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 Table of Contents  
ORIGINAL ARTICLE
Year : 2018  |  Volume : 13  |  Issue : 4  |  Page : 233-239

Real life experience of a screening strategy for latent tuberculosis before treatment with biologicals in indian patients with rheumatic diseases


Department of Rheumatology, “Joint Disease Clinic”, ISIC Superspeciality Hospital, New Delhi, India

Date of Web Publication18-Nov-2018

Correspondence Address:
Prof. Anand N Malaviya
Department of Rheumatology, “Joint Disease Clinic”, ISIC Superspeciality Hospital, Vasant Kunj, New Delhi - 110 070
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/injr.injr_66_18

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  Abstract 


Objective: The objective of the study was to study the effectiveness of a recommended screening strategy for latent tuberculosis infection (LTBI) in patients with systemic inflammatory rheumatic diseases (SIRDs) treated with biological disease-modifying antirheumatic drugs (bDMARDs).
Methods: The study included patients being considered for bDMARD treatment. Screening strategy included screening with “4S symptom complex (current cough, fever, weight loss, and night sweats) for TB,” augmented Mantoux test using ten tuberculin unit (TU) strength simultaneously with QuantiFERON®-TB Gold (QFTG) test. Those with a Mantoux test reading of ≥10 mm induration at 48–72 h and/or with a positive QFTG test, were given TB prophylaxis before initiating bDMARDs. They were followed and monitored for any features of tuberculosis flare.
Results: A total of 730 patients (265 rheumatoid arthritis, 400 axial spondyloarthritis [axSpA], 34 psoriatic arthritis, and 31 others) were considered for bDMARDs. Two hundred and sixty-seven (36.6%) were positive for LTBI. They were treated either with isoniazid monotherapy for 6 months or with rifampicin + isoniazid for 4 months. bDMARDs were started 1 month after initiating chemoprophylaxis. Five (0.68%) patients developed active TB disease in the follow-up. In a total of 2930 “control” patients with the same diseases but never having taken bDMARDs, 18 (0.61%) developed active TB disease. The proportion of patients developing active TBI during the same period of follow-up did not differ between those who were and those who were not treated with bDMARDs. None of the study participants had “4S” symptoms.
Conclusion: The strategy of clinical screening for active TBI with “4S complex,” standard chest radiograph, and an augmented Mantoux testing (10 TU purified protein derivative, [PPD]) simultaneously with QFTG test for the screening of LTBI, was successful in identifying active TBI in patients treated with bDMARDs.

Keywords: Biological disease-modifying antirheumatic drugs, India, latent tuberculosis infection, rheumatic diseases, TB flare prevention


How to cite this article:
Malaviya AN, Thakaran R, Rawat R, Kapoor S, Garg S, Baghel SS, Messi C, Vivekanand, Zaheer Q. Real life experience of a screening strategy for latent tuberculosis before treatment with biologicals in indian patients with rheumatic diseases. Indian J Rheumatol 2018;13:233-9

How to cite this URL:
Malaviya AN, Thakaran R, Rawat R, Kapoor S, Garg S, Baghel SS, Messi C, Vivekanand, Zaheer Q. Real life experience of a screening strategy for latent tuberculosis before treatment with biologicals in indian patients with rheumatic diseases. Indian J Rheumatol [serial online] 2018 [cited 2019 Jan 20];13:233-9. Available from: http://www.indianjrheumatol.com/text.asp?2018/13/4/233/241789




