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Screening for latent tuberculosis infection prior to biologic therapy in patients with chronic immune-mediated inflammatory diseases (IMID): Interferon-gamma release assay (IGRA) versus tuberculin skin test (TST)
The Egyptian Rheumatologist 41 (2019) 225–230
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Original Article
Screening for latent tuberculosis infection prior to biologic therapy in patients with chronic immune-mediated inflammatory diseases (IMID): Interferon-gamma release assay (IGRA) versus tuberculin skin test (TST) Meriem Sellami a,⇑, Alia Fazaa a, Myriam Cheikh b, Saousen Miladi a, Kmar Ouenniche a, Rym Ennaifer b, Kaouther Ben Abdelghani a, Ahmed Laatar a a b
Rheumatology Department, Mongi Slim Hospital, La Marsa, Tunis, Tunisia Gastroenterology Department, Mongi Slim Hospital, La Marsa, Tunis, Tunisia
a r t i c l e
i n f o
Article history: Received 4 November 2018 Accepted 5 November 2018 Available online 15 November 2018 Keywords: Biological agents Chronic immune-mediated inflammatory diseases (IMID) Latent tuberculosis Interferon-gamma release assays (IGRA) Tuberculin test
a b s t r a c t Background: The screening for latent tuberculosis infection (LTBI) is mandatory before initiating biologics in patients with chronic immune-mediated inflammatory disease (IMID). The recommendations are based on the tuberculin skin test (TST) and interferon-gamma release assay (IGRA). Aim of the work: To evaluate the agreement between the two tests in the diagnosis of LTBI and to identify risk factors associated with positive TST and IGRA results. Patients and methods: Medical records of 105 IMID patients going to receive a biologic agents were extracted in a cross sectional study (2015–2017). No biologics was undertaken before LTBI screening. All patients underwent IGRA and chest radiography. TST was performed in 94 cases. Results: The mean age of the patients was 47.7 ± 14.4 years and disease duration of 11.2 ± 7.6 years. Agreement between the 2 tests results was low (j coefficient = 0.08). The sensitivity of TST and IGRA was equally low but the specificity of IGRA was higher. Replacing TST results by positive IGRA showed that number of patients who would take anti-tuberculous chemoprophylaxis will be significantly reduced by 46.5% (from 40.9% to 21.9%; p = 0.0002). TST results were significantly less positive for patients receiving immunosuppressives than for those receiving no treatment (35.1% vs 42.5%, p = 0.031). IGRA results were associated with absence of Bacilli Calemtte-Guérin vaccination. Age was the only risk factor for LTBI associated with both IGRA and TST positivity (p = 0.031, p = 0.011 respectively). Conclusions: TST and IGRA have a low agreement. Both tests should be included in the strategy to diagnose LTBI prior to biologic therapy in IMID patients. Ó 2018 Egyptian Society of Rheumatic Diseases. Publishing services provided by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
1. Introduction The advent of biologic agents has revolutionized the treatment of many immune-mediated inflammatory diseases by reducing symptoms and preventing radiological progression [1]. However, one of the most adverse effects of biological disease-modifying anti-rheumatic drugs (bDMARDs) is an increased risk of reactivation of latent tuberculosis (TB) infection (LTBI) in patients previously exposed to TB bacilli [2–4]. Screening for LTBI has been hence recommended before initiating treatment with bDMARDs
Peer review under responsibility of Egyptian Society of Rheumatic Diseases. ⇑ Corresponding author. E-mail address: [email protected] (M. Sellami).
[5,6]. This screening has resulted in a decrease in the incidence of TB [7,8]. While active TB can possibly be retained by medical history, clinical examination, chest radiography and bacteriological examination, there is no gold standard for detecting LTBI. Guidelines have provided discordant recommendations about the place of screening tools such as tuberculin skin test (TST) and interferongamma release assays (IGRAs) [9]. TST has been used worldwide for over a century as a guide in diagnosing both LTBI and active TB [10]. IGRA has been developed in the last decade in order to overcome some of the limitations of TST and can be used in addition to or in its replacement. They have been shown to offer improved specificity and probably sensitivity [11,12] but their agreement levels differ across all studies [13,14].
https://doi.org/10.1016/j.ejr.2018.11.003 1110-1164/Ó 2018 Egyptian Society of Rheumatic Diseases. Publishing services provided by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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As there are conflicting findings regarding the specificity and the sensitivity of different LTBI screening protocols in inflammatory disease patients scheduled to receive biologic agents, this single-center study was conducted aiming to evaluate the agreement between IGRA and TST in detecting LTBI prior to biologic therapy and to investigate the effect of replacing TST with IGRA in deciding on the necessity of prophylactic anti-TB antibiotic therapy before bDMARDs. Identifying risk factors for LTBI associated with positive TST and IGRA results was also well thought-out.
2. Patients and methods This is a cross sectional, single center study conducted in a tertiary care hospital in North of Tunisia (Mongi Slim Hospital, La Marsa, Tunis) between 2015 and 2017. The study was carried out in departments of Rheumatology and Gastroenterology. The study was approved by the local Ethics Committee and in accordance to the Declaration of Helsinki. The medical records of patients with chronic immune-mediated inflammatory diseases (IMID) requiring biologic therapy (first-line therapy or switch) were retrospectively reviewed. Data were extracted before and after having biologics. Disease activity was evaluated by the disease activity score-28 (DAS28) with erythrocyte sedimentation rate (ESR) for rheumatoid arthritis (RA), the ankylosing spondylitis disease activity score (ASDAS)-ESR for spondyloarthritis (SpA) and Crohn’s disease activity index (CDAI) for Crohn’s disease (CD). Patients with RA, SpA and chronic inflammatory bowel disease (IBD); CD and ulcerative colitis (UC) with an indication for biologic treatment were included from the Rheumatology and Gastroenterology Departments respectively. They were diagnosed according to the 2010 classification criteria of the American College of Rheumatology/European League Against Rheumatism for the RA [15], the Assessment of SpondyloArthritis international Society classification criteria for the SpA [16], and histological examination for patients with IBD. Two patients with Still’s disease refractory to treatment with corticosteroids and methotrexate were also included. No biologics was undertaken before TB and LTBI screening. Previous biologics were discontinued at least 1 month before inclusion. Patients who were under the age of 18, with history of other autoimmune diseases or who had already receive an antiTB chemoprophylaxis were not included in the study. All patients were screened for active TB and LTBI prior to biologic therapy with anti-tumor necrosis factor (anti-TNFa) and tocilizumab according to French guidelines [17] including retrieving medical history and information including: personal or family history of TB, exposure to TB, bacillus Calmette-Guerin (BCG) status, smoking, clinical examination, chest radiography, sputum examination, immunodiagnostic tests for LTBI (TST or/and IGRA), LTBI treatment and any diagnosis of active TB after initiation of biologic therapy. The TST consists of intradermal injection of 10 tuberculin units of purified protein derivative on the anterior surface of the forearm. The main diameter of skin induration was recorded in millimeters (mm) by an experienced clinician 72 h after the inoculation and the result was considered positive if skin induration was 10 mm. IGRA (QuantiFERON-TB Gold Plus; QFT-Plus) was performed by enzyme-linked immunosorbent assay (ELISA) according to the manufacturer’s recommendations and interpreted by local immunologists blind to the TST results. Results were analyzed using the QFT In TUBE software and expressed as UI/ml IFNc. The blood sample for IGRA analysis was taken on the same day just before performing TST to avoid any result interferences. It was interpreted as positive, negative or indeterminate. In the case of indeterminate IGRA, the TST result was used. If patients were
tested positive for either analysis, a sputum examination and chest computerized tomography (CT) were carried out looking for signs of active TB.
