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Rheumatology 2006;45:228–243 Letters to the Editor Leflunomide-associated tuberculosis? 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--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. Cases of active TB following RA treatment with corticosteroids, methotrexate and TNF--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- signalling might be another possible mechanism for effectiveness in RA [8, 9]. It was demonstrated that leflunomide inhibits TNF--induced NF-B activation, TNF-mediated cytotoxicity and the generation of TNF-induced reactive oxygen intermediates and lipid peroxidation [10]. Optimal activity of TNF- and other cytokines (IFN-, IL-12, IL-15) is crucial in host defence against bacteria, including Mycobacterium tuberculosis. The essential role of TNF- has been shown in studies on animal models indicating that inhibition of TNF- 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- agents, where increased TB risk and frequency has been reported [12]. However, in contrast to reactivation TB disease in patients treated with TNF- 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. Key messages Rheumatology Rheumatology 2006;45:228–229 doi:10.1093/rheumatology/kei173 Advance Access publication 30 November 2005 Patients treated with leflunomide may develop tuberculosis. 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. TABLE 1. Patient characteristics Patient Sex Diagnosis Age/disease duration (yr) Previous DMARDs Corticosteroids Introduction of leflunomide (date) 1 2 3 4 5 F M F F F RA RA RA RA JCA 58/9 50/12 71/25 33/2 24/23 MTX, SSZ, Au, Cy, CQ MTX, SSZ, Au, CQ Au None SSZ, MTX CY, INFa Yes Yes No No Yes Monotherapy (April 2000) Monotherapy (April 2000) Monotherapy (March 2003) Monotherapy (July 2003) Combination with MTX (April 2003) Diagnosis of active pulmonary TB January 2002 September 2002 November 2003 March 2004 December 2004 F, female; M, male; RA, rheumatoid arthritis; JCA, juvenile chronic arthritis; MTX, methotrexate, SSZ, sulphasalazine; CQ, chloroquine; Au, parenteral gold; Cy, cyclosporin; INF, infliximab. aIneffective treatment with infliximab from November 2002 to February 2003. ß The Author 2005. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: [email protected] Letters to the Editor A. HOČEVAR, B. ROZMAN, S. PRAPROTNIK, B. LESTAN, D. ERŽEN1, V. PETRIC2, M. TOMŠIČ Department of Rheumatology, University Medical Centre, Ljubljana, 1University Clinic of Respiratory and Allergic Diseases, Golnik and 2Department of Internal Medicine, General Hospital, Murska Sobota, Slovenia Accepted 23 September 2005 Correspondence to: M. Tomšič, Department of Rheumatology, University Medical Centre, Vodnikova 62, 1000 Ljubljana, Slovenia. E-mail: [email protected] 1. Praprotnik S, Rozman B, Tomsic M. New issues in tuberculosis. Ann Rheum Dis 2005;64:795. 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. 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. 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. 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. 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. 7. Cannon GW, Kremer JM. Leflunomide. Rheum Dis Clin North Am 2004;30:295–309. 8. Alldred A, Emery P. Leflunomide: a novel DMARD for the treatment of rheumatoid arthritis. Expert Opin Pharmacother. 2001;2:125–37. 9. Miceli-Richard C, Dougados M. Leflunomide for the treatment of rheumatoid arthritis. Expert Opin Pharmacother 2003; 4:987–97. 10. Manna SK, Mukhopadhyay A, Aggarwal BB. Leflunomide suppresses TNF-induced cellular responses: effects on NF-B, activator protein-1, c-Jun N-terminal protein kinase and apoptosis. J Immunol 2000;165:5962–9. 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. 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. 