Main Article Content
Background: To determine the conversion and reversion rates of tuberculosis (TB) screening tests (Tuberculin Skin Test-TST, Interferon Gamma Release Assay-IGRA: T-SPOT.TB) during biologic treatment in patients with rheumatic diseases and negative baseline screening.
Methods: This was a long-term, longitudinal cohort study of 50 patients with rheumatic diseases and negative baseline TB screening (TST: < 5 mm, negative T-SPOT.TB) treated with tumor necrosis factor inhibitors (TNFi) or other non-TNFi biologics. Patients were rescreened at a mean time of 1.4 (first rescreening) and 6.9 (second rescreening) years from baseline, with both assays. The conversion (negative to positive) and reversion (positive to negative) rate was calculated for each TB screening test.
Results: Fifty patients (mean age = 60 years) with various rheumatic diseases (rheumatoid arthritis: n = 24, spondyloarthropathies: n = 23, other: n = 3) were enrolled. During the first phase (baseline to first rescreening), all patients were treated with TNFi while during the second phase (first to second rescreening), TNFi (54%) and non-TNFi (46%) were used. Fifteen patients (30%) displayed conversion of at least 1 screening assay during follow-up (10 at the first and 5 at the second rescreening). This conversion rate was higher with TST (n = 11, 22% or 3.47/100 patient-years) compared to T-SPOT.TB (n = 4, 8% or 1.74/100 patient-years). Among the 10 converters at the first rescreening, 5 received isoniazid (INH) preventive therapy and 5 did not; an equal number of patients (3/5, 60%) reverted to negative with or without INH therapy. None of the patients developed active TB during follow-up (6.9 ± 1.0 years).
Conclusions: Approximately one-third of patients with rheumatic diseases and negative baseline TB screening developed conversion of at least 1 screening test during long-term biologic treatment. This occurred most often with TST and was usually a transient event. These findings do not support routine serial TB retesting in biologic-treated patients with rheumatic diseases in the absence of TB risk factors.
Pathogens and Immunity abides by Creative Commons BY 4.0:
This license lets others distribute, remix, tweak, and build upon your work for any lawful purpose, even commercially, as long as they credit you for the original creation. This is the most accommodating of licenses offered. Recommended for maximum dissemination and use of licensed materials. The authors maintain copyright of their materal.
*Due to a template error on our pdfs, articles published from May 20, 2016 to June 24, 2022 incorrectly state the copyright is held by Pathogens and Immunity. Copyright of all articles is held by the authors of each article as noted in the above copyright policy.
1. Houben RM, Dodd PJ. The Global Burden of Latent Tuberculosis Infection: A Re-estimation Using Mathematical Modelling. PLoS Med 2016;13(10):e1002152. doi:10.1371/journal.pmed.1002152
2. Alsdurf H, Hill PC, Matteelli A, Getahun H, Menzies D. The cascade of care in diagnosis and treatment of latent tuberculosis infection: a systematic review and meta-analysis. Lancet Infect Dis 2016;16(11):1269-1278. doi: 10.1016/S1473-3099(16)30216-X
3. Lee E, Holzman RS. Evolution and current use of the tuberculin test. Clin Infect Dis 2002;34(3):365-370. doi: 10.1086/338149