2.1. Statistical analysis The Statistical package for social sciences (SPSS version 11.5) was used. Descriptive statistics were presented as frequencies and means ± standard deviations. Comparisons were performed using Student’s t-test and analysis of variance for normally distributed variables. Concordance between IGRA and TST was performed using Cohen’s kappa coefficient (k). If the two tests are totally in agreement, the j coefficient will be equal to 1. Discrepancies between the tested variables will be expressed by decreased j coefficient (<1). If variables totally disagree, j coefficient will be 0. The gold standard used to calculate the sensitivity and specificity was the chest computerized tomography. Sensitivity was defined as the number of positive results divided by the total number tested at enrolment. Specificity was defined as the number of negative results divided by the total number tested at enrolment. The denominator included indeterminate results for IGRA. Both values are expressed as a percentage. To identify factors associated with positive TST or IGRA results, bivariate analysis (v2 tests) was performed. Results are presented with odds ratio (OR) and their 95% CI. The level of significance was set at 0.05.
3. Results A total of 105 immunocompetent patients with an IMID were included in the study. There were 44 men (41.9%) and 61 women (58.1%), with a sex ratio of 0.72. The demographic and clinical characteristics of patients are summarized in Table 1. Fifty two (49.5%) patients had extra-articular or extra-digestive manifestations especially coxitis (21.1%), osteoporosis (21.1%), osteopenia (17.3%) and anterior uveitis (17.3%). Eighty three (79%) patients were treated with a single biologic agent while 22 (20.9%) had 2 or 3 kinds of bDMARDs. The average duration of follow-up for the patients after the beginning of the biologic therapy was 4.8 ± 1.4 years (2–7 years). All patients underwent screening for LTBI before starting the first biologic and among them 20 (19%) patients were screened while switching to the second or third biologic. Physical examination was normal in all cases. The chest radiography was suggestive of active TB in 3 cases confirmed by chest CT in only one case. The sputum examination was negative in all cases. TST performed in 94 (89.5%) cases was negative in 51 (54.2%) and 10 mm in 43 (45.7%). The mean TST induration was 7.63 ± 9.27 mm (0–32). IGRA, performed in all cases was negative in 81 (77.1%), undermined in 1 (1%) and positive in 23 (21.9%) allowing the diagnosis of LTBI. None of the patients had a history of TB exposure or a reactivation of tuberculosis during biologic treatment. No side effects from both tests were reported. On comparison between TST and IGRA results, 30 discordant results were found: 25 (23.8%) with positive TST and negative QFT and 5 (4.7%) with negative TST and positive IGRA (Table 2). These divergent results were mostly found in patients on systemic corticosteroids (80%). Positive TST (cut-off of 15 mm) and positive IGRA were comparable (17.1% vs 21.9%, p = 0.09), although discordant results remained high (11.4%). Agreement between TST and IGRA was low (j = 0.08, 95% CI 0.003–0.162) and improved in patients not taking concurrent systemic corticosteroids (j = 0.12). The sensitivity of TST and IGRA was equally low but the specificity of IGRA was higher (Table 3). The specificity of TST increased concomitantly with the rise of the TST cut-off point.
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M. Sellami et al. / The Egyptian Rheumatologist 41 (2019) 225–230 Table 1 Demographic, clinical and therapeutic characteristics of the patients with chronic immune-mediated inflammatory disease requiring a biologic therapy. Variable mean ± SD or n (%)
Chronic IMID patients (n = 105)
Age (years) Age at diagnosis (years) Disease duration (years) Residency (rural/urban) Unemployed person Socioeconomic class (low/med/high) Current smoking BCG vaccine (at birth/at age 6 yr) Diagnosis Rheumatoid arthritis (RA) Spondyloarthritis (SpA) Crohn’s disease (CD) Ulcerative colitis Still’s disease RA Rheumatoid factor positive Anti-CCP-positive Erosive DAS28 3.2 SpA Axial Peripheral Axial/peripheral Associated with IBD ASDAS 1.3 CD Stenosis Fistula Stenosis and fistula Inflammatory CDAI 150 Corticosteroids Current dose (mg/day) DMARDs Methotrexate Leflunomide Azathioprine Sulphasalazine 5-aminosalicylic acid Hydroxychloroquine bDMARD Infliximab Etanercept Adalimumab Certolizumab Tocilizumab Rituximab
47.7 ± 14.4 36.5 ± 13.2 11.2 ± 7.6 17/88 (16.2/83.8) 51 (48.6) 3/71/31 (2.9/67.6/29.5) 42 (40) 93/71 (88.5/67.6) 47 (44.8) 26 (24.7) 21 (20) 9 (8.6) 2 (1.9) 35 (74.4) 36 (76.5) 37 (78.7) 33 (70.2) 10 (38.4) 4 (15.3) 6 (23.0) 6 (23.0) 18 (69.2) 5 (23.8) 4 (19) 10 (47.6) 2 (9.5) 15 (71.4) 81 (77.1) 10.2 ± 4.5 35 (33.3) 14 (13.3) 30 (28.6) 48 (45.7) 18 (17.1) 6 (5.7) 37 (35.2) 29 (27.6) 39 (37.1) 14 (13.3) 10 (9.5) 6 (5.7)
IMID: immune-mediated inflammatory disease, BCG: Bacilli Calemtte-Guérin; DAS28: Disease activity score for rheumatoid arthritis; IBD: inflammatory bowel disease; ASDAS: Ankylosing Spondylitis Disease Activity Score; CDAI: Crohn’s Disease Activity Index, DMARDs: disease modifying antirheumatic drug, bDMARD: biologic DMARD.