13. Keane J. Tumor necrosis factor blockers and reactivation of latent tuberculosis. Clin Infect Dis 2004:39:300–2. Rheumatology 2006;45:229–230 doi:10.1093/rheumatology/kei196 Advance Access publication 13 December 2005 Sequential synovial fluid sampling suggests plasma and synovial fluid IL-6 vary independently in rheumatoid arthritis SIR, Inflammatory cytokines, including interleukin-6 (IL-6), are raised in rheumatoid arthritis (RA). Single paired daytime samples show that the IL-6 and TNF- concentrations in synovial fluid exceed blood concentrations during the day [1–3], and these and 229 other data suggest that joints are the source. Recent data have shown that plasma IL-6 in RA follows a circadian pattern with a peak at 6 a.m. [4]. If IL-6 is generated inside joints and diffuses into plasma, it might be expected that the synovial fluid IL-6 concentration would also undergo a large diurnal variation. Such investigations necessitate the development of a safe and acceptable synovial catheter allowing sequential synovial fluid sampling. Following the approval of the United Bristol Healthcare Trust Research Ethics Committee, we undertook a daytime pilot study for this purpose. In addition we obtained preliminary data for IL-6 variations in paired synovial fluid and plasma samples. We recruited six volunteers aged 36–64 yr with RA according to the criteria of the American College of Rheumatology. Each volunteer had active disease (at least three swollen and three tender joints) and a large knee effusion. After establishing the technique, we obtained paired blood and synovial fluid samples in three patients. One patient was taking prednisolone 7.5 mg daily, but no other patient was taking glucocorticoids and none had had intra-articular or intra-muscular glucocorticoids for more than 10 weeks. After we had obtained written consent, each patient was admitted and remained on bed rest between 8.30 a.m. and 5.30 p.m. With the patient on the bed, we used an aseptic non-touch technique including sterile gown and gloves to insert a synovial catheter. The knee was exposed, a large area of skin carefully cleaned with iodine 1% antiseptic solution, and sterile drapes were used to produce an aseptic field. Up to 2 ml bupivacaine 0.5% was infiltrated under the skin adjacent to the lateral parapatellar joint space and towards the synovial membrane. After local anaesthesia was obtained, a sterile disposable intravenous (i.v.) cannula (14 gauge BD Venflon; Becton Dickinson Infusion Therapy, Sweden) was inserted into the parapatellar joint space. The cannula was connected to a three-way tap with flexible extension (BD Connecta Plus 3; Becton Dickinson Infusion Therapy). Sterile film wound dressings (C-View; Unomedical, UK) enabled the synovial cannula to remain perpendicular to the skin. After taking microbiological and orthopaedic advice, we chose not to use prophylactic antibiotics. A standard i.v. cannula was used for sequential blood sampling. No samples were taken for at least 1 h after cannulae insertion. The i.v. cannula was flushed with 10 ml 0.9% saline after insertion and before and after each blood sample. The first 2 ml of each sample taken from the knee and the first 4 ml of each sample taken from the i.v. cannula were discarded. Paired blood and synovial fluid samples were taken through the day. Plasma and synovial fluid samples were stored at 80 C and analysed using solid-phase sandwich ELISA (enzyme-linked immunosorbent assay) kits (Diaclone Research, detection limit 2 pg/ml, inter- and intra-assay variation <6%). A colleague not directly involved in the project asked each volunteer for comments about their experience. The synovial catheter allowed sequential synovial fluid sampling over 8 h. From the independent interviews, the procedure was acceptable to volunteers. The only adverse effect noted was slight knee stiffness in two volunteers, and there were no other adverse effects. In addition we obtained a small number of paired synovial fluid and blood samples (Fig. 1). Plasma IL-6 decreased exponentially by 95%, from a mean [95% confidence interval (CI)] of 19.1 (34.1, 4.1) pg/ml at 10 a.m. to <2 (<2, <2) pg/ml at 5 p.m. (paired t-test, P<0.05). These results are similar to previously published data [4]. Synovial fluid IL-6 changed little during the 8 h (non-significant decrease of 30%), with 10 a.m. IL-6 mean (95% CI) 12.0 (17.5, 6.5) ng/ml and 5 p.m. mean 7.9 (11.1, 4.7) ng/ml. The patient with the highest synovial fluid IL-6 concentration had the lowest plasma IL-6 concentration. Developing a safe and acceptable synovial catheter was the prime reason for this study. We found that sequential synovial fluid samples can be taken safely through a synovial catheter over 8 h by a technique that is acceptable to volunteers and avoids repeated arthrocentesis. Our very preliminary values are similar to previous