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To the Editor:

Rheumatoid arthritis (RA) is a common chronic inflammatory and destructive arthropathy that cannot be cured and that has substantial personal, social, and economic costs. Because of the imbalance existing in RA between the mediators that initiate and maintain inflammation and mediators that shut down the process leading to cellular damage¹, therapy in RA demands agents that block inflammation, retard synovial proliferation, and prevent joint erosion. Since proliferation is linked to inflammation, agents that limit immune responses may affect the entire process². Weekly methotrexate (MTX) played a dominant role in the 1980s and 1990s because its efficacy and safety were proved in short term trials and longterm observational studies³, but because of evidence of progressive bone loss and the inability to eliminate synovial proliferation with MTX, it became apparent that therapy for RA needed further advancement.

Infliximab is a humanized antibody against tumor necrosis factor-a (TNF-a) that is used in the treatment of RA. Infliximab neutralizes the TNF-a inflammatory effect by binding with its soluble subunit and membranous TNF-a so that it may not interact with its receptor⁴. The understanding of some of the biologic functions of TNF-a has led to concerns that agents inhibiting TNF-a may increase the risk of certain infections^5,6. In the last few months there have been reports of tuberculosis (TB) in patients treated with one such anti-TNF agent, infliximab⁷.

We describe the case of a 65-year-old woman with RA for 3 years, who had previously received treatment with MTX, azathioprine, sulfasalazine, hydroxychloroquine, corticosteroids, and nonsteroidal antiinflammatory drugs (NSAID), alone or in combination. Initially she improved, but therapy failed to suppress symptoms and prevent progression of the RA. Because of the inadequate response to other disease modifying antirheumatic drugs, she started infliximab as a part of her RA therapy, which by that time included prednisone 10 mg/day, azathioprine 50 mg/day, and NSAID. She had been found to be Mantoux positive, so after active disease was ruled out by chest radiograph and sputum culture, which were normal and negative, respectively, she had completed a course of prophylactic therapy with isoniazid for 6 months prior to starting infliximab. After 11 doses of infliximab (19 mo of therapy), she presented persistent aseptic leukocyturia. On urinalysis Mycobacterium tuberculosis was observed in the urine culture. Treatment with infliximab was immediately discontinued and tuberculostatic treatment started. The isolate had no resistance to usual anti-tuberculous medication.

It has been proposed that all patients in whom infliximab therapy is considered should be screened for both active and latent TB. In the event of active TB, patients should not receive infliximab or other anti-TNF agents. If latent TB is diagnosed, prophylactic therapy should be initiated prior to starting infliximab⁷, but because of the profound alterations in the immune response caused by infliximab, it may be reasonable to complete a course of prophylactic therapy with isoniazid. A course of 9 months may be necessary, as recommended by the US Centers for Disease Control in patients with human immunodeficiency virus infection⁸, in contrast to our local Spanish recommendations⁹, because of the absence of evidence that the traditional 6-month prophylactic therapy is efficacious in all such patients. Even in the healthy host there is no evidence of efficacy greater than 70%¹⁰.

Although TB is usually reactivated within the first few doses of infliximab, we believe that reactivation of latent TB was the mechanism in our patient. Nevertheless we cannot exclude the possibility, albeit rare, of recent infection nor the contribution of prednisone to the development of active disease. Finally, we would like to stress the need to rule out active TB, and if necessary, to complete at least 9 months of prophylactic therapy with INH, before starting infliximab¹¹.

JORGE PARRA RUIZ, MD; NORBERTO ORTEGO CENTENO, MD, ENRIQUE RAYA ALVAREZ, MD, Unidad de Enfermedades Autoimmunes Sistémicas, Servicio de Medicina Interna B, Servicio de Reumatología, Hospital Clínico San Cecilio, Granada, Spain.

REFERENCES

1. Epstein FH. Cytokine pathways and joint inflammation in rheumatoid arthritis. N Engl J Med 2001;344:907-16.

2. Pisetsky DS, St. Clair EW. Progress in the treatment of rheumatoid arthritis. JAMA 2001;286:2787-90.

3. Kremer JD. Rational use of new and existing disease-modifying agents in rheumatoid arthritis. Ann Intern Med 2001;134:695-706.

4. Scallon B, Cai A, Solowski N, et al. Binding and functional comparisons of two types of tumor necrosis factor antagonist. J Pharmacol Exp Ther 2002;301:418-26.

5. Nuñez Martínez O, Ripoll Noiseaux C, Carneros Martín JA, et al. Reactivation tuberculosis in a patient with anti-TNF alpha treatment. Am J Gastroenterol 2001;96:1665-6.

6. Keane J, Gershon S, Wise RP, et al. Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent. N Engl J Med 2001;345:1098-104.

7. Baker DG, Clark J, Keenan GF, et al. Tuberculosis occurring in patients receiving the anti-TNF agent infliximab [abstract]. Arthritis Rheum 2001;44 Suppl:S105.

8. Targeted tuberculin testing and treatment of latent tuberculosis infection. This official statement of the American Thoracic Society was adopted by the ATS Board of Directors, July 1999. This is a Joint Statement of the American Thoracic Society (ATS) and the Centers for Disease Control and Prevention (CDC). This statement was endorsed by the Council of the Infectious Diseases Society of America (IDSA), September 1999, and the sections of this statement. Am J Respir Crit Care Med 2000;161 Pt 2:S221-47.

9. Consensus document for tuberculosis prevention and control in Spain. Med Clin Barc 1999;113:710-5.

10. International Union Against Tuberculosis Committee on Prophylaxis. Efficacy of various durations of isoniazid preventive therapy for tuberculosis: five years of follow-up in the IUAT trial. Bull World Health Organ 1982;60:555-64.

11. Comstock GW. How much isoniazid is needed for prevention of tuberculosis among immunocompetent adults? Int J Tuberc Lung Dis 1999;3:847-50.