The number of patients requiring chemoprophylaxis before biologics introduction was different depending on the LTBI screening method. Taking into account only the TST results, 43 (40.9%) patients had to be treated. Replacing TST by IGRA positive results showed that only 23 (21.9%) required antibiotic prophylaxis. Then, the number of patients who would take chemoprophylaxis will be significantly reduced 46.5% (from 40.9% to 21.9%, p = 0.0002). Thereafter, according to IGRA positive results, biologic treatment
Table 3 Sensitivity, specificity and accuracy of tuberculin skin test (TST) and interferon gamma release assay (IGRA) results in predicting latent tuberculosis infection (LTBI) in patients with chronic immune-mediated inflammatory disease requiring a biologic therapy. Test
Chronic IMID patients (n = 105) Sensitivity (%)
Specificity (%)
Accuracy (%)
IGRA TST 5–9 mm 10–14 mm 15–19 mm 20–24 mm 25 mm
26.14 73.9 73.9 73.9 52.1 39.1 4.3
100 80.6 79.1 80.6 97.0 98.5 98.5
75.3 73.6 71.2 72.5 74.1 74.4 75.6
IMID: immune-mediated inflammatory disease IGRA: interferon gamma release assay, TST: tuberculin skin test.
was delayed in 23 cases (21.9%) with mean delay duration of 0.54 ± 1.42 month (0–8). The anti-TB chemoprophylaxis used included isoniazid for 6 months in 4 cases (17.3%) and an association of isoniazid and rifampicin for 3 months in 19 cases (82.6%). The risk factors for LTBI associated with positive both IGRA and TST results are shown in Table 4. Conventional risk factors for LTBI reactivation such as history of active TB, close contact with a patient with active TB, and chest radiography suggestive of previous TB infection were not tested as risk factors as they were all negative. Corticosteroids or immunosuppressives did not affect the positivity of IGRA (15.3% vs 14.4%, p = 0.221). IGRA positivity was associated with the absence of BCG vaccination. TST results were significantly less positive for patients receiving corticosteroids or immunosuppressives, independent of the dose, than for those receiving no treatment (35.1% vs 42.5%, p = 0.031). Age was the only risk factor associated with both IGRA and TST positivity. 4. Discussion This study on 105 IMID patients, IGRA and TST were evaluated and the importance of LTBI screening before starting or switching bDMARDs in daily practice was highlightened, especially with the constant increase in the number of patients treated with biologics. The poor agreement between TST and IGRA results was confirmed. Unsurprisingly, the substitution of TST by QFT in LTBI screening led to a substantial reduction of antibiotics prophylaxis introduction, in agreement with others [18]. Systematic screening of LTBI in inflammatory disease patients may be an important disease control item which is currently being re-evaluated as part of the new End TB strategy [19]. Recently, a retrospective study conducted in 2016 showed that LTBI was diagnosed in 20% of biologic therapy candidates using TST or IGRA [20], highlighting again the importance of such screening in these patients. As a matter of fact, detecting and treating LTBI or active TB before starting biotherapy aims to reduce several morbidities,
Table 2 Comparison between tuberculin skin test (TST) and interferon gamma release assay (IGRA) results patients with chronic immune-mediated inflammatory disease requiring a biologic therapy. IGRA in chronic IMID patients (n = 105)
TST
0–9 mm 10 mm missing Total
Total
( )
(+)
Undetermined
45 25 11 81
5 (4.7) 18 (17.1) 0 (0) 23 (21.9)
1 0 0 1
(42.8) (23.8) (10) (77.1)
IMID: immune-mediated inflammatory disease, IGRA: interferon gamma release assay, TST: tuberculin skin test.
(1) (0) (0) (1)
51 (48.5) 43 (40.9) 11 (10.4) 105 (1 0 0)
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Table 4 Risk factors for latent tuberculosis infection (LTBI) associated with positive interferon gamma release assay (IGRA) and tuberculin skin test (TST) results in patients with chronic immune-mediated inflammatory disease requiring a biologic therapy. Risk factor
Age Disease duration Immunosuppressives Steroids dose DAS28 3.2 ASDAS 1.3 CDAI 150 Previous biologic Absence of BCG
Positive TST (n = 43)
Positive IGRA (n = 23)
OR (95%CI)
p
OR (95%CI)
p
1.12–1.51 0.14–0.23 1.36–1.71 0.25–0.81 0.14–0.51 0.18–0.43 0.13–0.29 0.12–0.44 0.41–0.77
0.01 0.16 0.03 0.12 0.48 0.24 0.36 0.21 0.51
1.01–1.22 1.04–1.12 1.01–1.15 0.02–0.05 0.03–0.08 0.02–0.05 0.04–0.09 0.07–0.51 1.11–1.27
0.03 0.19 0.22 0.24 0.15 0.28 0.34 0.36 0.04
ASDAS: Ankylosing Spondylitis Disease Activity Score; BCG: Bacilli Calemtte-Guérin; CDAI: Crohn’s Disease Activity Index; DAS28: disease activity score; OR: Odds ratio, IGRA: interferon gamma release assay, TST: tuberculin skin test. P-values are significant at p < 0.05.
to avoid chronic underlying disease decompensation and to prevent from biologics abrupt withdrawal which may trigger inflammatory disease flares. The recommendations for detecting LTBI differ worldwide [5,6,21] but are based mainly on TST which has several limitations. The major disadvantage of TST is the subjective interpretation of the induration, leading to misclassification of the results, unnecessary analysis and may delay the onset of biologic therapy. In fact, the specificity and sensitivity of TST are affected by a number of factors mainly a prior BCG vaccination or a ‘‘booster” phenomenon of repeated TST testing may lead to false positivity [22], poor sensitivity in immunocompromised patients [23,24] and poor reproducibility due to operator-related variability in the administration and reading of the test [25,26]. These drawbacks could lead to unnecessary preventive treatment of LTBI or, on the contrary, to the evolution of active TB. The TST is therefore a test with limited validity and reliability [27]. On the other side, it has been suggested that the increase of TST cut-off point from 5 to 10 mm is associated with a loss in sensitivity but enhanced specificity and accuracy in the screening of LTBI [28], which was accurately demonstrated in the present study. In the past decade, the identification of genes in the TB genome, that are absent in BCG and most environmental mycobacteria, offered an opportunity to develop more specific tests to investigate TB infection, particularly LTBI [29]. Recently, IGRAs were developed to overcome some of the limitations of TST especially crossreactivity in BCG vaccinated people, error in measuring the size of induration of the skin reaction and requirement of two patient visits [30]. In fact, IGRA has a high specificity and low sensitivity in detection of LTBI [31] which is in line with the present results. The better specificity of IGRAs was confirmed by reducing the number of patients who should receive anti-TB chemoprophylaxis using IGRA instead of TST. This outcome has certainly important practical consequences. Firstly by reducing the need of prophylactic TB treatment, commonly known by the frequent moderate to severe side effects and secondarily by avoiding delay in setting up the biologics; estimated to 0.54 ± 1.42 months in this work. Several meta-analysis and systematic review aimed to compare the two tests confirming sparse and inconsistent results [30,32]. The current data support recent expert recommendations suggesting, without evidence, that IGRAs are superior to the TST in identifying individuals with a prior history of BCG vaccination [28]. Indeed, IGRAs are very useful in countries where BCG was administered post infancy or in cases of repeated boosters [33–35]. On the other hand, IGRAs had some disadvantages, such as additional costs, a need for a well-equipped laboratory and the need for blood sampling [36]. Moreover, the rate of indeterminate results has been reported to be as high as 40% [37], which are commonly