  Introduction Top


The risk of flare of tuberculosis infection (TBI) in patients with rheumatic musculoskeletal diseases (RMDs) treated with tumor necrosis factor-α inhibitor (TNFi) biological/targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) is well established.[1],[2] This issue is more serious in high-burden TB countries in Asia,[3] more specifically in India.[4] It was obvious that a strategy for appropriate screening for the patients at risk for latent TBI (LTBI)-flare was urgently needed. The time-honored tuberculin skin test (TST) for the screening of LTBI in rheumatoid arthritis (RA) was earlier reported from India to give only 50% positivity rate compared to the normal controls.[5] Therefore, it was necessary to find method(s) to improve the sensitivity of the LTBI-screening test(s). Toward this aim, in 2009, a group from Delhi reported a strategy for the screening of LTBI and its follow-up.[6],[7] It recommended (i) systematic clinical screening for TBI; (ii) an “augmented Mantoux test” using ten tuberculin units (TUs), of purified protein derivative (PPD) RT23, with Tween-80; as against the National standard 1 TU PPD recommended by National Tuberculosis Institute (NIT), Ministry of Health, Government of India for the Mantoux test;[8],[9],[10] (iii) simultaneously carried out the QuantiFERON®-TB Gold (QFTG) test;[11] (iv) standard chest radiograph; and (v) contrast-enhanced computed tomography (CECT) of the chest. This study demonstrated high efficacy in curtailing the LTBI flare in a small number of patients. In a follow-up report, it was also shown that instead of getting CECT done in every patient, only in those with positive Mantoux and/or QFTG test, was still equally effective in controlling LTBI flare.[7] Continuing the same work, the latest report in the series showed that doing away completely with the CECT also did not affect the efficacy of the LTBI-screening method proposed (above).[12] The same report also provided an evidence base for the higher efficacy of 10 TU PPD as against the NIT-recommended standard 1 TU strength for performing the Mantoux test.[8],[9] Based on these three reports, we present the results of applying the above-mentioned LTBI-screening strategy in a larger number patients with systemic inflammatory rheumatic diseases (SIRDs) with the intention to treat with b/tsDMARDs.


  Methods Top


Study participants

Patients with systemic inflammatory RMDs (mostly RA and SPA) initiated on bDMARDs between the beginning of January 2013 and the end of August 2017 were the participants of the study. They were screened clinically for active TBI using the “four-symptom complex for TB screening” (”4S” strategy) for adults, i.e., current 1. cough, 2. fever, 3. weight loss, and 4. night sweats.[13] The sensitivity of 4S complex is 85%, with a negative predictive value (NPV) for cases of pulmonary TB (NPV 97.7% [95% confidence interval: 97.4–98.0]). Those with such symptoms were not included in the present study but referred to the pulmonologist of the team for the further evaluation and treatment of active TBI. If needed, they were given biological drugs only after getting clearance from the pulmonologist.

Patients without “4S” symptoms underwent a standard anteroposterior view chest radiograph. If the “4S” symptoms, as well as the standard chest radiograph, were negative/normal, the patients were considered as “not having active TBI.” They were then screened for LTBI exactly as described in detail in a recent publication.[11] In summary, two additional tests were performed to detect LTBI as follows:

  1. Augmented Mantoux test: 10 TU PPD RT23 with stabilizer Tween 80 in 0.1 ml volume, was performed using PPD with 10 IU strength/0.1 mL, obtained on special request from Span Diagnostics (Arkray Health Care Pvt. Ltd, Plot No. 336,338,340, Road No. 3, G.I.D.C., Sachin-394230 (Surat), Gujarat, India), as was used by Malaviya et al. earlier,[12] following the exact technique recommended by the NIT, Ministry of Health, Government of India, Bengaluru.[8] The reading of the test was carried out between 48 and 72 h. Induration at the injection site was measured at the largest horizontal plane in millimeters. The test was interpreted exactly as recommended by NIT,[8] i.e., no induration was considered “negative;” 1–9 mm was considered “nonspecific reaction most likely due to environmental mycobacteria or old BCG vaccination history;” and ≥10 mm induration was considered LTBI. Such patients were given chemoprophylaxis for LTBI as described below
  2. (ii) QFTG test: just before conducting the Mantoux test, a blood sample was drawn for carrying out the QFTG test using the commercially available test kit (Cellestis, Melbourne, Australia). The test results were reported as “positive,” “negative,” or “indeterminate.” Those with positive results were considered as having LTBI. They were initiated on TB prophylaxis treatment as described below.


Treatment regimen for participants detected as having latent tuberculosis infection

Any of the two recommended regimens[14] were prescribed. The choice was left on the treating rheumatologist (there were three consultant rheumatologists providing treatment for the patients) and the patient. One regimen consisted of isoniazid monotherapy at the dose of 5 mg/kg/day as the single daily dose (max, 300 mg/day) for 6 months. The alternative regimen was rifampicin 600 mg + isoniazid 300 mg fixed-dose combination daily dose for 4 months. bDMARDs were initiated after 15 days (if there was an urgency to initiate treatment of the underlying SIRD) or after 1 month of starting the treatment for LTBI.

