Rheumatology Advance Access published March 27, 2014

RHEUMATOLOGY

Concise report

53

doi:10.1093/rheumatology/keu041

Safety of resuming tumour necrosis factor inhibitors in patients who developed tuberculosis as a complication of previous TNF inhibitors You Jae Kim1, Yong-Gil Kim1, Tae Sun Shim2, Bon San Koo1, Seokchan Hong1, Chang-Keun Lee1 and Bin Yoo1

Methods. The medical records of all patients (n = 683) that received TNFi treatment at a single rheumatology clinic between June 2003 and December 2012 were retrospectively reviewed. Among them, data from patients who developed active TB infection were collected and patient outcomes were evaluated for those who resumed TNFis after TB treatment. Results. Of 683 patients, 13 patients developed an active TB infection during TNFi treatment (4 on etanercept, 4 on adalimumab and 5 on infliximab). The median duration of TNFi treatment before TB infection was 20 months. TNFi treatment was reinitiated in six patients: four within 2 months after TB treatment and two after completion of TB treatment. Four patients reinitiated with the same TNFi, whereas two patients started with another TNFi. During a mean follow-up of 30.6 months, all six patients successfully completed TB treatment with no TB infection relapses. Conclusion. Our results suggest that resuming TNFi therapy in patients following adequate TB treatment is safe, even before completion of TB treatment. Key words: tumour necrosis factor, inhibitor, Mycobacterium tuberculosis, tuberculosis, rheumatic disease, safety.

Introduction TNF inhibitors (TNFis) are currently used to treat a variety of chronic inflammatory diseases, including RA, AS, Behc¸et’s disease and psoriasis. However, TNF-a is a potent proinflammatory cytokine that plays an important role in the immune response to intracellular bacteria, and in particular to infection with Mycobacterium tuberculosis. Since TNF-a is essential for granuloma formation and maintenance [1, 2], the use of TNF-a antagonists 1

Division of Rheumatology and 2Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea. Submitted 19 August 2013; revised version accepted 29 January 2014. Correspondence to: Yong-Gil Kim, Division of Rheumatology, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, 388-1, Pungnap-dong, Songpa-gu, Seoul 138-736, South Korea. E-mail: [email protected]

increases patient risk for developing tuberculosis (TB) and, in particular, for reactivation of a latent TB infection (LTBI) [3]. Moreover, the overall incidence of TB in patients with rheumatic disease who are treated with a TNFi varies by population (range 1.6- to 25.1-fold increase compared with non-treated). South Korea is considered to have an intermediate TB burden (79/100 000 patient-years), with a higher relative overall risk of TB infection associated with both rheumatic disease and TNF treatment [4]. Patients who develop a TB infection following TNFi treatment typically discontinue TNFi use and receive standard TB treatment. However, there is currently insufficient information on patient outcomes following resumption of TNFi treatment during ongoing TB treatment. Guidelines from France [5], Ireland [6] and TBNET [4] recommend delaying further TNFi use until after completion of a full course of TB treatment, whereas the British Thoracic Society [7] and the Centers for Disease Control

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CLINICAL SCIENCE

Objectives. There is no consensus on whether restarting TNF inhibitors (TNFis) after treatment of an active tuberculosis (TB) infection caused by previous TNFi exposure is safe. In this study we sought to determine the safety of resuming TNFis in patients following TB treatment.

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Abstract

You Jae Kim et al.

and Prevention [8] both recommend cautious resumption of TNFi treatment following initiation of TB treatment if there is a large perceived clinical value and good compliance is guaranteed. This study sought to validate the safety of resuming TNFi therapy following TB treatment in a population with an intermediate TB burden.

Patients and methods Study population

LTBI screening and treatment At screening, simple chest X-rays, tuberculin skin test (TSTs) and/or IFN-g release assays (IGRAs), including the QuantiFERON TB-Gold In Tube assay (QFT-GIT; Cellestis, Carnegie, VIC, Australia) and the T-SPOT TB test (Oxford Immunotec, Abingdon, UK) were performed. Positive LTBI was defined by both the size of the skin induration (TST) and the IGRA test results [13]. LTBI treatment was performed by a pulmonologist according to the Korean Center for Disease Control and Prevention guidelines, which recommend isoniazid for 9 months or rifampicin for 4 months [14]. Chest X-ray was usually performed 3 and 9 months after the commencement of anti-TNF treatment and every 12 months thereafter to evaluate TB development.

Diagnosis of TB and TNFi treatment A diagnosis of TB was made if M. tuberculosis was isolated in any culture of clinical specimens or if M. tuberculosis DNA was detected in any clinical specimen by PCR analysis. Patients with negative culture findings but a high clinical likelihood of active TB, including good clinical and radiographic response to TB treatment, were also included as active TB patients. TNFi treatment was stopped if active TB was diagnosed, unless a therapeutic benefit from continuation of TNFi treatment was expected. TNFi treatment was resumed when clinically indicated in patients experiencing a flare-up of an underlying disease or who showed clear clinical deterioration. Selection of a specific TNFi was at the discretion of each attending physician.