reported in patients with, immunodeficiency, malignancy and chronic renal failure. In comparison with studies in inflammatory disease patients [38,39], it is considerable that in this work only one indeterminate IGRA result was detected. Recommendations for LTBI screening in current guidelines vary on the subject of replacing TST with IGRAs or of using both tests [40] especially by reviewing recent data defending that IGRAs alone are ineffective to detect all patients at risk. The lack of a gold standard for diagnosing LTBI makes the assessment of the performance of TST and the IGRAs contentious [41]. To explain the different concordance figures between IGRAs and TST, it has been suggested that the mismatch is probably the result of heterogeneity expressed by differing background TB prevalence, variable immunosuppressive therapies and underlying BCG status [42]. In accordance with the present results, Kim et al. [24] showed that the agreement between the TST and IGRAs was low. The discordant results of the two tests in this study could be explained by the influence of receiving steroids or immunosuppressives on the TST results inducing false negative results. However, in United Kingdom and in Denmark where incidence of TB infection is low, agreement between TST and IGRAs seems to be good [43], confirming hence that the incidence of TB is the most decisive determinant of agreement between the two tests. Then, for some authors, using both TST and IGRAs may maximize sensitivity in detecting LTBI in spite of significant reduction of specificity [44]. Furthermore, in this study both IGRA and TST positive results were associated with age in line with others [45], while IGRA results alone were associated with absence of BCG vaccination. Thus, we can suggest in accordance with others and as observed in pediatric LTBI, that BCG vaccination can play a protective role for LTBI [45]. In addition, the negative influence of immunosuppressives on TST results has already been demonstrated; however, with no influence on IGRA results [18]. So to improve TST sensitivity, it would be necessary to perform the test before introduction of any immunosuppressive drug [45]. Unfortunately, conventional risk factors for LTBI reactivation as birth in endemic TB zones, absence/unknown BCG vaccination, were negative in this work preventing their evaluation as risk factors, but commonly demonstrated to be related to positive TST or IGRA [45]. The assessment of risk factors associated with positive TST and IGRAs in the present study and in literature, lead to establish several recommendations to improve the results of LTBI screening in inflammatory disease patients. Indeed, to limit the influence of immunosuppressive drugs, it would be more rewarding to screen for LTBI as soon as possible after the diagnosis using if possible TST and IGRAs [44]. Otherwise, IGRA should be preferred to TST particularly with the history of immunosuppressive and corticosteroids treatment. To limit indeterminate IGRAs results, optimal
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pre-analytical conditions are required, and it would be better to perform the test when disease activity is as low as possible [40]. If the test is indeterminate, a new test would be recommended and TST results should be taken into account. In conclusion, the benefits and limitations of both TST and IGRA and the low agreement between the two tests have been confirmed. This makes the decision of choosing the gold standard for LTBI screening challenging and depending on the countries’ incidence of TB and economic status. Given the most of the specificity, IGRAs should be included in the strategy to diagnose LTBI in patients with chronic inflammatory diseases before starting or switching biologic treatment, particularly as the substitution of TST by IGRA led to a significant reduction in the need of antibiotics prophylaxis. Conflict of interest None Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. References [1] Kuek A, Hazleman BL, Ostör AJ. Immune-mediated inflammatory diseases (IMIDs) and biologic therapy: a medical revolution. Postgrad Med J 2007;83:251–60. [2] Keane J, Gershon S, Wise RP, Mirabile-Levens E, Kasznica J, Schwieterman WD, et al. Tuberculosis associated with infliximab, a tumor necrosis factor alphaneutralizing agent. N Engl J Med 2001;345:1098–104. [3] Gómez-Reino JJ, Carmona L, Valverde VR, Mola EM, Montero MD. BIOBADASER Group. Treatment of rheumatoid arthritis with tumor necrosis factor inhibitors may predispose to significant increase in tuberculosis risk: a multicenter active-surveillance report. Arthritis Rheum 2003;48:2122–7. [4] Horsburgh Jr CR. Priorities for the treatment of latent tuberculosis infection in the United States. N Engl J Med 2004;350:2060–7. [5] Hamilton CD. Tuberculosis in the cytokine era: what rheumatologists need to know. Arthritis Rheum 2003;48:2085–91. [6] Furst DE, Cush J, Kaufmann S, Siegel J, Kurth R. Preliminary guidelines for diagnosing and treating tuberculosis in patients with rheumatoid arthritis in immunosuppressive trials or being treated with biological agents. Ann Rheum Dis 2002;61(Suppl 2). ii62–3. [7] Dixon WG, Hyrich KL, Watson KD, Lunt M, Galloway J, Ustianowski A. Drugspecifi c risk of tuberculosis in patients with rheumatoid arthritis treated with anti-TNF therapy: results from the British Society for Rheumatology Biologics Register (BSRBR). Ann Rheum Dis 2010;69:522–8. [8] Tubach F, Salmon D, Ravaud P, Allanore Y, Goupille P, Bréban M, et al. Risk of tuberculosis is higher with anti-tumor factor monoclonal antibody therapy than with soluble tumor necrosis factor receptor therapy: the three-year prospective French Research Axed on Tolerance of Biotherapies registry. Arthritis Rheum 2009;60:1884–94. [9] Ayubi E, Doosti-Irani A, Sanjari Moghaddam A, Khazaei S, Mansori K, Safiri S, et al. Comparison of QuantiFERON-TB Gold In-Tube (QFT-GIT) and tuberculin skin test (TST) for diagnosis of latent tuberculosis in haemodialysis (HD) patients: a meta-analysis of j estimates. Epidemiol Infect 2017;145:1824–33. [10] Abd El-Mohsen DH, Abd El-Moneim RH, El-Azizi N, Salah El-Deen N, Morad C, Hawwash A. Mycobacterium tuberculosis infection in systemic lupus erythematosus patients. Egypt Rheumatol 2017;39:227–31. [11] Matulis G, Jüni P, Villiger PM, Gadola SD. Detection of latent tuberculosis in immunosuppressed patients with autoimmune diseases: performance of a Mycobacterium tuberculosis antigen-specific interferon gamma assay. Ann Rheum Dis 2008;67:84–90. [12] Ponce de Leon D, Acevedo-Vasquez E, Alvizuri S, Gutierrez C, Cucho M, Alfaro J, et al. Comparison of an interferon-gamma assay with tuberculin skin testing for detection of tuberculosis (TB) infection in patients with rheumatoid arthritis in a TB-endemic population. J Rheumatol 2008;35:776–81. [13] Camlar SA, Makay B, Appak O, Appak YC, Esen N, Günay T, et al. Performance of tuberculin skin test and interferon gamma assay for the diagnosis of latent tuberculosis infection in juvenile idiopathic arthritis. Clin Rheumatol 2011;30:1189–93. [14] Xie X, Chen JW, Li F, Tian J, Gao JS, Zhang D. A T-cell based enzyme-linked immunospot assay for tuberculosis screening in Chinese patients with rheumatic diseases receiving infliximab therapy. Clin Exp Med 2011;11:155–61.