4. Lobue P, Menzies D. Treatment of latent tuberculosis infection: An update. Respirology 2010;15(4):603-622. doi: 10.1111/j.1440-1843.2010.01751.x
5. Wong SH, Gao Q, Tsoi KK, Wu WK, Tam LS, Lee N, Chan FK, Wu JC, Sung JJ, Ng SC. Effect of immunosuppressive therapy on interferon gamma release assay for latent tuberculosis screening in patients with autoimmune diseases: a systematic review and meta-analysis. Thorax 2016;71(1):64-72. doi: 10.1136/thoraxjnl-2015-207811
6. Lewinsohn DM, Leonard MK, LoBue PA, Cohn DL, Daley CL, Desmond E, Keane J, Lewinsohn DA, Loeffler AM, Mazurek GH, O'Brien RJ, Pai M, Richeldi L, Salfinger M, Shinnick TM, Sterling TR, Warshauer DM, Woods GL. Official American Thoracic Society/Infectious Diseases Society of America/Centers for Disease Control and Prevention Clinical Practice Guidelines: Diagnosis of Tuberculosis in Adults and Children. Clin Infect Dis 2017;64(2):111-115. doi: 10.1093/cid/ciw778
7. Keane J, Gershon S, Wise RP, Mirabile-Levens E, Kasznica J, Schwieterman WD, Siegel JN, Braun MM. Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent. N Engl J Med 2001;345(15):1098-1104. doi: 10.1056/NEJMoa011110
8. Wolfe F, Michaud K, Anderson J, Urbansky K. Tuberculosis infection in patients with rheumatoid arthritis and the effect of infliximab therapy. Arthritis Rheum 2004;50(2):372-379. doi: 10.1002/art.2000
9. Solovic I, Sester M, Gomez-Reino JJ, Rieder HL, Ehlers S, Milburn HJ, Kampmann B, Hellmich B, Groves R, Schreiber S, Wallis RS, Sotgiu G, Scholvinck EH, Goletti D, Zellweger JP, Diel R, Carmona L, Bartalesi F, Ravn P, Bossink A, Duarte R, Erkens C, Clark J, Migliori GB, Lange C. The risk of tuberculosis related to tumour necrosis factor antagonist therapies: a TBNET consensus statement. Eur Respir J 2010;36(5):1185-1206. doi:10.1183/09031936.00028510
10. Koike T, Harigai M, Inokuma S, Ishiguro N, Ryu J, Takeuchi T, Takei S, Tanaka Y, Ito K, Yamanaka H. Postmarketing surveillance of tocilizumab for rheumatoid arthritis in Japan: interim analysis of 3881 patients. Ann Rheum Dis 2011;70(12):2148-2151. doi: 10.1136/ard.2011.151092
11. Winthrop KL, Park SH, Gul A, Cardiel MH, Gomez-Reino JJ, Tanaka Y, Kwok K, Lukic T, Mortensen E, Ponce de LD, Riese R, Valdez H. Tuberculosis and other opportunistic infections in tofacitinib-treated patients with rheumatoid arthritis. Ann Rheum Dis 2016;75(6):1133-1138. doi: 10.1136/annrheumdis-2015-207319
12. Pettipher C, Benitha R. Tuberculosis in biologic users for rheumatic diseases: results from the South African Biologics Registry (SABIO). Ann Rheum Dis 2019 [Epub ahead of print]. doi: 10.1136/annrheumdis-2019-216128
13. Carmona L, Gomez-Reino JJ, Rodriguez-Valverde V, Montero D, Pascual-Gomez E, Mola EM, Carreno L, Figueroa M. Effectiveness of recommendations to prevent reactivation of latent tuberculosis infection in patients treated with tumor necrosis factor antagonists. Arthritis Rheum 2005;52(6):1766-1772. doi: 10.1002/art.21043
14. Singh JA, Saag KG, Bridges SL, Jr., Akl EA, Bannuru RR, Sullivan MC, Vaysbrot E, McNaughton C, Osani M, Shmerling RH, Curtis JR, Furst DE, Parks D, Kavanaugh A, O'Dell J, King C, Leong A, Matteson EL, Schousboe JT, Drevlow B, Ginsberg S, Grober J, St Clair EW, Tindall E, Miller AS, McAlindon T. 2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Rheumatol 2016;68(1):1-26. doi: 10.1002/art.39480
