Joint Statement (DZK, DGRh, DDG) on the Tuberculosis Risk with Treatment Using Novel Non-TNF-Alpha Biologicals

Abstract

Background While the risk of tuberculosis (TB) reactivation is adequately documented in relation to TNF-alpha inhibitors (TNFi), the question of what the tuberculosis risk is for newer, non-TNF biologics (non-TNFi) has not been thoroughly addressed.

Methods We conducted a systematic review of randomized phase 2 and phase 3 studies, and long-term extensions of same, published through March 2019. Of interest was information pertaining to screening and treating of latent tuberculosis (LTBI) in association with the use of 12 particular non-TNFi. Only rituximab was excluded. We searched MEDLINE and the ClinicalTrial.gov database for any and all candidate studies meeting these criteria.

Results 677 citations were retrieved; 127 studies comprising a total of 34,293 patients who received non-TNFi were eligible for evaluation. Only 80 out of the 127 studies, or 63 %, captured active TB (or at least opportunistic diseases) as potential outcomes and 25 TB cases were reported. More than two thirds of publications (86/127, 68 %) mentioned LTBI screening prior to inclusion of study participants in the respective trial, whereas in only 4 studies LTBI screening was explicitly considered redundant. In 21 studies, patients with LTBI were generally excluded from the trials and in 42 out of the 127 trials, or 33 %, latently infected patients were reported to receive preventive therapy (PT) at least 3 weeks prior to non-TNFi treatment.

Conclusions The lack of information in many non-TNFi studies on the number of patients with LTBI who were either excluded prior to participating or had been offered PT hampers assessment of the actual TB risk when applying the novel biologics. Therefore, in case of insufficient information about drugs or drug classes, the existing recommendations of the German Central Committee against Tuberculosis should be applied in the same way as is done prior to administering TNFi. Well designed, long-term “real world” register studies on TB progression risk in relation to individual substances for IGRA-positive cases without prior or concomitant PT may help to reduce selection bias and to achieve valid conclusions in the future.

Zusammenfassung

Hintergrund Während das Risiko einer Reaktivierung der Tuberkulose (TB) durch TNF-alpha-Inhibitoren (TNFi) hinreichend dokumentiert ist, kann das Tuberkulose-Risiko beim Einsatz neuerer Nicht-TNFi-Biologika bislang nur unzureichend eingeschätzt werden.

Methoden Wir führten ein systematisches Review zu 12 Nicht-TNFi-Biologika durch und bezogen alle randomisierten Phase-2- und Phase-3-Originalstudien sowie deren Anschlussstudien ein, die bis März 2019 veröffentlicht wurden. Nur Rituximab wurde ausgeschlossen. Im Mittepunkt des Interesses standen Informationen zum Screening auf und zur Behandlung von latenter Tuberkulose (LTBI). Durchsucht wurden die MEDLINE-Datenbank und das ClinicalTrial.gov-Register.

Ergebnisse 677 Publikationen wurden ermittelt, von denen 127 Studien mit insgesamt 34 293 Patienten, die Nicht-TNFi-Biologika erhalten hatten, evaluiert werden konnten. Nur in 80 der 127 Studien (63 %) war eine Tuberkulose (oder zumindest opportunistische Krankheiten) als potenzielle Nebenwirkung überhaupt erfasst worden; insgesamt wurden 25 TB-Fälle gemeldet. Mehr als ⅔ der Veröffentlichungen (86/127, 68 %) erwähnten ein LTBI-Screening vor Einbeziehung der Probanden in die jeweilige Studie, während ein LTBI-Screening in nur 4 Studien ausdrücklich als redundant angesehen wurde. In 21 Studien wurden Patienten mit LTBI grundsätzlich von der Studienteilnahme ausgeschlossen, und in 42 der 127 Studien (33 %) wurde berichtet, dass latent infizierte Patienten mindestens 3 Wochen vor der Nicht-TNFi-Behandlung eine präventive Therapie erhalten hatten.

Schlussfolgerungen Der Mangel an Informationen hinsichtlich der Zahl der Patienten mit LTBI, die entweder vor der Teilnahme an einer Studie mit Nicht-TNFi-Biologika ausgeschlossen wurden oder denen eine präventive Therapie angeboten wurde, erschwert die Einschätzung des tatsächlichen TB-Risikos beim Einsatz der neuen Substanzen. Bei unzureichenden Informationen über das Studiendesign bei neuen Biologika oder Biologika-Arten sollten daher die bestehenden Empfehlungen des Deutschen Zentralkomitees gegen Tuberkulose in gleicher Weise angewendet werden wie vor der Verabreichung von TNFi. Gut konzipierte Langzeitregisterstudien zum TB-Progressionsrisiko bei IGRA-positiven Patienten ohne vorherige oder begleitende präventive Therapie könnten dazu beitragen, einen Selektionsbias zu vermeiden und valide Schlussfolgerungen zu ermöglichen.

Publication History

Received: 12 October 2020

Accepted: 12 October 2020

Article published online:
17 February 2021

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