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The Egyptian Rheumatologist journal homepage: www.elsevier.com/locate/ejr
Original Article
Screening for latent tuberculosis infection prior to biologic therapy in patients with chronic immune-mediated inflammatory diseases (IMID): Interferon-gamma release assay (IGRA) versus tuberculin skin test (TST) Meriem Sellami a,⇑, Alia Fazaa a, Myriam Cheikh b, Saousen Miladi a, Kmar Ouenniche a, Rym Ennaifer b, Kaouther Ben Abdelghani a, Ahmed Laatar a a b
Rheumatology Department, Mongi Slim Hospital, La Marsa, Tunis, Tunisia Gastroenterology Department, Mongi Slim Hospital, La Marsa, Tunis, Tunisia
a r t i c l e
i n f o
Article history: Received 4 November 2018 Accepted 5 November 2018 Available online 15 November 2018 Keywords: Biological agents Chronic immune-mediated inflammatory diseases (IMID) Latent tuberculosis Interferon-gamma release assays (IGRA) Tuberculin test
a b s t r a c t Background: The screening for latent tuberculosis infection (LTBI) is mandatory before initiating biologics in patients with chronic immune-mediated inflammatory disease (IMID). The recommendations are based on the tuberculin skin test (TST) and interferon-gamma release assay (IGRA). Aim of the work: To evaluate the agreement between the two tests in the diagnosis of LTBI and to identify risk factors associated with positive TST and IGRA results. Patients and methods: Medical records of 105 IMID patients going to receive a biologic agents were extracted in a cross sectional study (2015–2017). No biologics was undertaken before LTBI screening. All patients underwent IGRA and chest radiography. TST was performed in 94 cases. Results: The mean age of the patients was 47.7 ± 14.4 years and disease duration of 11.2 ± 7.6 years. Agreement between the 2 tests results was low (j coefficient = 0.08). The sensitivity of TST and IGRA was equally low but the specificity of IGRA was higher. Replacing TST results by positive IGRA showed that number of patients who would take anti-tuberculous chemoprophylaxis will be significantly reduced by 46.5% (from 40.9% to 21.9%; p = 0.0002). TST results were significantly less positive for patients receiving immunosuppressives than for those receiving no treatment (35.1% vs 42.5%, p = 0.031). IGRA results were associated with absence of Bacilli Calemtte-Guérin vaccination. Age was the only risk factor for LTBI associated with both IGRA and TST positivity (p = 0.031, p = 0.011 respectively). Conclusions: TST and IGRA have a low agreement. Both tests should be included in the strategy to diagnose LTBI prior to biologic therapy in IMID patients. Ó 2018 Egyptian Society of Rheumatic Diseases. Publishing services provided by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
1. Introduction The advent of biologic agents has revolutionized the treatment of many immune-mediated inflammatory diseases by reducing symptoms and preventing radiological progression [1]. However, one of the most adverse effects of biological disease-modifying anti-rheumatic drugs (bDMARDs) is an increased risk of reactivation of latent tuberculosis (TB) infection (LTBI) in patients previously exposed to TB bacilli [2–4]. Screening for LTBI has been hence recommended before initiating treatment with bDMARDs
Peer review under responsibility of Egyptian Society of Rheumatic Diseases. ⇑ Corresponding author. E-mail address: [email protected] (M. Sellami).
[5,6]. This screening has resulted in a decrease in the incidence of TB [7,8]. While active TB can possibly be retained by medical history, clinical examination, chest radiography and bacteriological examination, there is no gold standard for detecting LTBI. Guidelines have provided discordant recommendations about the place of screening tools such as tuberculin skin test (TST) and interferongamma release assays (IGRAs) [9]. TST has been used worldwide for over a century as a guide in diagnosing both LTBI and active TB [10]. IGRA has been developed in the last decade in order to overcome some of the limitations of TST and can be used in addition to or in its replacement. They have been shown to offer improved specificity and probably sensitivity [11,12] but their agreement levels differ across all studies [13,14].
https://doi.org/10.1016/j.ejr.2018.11.003 1110-1164/Ó 2018 Egyptian Society of Rheumatic Diseases. Publishing services provided by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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As there are conflicting findings regarding the specificity and the sensitivity of different LTBI screening protocols in inflammatory disease patients scheduled to receive biologic agents, this single-center study was conducted aiming to evaluate the agreement between IGRA and TST in detecting LTBI prior to biologic therapy and to investigate the effect of replacing TST with IGRA in deciding on the necessity of prophylactic anti-TB antibiotic therapy before bDMARDs. Identifying risk factors for LTBI associated with positive TST and IGRA results was also well thought-out.
2. Patients and methods This is a cross sectional, single center study conducted in a tertiary care hospital in North of Tunisia (Mongi Slim Hospital, La Marsa, Tunis) between 2015 and 2017. The study was carried out in departments of Rheumatology and Gastroenterology. The study was approved by the local Ethics Committee and in accordance to the Declaration of Helsinki. The medical records of patients with chronic immune-mediated inflammatory diseases (IMID) requiring biologic therapy (first-line therapy or switch) were retrospectively reviewed. Data were extracted before and after having biologics. Disease activity was evaluated by the disease activity score-28 (DAS28) with erythrocyte sedimentation rate (ESR) for rheumatoid arthritis (RA), the ankylosing spondylitis disease activity score (ASDAS)-ESR for spondyloarthritis (SpA) and Crohn’s disease activity index (CDAI) for Crohn’s disease (CD). Patients with RA, SpA and chronic inflammatory bowel disease (IBD); CD and ulcerative colitis (UC) with an indication for biologic treatment were included from the Rheumatology and Gastroenterology Departments respectively. They were diagnosed according to the 2010 classification criteria of the American College of Rheumatology/European League Against Rheumatism for the RA [15], the Assessment of SpondyloArthritis international Society classification criteria for the SpA [16], and histological examination for patients with IBD. Two patients with Still’s disease refractory to treatment with corticosteroids and methotrexate were also included. No biologics was undertaken before TB and LTBI screening. Previous biologics were discontinued at least 1 month before inclusion. Patients who were under the age of 18, with history of other autoimmune diseases or who had already receive an antiTB chemoprophylaxis were not included in the study. All patients were screened for active TB and LTBI prior to biologic therapy with anti-tumor necrosis factor (anti-TNFa) and tocilizumab according to French guidelines [17] including retrieving medical history and information including: personal or family history of TB, exposure to TB, bacillus Calmette-Guerin (BCG) status, smoking, clinical examination, chest radiography, sputum examination, immunodiagnostic tests for LTBI (TST or/and IGRA), LTBI treatment and any diagnosis of active TB after initiation of biologic therapy. The TST consists of intradermal injection of 10 tuberculin units of purified protein derivative on the anterior surface of the forearm. The main diameter of skin induration was recorded in millimeters (mm) by an experienced clinician 72 h after the inoculation and the result was considered positive if skin induration was 10 mm. IGRA (QuantiFERON-TB Gold Plus; QFT-Plus) was performed by enzyme-linked immunosorbent assay (ELISA) according to the manufacturer’s recommendations and interpreted by local immunologists blind to the TST results. Results were analyzed using the QFT In TUBE software and expressed as UI/ml IFNc. The blood sample for IGRA analysis was taken on the same day just before performing TST to avoid any result interferences. It was interpreted as positive, negative or indeterminate. In the case of indeterminate IGRA, the TST result was used. If patients were
tested positive for either analysis, a sputum examination and chest computerized tomography (CT) were carried out looking for signs of active TB.
