Elsevier

Tuberculosis

Volume 89, Issue 2, March 2009, Pages 136-141
Tuberculosis

Screening of tuberculosis by interferon-γ assay before biologic therapy for rheumatoid arthritis

https://doi.org/10.1016/j.tube.2008.12.004Get rights and content

Summary

Infection with Mycobacterium tuberculosis (M. tuberculosis) is a critical complication in anti-TNF therapies. In 141 BCG vaccinated healthy individuals and 71 rheumatoid arthritis (RA) patients as screening before anti-TNF therapies, M. tuberculosis specific immune responses were evaluated by tuberculin skin test (TST) and enzyme-linked immunospot assay (ELISPOT), which detected antigen specific IFN-γ secreting cells in peripheral blood mononuclear cells simulated with either purified protein derivative (PPD), early secretory antigen target 6 (ESAT-6) or culture filtrate protein 10 (CFP-10). Induration over 5 mm in TST was found in 87.9% of controls and 21.4% of RA patients. Erythema size in TST was significantly suppressed in RA patients, especially those receiving prednisolone (PSL), whereas the PPD specific IFN-γ secretion was less attenuated. Significant responses to either ESAT-6 or CFP-10 in ELISPOT were detected in 14.1% of RA patients including those having positive TST, while the ELISPOT assay was negative in all healthy individuals and 73.3% of RA patients having positive TST. Of ELISPOT positive RA patients, mean dosage of PSL was 4.58 mg and 1.25 mg in TST negative and positive patients, respectively. Thus, ELISPOT is useful for screening of tuberculosis in RA patients, even in those receiving corticosteroids.

Introduction

Tumor necrosis factor (TNF) antagonists are efficacious in several autoimmune diseases, including rheumatoid arthritis (RA),1, 2 whereas the therapies increase the risk of opportunistic infections such as tuberculosis (TB) because of the potent immunosuppressive effects.3, 4, 5, 6, 7 In 2001, Keane et al. reported that the estimated incidence of TB in patients receiving infliximab was 24.4 cases per 100,000 patient-year, while that was 6.2 cases in the general population of the United States.5 Moreover, the relative risk of TB in RA patients receiving infliximab was shown to exceed 50 to the background rate in Spain.8 Similar data have been reported from Portugal, Greece, and Japan.9, 10, 11

Reactivation of latent TB is observed within a half-year after initiation of anti-TNF therapy.5 Besides radiological examinations, tuberculin skin test (TST) using purified protein derivative (PPD) is recommended as screening for latent TB prior to anti-TNF therapy. However, not only TB patients but also bacilli de Calmette–Guérin (BCG) vaccinated individuals show a positive TST, whereas a false negative is found in patients receiving immunosuppressive therapies including anti-rheumatic agents. Thus, TST based screening might cause over- and under-estimation of risk of TB under some conditions.

Enzyme-linked immunospot assay (ELISPOT) to detect the interferon-gamma (IFN-γ) released by T cells has recently been proposed as a diagnostic procedure for TB.12, 13, 14Mycobacterium tuberculosis (M. tuberculosis) specific antigens such as early secretory antigen target 6 (ESAT-6) and culture filtrate protein 10 (CFP-10) are used in the assay, because the antigens exist in M. tuberculosis, but not in BCG.14, 15, 16 Unlike TST, the immune responses against these antigens distinguish between TB patients and BCG vaccinated individuals.12, 13, 14, 17, 18 The technique is sensitive enough to detect the antigen specific responses even in immunocompromised hosts such as human immunodeficiency virus (HIV) infected patients and malnutritional infants.12, 19, 20, 21, 22

There is accumulating evidence that M. tuberculosis specific IFN-γ release assays using ELISA and flow-cytometric analysis are alternative strategies to overcome the insufficient diagnostic performance of TST in screening RA patients on immunosuppressive therapy for TB infection.23, 24, 25, 26 The present study investigated accuracy of the ELISPOT based diagnostic procedure for latent TB in comparison with TST in Japanese RA patients, who had received BCG vaccination in their childhood.

Section snippets

Study population

We studied 35 TB patients (male 24, female 11, mean age 59.1 ± 16.5) and 71 RA patients (male 5, female 66, mean age 55.2 ± 11.5) at Yokohama City University Hospital, Yokohama City University Medical Center, and Kanagawa Cardiovascular and Respiratory Center between April 2005 and 2007. All of the RA patients were treated with disease modifying anti-rheumatic drugs (DMARDs) including methotrexate (MTX), bucillamine and salazosulfapyridine. Of 71 RA patients, 51 patents were given prednisolone

Attenuated TST in patients with rheumatoid arthritis (RA)

TST was compared between 141 healthy individuals and 71 RA patients who were considered to receive anti-TNF therapy for screening latent TB infection. Both groups were all Japanese and had received BCG vaccination in their childhood. On the basis of the guideline of CDC, which relies on the presence of induration, frequency of positive TST was significantly lower in RA patients than that in healthy individuals (RA, 21.1% vs control, 85.1%, p < 0.0001). Induration diameter was significantly

Discussion

Since anti-TNF therapy is considered to reactivate latent TB, the pre-therapeutic screening is critical. Indeed, usefulness of screening based on TST and radiological examinations, including chest X-ray or CT scan, has been shown in several countries.8, 31, 32 TST is judged based on the guidelines of CDC and ATS, in which the test is considered as positive when the induration is more 5 mm.27 The Japanese guidelines for the use of infliximab and etanercept in RA patients recommend that

Acknowledgements

We wish to thank Mr. Tom Kiper for his critical review in preparing the manuscript.

This work was supported in part by grants from The Yokohama City University Center of Excellence Program of the Ministry of Education, Culture, Sports, Science and Technology of Japan (to Y. Ishigatsubo), Research on Specific Disease of the Health Science Research Grants of the Ministry of Health, Labour, and Welfare (to Y. Ishigatsubo), and the 2006 Strategic Research Project No. K18006 from Yokohama City

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      The estimated incidence of LTBI in Danish patients undergoing anti-TNF-α treatment is 25/100,000 per year3; this equals a four-fold increase compared to the background incidence of 6/100,000 per year4 In Denmark, following international guidelines,5 all patients are screened for LTBI before the initiation of immunomodulating drug therapy. The traditional method for detecting LTBI, the tuberculin skin test (TST), has a lower sensitivity in patients receiving corticosteroids,6 and the specificity is dependant of the bacilli Calmette-Guerin (BCG) vaccination status of the patient. The Mycobacterium tuberculosis-specific interferon-γ release assays (IGRA) have proven superior to the TST in having a higher specificity in BCG vaccinated patients and a slightly higher sensitivity generally – even in immune compromised hosts there are generally more responses to IGRA compared to TST.7

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