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Characteristics of TB patients exposed to TNFi Of the 683 patients who were treated with a TNFi, 13 (1.9%) patients (9 with AS, 3 with RA, 1 with Behc¸et’s disease) were diagnosed with active TB during a median observation period of 68 months (interquartile range 42–76) after starting TNFi. The median time between the first dose of a TNFi and the development of TB was 20.0 months (S.D. 23.5, range 3–72). Only 2 (15.3%) patients had a history of TB and no patients reported a history of recent M. tuberculosis exposure. Four of 13 (30.8%) patients showed a positive LTBI result and received LTBI prophylaxis prior to TNFi treatment initiation. One patient had low adherence to chemoprophylaxis and developed TB 3 months after starting a TNFi, however, the other three patients finished their full chemoprophylaxis and developed TB after 25, 29 and 36 months of treatment with TNFi. TB was suspected in one patient based on chest X-ray screening and in others based on the development of TBassociated symptoms, including fever, cough, enlarged lymph nodes and abdominal pain. Patients with suspected TB were referred to a pulmonologist or gastroenterologist and 13 patients were ultimately confirmed as having active TB (Table 1). Diagnosis was based on positive M. tuberculosis culture in 10 patients. Among the three patients with negative culture results, one yielded an endoscopic colon biopsy that was positive for a M. tuberculosis complex-specific PCR result, while the other two patients had high adenosine deaminase (ADA) levels with compatible clinical symptoms. Among these 13 patients, 6 (46.1%) were diagnosed with pulmonary TB including pleurisy and 7 (53.8%) with extrapulmonary TB: gastrointestinal, pericardial or miliary (n = 1 each); disseminated (n = 2) and lymph nodes (n = 2). All 13 patients were treated with standard first-line TB medication (isoniazid, rifampicin, ethambutol or pyrazinamide) for a median treatment duration of 6 months (range 6–27). Mycobacterial cultures showed no resistance to isoniazid and rifampicin and patients were confirmed by negative culture conversion. The other patients improved clinically and radiographically following TB treatment with no evidence of aggravation or recurrence.

Patient outcomes after resuming TNFi treatment Among the 13 patients with TB, TNFi treatment was resumed in 6 (46.1%) patients: in 4 patients within 2 months of initiating TB treatment and in 2 patients after completion of TB treatment. Four patients recommenced with the same agents—etanercept (n = 1) or adalimumab (n = 3)—whereas two patients who had previously received infliximab switched to the other agents—etanercept (n = 1) and adalimumab (n = 1). One patient with RA, who was clinically diagnosed as TB pleurisy, continued adalimumab with TB treatment. Her TB diagnosis was based on a high pleural fluid concentration of ADA (54 U/l) and the presence of dominant

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This retrospective study evaluated the records of 683 patients (362 with AS, 307 with RA, 10 with PsA, and 4 with Behc¸et’s disease) who received a TNFi (327 on etanercept, 252 on adalimumab, 104 on infliximab) at the Asan Medical Center, a tertiary referral hospital in South Korea, between June 2003 and December 2012. Clinical, microbiological and radiographic data were evaluated with the approval of the Asan Medical Center Institutional Review Board. RA, AS, and Behc¸et’s disease were diagnosed according to the criteria of the ACR [9], the modified New York criteria [10] and International Study Group criteria [11], respectively. Diagnosis of PsA was based on both clinical and radiographical findings [12].

Results

Resumption of TNF inhibitors and safety

TABLE 1 Clinical characteristics of patients with TB treated with TNFi Patients (n = 13)

Age, mean (range), years Sex, female, n (%) Diagnosis, n (%) AS RA Behc¸et’s disease Disease duration, median (IQR), months Predisposing TNFi, n (%) Exposure to one TNFi Adalimumab Etanercept Infliximab Exposure to two or morea Duration of TNFi use to TB onset, median (IQR), months TB prophylaxis, n (%) Type of TB infection Pulmonary ± pleurisy, n (%) Extrapulmonary, n (%) Pericardial, n Gastrointestinal, n Miliary, n Lymph node, n Disseminated, n

45 (22–71) 5 (38.5) 9 3 1 44

(69.2) (23.1) (7.7) (13–74)

10 3 3 4 3 20 4

(76.9) (23.1) (23.1) (30.8) (23.1) (3–72) (30.7)

6 (46.1) 7 (53.8) 1 1 1 2 2

TB: tuberculosis; TNFi: tumour necrosis factor inhibitor; IQR: interquartile range. aExposure to two or more: etanercept ! remicade (n = 1), etanercept ! adalimumab (n = 1), remicade ! adalimumab ! etanercept (n = 1).