2.1. Statistical analysis The Statistical package for social sciences (SPSS version 11.5) was used. Descriptive statistics were presented as frequencies and means ± standard deviations. Comparisons were performed using Student’s t-test and analysis of variance for normally distributed variables. Concordance between IGRA and TST was performed using Cohen’s kappa coefficient (k). If the two tests are totally in agreement, the j coefficient will be equal to 1. Discrepancies between the tested variables will be expressed by decreased j coefficient (<1). If variables totally disagree, j coefficient will be 0. The gold standard used to calculate the sensitivity and specificity was the chest computerized tomography. Sensitivity was defined as the number of positive results divided by the total number tested at enrolment. Specificity was defined as the number of negative results divided by the total number tested at enrolment. The denominator included indeterminate results for IGRA. Both values are expressed as a percentage. To identify factors associated with positive TST or IGRA results, bivariate analysis (v2 tests) was performed. Results are presented with odds ratio (OR) and their 95% CI. The level of significance was set at 0.05.
3. Results A total of 105 immunocompetent patients with an IMID were included in the study. There were 44 men (41.9%) and 61 women (58.1%), with a sex ratio of 0.72. The demographic and clinical characteristics of patients are summarized in Table 1. Fifty two (49.5%) patients had extra-articular or extra-digestive manifestations especially coxitis (21.1%), osteoporosis (21.1%), osteopenia (17.3%) and anterior uveitis (17.3%). Eighty three (79%) patients were treated with a single biologic agent while 22 (20.9%) had 2 or 3 kinds of bDMARDs. The average duration of follow-up for the patients after the beginning of the biologic therapy was 4.8 ± 1.4 years (2–7 years). All patients underwent screening for LTBI before starting the first biologic and among them 20 (19%) patients were screened while switching to the second or third biologic. Physical examination was normal in all cases. The chest radiography was suggestive of active TB in 3 cases confirmed by chest CT in only one case. The sputum examination was negative in all cases. TST performed in 94 (89.5%) cases was negative in 51 (54.2%) and 10 mm in 43 (45.7%). The mean TST induration was 7.63 ± 9.27 mm (0–32). IGRA, performed in all cases was negative in 81 (77.1%), undermined in 1 (1%) and positive in 23 (21.9%) allowing the diagnosis of LTBI. None of the patients had a history of TB exposure or a reactivation of tuberculosis during biologic treatment. No side effects from both tests were reported. On comparison between TST and IGRA results, 30 discordant results were found: 25 (23.8%) with positive TST and negative QFT and 5 (4.7%) with negative TST and positive IGRA (Table 2). These divergent results were mostly found in patients on systemic corticosteroids (80%). Positive TST (cut-off of 15 mm) and positive IGRA were comparable (17.1% vs 21.9%, p = 0.09), although discordant results remained high (11.4%). Agreement between TST and IGRA was low (j = 0.08, 95% CI 0.003–0.162) and improved in patients not taking concurrent systemic corticosteroids (j = 0.12). The sensitivity of TST and IGRA was equally low but the specificity of IGRA was higher (Table 3). The specificity of TST increased concomitantly with the rise of the TST cut-off point.
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M. Sellami et al. / The Egyptian Rheumatologist 41 (2019) 225–230 Table 1 Demographic, clinical and therapeutic characteristics of the patients with chronic immune-mediated inflammatory disease requiring a biologic therapy. Variable mean ± SD or n (%)
Chronic IMID patients (n = 105)
Age (years) Age at diagnosis (years) Disease duration (years) Residency (rural/urban) Unemployed person Socioeconomic class (low/med/high) Current smoking BCG vaccine (at birth/at age 6 yr) Diagnosis Rheumatoid arthritis (RA) Spondyloarthritis (SpA) Crohn’s disease (CD) Ulcerative colitis Still’s disease RA Rheumatoid factor positive Anti-CCP-positive Erosive DAS28 3.2 SpA Axial Peripheral Axial/peripheral Associated with IBD ASDAS 1.3 CD Stenosis Fistula Stenosis and fistula Inflammatory CDAI 150 Corticosteroids Current dose (mg/day) DMARDs Methotrexate Leflunomide Azathioprine Sulphasalazine 5-aminosalicylic acid Hydroxychloroquine bDMARD Infliximab Etanercept Adalimumab Certolizumab Tocilizumab Rituximab
47.7 ± 14.4 36.5 ± 13.2 11.2 ± 7.6 17/88 (16.2/83.8) 51 (48.6) 3/71/31 (2.9/67.6/29.5) 42 (40) 93/71 (88.5/67.6) 47 (44.8) 26 (24.7) 21 (20) 9 (8.6) 2 (1.9) 35 (74.4) 36 (76.5) 37 (78.7) 33 (70.2) 10 (38.4) 4 (15.3) 6 (23.0) 6 (23.0) 18 (69.2) 5 (23.8) 4 (19) 10 (47.6) 2 (9.5) 15 (71.4) 81 (77.1) 10.2 ± 4.5 35 (33.3) 14 (13.3) 30 (28.6) 48 (45.7) 18 (17.1) 6 (5.7) 37 (35.2) 29 (27.6) 39 (37.1) 14 (13.3) 10 (9.5) 6 (5.7)
IMID: immune-mediated inflammatory disease, BCG: Bacilli Calemtte-Guérin; DAS28: Disease activity score for rheumatoid arthritis; IBD: inflammatory bowel disease; ASDAS: Ankylosing Spondylitis Disease Activity Score; CDAI: Crohn’s Disease Activity Index, DMARDs: disease modifying antirheumatic drug, bDMARD: biologic DMARD.