Control participants

Patients with SIRDs in the follow-up of this clinic having completed at least 1 year of follow-up on conventional sDMARDs (csDMARDs) during the same time interval as the study participants (i.e., beginning of Jan 2013 to the end of August 2017) but not having received bDMARDs were included as “controls.” They were asked as well as their records examined for having developed active TBI since the initiation of csDMARDs. The number of “control” patients developing active TBI after the initiation of csDMARDs was compared with the number of “study” patients developing active TBI after the initiation of bDMARDs.

Standard disease-modifying antirheumatic drug treatment regimen used in this clinic

The standard csDMARD used in this clinic includes methotrexate (MTX), hydroxychloroquine (HCQ), sulfasalazine (SSZ), leflunomide (LFN), and glucocorticoids (GCs).[15] The standard treatment regimen for the patients with RA and other SIRDs with inflammatory synovitis in this clinic has been as follows: treatment was initiated with MTX + HCQ + tapering GC (usually 6–8 weeks). If they do not achieve “low disease activity” or “remission” by 6 months, either SSZ or LFN is added depending on patient's pregnancy-related issues. If the patient wanted pregnancy in the near future, then SSZ is added to the regimen. However, if that was not an issue, LFN is added to the regimen. A short tapering course of GC is always given whenever another csDMARD was added to the treatment regimen. For patients with psoriatic arthritis (PsA), the initial csDMARDs usually are MTX + SSZ + tapering GC. If they do not achieve low disease activity or remission, then LFN is added in the regimen along with a short of low-dose tapering GC. It is to be noted that SIRD patients being initiated of csDMARDs are only clinically screened for active TBI (using “4S” screening symptoms) as well as a standard chest radiograph. They are not screened for LTBI before initiating csDMARDs routinely. At each follow-up clinic visits the patients were evaluated for the appearance of any new clinical symptoms indicative of comorbidity or infection including active TBI (using the “4S” symptoms, as described above). Patients who did not achieve “low disease activity” or “remission” by 6 months were offered the bDMARD treatment.

Statistical analysis

For statistical analyses, simple 't' test was used for continuous variables and for categorical data Fisher's exact test was used.

Ethical approval

The auhtors obtained necessary waiver from the ethics committee of the institute. Informed written consent was obtained from all patients prior to their enrollment in this study.


  Results Top


Demography of the “study” group of patients

There were 730 patients in the “study” group considered for bDMARDs treatment. There were 409 (57%) males with a male:female ratio of 1.3:1. The age range was 23–71 years with a median of 32 years and the mean of 33.7 years with a standard deviation (SD) of + 16.2. There were 265 (36%) patients with RA, 400 (54%) with SpA, 34 (5.6%) with PsA, and 31 (4%) with miscellaneous conditions, mainly systemic lupus erythematosus (SLE) and systemic sclerosis (SSc).

Demography of the “control” group of patients

There were a total of 2930 patients in the “control” group who had never received bDMARDs. These patients were treated with csDMARDs with a minimum follow-up duration of 1 year. Their age ranged from 18 to 79 years, with a median of 37 years and mean of 38 years with a SD of +19.6. The group included a total of 2145 patients with RA (seropositive 1674, females 1395 and seronegative 471, females 388) with a male-to-female ratio of 1:5; 592 patients with axSpA (131 females) with a male-to-female ratio was 3.5:1; 122 patients with PsA (57 females) with a male-to-female ratio of 1.1:1; 67 patients with SLE (65 females) with a male-to-female ratio of 32.5:1; and 4 patients (all females) with SSC. Results are summarized in [Table 1].
Table 1: Gender and age distribution among “controls” and the “participants”

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Participants with “4S” symptoms

The “4S complex” symptoms were neither detected in any of the “control” group of patients nor the “study” group of patients.

