High rates of tuberculin skin test positivity due to methotrexate therapy: False positive results?

https://doi.org/10.1016/j.semarthrit.2018.03.018Get rights and content

Abstract

Rationale

The tuberculin skin test (TST) and interferon ? release assays (IGRAs) are commonly used for latent tuberculosis infection (LTBI) screening. Unexpectedly high TST positivity rates have been reported in patients with rheumatic diseases, and methotrexate is frequently used in this population. We hypothesized that methotrexate use could be associated with false-positive TST results.

Objectives

To investigate whether treatment with methotrexate and other factors are associated with false-positive TST results in patients with rheumatic diseases.

Methods

Prospective single-center study conducted between April 2013 and March 2016. Adult patients with rheumatic diseases were evaluated with a TST and two IGRAs for LTBI screening. We compared TST and IGRA results in patients treated and not treated with methotrexate and analyzed for factors associated with positive TST results.

Conclusions

Our data suggest false-positive TST results associated with methotrexate therapy. Thus, we recommend against using the TST for LTBI screening in patients receiving methotrexate and the preferential use of IGRAs in such patients.

Measurements and Main Results

We studied 393 patients with rheumatic diseases, including ankylosing spondylitis (ASP, n = 90), rheumatoid arthritis (RA; n = 120), psoriatic arthritis (PA, n = 126), and other disorders (n = 57). The rate of TST positivity varied across the groups: ASP 22.2%, RA 25%, PA 35.7%, and other disorders (22.8%). Positivity rates were lower with IGRAs. Methotrexate use was associated with a statistically significant two-fold increase in the risk of a positive TST and a dose\x96 response relationship was observed. We found no statistically significant associations between methotrexate use and IGRA test positivity.

Introduction

Latent tuberculosis infection (LTBI) is the most prevalent form of tuberculosis worldwide [1]. Screening for LTBI is recommended before the initiation of tumor necrosis factor (TNF) antagonist therapy 2., 3., which is associated with an increased risk of tuberculosis reactivation in LTBI 4., 5., 6., 7.. Treatment for LTBI greatly reduces the risk of developing active disease, but potential side effects can occur, including hepatotoxicity [8]. A substantial reduction in the rate of tuberculosis reactivation in patients receiving anti-TNF therapy has been observed after LTBI screening and prevention interventions were implemented [9].

LTBI triggers an immune response to the tuberculin skin test (TST) and/or interferon (IFN) ? release assays (IGRAs) [10]. The TST detects the recall response to the purified protein derivative of Mycobacterium tuberculosis. Following this intradermal challenge in a previously exposed individual, antigen-specific T cells are activated to secrete IFN-?, which activates macrophages to produce TNF and interleukin 1. IFN-? is also produced by natural killer cells, as part of the innate immune response, and it is essential for the activation of phagocytes and antigen presentation cells besides promoting cell proliferation, adhesion, and apoptosis [11]. However, immunosuppressive drugs can alter these immune responses and decrease the sensitivity of both TST and IGRAs in treated patients with immune-mediated inflammatory diseases [12].

Biologic agents have dramatically changed prognosis in rheumatic diseases. Therefore their use has increased greatly. However, these drugs are not free of side effects, and tuberculosis reactivation is a major concern. Disease-modifying antirheumatic drugs (DMARDs), a group of medications commonly used in patients with rheumatoid arthritis (RA) and other inflammatory disorders, suppress overactive immune and/or inflammatory pathways. The most commonly used DMARDs are methotrexate, sulfasalazine, hydroxychloroquine and leflunomide [13]. Methotrexate is an immunomodulator that has been associated with a two-fold higher incidence of LTBI after 12 months of treatment [14]. Although the mechanism of action underlying this drug\x92s anti-inflammatory effect has not been completely characterized, its effectiveness in halting disease progression has made it a first-line treatment in RA and other inflammatory conditions 15., 16.. However, DMARDs, including methotrexate, can also modify T-cell function and potentially affect LTBI diagnostics [17].

Unexpectedly high rates of TST positivity have been reported in patients with RA, which was also reported in a meta-analysis 18., 19.. We therefore hypothesized that the observed increase in TST positivity in patients receiving DMARDs is related to false-positives associated with methotrexate use. Our study aimed to prospectively test this hypothesis and explore other factors that might be associated with false-positive TST results in patients with rheumatic diseases. We also used flow cytometry to analyze whether nonspecific T-cell subset activation could explain false-positive TST or IGRA testing results.

Section snippets

Subjects

The study was approved by the research ethics committee of Hospital Universitario Central de Asturias. All patients signed an informed written consent prior to study participation. Between April 2013 and March 2016, we prospectively enrolled patients with rheumatic diseases referred by rheumatologists for LTBI screening prior to initiation of biologic therapy. Additional information about the study subjects, clinical data gathering, and setting are provided in the online Data supplement.

