Higher risk of tuberculosis reactivation when anti-TNF is combined with immunosuppressive agents: a systematic review of randomized controlled trials

Lorenzetti, Roberto; Zullo, Angelo; Ridola, Lorenzo; Diamanti, Andrea Picchianti; Laganà, Bruno; Gatta, Luigi; Migliore, Alberto; Armuzzi, Alessandro; Hassan, Cesare; Bruzzese, Vincenzo

doi:10.3109/07853890.2014.941919

Cited by 102 publications

(95 citation statements)

References 67 publications

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“…This trend is similar to a study by Lorenzetti et al published in 2014. 12 This systematic literature review showed that the risk of tuberculosis under anti-TNF-α therapy was higher when these agents were used in combination with methotrexate than in monotherapy with an RR of 13.3 (95% CI (3.7 to 100)). However, this work took into account the use of anti-TNF-α in rheumatic diseases (RA, ankylosing spondylitis, psoriatic arthritis) and also in skin ( psoriasis) and digestive (chronic inflammatory bowel) diseases.…”

Section: Discussionmentioning

confidence: 89%

No impact of concomitant methotrexate use on serious adverse event and serious infection risk in patients with rheumatoid arthritis treated with bDMARDs: a systematic literature review and meta-analysis

et al. 2017

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ObjectivesTo compare the risk of serious adverse events, serious infections and death caused by methotrexate and biological disease-modifying antirheumatic drug (bDMARD) combination therapy versus a bDMARD prescribed as monotherapy in rheumatoid arthritis (RA).MethodsA systematic literature review was conducted until February 2016 in PubMed, Embase and Cochrane Library databases by selecting randomised controlled trials comparing methotrexate and bDMARD combination therapy to bDMARD monotherapy in RA. The meta-analysis compared the occurrence of (1) serious adverse events, (2) serious infections and (3) death among these groups by the Mantel-Haenszel method.ResultsThe literature review selected 16 controlled trials comparing methotrexate and bDMARD combination therapy to bDMARD monotherapy. After meta-analysis comparing patients under monotherapy to those under combination therapy: (1) the risk of occurrence of serious adverse events was comparable in 12 trials: RR (95% CI) 0.92 (0.78 to 1.08). (2) No significant difference was observed in the risk of occurrence of serious infections in 13 trials: RR (95% CI) 1.15 (0.84 to 1.58). We noted a trend, although insignificant, towards a high risk of the occurrence of tuberculosis in 10 studies: RR (95% CI) 1.78 (0.63 to 4.99). (3) The risk of death was comparable in 12 trials: RR (95% CI) 0.73 (0.40 to 1.35).ConclusionsThe results showed no significant difference between the two groups, confirming that the use of methotrexate and bDMARD combination therapy in RA does not cause an increased risk of serious adverse events or serious infections or death compared with bDMARD monotherapy.

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Section: Discussionmentioning

confidence: 89%

No impact of concomitant methotrexate use on serious adverse event and serious infection risk in patients with rheumatoid arthritis treated with bDMARDs: a systematic literature review and meta-analysis

et al. 2017

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“…In a Spanish series, risk continues to be high at 1.2% (4) or 1.7% (6), in contrast with 0% in a US series and 0.16% in a Belgian series (22,23). Likewise, regional differences in TB risk associated with anti-TNF therapy also emerged in a recent systematic review (20). Most of the cases occurred in countries where the incidence of active TB was high in the general population.…”

Section: Discussionmentioning

confidence: 97%

“…In patients with a history of LTBI, isoniazid therapy does not confer complete protection against active TB in anti-TNF-treated patients (6,20). Risk is very low, however, as shown by data from a Spanish registry of 1,154 rheumatic patients with LTBI who had taken anti-TB prophylaxis: only one of them developed TB while on anti-TNF therapy, whereas 2 of the 94 patients who received no prophylaxis did develop active disease (3).…”

Section: Discussionmentioning

confidence: 99%

“…Current evidence sug- gests that patients with IBD on immunomodulators are at greater risk of TB only if they are also taking corticosteroids and/or anti-TNF agents (8). Likewise, patients already on an anti-TNF agent who begin taking an immunomodulator increase their risk further (19,20). Both the multivariate analysis and the CHAID algorithm showed that receiving treatment with an anti-TNF agent in the previous 12 months was the main risk factor for active TB.…”