TABLE 2 Clinical and demographic characteristics of six patients who resumed TNFi treatment Time to Duration resume TNFi after Duration after Age, Underlying of TNFi, Method of TB TB treatment, resuming TNFi, TNFi before TNFi after years/sex disease months TB diagnosis type months months TB infection TB infection 57/M 26/M 30/M 25/M 63/F 71/F

AS AS AS AS RA RA

3 20 36 67 5 32

Culture Clinical Culture Culture Culture Clinical

P P E P E P

2 7 2 2 27 0

24 55 44 5 37 19

A E I I A A

A E A E A A

TNFi: TNF inhibitor; TB: tuberculosis; P: pulmonary; E: extrapulmonary; E: etanercept; A: adalimumab; I: infliximab.

lymphocytes (70%) in the pleural fluid. Right-sided pleural effusion was improved after 6 months of TB medication. No TB relapse was noted during 19 months of follow-up. All six patients showed a good response to TB treatment and all successfully completed treatment. Moreover, none of the patients who recommenced TNFi use redeveloped active TB. The mean follow-up duration from recommencement of TNFi therapy was 30.6 months (S.D. 18.1, range 5–55). The characteristics and outcomes of those patients who resumed TNFi use are described in Table 2.

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Discussion The risk for TB development with TNFi use is relatively well established. However, the safety of recommencing TNFi therapy after diagnosis of TB infection as a complication of previous TNFi use has not been established and remains an important concern. In this study we evaluated patient characteristics and outcomes following resumption of TNFi use in patients who are being treated with an appropriate TB regimen. Among the 13 patients with TB secondary to TNFi use, 6 patients had restarted TNFi

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Characteristics

You Jae Kim et al.

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of extrapulmonary TB among TNFi users constituted 56% of the total TB cases [3]. It is possible that this high proportion of extrapulmonary TB with TNFi use is associated with inadequate compartmentalization of viable mycobacterial bacilli by granulomas due to the presence of the TNFi [20]. Thus patients treated with TNFi should be monitored carefully for any clinical signs and symptoms suggesting TB infection. Moreover, timely diagnoses are required, since routine chest X-ray will not help in the diagnosis of most cases of TB reactivation [21]. In conclusion, we hypothesize that early resumption of TNFi use could prevent underlying disease flare-up and the steady deterioration of quality of life in cases of inflammatory disease. Based on our present findings, our current study results suggest that resuming TNFi in patients undergoing concomitant treatment with an adequate TB treatment might be safe, even in global regions where TB is prevalent. Rheumatology key messages Early resumption of TNF inhibitors (TNFis) with adequate anti-tuberculosis (TB) treatment might be safe in inflammatory disease. . TB is not a contraindication to recommencing TNFi therapy. .

Disclosure statement: The authors have declared no conflicts of interest.

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therapy either during or after TB treatment. TB treatment was successful in all patients in this cohort and there have been no recurrences during a mean follow-up period of 30.6 months (S.D. 18.1). Indeed, our data support the concept that TNFi can be used safely in patients with TB even before a full course of TB treatment. Any person with active pulmonary or non-pulmonary TB as a complication of TNFi therapy should discontinue antiTNF treatment. However, the guidelines of the British Society for Rheumatology [7] recommend continuation of TNF blockers (in parallel with TB treatment) if the expected benefits of treatment of the inflammatory disease are significant. To our knowledge there are insufficient data regarding the safety of continuing TNFi use together with TB treatment. Six patients in a French study [15] had recommenced TNFi use after appropriate TB treatment. The mean follow-up time since commencing TB treatment was 42.7 months and none of these six patients experienced TB reactivation. In our current study, four patients reinitiated TNFi treatment after a median TB treatment period of 2 months (range 0–2). Three patients recommenced TNFi use at the time the organism’s drug susceptibility profile in culture was established. Moreover, one patient continued using adalimumab with TB treatment after TB infection. None of the four patients treated concurrently with a TNFi and TB therapy developed a reactivation of TB, and all responded to TB chemotherapy along with reporting an improved quality of life. These effects might be explained by a paradoxical response, an exaggerated cell-mediated immune response against mycobacteria that are damaged or killed by chemotherapy [16]. Shortly after initiation of TB treatment, increasing TNF-a serum levels can lead to tissue destruction, inflammation and necrosis, with the resulting tissue hypoxia then promoting bacterial survival. Thus use of an TNFi together with TB treatment may paradoxically be beneficial through modulation of TNF-a activity and subsequent promotion of bacterial clearance. That might be associated with enhancing the penetration of TB drugs into granulomas and increasing drug bactericidal activity [16, 17]. In the most recent report on this topic from the British Society for Rheumatology Biologics Register [18], the rate of TB in patients with RA treated with a TNFi was 3- to 4-fold higher in patients receiving infliximab than in those receiving etanercept. A similar result was observed in our study in that infliximab was the most frequently prescribed TNFi (4.8%, 5/104) in patients with an active TB infection. To avoid reactivation, patients who received infliximab switched to another TNFi after contracting active TB. Furthermore, when TB occurs in patients with rheumatic disease who have been treated with a TNFi, the disease usually progresses rapidly and is frequently disseminated. In this study, the frequencies of extrapulmonary (53.8%) and disseminated (15.3%) forms of TB were somewhat higher than the expected extrapulmonary frequency of 18.9% relative to all TB cases in South Korea [19]. However, this elevated frequency of extrapulmonary TB is similar to a previous study reporting that the proportion

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