Latent tuberculosis infection screening results among the “study” patients

All the 730 patients were tested using the augmented Mantoux test (10 TU PPD) and QFTG test (described above). A total of 267 patients (36.6%) gave a positive result. Among them, only augmented Mantoux was positive in 165 (61.8%), QFTG in 83 (31.1%) and both of them were positive in 19 (7%) of the patients. [Table 2] provides the results of the LTBI-screening tests in patients intended for the bDMARD treatment.
Table 2: LTBI screening in patients intended for biological disease modifying antirheumatic drug treatment

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These patients were considered as having LTBI (i.e., induration of ≥10 mm and/or a positive QFTG test and/or healed TB scar on standard chest radiograph) were given chemoprophylaxis regimen for LTBI as described above. Type and doses of the bDMARDs taken by the “study” participants: the details are provided in [Table 3].
Table 3: The number of patients who took the biological drug(s) and the number of doses of these drugs taken

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Of the total of 730 “study” patients who were considered for treatment with a bDMARD during the period of the study, five patients (0.68%) developed active TBI after the initiation of bDMARD treatment. Among 2930 “control” patients (never given bDMARDs), 22 (0.75%) developed active TBI while taking standard csDMARD treatment. The details are provided in [Table 4]a and [Table 4]b. A striking feature was that among “controls” (patients who only received csDMARDs) TB developed only in patients with RA but not in axSpA patients. In contrast, five of the bDMARD-treated patients who developed TBI, two were patients with axSpA.


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  Discussion Top


Appropriate LTBI screening is the key to preventing TBI flare in patients receiving b/tsDMARDs. However, the screening strategy would vary in different parts of the world, from region to region, depending on the incidence and the prevalence of TBI and LTBI. The discussion on the differences in the strategies for the screening of LTBI by the various authorities (World Health Organization, Centers for Disease Control, USA, The American Thoracic Society, The NIT (Bengaluru), Ministry of Health, Govt. of India) is beyond the scope of this work; for that the reader is referred to several key references cited in this paper.[6],[7],[8],[9],[10],[11],[12] A very detailed discussion of the different LTBI-screening strategies has recently been published by Handa et al.[16] In this regard, the extensive work by Madhukar Pai deserves mention. In his 2005 publication, he describes the current evidence on the performance of interferon-gamma (IFN-γ) assays and the TST. He suggests that both the TST and the IFN-γ assays have advantages and limitations and both the tests appear to be useful at this time.[17] In his 2008 publication, he discusses the promise of the newer tests but cautions against routine use till more evidence is available.[18] In their 2009, chapter entitled “Diagnosis of LTBI: Recent advances and future direction,” in Sharma and Mohan's textbook of tuberculosis Pai and Kalantri opine. “At this time (2009), the role of IGRA in low-income, high-burden setting (e.g., India) is rather limited.”[19] In a 2016 paper, Pai et al. conclude “Both TSTs and IGRAs are now a part of the LTBI testing landscape, and current guidelines allow the use of both tools, although guidelines vary considerably across countries.”[20] Being a high-burden TB country, India would need a different strategy than any of the low-burden TB countries. Moreover, the prevalence of sensitization to different mycobacterial antigens may also vary in different regions depending on the prevalence of the environmental (mostly saprophytic) mycobacteria. Therefore, it was necessary to develop an evidence-based strategy for the LTBI screening that would be suitable for India and possibly other similar high-burden TB countries.

Over the past ~10 years, several Indian studied have dwelled with this issue systematically to provide an evidence base for recommending a suitable LTBI-screening strategy for our country.[6],[7],[12],[16] In the beginning, an “all-encompassing, wide-net” strategy to detect LTBI was used arbitrarily.[6] It included clinical screening, routine imaging (standard radiograph of the chest), advanced imaging (CECT chest), augmented TST (using 10 TU PPD),[21] and QFTG test.[11] These approaches were shown to be highly effective for the LTBI screening. However, these strategies were expensive due to the inclusion of mandatory CECT chest. Moreover, the use of augmented TST was not evidence based, i.e., its higher sensitivity compared to the standard 1 TU PPD officially recommended for use in India, had not been tested. Over the next several years, the comparative efficacy of 10 TU PPD over 1 TU PPD was demonstrated in a head to comparison,[12] thus doing away with the two-step Mantoux testing. This work had also shown that CECT was not essential for the LTBI screening in India.[12]