15. Kleinert S, Tony HP, Krueger K, Detert J, Mielke F, Rockwitz K, Schwenke R, Burmester GR, Diel R, Feuchtenberger M, Kneitz C. Screening for latent tuberculosis infection: performance of tuberculin skin test and interferon-gamma release assays under real-life conditions. Ann Rheum Dis 2012;71(11):1791-1795. doi: 10.1136/annrheumdis-2011-200941
16. Winthrop KL, Weinblatt ME, Daley CL. You can't always get what you want, but if you try sometimes (with two tests--TST and IGRA--for tuberculosis) you get what you need. Ann Rheum Dis 2012;71(11):1757-1760. doi: 10.1136/annrheumdis-2012-201979
17. Vassilopoulos D, Tsikrika S, Hatzara C, Podia V, Kandili A, Stamoulis N, Hadziyannis E. Comparison of two gamma interferon release assays and tuberculin skin testing for tuberculosis screening in a cohort of patients with rheumatic diseases starting anti-tumor necrosis factor therapy. Clin Vaccine Immunol 2011;18(12):2102-2108. doi: 10.1128/CVI.05299-11
18. Gran G, Assmus J, Dyrhol-Riise AM. Screening for latent tuberculosis in Norwegian health care workers: high frequency of discordant tuberculin skin test positive and interferon-gamma release assay negative results. BMC Public Health 2013;13(353. doi: 10.1186/1471-2458-13-353
19. Pai M, Banaei N. Occupational screening of health care workers for tuberculosis infection: tuberculin skin testing or interferon-gamma release assays? Occup Med (Lond) 2013;63(7):458-460. doi: 10.1093/occmed/kqt105
20. Hatzara C, Hadziyannis E, Kandili A, Koutsianas C, Makris A, Georgiopoulos G, Vassilopoulos D. Frequent conversion of tuberculosis screening tests during anti-tumour necrosis factor therapy in patients with rheumatic diseases. Ann Rheum Dis 2015;74(10):1848-1853. doi: 10.1136/annrheumdis-2014-205376
21. Kim KH, Lee SW, Chung WT, Kim BG, Woo KS, Han JY, Kim JM. Serial interferon-gamma release assays for the diagnosis of latent tuberculosis infection in patients treated with immunosuppressive agents. Korean J Lab Med 2011;31(4):271-278. doi: 10.3343/kjlm.2011.31.4.271
22. Jung YJ, Woo HI, Jeon K, Koh WJ, Jang DK, Cha HS, Koh EM, Lee NY, Kang ES. The Significance of Sensitive Interferon Gamma Release Assays for Diagnosis of Latent Tuberculosis Infection in Patients Receiving Tumor Necrosis Factor-alpha Antagonist Therapy. PLoS One 2015;10(10):e0141033. doi: 10.1371/journal.pone.0141033
23. Son CN, Jun JB, Kim JH, Sung IH, Yoo DH, Kim TH. Follow-up testing of interferon-gamma release assays are useful in ankylosing spondylitis patients receiving anti-tumor necrosis factor alpha for latent tuberculosis infection. J Korean Med Sci 2014;29(8):1090-1093. doi: 10.3346/jkms.2014.29.8.1090
24. WHO. Global tuberculosis control 2019. Accessed at: https:// www.who.int/tb/publications/global_report/en/ on December 29, 2019.
25. Hsia EC, Cush JJ, Matteson EL, Beutler A, Doyle MK, Hsu B, Xu S, Rahman MU. Comprehensive tuberculosis screening program in patients with inflammatory arthritides treated with golimumab, a human anti-tumor necrosis factor antibody, in Phase III clinical trials. Arthritis Care Res (Hoboken ) 2013;65(2):309-313. doi: 10.1002/acr.21788
26. Chen DY, Shen GH, Chen YM, Chen HH, Hsieh CW, Lan JL. Biphasic emergence of active tuberculosis in rheumatoid arthritis patients receiving TNFalpha inhibitors: the utility of IFNgamma assay. Ann Rheum Dis 2012;71(2):231-237. doi: 10.1136/annrheumdis-2011-200489