Section: Discussionmentioning

confidence: 99%

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Risk factors for tuberculosis in inflammatory bowel disease: anti-tumor necrosis factor and hospitalization

et al. 2016

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Aims: To determine risk factors for active tuberculosis in patients with inflammatory bowel diseases.Methods: Retrospective, case-control study at 4 referral hospitals in Spain. Cases developed tuberculosis after a diagnosis of inflammatory bowel disease. Controls were inflammatory bowel disease patients who did not develop tuberculosis. For each case, we randomly selected 3 controls matched for sex, age (within 5 years) and time of inflammatory bowel disease diagnosis (within 3 years). Inflammatory bowel disease characteristics, candidate risk factors for tuberculosis and information about the tuberculosis episode were recorded. Multivariate analysis and a Chi-squared automatic interaction detector were used.Results: Thirty-four cases and 102 controls were included. Nine of the 34 cases developed active tuberculosis between 1989 and 1999, and 25 became ill between 2000 and 2012. Multivariate regression showed an association between active tuberculosis and anti-TNF (tumor necrosis factor) therapy in the previous 12 months (OR 7.45; 95% CI, 2.39-23.12; p = 0.001); hospitalization in the previous 6 months (OR 4.38; 95% CI, 1.18-16.20; p = 0.027); and albumin levels (OR 0.88; 95% CI, 0.81-0.95; p = 0.001). The median time between the start of biologic therapy and the onset of active tuberculosis was 13 (interquartile range, 1-58) months. Tuberculosis developed after a year of anti-TNF therapy in 53%, and late reactivation occurred in at least 3 of 8 patients.Conclusions: The main risks factors for developing tuberculosis were anti-TNF therapy and hospitalization. Over half the cases related to anti-TNF treatment occurred after a year.

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“…It is well established that the previous use of biological agents for RA significantly increases the prevalence of TB [6,28,29]. In this cohort, none of the patients had previously received biologic drugs as a part of their RA treatment.…”

Section: Discussionmentioning

confidence: 97%

Increased detection of latent tuberculosis by tuberculin skin test and booster phenomenon in early rheumatoid arthritis patients

et al. 2015

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The incidence of tuberculosis (TB) in rheumatoid arthritis (RA) patients is up to four times higher when compared to the general population, but their risk increases with the use of TNF-a drugs. Appropriate screening of latent tuberculosis infection (LTBI) and proper management of such cases substantially reduce the incidence of active TB. Tuberculin skin test (TST) is a widely used method for the detection of LTBI. The time of diagnosis of RA as well as the age of the patient might modify the TST performance. We did an observational, comparative study of RA patients with early and established disease, with the objective to know the prevalence of LTBI using the TST and booster test; an induration ≥5 mm was considered reactive. We evaluated 143 patients (83 [58 %] early RA patients). We found 31.3 and 21.7 % TST positivity in early and established RA patients, respectively. With the use of booster test, the positivity increased to 46.5 and 28.8 %, respectively (p = 0.048, OR 1.33, 95 % CI 1.01-1.75). In conclusion, we found that TST and booster test increased LTBI detection in early RA patients, which may suggest that time of RA diagnosis might affect cellular immunity and therefore the TST response.

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Higher risk of tuberculosis reactivation when anti-TNF is combined with immunosuppressive agents: a systematic review of randomized controlled trials

Abstract: TB risk with anti-TNF agents appeared to be increased when these agents were used in combination with methotrexate or azathioprine as compared with monotherapy regimen. TB risk seemed to be higher than placebo, even when monotherapy is prescribed.

Cited by 102 publications

References 67 publications

No impact of concomitant methotrexate use on serious adverse event and serious infection risk in patients with rheumatoid arthritis treated with bDMARDs: a systematic literature review and meta-analysis

No impact of concomitant methotrexate use on serious adverse event and serious infection risk in patients with rheumatoid arthritis treated with bDMARDs: a systematic literature review and meta-analysis

Risk factors for tuberculosis in inflammatory bowel disease: anti-tumor necrosis factor and hospitalization

Increased detection of latent tuberculosis by tuberculin skin test and booster phenomenon in early rheumatoid arthritis patients

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