The number of patients requiring chemoprophylaxis before biologics introduction was different depending on the LTBI screening method. Taking into account only the TST results, 43 (40.9%) patients had to be treated. Replacing TST by IGRA positive results showed that only 23 (21.9%) required antibiotic prophylaxis. Then, the number of patients who would take chemoprophylaxis will be significantly reduced 46.5% (from 40.9% to 21.9%, p = 0.0002). Thereafter, according to IGRA positive results, biologic treatment
Table 3 Sensitivity, specificity and accuracy of tuberculin skin test (TST) and interferon gamma release assay (IGRA) results in predicting latent tuberculosis infection (LTBI) in patients with chronic immune-mediated inflammatory disease requiring a biologic therapy. Test
Chronic IMID patients (n = 105) Sensitivity (%)
Specificity (%)
Accuracy (%)
IGRA TST 5–9 mm 10–14 mm 15–19 mm 20–24 mm 25 mm
26.14 73.9 73.9 73.9 52.1 39.1 4.3
100 80.6 79.1 80.6 97.0 98.5 98.5
75.3 73.6 71.2 72.5 74.1 74.4 75.6
IMID: immune-mediated inflammatory disease IGRA: interferon gamma release assay, TST: tuberculin skin test.
was delayed in 23 cases (21.9%) with mean delay duration of 0.54 ± 1.42 month (0–8). The anti-TB chemoprophylaxis used included isoniazid for 6 months in 4 cases (17.3%) and an association of isoniazid and rifampicin for 3 months in 19 cases (82.6%). The risk factors for LTBI associated with positive both IGRA and TST results are shown in Table 4. Conventional risk factors for LTBI reactivation such as history of active TB, close contact with a patient with active TB, and chest radiography suggestive of previous TB infection were not tested as risk factors as they were all negative. Corticosteroids or immunosuppressives did not affect the positivity of IGRA (15.3% vs 14.4%, p = 0.221). IGRA positivity was associated with the absence of BCG vaccination. TST results were significantly less positive for patients receiving corticosteroids or immunosuppressives, independent of the dose, than for those receiving no treatment (35.1% vs 42.5%, p = 0.031). Age was the only risk factor associated with both IGRA and TST positivity. 4. Discussion This study on 105 IMID patients, IGRA and TST were evaluated and the importance of LTBI screening before starting or switching bDMARDs in daily practice was highlightened, especially with the constant increase in the number of patients treated with biologics. The poor agreement between TST and IGRA results was confirmed. Unsurprisingly, the substitution of TST by QFT in LTBI screening led to a substantial reduction of antibiotics prophylaxis introduction, in agreement with others [18]. Systematic screening of LTBI in inflammatory disease patients may be an important disease control item which is currently being re-evaluated as part of the new End TB strategy [19]. Recently, a retrospective study conducted in 2016 showed that LTBI was diagnosed in 20% of biologic therapy candidates using TST or IGRA [20], highlighting again the importance of such screening in these patients. As a matter of fact, detecting and treating LTBI or active TB before starting biotherapy aims to reduce several morbidities,
Table 2 Comparison between tuberculin skin test (TST) and interferon gamma release assay (IGRA) results patients with chronic immune-mediated inflammatory disease requiring a biologic therapy. IGRA in chronic IMID patients (n = 105)
TST
0–9 mm 10 mm missing Total
Total
( )
(+)
Undetermined
45 25 11 81
5 (4.7) 18 (17.1) 0 (0) 23 (21.9)
1 0 0 1
(42.8) (23.8) (10) (77.1)
IMID: immune-mediated inflammatory disease, IGRA: interferon gamma release assay, TST: tuberculin skin test.
(1) (0) (0) (1)
51 (48.5) 43 (40.9) 11 (10.4) 105 (1 0 0)
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Table 4 Risk factors for latent tuberculosis infection (LTBI) associated with positive interferon gamma release assay (IGRA) and tuberculin skin test (TST) results in patients with chronic immune-mediated inflammatory disease requiring a biologic therapy. Risk factor
Age Disease duration Immunosuppressives Steroids dose DAS28 3.2 ASDAS 1.3 CDAI 150 Previous biologic Absence of BCG
Positive TST (n = 43)
Positive IGRA (n = 23)
OR (95%CI)
p
OR (95%CI)
p
1.12–1.51 0.14–0.23 1.36–1.71 0.25–0.81 0.14–0.51 0.18–0.43 0.13–0.29 0.12–0.44 0.41–0.77
0.01 0.16 0.03 0.12 0.48 0.24 0.36 0.21 0.51
1.01–1.22 1.04–1.12 1.01–1.15 0.02–0.05 0.03–0.08 0.02–0.05 0.04–0.09 0.07–0.51 1.11–1.27
0.03 0.19 0.22 0.24 0.15 0.28 0.34 0.36 0.04
ASDAS: Ankylosing Spondylitis Disease Activity Score; BCG: Bacilli Calemtte-Guérin; CDAI: Crohn’s Disease Activity Index; DAS28: disease activity score; OR: Odds ratio, IGRA: interferon gamma release assay, TST: tuberculin skin test. P-values are significant at p < 0.05.
to avoid chronic underlying disease decompensation and to prevent from biologics abrupt withdrawal which may trigger inflammatory disease flares. The recommendations for detecting LTBI differ worldwide [5,6,21] but are based mainly on TST which has several limitations. The major disadvantage of TST is the subjective interpretation of the induration, leading to misclassification of the results, unnecessary analysis and may delay the onset of biologic therapy. In fact, the specificity and sensitivity of TST are affected by a number of factors mainly a prior BCG vaccination or a ‘‘booster” phenomenon of repeated TST testing may lead to false positivity [22], poor sensitivity in immunocompromised patients [23,24] and poor reproducibility due to operator-related variability in the administration and reading of the test [25,26]. These drawbacks could lead to unnecessary preventive treatment of LTBI or, on the contrary, to the evolution of active TB. The TST is therefore a test with limited validity and reliability [27]. On the other side, it has been suggested that the increase of TST cut-off point from 5 to 10 mm is associated with a loss in sensitivity but enhanced specificity and accuracy in the screening of LTBI [28], which was accurately demonstrated in the present study. In the past decade, the identification of genes in the TB genome, that are absent in BCG and most environmental mycobacteria, offered an opportunity to develop more specific tests to investigate TB infection, particularly LTBI [29]. Recently, IGRAs were developed to overcome some of the limitations of TST especially crossreactivity in BCG vaccinated people, error in measuring the size of induration of the skin reaction and requirement of two patient visits [30]. In fact, IGRA has a high specificity and low sensitivity in detection of LTBI [31] which is in line with the present results. The better specificity of IGRAs was confirmed by reducing the number of patients who should receive anti-TB chemoprophylaxis using IGRA instead of TST. This outcome has certainly important practical consequences. Firstly by reducing the need of prophylactic TB treatment, commonly known by the frequent moderate to severe side effects and secondarily by avoiding delay in setting up the biologics; estimated to 0.54 ± 1.42 months in this work. Several meta-analysis and systematic review aimed to compare the two tests confirming sparse and inconsistent results [30,32]. The current data support recent expert recommendations suggesting, without evidence, that IGRAs are superior to the TST in identifying individuals with a prior history of BCG vaccination [28]. Indeed, IGRAs are very useful in countries where BCG was administered post infancy or in cases of repeated boosters [33–35]. On the other hand, IGRAs had some disadvantages, such as additional costs, a need for a well-equipped laboratory and the need for blood sampling [36]. Moreover, the rate of indeterminate results has been reported to be as high as 40% [37], which are commonly
