatment with leflunomide. Major characteristics of our patients are presented in Table 1.


View this table:
[in this window]
[in a new window]
  		TABLE 1. Patient characteristics

 
Cases of active TB following RA treatment with corticosteroids, methotrexate and TNF-{alpha}-blocking agents have already been reported. So far, to our knowledge, active TB in association with leflunomide treatment has not been described. Nevertheless, leflunomide might increase susceptibility to reactivation TB disease.

Two possible explanations exist: general immunosuppression and/or specific anti-TNF activity of leflunomide.

Leflunomide has anti-inflammatory and immunomodulatory properties. Its active metabolite mediates the suppression of B and T cells, inhibiting the de novo synthesis of pyrimidine nucleotides. Higher doses also inhibit tyrosine kinases, responsible for T and B cell signalling, with subsequent reduction in proinflammatory cytokines [7].

The suppressive effect of leflunomide on TNF-{alpha} signalling might be another possible mechanism for effectiveness in RA [8, 9]. It was demonstrated that leflunomide inhibits TNF-{alpha}-induced NF-{kappa}B activation, TNF-mediated cytotoxicity and the generation of TNF-induced reactive oxygen intermediates and lipid peroxidation [10].

Optimal activity of TNF-{alpha} and other cytokines (IFN-{gamma}, IL-12, IL-15) is crucial in host defence against bacteria, including Mycobacterium tuberculosis. The essential role of TNF-{alpha} has been shown in studies on animal models indicating that inhibition of TNF-{alpha} increases the frequency and severity of reactivation TB disease. This cytokine acts in granuloma formation [11].

An analogy can be drawn with the use of biological anti-TNF-{alpha} agents, where increased TB risk and frequency has been reported [12]. However, in contrast to reactivation TB disease in patients treated with TNF-{alpha} blockers, where presentation is frequently atypical, disseminated and extrapulmonary, the pattern of TB disease in our cases was classical pulmonary. This difference also exists in the period between introduction of the immunosuppressive therapy and the occurrence of TB, which in our cases was longer (average duration 66 weeks) than in TB cases associated with infliximab, where the median duration reported was 11 weeks [13].

In four out of five patients, leflunomide was the only DMARD used at the time of TB manifestation, in three cases it was combined with corticosteroids (methylprednisolone ≤8 mg daily), and in one case with methotrexate (7.5 mg weekly). In the patients treated with a combination of leflunomide and methotrexate or corticosteroids, we cannot exclude the contribution of both concomitant drugs to active TB disease. However, it is less likely since methotrexate is a standard treatment and the most commonly prescribed drug for RA patients at our department, but until now we are not aware of any TB case connected with either methotrexate or corticosteroids in the last 5 yr.

In conclusion, it is unclear whether leflunomide therapy increases the risk of reactivation TB beyond the elevated rates of reactivation TB documented for RA patients. However, temporal association of reactivation TB disease and leflunomide treatment may suggest this possibility. Reported cases underline the necessity of careful monitoring for reactivation TB disease during treatment with leflunomide.
Figure 1

The authors have declared no conflicts of interest. B.R. has participated as a site investigator in phase II and III clinical trials of leflunomide and S.P. and M.T. as co-investigators.

References

  1. Praprotnik S, Rozman B, Tomsic M. New issues in tuberculosis. Ann Rheum Dis 2005;64:795.[Free Full Text]
  2. Carmona L, Hernandez-Garcia C, Vadillo C et al. Increased risk of tuberculosis in patients with rheumatoid arthritis. J Rheumatol 2003;30:1436–9.[Abstract/Free Full Text]
  3. Wolfe F, Michaud K, Anderson J, Urbansky K. Tuberculosis infection in patients with rheumatoid arthritis and the effect of infliximab therapy. Arthritis Rheum 2004;50:372–9.[CrossRef][Web of Science][Medline]
  4. Mladenovic V, Domljan Z, Rozman B et al. Safety and effectiveness of leflunomide in the treatment of patients with active rheumatoid arthritis. Results of a randomized, placebo-controlled, phase II study. Arthritis Rheum 1995;38:1595–603.[Web of Science][Medline]
  5. Smolen JS, Kalden JR, Scott DL et al. Efficacy and safety of leflunomide compared with placebo and sulphasalazine in active rheumatoid arthritis: a double-blind randomised, multicentre trial. European Leflunomide Study Group. Lancet 1999;353:259–66.[CrossRef][Web of Science][Medline]
  6. Kalden JR, Schattenkirchner M, Sorensen H et al. The efficacy and safety of leflunomide in patients with active rheumatoid arthritis: a five-year followup study. Arthritis Rheum 2003;48:1513–20.[CrossRef][Web of Science][Medline]
  7. Cannon GW, Kremer JM. Leflunomide. Rheum Dis Clin North Am 2004;30:295–309.[Medline]
  8. Alldred A, Emery P. Leflunomide: a novel DMARD for the treatment of rheumatoid arthritis. Expert Opin Pharmacother. 2001;2:125–37.[Medline]
  9. Miceli-Richard C, Dougados M. Leflunomide for the treatment of rheumatoid arthritis. Expert Opin Pharmacother 2003;4:987–97.[CrossRef][Web of Science][Medline]
  10. Manna SK, Mukhopadhyay A, Aggarwal BB. Leflunomide suppresses TNF-induced cellular responses: effects on NF-{kappa}B, activator protein-1, c-Jun N-terminal protein kinase and apoptosis. J Immunol 2000;165:5962–9.[Abstract/Free Full Text]
  11. Bieber J, Kavanaugh A. Consideration of the risk and treatment of tuberculosis in patients who have rheumatoid arthritis and receive biologic treatments. Rheum Dis Clin North Am 2004;30:257–70.[CrossRef][Medline]
  12. Wallis RS, Broder MS, Wong JY, Hanson ME, Beenhouwer DO. Granulomatous infectious diseases associated with tumor necrosis factor antagonists. Clin Infect Dis 2004;38:1261–5.[CrossRef][Web of Science][Medline]
  13. Keane J. Tumor necrosis factor blockers and reactivation of latent tuberculosis. Clin Infect Dis 2004:39:300–2.[CrossRef][Medline]
Accepted 23 September 2005


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Rheumatology (Oxford)Home page
R. Grover, V. Dhir, R. Aneja, V. Arya, A. Galle, V. Marwaha, and A. Kumar
Severe infections following leflunomide therapy for Rheumatoid Arthritis
Rheumatology, July 1, 2006; 45(7): 918 - 920.
[Full Text] [PDF]

This Article
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
45/2/228    most recent
kei173v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (6)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Hocevar, A.
Right arrow Articles by Tomsic, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Hocevar, A.
Right arrow Articles by Tomsic, M.
Related Collections
Right arrow Rheumatoid Arthritis
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?