27. Iannone F, Cantini F, Lapadula G. Diagnosis of latent tuberculosis and prevention of reactivation in rheumatic patients receiving biologic therapy: international recommendations. J Rheumatol 2014;Suppl. 91:41-46. doi: 10.3899/jrheum.140101
28. Menter A, Strober BE, Kaplan DH, Kivelevitch D, Prater EF, Stoff B, Armstrong AW, Connor C, Cordoro KM, Davis DMR, Elewski BE, Gelfand JM, Gordon KB, Gottlieb AB, Kavanaugh A, Kiselica M, Korman NJ, Kroshinsky D, Lebwohl M, Leonardi CL, Lichten J, Lim HW, Mehta NN, Paller AS, Parra SL, Pathy AL, Rupani RN, Siegel M, Wong EB, Wu JJ, Hariharan V, Elmets CA. Joint AAD-NPF guidelines of care for the management and treatment of psoriasis with biologics. J Am Acad Dermatol 2019;80(4):1029-1072. doi: 10.1016/j.jaad.2018.11.057
29. Tran NQ, Garcia-Rosell M, Pattanaik D, Raza SH, Carbone L. Screening and Treatment of Latent Tuberculosis Among Patients Receiving Biologic Agents: A National and International Survey of Rheumatologists. J Clin Rheumatol 2017;23(1):6-11. doi: 10.1097/RHU.0000000000000466
30. Chen DY, Shen GH, Hsieh TY, Hsieh CW, Lan JL. Effectiveness of the combination of a whole-blood interferon-gamma assay and the tuberculin skin test in detecting latent tuberculosis infection in rheumatoid arthritis patients receiving adalimumab therapy. Arthritis Rheum 2008;59(6):800-806. doi: 10.1002/art.23705
31. Park JH, Seo GY, Lee JS, Kim TH, Yoo DH. Positive conversion of tuberculin skin test and performance of interferon release assay to detect hidden tuberculosis infection during anti-tumor necrosis factor agent trial. J Rheumatol 2009;36(10):2158-2163. doi: 10.3899/jrheum.090150
32. Garcovich S, Ruggeri A, D'Agostino M, Ardito F, De SC, Delogu G, Fadda G. Clinical applicability of Quantiferon-TB-Gold testing in psoriasis patients during long-term anti-TNF-alpha treatment: a prospective, observational study. J Eur Acad Dermatol Venereol 2012;26(12):1572-1576. doi: 10.1111/j.1468-3083.2011.04220.x
33. Hatemi G, Melikoglu M, Ozbakir F, Tascilar K, Yazici H. Quantiferon-TB Gold in tube assay for the screening of tuberculosis before and during treatment with tumor necrosis factor alpha antagonists. Arthritis Res Ther 2012;14(3):R147. doi: 10.1186/ar3882
34. Papay P, Primas C, Eser A, Novacek G, Winkler S, Frantal S, Angelberger S, Mikulits A, Dejaco C, Kazemi-Shirazi L, Vogelsang H, Reinisch W. Retesting for latent tuberculosis in patients with inflammatory bowel disease treated with TNF-alpha inhibitors. Aliment Pharmacol Ther 2012;36(9):858-865. doi: 10.1111/apt.12037 .
35. Scrivo R, Sauzullo I, Mengoni F, Priori R, Coppola M, Iaiani G, DI FM, Vullo V, Mastroianni CM, Valesini G. Mycobacterial interferon-gamma release variations during longterm treatment with tumor necrosis factor blockers: lack of correlation with clinical outcome. J Rheumatol 2013;40(2):157-165. doi: 10.3899/jrheum.120688
36. Abreu C, Afonso J, Camila DC, Ruas R, Sarmento A, Magro F. Serial Tuberculosis Screening in Inflammatory Bowel Disease Patients Receiving Anti-TNFalpha Therapy. J Crohns Colitis 2017;11(10):1223-1229. doi: 10.1093/ecco-jcc/jjx080
37. Lee CK, Wong SHV, Lui G, Tang W, Tam LS, Ip M, Hung E, Chen M, Wu JC, Ng SC. A Prospective Study to Monitor for Tuberculosis During Anti-tumour Necrosis Factor Therapy in Patients With Inflammatory Bowel Disease and Immune-mediated Inflammatory Diseases. J Crohns Colitis 2018;12(8):954-962. doi: 10.1093/ecco-jcc/jjy057
