EJINME-02911; No of Pages 2 European Journal of Internal Medicine xxx (2015) xxx–xxx

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Letter to the Editor Association of tuberculosis and deep venous thromboembolism in patients with autoimmune diseases Keywords: Tuberculosis Deep venous thromboembolism Autoimmune diseases Corticosteroids TNF-alpha inhibitors

Tuberculosis (TB) can complicate the course of various autoimmune diseases, especially with prolonged use of immunosuppressive treatment [1–9]. Limited data are currently available regarding risk factors for, and clinical presentation of, TB in patients with autoimmune diseases. We performed an observational study of all cases of TB diagnosed during years 1992–2012 within a cohort of patients followed for autoimmune diseases in a 1800-bed university hospital, which serves as a referral center for autoimmune diseases in Western France (population catchment area, one million inhabitants). Inclusion criteria were those requested within the national TB mandatory notification form: TB diagnosed either by culture of any specimen positive for Mycobacterium tuberculosis complex, or by the combination of i) clinical or radiological signs suggestive of TB, and ii) initiation of anti-TB treatment. Data were collected from medical charts on a standardized questionnaire. Extrapulmonary TB was defined as TB with any location outside of the lung parenchyma, with or without pulmonary involvement. Institutional review board approval was waived because the study was observational and data were collected anonymously. During the study period, 32 patients (19 men, 13 women) fulfilled inclusion criteria, with a median age at TB diagnosis of 69 years [interquartile range, 46–72]. Underlying autoimmune diseases were rheumatoid arthritis (n = 13), giant-cells arteritis (n = 4), polymyalgia rheumatica (n = 2), dermatomyositis (n = 2), systemic sclerosis (n = 2), ankylosing spondylitis (n = 2), Still's disease (n = 2), and Sjögren's syndrome, cryoglobulinemia, Henoch–Schönlein purpura, granulomatosis with polyangiitis (formerly Wegener's granulomatosis), and lupus (one patient each). Median time since autoimmune disease diagnosis was 36 months

[5–83]. Most patients (n = 28, 88%) had received immunosuppressive drugs before TB diagnosis, including corticosteroids (n = 24, with a mean cumulative dose of 12.8 g, and a mean daily dose of 19.7 mg by the time TB was diagnosed), methotrexate (n = 12), TNF-α inhibitors (n = 5), cyclophosphamide (n = 2), azathioprine, mycophenolate mofetil, and leflunomide (one patient each). Most common symptoms were weight loss and fever. The diagnosis was documented by positive cultures in 21 patients, all with susceptible tuberculosis. In the remaining 11 patients, the diagnosis was based on clinical, radiological, and/or histological patterns, with favorable outcome on anti-TB treatment. Seventeen patients had pulmonary TB, and 15 had extra pulmonary TB. Median delay from symptoms onset to diagnosis was 71 days [22–103] for pulmonary TB, and 123 days [77–175] for extra-pulmonary TB (p = 0.04). Previous use of TNF-α inhibitor was more common in extra-pulmonary, than in pulmonary TB (33% vs. 6%, p = 0.007). All patients received a combination of isoniazid, rifampicin, and pyrazinamide during the first two months of TB treatment, associated with ethambutol in 18 patients. Major adverse events reported in medical charts were death (n = 5, all during the first 2 months of treatment), drug toxicity requiring treatment changes (n = 4), and a flare of the underlying disease (n = 15). Of note, 10 patients (31%) were diagnosed with clinically significant deep venous thrombosis, of whom 3 were complicated by pulmonary embolism. The only variable associated with lethality was age at TB diagnosis, with a median of 66 years in survivors vs. 84 years in patients who died, p = 0.009. Patients with autoimmune diseases may be at increased risk of TB because of immunodeficiency related to their underlying disease (e.g. impaired macrophage function in patients with systemic lupus erythematosus or rheumatoid arthritis), their immunosuppressive treatment, or a combination of both. As previously reported (Table 1), extra-pulmonary TB was almost as common as pulmonary TB in this cohort of patients with autoimmune diseases, while only 25% of current TB is extra-pulmonary in France, a low-endemic country (http://www.invs.sante.fr). We found that extra-pulmonary TB is associated with delayed diagnosis, and TNF-α inhibitor use, as previously shown. Flare of the underlying auto-immune disease was observed in 47% of patients (15/32) following initiation of TB treatment, and was ascribed to drug interactions with rifampicin in

Table 1 Tuberculosis and autoimmune diseases: literature review. First author, reference

Country

Study years

Number of cases

Patients receiving corticosteroids n (%)

Pulmonary/extra-pulmonary TB n (%)

Death n (%)

Darras-Joly [1] Allali [2] Carmona [3] Kim [4] Diallo [5] Yun [6] Feng [7] Hernandez-Cruz [8] Kim [9]

France Morocco Spain Korea Senegal Korea Singapore Mexico Korea

1976–1993 2004 1990–2000 1989–1997 2000–2007 1979–2000 1963–1979 1987–1994 1990–1995

16 18 7 22 8 22 16 30 21

16 (100%) 11 (61%) 5 (71%) 22 (100%) 8 (100%) NA 15 (94%) 22 (73%) 21 (100%)