reported in patients with, immunodeficiency, malignancy and chronic renal failure. In comparison with studies in inflammatory disease patients [38,39], it is considerable that in this work only one indeterminate IGRA result was detected. Recommendations for LTBI screening in current guidelines vary on the subject of replacing TST with IGRAs or of using both tests [40] especially by reviewing recent data defending that IGRAs alone are ineffective to detect all patients at risk. The lack of a gold standard for diagnosing LTBI makes the assessment of the performance of TST and the IGRAs contentious [41]. To explain the different concordance figures between IGRAs and TST, it has been suggested that the mismatch is probably the result of heterogeneity expressed by differing background TB prevalence, variable immunosuppressive therapies and underlying BCG status [42]. In accordance with the present results, Kim et al. [24] showed that the agreement between the TST and IGRAs was low. The discordant results of the two tests in this study could be explained by the influence of receiving steroids or immunosuppressives on the TST results inducing false negative results. However, in United Kingdom and in Denmark where incidence of TB infection is low, agreement between TST and IGRAs seems to be good [43], confirming hence that the incidence of TB is the most decisive determinant of agreement between the two tests. Then, for some authors, using both TST and IGRAs may maximize sensitivity in detecting LTBI in spite of significant reduction of specificity [44]. Furthermore, in this study both IGRA and TST positive results were associated with age in line with others [45], while IGRA results alone were associated with absence of BCG vaccination. Thus, we can suggest in accordance with others and as observed in pediatric LTBI, that BCG vaccination can play a protective role for LTBI [45]. In addition, the negative influence of immunosuppressives on TST results has already been demonstrated; however, with no influence on IGRA results [18]. So to improve TST sensitivity, it would be necessary to perform the test before introduction of any immunosuppressive drug [45]. Unfortunately, conventional risk factors for LTBI reactivation as birth in endemic TB zones, absence/unknown BCG vaccination, were negative in this work preventing their evaluation as risk factors, but commonly demonstrated to be related to positive TST or IGRA [45]. The assessment of risk factors associated with positive TST and IGRAs in the present study and in literature, lead to establish several recommendations to improve the results of LTBI screening in inflammatory disease patients. Indeed, to limit the influence of immunosuppressive drugs, it would be more rewarding to screen for LTBI as soon as possible after the diagnosis using if possible TST and IGRAs [44]. Otherwise, IGRA should be preferred to TST particularly with the history of immunosuppressive and corticosteroids treatment. To limit indeterminate IGRAs results, optimal
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pre-analytical conditions are required, and it would be better to perform the test when disease activity is as low as possible [40]. If the test is indeterminate, a new test would be recommended and TST results should be taken into account. In conclusion, the benefits and limitations of both TST and IGRA and the low agreement between the two tests have been confirmed. This makes the decision of choosing the gold standard for LTBI screening challenging and depending on the countries’ incidence of TB and economic status. Given the most of the specificity, IGRAs should be included in the strategy to diagnose LTBI in patients with chronic inflammatory diseases before starting or switching biologic treatment, particularly as the substitution of TST by IGRA led to a significant reduction in the need of antibiotics prophylaxis. Conflict of interest None Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. References [1] Kuek A, Hazleman BL, Ostör AJ. Immune-mediated inflammatory diseases (IMIDs) and biologic therapy: a medical revolution. Postgrad Med J 2007;83:251–60. [2] Keane J, Gershon S, Wise RP, Mirabile-Levens E, Kasznica J, Schwieterman WD, et al. Tuberculosis associated with infliximab, a tumor necrosis factor alphaneutralizing agent. N Engl J Med 2001;345:1098–104. [3] Gómez-Reino JJ, Carmona L, Valverde VR, Mola EM, Montero MD. BIOBADASER Group. Treatment of rheumatoid arthritis with tumor necrosis factor inhibitors may predispose to significant increase in tuberculosis risk: a multicenter active-surveillance report. Arthritis Rheum 2003;48:2122–7. [4] Horsburgh Jr CR. Priorities for the treatment of latent tuberculosis infection in the United States. N Engl J Med 2004;350:2060–7. [5] Hamilton CD. Tuberculosis in the cytokine era: what rheumatologists need to know. Arthritis Rheum 2003;48:2085–91. [6] Furst DE, Cush J, Kaufmann S, Siegel J, Kurth R. Preliminary guidelines for diagnosing and treating tuberculosis in patients with rheumatoid arthritis in immunosuppressive trials or being treated with biological agents. Ann Rheum Dis 2002;61(Suppl 2). ii62–3. [7] Dixon WG, Hyrich KL, Watson KD, Lunt M, Galloway J, Ustianowski A. Drugspecifi c risk of tuberculosis in patients with rheumatoid arthritis treated with anti-TNF therapy: results from the British Society for Rheumatology Biologics Register (BSRBR). Ann Rheum Dis 2010;69:522–8. [8] Tubach F, Salmon D, Ravaud P, Allanore Y, Goupille P, Bréban M, et al. Risk of tuberculosis is higher with anti-tumor factor monoclonal antibody therapy than with soluble tumor necrosis factor receptor therapy: the three-year prospective French Research Axed on Tolerance of Biotherapies registry. Arthritis Rheum 2009;60:1884–94. [9] Ayubi E, Doosti-Irani A, Sanjari Moghaddam A, Khazaei S, Mansori K, Safiri S, et al. Comparison of QuantiFERON-TB Gold In-Tube (QFT-GIT) and tuberculin skin test (TST) for diagnosis of latent tuberculosis in haemodialysis (HD) patients: a meta-analysis of j estimates. Epidemiol Infect 2017;145:1824–33. [10] Abd El-Mohsen DH, Abd El-Moneim RH, El-Azizi N, Salah El-Deen N, Morad C, Hawwash A. Mycobacterium tuberculosis infection in systemic lupus erythematosus patients. Egypt Rheumatol 2017;39:227–31. [11] Matulis G, Jüni P, Villiger PM, Gadola SD. Detection of latent tuberculosis in immunosuppressed patients with autoimmune diseases: performance of a Mycobacterium tuberculosis antigen-specific interferon gamma assay. Ann Rheum Dis 2008;67:84–90. [12] Ponce de Leon D, Acevedo-Vasquez E, Alvizuri S, Gutierrez C, Cucho M, Alfaro J, et al. Comparison of an interferon-gamma assay with tuberculin skin testing for detection of tuberculosis (TB) infection in patients with rheumatoid arthritis in a TB-endemic population. J Rheumatol 2008;35:776–81. [13] Camlar SA, Makay B, Appak O, Appak YC, Esen N, Günay T, et al. Performance of tuberculin skin test and interferon gamma assay for the diagnosis of latent tuberculosis infection in juvenile idiopathic arthritis. Clin Rheumatol 2011;30:1189–93. [14] Xie X, Chen JW, Li F, Tian J, Gao JS, Zhang D. A T-cell based enzyme-linked immunospot assay for tuberculosis screening in Chinese patients with rheumatic diseases receiving infliximab therapy. Clin Exp Med 2011;11:155–61.
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