LTBI evaluations and screening procedures

LTBI

Results

The prospectively enrolled cohort of 393 patients included 90 patients with ASP, 120 with RA, 126 with PA, and 57 with other rheumatic or inflammatory disorders (i.e., undifferentiated spondyloarthropathies, axial spondyloarthropathy, and SAPHO [synovitis, acne, pustulosis, hyperostosis, and osteitis] syndrome). Patient characteristics and LTBI testing (i.e., TST, QTF-GIT, and TSPOT) results were compared across the study groups (Table 1). As expected for this area of Spain, most patients had a

Discussion

To our knowledge, this study is the first to demonstrate an association between methotrexate use and a high likelihood of false-positive TST results in patients with rheumatic diseases, in particular in the PA subgroup. Our findings are important because the TST is frequently used to screen for LTBI in an increasing number of patients who are candidates for biologic therapy, and methotrexate is very commonly prescribed for RA and PA patients before a biologic drug is considered. A substantial

Conclusions

LTBI screening remains strongly recommended for patients who are candidates for biologic treatment, but the TST is associated with a high rate of probably false-positive results in patients receiving methotrexate, regardless of BCG vaccination status. IGRA test results do not seem to be affected by methotrexate treatment in these patients. Furthermore, peripheral blood T cells in methotrexate-treated patients produce more IFN-? after nonspecific stimulation but it is unclear if this T-cell

Author contributions

Miguel Arias-Guillén was involved in the study\x92s conception and design, acquisition of data, analysis and interpretation of data, and drafting of the manuscript. He was also a supervisor for the study.

Marta M. Sánchez Menéndez was involved in the study\x92s conception and design, acquisition of data, analysis and interpretation of data, and drafting of the manuscript.

Mercedes Alperi was involved in the study\x92s conception and design, acquisition of data, analysis and interpretation of

Significance of this study

Scientific Knowledge on the Subject.

Screening for latent tuberculosis infection (LTBI) has become mandatory before the initiation of anti-tumor necrosis factor (TNF) therapy. Treatment for LTBI greatly reduces the risk of active disease, but potential side effects such as hepatoxicity can occur. Methotrexate is an immunomodulatory agent that has been associated with a two-fold higher incidence of LTBI.

What This Study Adds to the Field

We found an unexpectedly high rate of positive tuberculin

Acknowledgments

The authors would like to thank Dr. José María García García (Sociedad Española de Neumología y Cirugía Torácica-SEPAR) and Prof. Dr. med. J\xFCrgen Behr (Direktor der Medizinischen Klinik und Poliklinik V. Klinikum der Ludwig-Maximilians-Universit\xE4t M\xFCnchen. CA und \xC4D Asklepios Fachkliniken M\xFCnchen Gauting. Comprehensive Pneumology Center Munich (CPC-M). Mitglied des Deutschen Zentrums f\xFCr Lungenforschung (DZL)) for their critical reading of this manuscript

Portions of the

References (27)

  • I. Mir Viladrich et al.

    Consensus document on prevention and treatment of tuberculosis in patients for biological treatment

    Arch Bronconeumol

    (2016)
  • World Health Organization: Global Tuberculosis Report 2016. Geneva, Switzerland, 2016....
  • F. Costantino et al.

    Screening for latent tuberculosis infection in patients with chronic inflammatory arthritis: discrepancies between tuberculin skin test and interferon-? release assay results

    J Rheumatol

    (2013)
  • O. N\xFAñez Martínez et al.

    Reactivation tuberculosis in a patient with anti-TNF-alpha treatment

    Am J Gastroenterol

    (2001)
  • J. Keane et al.

    Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent

    N Engl J Med

    (2001)
  • A.C. Ford et al.

    Opportunistic infections with anti-tumor necrosis factor-a therapy in inflammatory bowel disease: meta-analysis of randomized controlled trials

    Am J Gastroenterol

    (2013)
  • T. Bongartz et al.

    Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials

    J Am Med Assoc

    (2006)
  • I. Solovic et al.

    The risk of tuberculosis related to tumour necrosis factor antagonist therapies: a TBNET consensus statement

    Eur Respir J

    (2010)
  • J.J. Saukkonen et al.

    An official ATS statement: hepatotoxicity of antituberculosis therapy

    Am J Respir Crit Care Med

    (2006)
  • J.J. Gomez-Reino et al.

    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)
  • U. Mack et al.

    LTBI: latent tuberculosis infection or lasting immune responses to M. tuberculosis? A TBNET consensus statement

    Eur Respir J

    (2009)
  • G. Arango Duque et al.

    Macrophage cytokines: involvement in immunity and infectious diseases

    Front Immunol

    (2014)
  • M. Pai et al.

    Gamma interferon release assays for detection of Mycobacterium tuberculosis infection

    Clin Microbiol Rev

    (2014)
  • Cited by (20)

    • Frequency of anergy in a group of patients with rheumatoid arthritis on immunosuppressive therapy

      2021, Revista Colombiana de Reumatologia
      Citation Excerpt :

      The female gender behaved as a protective factor to present anergy, there's plausibility that sex hormones have a role in the cellular immune response that needs further research.96 The prevalence of positive tuberculin in patients with RA was low in this study (13%) compared to other studies in high prevalence countries where it ranges between 20 and 40%.66,94,97 In the Indian study by Agarwal et al.66 a prevalence of tuberculin positivity of 20.4% was found.

    • Tuberculosis

      2023, Dermatology in Public Health Environments: A Comprehensive Textbook, Second Edition
    View all citing articles on Scopus
    View full text