5 (31%)/11 (69%) 8 (44%)/10 (56%) 5 (71%)/2 (29%) NA 5 (63%)/3 (37%) 13 (59%)/9 (41%) 7 (44%)/9 (56%) 10 (33%)/20 (67%) 12 (57%)/9 (43%)

0 (0%) 0 (0%) NA NA 2 (25%) 2 (9%) 7 (44%) 2 (7%) 1 (5%)

TB, tuberculosis; NA, not available.

http://dx.doi.org/10.1016/j.ejim.2015.04.011 0953-6205/© 2015 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

Please cite this article as: Valence M, et al, , Eur J Intern Med (2015), http://dx.doi.org/10.1016/j.ejim.2015.04.011

2

Letter to the Editor

most cases, which led to transient increase in immunosuppressive drug dosage, mostly corticosteroids. Finally, the main striking finding of this study is the association of TB diagnosis with venous thromboembolic events (VTE), documented in 31% of cases. In a recent study, TB was found to be an independent risk factor for VTE with a VTE prevalence of 2% among patients with active TB [10]. The much higher prevalence in our study could be explained by the conjunction of two pro-inflammatory states (i.e. TB, and autoimmune diseases), in patients with limited mobility. However, our study is limited by its monocentric, retrospective design, with limited sample size, and by its reliance on data reported in medical charts. This suspected association of TB with VTE in patients with autoimmune diseases requires larger scale, multicentric studies for confirmation. In the meantime, this should be kept in mind, so that preventive measures for VTE are carefully implemented in patients with active TB and auto-immune diseases, and the threshold to suspect VTE remains low in this setting. Conflict of interest The authors declare that there are no conflicts of interest. References [1] Darras-Joly C, Wechsler B, Blétry O, Du LT, Raguin G, Godeau P, et al. Tuberculosis and systemic diseases. Apropos of 16 cases. Rev Med Interne 1998;19(2):91–7. [2] Allali F, Rkain H, Faik A, El Hassani S, Hajjaj-Hassouni N. Prevalence and clinical characteristics of tuberculosis in rheumatoid arthritis patients. Clin Rheumatol 2005;24(6):656–7. [3] Carmona L, Hernández-García C, Vadillo C, Pato E, Balsa A, González-Alvaro I, et al. Increased risk of tuberculosis in patients with rheumatoid arthritis. J Rheumatol 2003;30(7):1436–9. [4] Kim HY, Im JG, Goo JM, Lee JK, Song JW, Kim SK. Pulmonary tuberculosis in patients with systematic lupus erythematosus. AJR Am J Roentgenol 1999;173(6):1639–42. [5] Diallo S, Ndongo S, Leye A, Pouye A, Ka MM, Diop TM. Tuberculosis and systemic diseases: study of 8 Senegalese cases. Med Trop (Mars) 2009;69(3):307–8. [6] Yun JE, Lee SW, Kim TH, Jun JB, Jung S, Bae SC, et al. The incidence and clinical characteristics of Mycobacterium tuberculosis infection among systemic lupus erythematosus and rheumatoid arthritis patients in Korea. Clin Exp Rheumatol 2002;20(2):127–32. [7] Feng PH, Tan TH. Tuberculosis in patients with systemic lupus erythematosus. Ann Rheum Dis 1982;41(1):11–4.

[8] Hernández-Cruz B, Sifuentes-Osornio J, Ponce-de-León Rosales S, Ponce-de-León Garduño A, Díaz-Jouanen E. Mycobacterium tuberculosis infection in patients with systemic rheumatic diseases. A case-series. Clin Exp Rheumatol 1999;17(3):289–96. [9] Kim HA, Yoo CD, Baek HJ, Lee EB, Ahn C, Han JS, et al. Mycobacterium tuberculosis infection in a corticosteroid-treated rheumatic disease patient population. Clin Exp Rheumatol 1998;16(1):9–13. [10] Dentan C, Epaulard O, Seynaeve D, Genty C, Bosson JL. Active tuberculosis and venous thromboembolism: association according to International Classification of Diseases, Ninth Revision Hospital Discharge Diagnosis Codes. Clin Infect Dis 2014; 58(4):495–501.

Marion Valence Internal Medicine, Hôpital Sud, University Hospital, Rennes, France Infectious Diseases and Intensive Care Unit, University Hospital, Rennes, France Olivier Decaux Internal Medicine, Hôpital Sud, University Hospital, Rennes, France Matthieu Revest Infectious Diseases and Intensive Care Unit, University Hospital, Rennes, France Patrick Jégo Internal Medicine, Hôpital Sud, University Hospital, Rennes, France Pierre Tattevin⁎ Infectious Diseases and Intensive Care Unit, University Hospital, Rennes, France Corresponding author at: Service des Maladies Infectieuses et de Réanimation Médicale, CHU Pontchaillou, 2 rue Henri Le Guilloux, 35033 Rennes Cedex, France. Tel.: +33 299289564; fax: +33 299282452. E-mail address: [email protected].

Please cite this article as: Valence M, et al, , Eur J Intern Med (2015), http://dx.doi.org/10.1016/j.ejim.2015.04.011

3 April 2015 Available online xxxx