In the present report, it has been reconfirmed on a large number patients that the recommended strategy for LTBI screening in India, i.e., clinical screening using “4S” symptoms, augmented (10 TU PPD) Mantoux testing, simultaneously performed QFTG test, and a standard plain chest radiograph, is highly successful. This strategy has brought down the rate of LTBI flare in patients taking b/tsDMARDs to the same level as those on csDMARDs which is comparable to the general population. Based on these findings, we feel that the Indian Rheumatology Association may consider revising its 2006 recommendations that may now be considered outdated.[22] An algorithm depicting the recommended LTBI screening for India is given in [Figure 1]. The evidence base for the suggested recommendations has now been provided in detail in this paper.
Figure 1: Recommended LTBI screening algorithm for starting bDMARDs treatment. LTBI: Latent tuberculosis infection, bDMARDs: Biological disease-modifying antirheumatic drugs, “4S”: Four-symptom complex for TB screening, +ve: Positive, −ve: Negative, TBI: Active tuberculosis infection, 10 TU: 10 international units of RT23 strain of tuberculin purified protein derivative (PPD), QFTG = Quantiferon TB Gold® test, ATT: Antituberculosis treatment

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An intriguing observation made in this study was that among 2930 “control” group of patients who never received bDMARDs but only csDMARDs, active TBI occurred only in RA (18 cases out of 2145, 0.83%) but not in the other diseases (592 axSpA, 122 PsA, 67 SLE, and 4 SSc patients). It could have been because the number of patients other than RA was about one-third. However, it is of note that some relationship of RA with TB has been reported in the literature.[23] Of interest is the fact that treatment with bDMARDs (mainly TNFi) as seen in the present study, this difference seems to have disappeared; even the patients with asSpA developed active TBI.

It is possible that the LTBI screening algorithm given above [Figure 1] may also be suitable for patients who may be treated with targeted small molecule DMARDs (tsDMARDs). However, that would need another study.

The main weakness of this study was that LTBI screening was not carried out in “control” patients who were treated only with csDMARDs. However, this was in accordance with the national and international recommendations for the treatment of the SIRDs diseases included as “controls.” These recommendations do not advise routine LTBI screening for those treated with standard csDMARD regimens.

In conclusion, we found that the strategy of clinical screening for active TB infection with '4S complex', standard chest radiograph, augmented Mantoux testing (10 TU Purified Protein Derivative, {PPD}) simultaneously with QFTG was successful in identifying active TB infection among patients treated with bDMARDs.

Acknowledgment

No external funding was received for conducting this study. The expenses involved in this work were provided intramurally from the departmental funds. The authors would like to thank Mr Himanshu Negi for the secretarial help provided in the preparation of this manuscript.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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Navarra SV, Tang B, Lu L, Lin HY, Mok CC, Asavatanabodee P, et al. Risk of tuberculosis with anti-tumor necrosis factor-α therapy: Substantially higher number of patients at risk in Asia. Int J Rheum Dis 2014;17:291-8.  Back to cited text no. 3
    
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Kumar A. Experience with anti-tumor necrosis factor-α therapy in India. APLAR J Rheumatol 2006;9:136-41.  Back to cited text no. 4
    
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Malaviya AN, Aggarwal VK, Rawat R, Baghel S, Thakran R, Zaheer Q, et al. Screening for latent tuberculosis infection among patients with rheumatoid arthritis in the era of biologics and targeted synthetic disease-modifying anti-rheumatic drugs in India, a high-burden TB country: The importance of mantoux and quantiferon-TB gold tests. Int J Rheum Dis 2018;21:1563-71.  Back to cited text no. 12
    
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Malaviya AN, Gogia SB. Treatment of rheumatoid arthritis (RA) in India-how and by whom: Results from a speciality clinic-use of low-dose methotrexate (MTX) was inexplicably suboptimal. Clin Rheumatol 2016;35:2163-73.  Back to cited text no. 15
    
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[PUBMED]  [Full text]  
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Pai M, Ramsay A, O'Brien R. Evidence-based tuberculosis diagnosis. PLoS Med 2008;5:e156.  Back to cited text no. 18
    
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Pai M, Kalantri S. Diagnosis of latent tuberculosis infection: Recent advances and future direction. In: Sharma SK, Mohan A, editors. Tuberculosis. 2nd ed. New Delhi: Jaypee Publishers; 2009. p. 186-99.  Back to cited text no. 19
    
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Pai M, Behr M. Latent mycobacterium tuberculosis infection and interferon-gamma release assays. Microbiol Spectr 2018;21:1563-71.  Back to cited text no. 20
    
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Phadke MA, Kshirsagar NA. Blood tests for diagnosis of tuberculosis. Lancet 2006;368:282.  Back to cited text no. 21
    
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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;30:1436-9.  Back to cited text no. 23
    


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