38. Taxonera C, Ponferrada A, Riestra S, Bermejo F, Saro C, Martin-Arranz MD, Cabriada JL, Barreiro-de AM, de Castro ML, Lopez-Serrano P, Barrio J, Suarez C, Iglesias E, Arguelles-Arias F, Ferrer I, Marin-Jimenez I, Hernandez-Camba A, Bastida G, Van DM, Martinez-Montiel P, Olivares D, Rivero M, Fernandez-Salazar L, Nantes O, Merino O, Alba C, Gisbert JP. Serial Tuberculin Skin Tests Improve the Detection of Latent Tuberculosis Infection in Patients With Inflammatory Bowel Disease. J Crohns Colitis 2018;12(11):1270-1279. doi: 10.1093/ecco-jcc/jjy104
39. He D, Bai F, Zhang S, Jiang T, Shen J, Zhu Q, Yue T, Shao L, Gao Y, Feng Y, Weng X, Zou H, Zhang Y, Zhang W. High incidence of tuberculosis infection in rheumatic diseases and impact for chemoprophylactic prevention of tuberculosis activation during biologics therapy. Clin Vaccine Immunol 2013;20(6):842-847. doi: 10.1128/CVI.00049-13
40. Chung J, Aronson AB, Srikantha R, Vogelgesang SA, Wanat KA. Low conversion rate of QuantiFERON-TB Gold screening tests in patients treated with tumor necrosis factor inhibitors: A retrospective cohort study identifying an important practice gap. J Am Acad Dermatol 2018;79(1):169-171. doi: 10.1016/j.jaad.2018.03.025
41. Kim HW, Kwon OC, Han SH, Park MC. Positive conversion of interferon-gamma release assay in patients with rheumatic diseases treated with biologics. Rheumatol Int 2020 [Epub ahead of print]. doi: 10.1007/s00296-019-04510-6
42. Scrivo R, Sauzullo I, Mengoni F, Iaiani G, Vestri AR, Priori R, Di FE, Di FM, Spinelli FR, Vullo V, Mastroianni CM, Valesini G. Serial interferon-gamma release assays for screening and monitoring of tuberculosis infection during treatment with biologic agents. Clin Rheumatol 2012;31(11):1567-1575. doi: 10.1007/s10067-012-2049-6
43. Nienhaus A, Ringshausen FC, Costa JT, Schablon A, Tripodi D. IFN-gamma release assay versus tuberculin skin test for monitoring TB infection in healthcare workers. Expert Rev Anti Infect Ther 2013;11(1):37-48. doi: 10.1586/eri.12.150
44. Dorman SE, Belknap R, Graviss EA, Reves R, Schluger N, Weinfurter P, Wang Y, Cronin W, Hirsch-Moverman Y, Teeter LD, Parker M, Garrett DO, Daley CL. Interferon-gamma Release Assays and Tuberculin Skin Testing for Diagnosis of Latent Tuberculosis Infection in Healthcare Workers in the United States. Am J Respir Crit Care Med 2014;189(1):77-87. doi: 10.1164/rccm.201302-0365OC
45. Moses MW, Zwerling A, Cattamanchi A, Denkinger CM, Banaei N, Kik SV, Metcalfe J, Pai M, Dowdy D. Serial testing for latent tuberculosis using QuantiFERON-TB Gold In-Tube: A Markov model. Sci Rep 2016;6:30781. doi: 10.1038/srep30781
46. Sosa LE, Njie GJ, Lobato MN, Bamrah MS, Buchta W, Casey ML, Goswami ND, Gruden M, Hurst BJ, Khan AR, Kuhar DT, Lewinsohn DM, Mathew TA, Mazurek GH, Reves R, Paulos L, Thanassi W, Will L, Belknap R. Tuberculosis Screening, Testing, and Treatment of U.S. Health Care Personnel: Recommendations from the National Tuberculosis Controllers Association and CDC, 2019. MMWR Morb Mortal Wkly Rep 2019;68(19):439-443. doi: 10.15585/mmwr.mm6819a3
47. Roth PJ, Grim SA, Gallitano S, Adams W, Clark NM, Layden JE. Serial testing for latent tuberculosis infection in transplant candidates: a retrospective review. Transpl Infect Dis 2016;18(1):14-21. doi: 10.1111/tid.12489