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. 2022 Sep;8(2):e002359.
doi: 10.1136/rmdopen-2022-002359.

A systematic literature review informing the consensus statement on efficacy and safety of pharmacological treatment with interleukin-6 pathway inhibition with biological DMARDs in immune-mediated inflammatory diseases

Kastriot Kastrati  1 , Daniel Aletaha  2 , Gerd R Burmester  3 , Eva Chwala  4 , Christian Dejaco  5   6 , Maxime Dougados  7 , Iain B McInnes  8 , Angelo Ravelli  9 , Naveed Sattar  10 , Tanja A Stamm  11 , Tsutomu Takeuchi  12 , Michael Trauner  13 , Desirée van der Heijde  14 , Marieke J H Voshaar  15   16 , Kevin Winthrop  17 , Josef S Smolen  1 , Andreas Kerschbaumer  1
Affiliations

A systematic literature review informing the consensus statement on efficacy and safety of pharmacological treatment with interleukin-6 pathway inhibition with biological DMARDs in immune-mediated inflammatory diseases

Kastriot Kastrati et al. RMD Open. 2022 Sep.

Abstract

Objectives: Informing an international task force updating the consensus statement on efficacy and safety of biological disease-modifying antirheumatic drugs (bDMARDs) selectively targeting interleukin-6 (IL-6) pathway in the context of immune-mediated inflammatory diseases.

Methods: A systematic literature research of all publications on IL-6 axis inhibition with bDMARDs published between January 2012 and December 2020 was performed using MEDLINE, EMBASE and Cochrane CENTRAL databases. Efficacy and safety outcomes were assessed in clinical trials including their long-term extensions and observational studies. Meeting abstracts from ACR, EULAR conferences and results on clinicaltrials.gov were taken into consideration.

Results: 187 articles fulfilled the inclusion criteria. Evidence for positive effect of IL-6 inhibition was available in various inflammatory diseases such as rheumatoid arthritis, juvenile idiopathic arthritis, giant cell arteritis, Takayasu arteritis, adult-onset Still's disease, cytokine release syndrome due to chimeric antigen receptor T cell therapy and systemic sclerosis-associated interstitial lung disease. Newcomers like satralizumab and anti-IL-6 ligand antibody siltuximab have expanded therapeutic approaches for Castleman's disease and neuromyelitis optica, respectively. IL-6 inhibition did not provide therapeutic benefits in psoriatic arthritis, ankylosing spondylitis and certain connective tissue diseases. In COVID-19, tocilizumab (TCZ) has proven to be therapeutic in advanced disease. Safety outcomes did not differ from other bDMARDs, except higher risks of diverticulitis and lower gastrointestinal perforations. Inconsistent results were observed in several studies investigating the risk for infections when comparing TCZ to TNF-inhibitors.

Conclusion: IL-6 inhibition is effective for treatment of several inflammatory diseases with a safety profile that is widely comparable to other bDMARDs.

Keywords: Autoimmune Diseases; Cytokines; Inflammation.

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Conflict of interest statement

Competing interests: KK: honoraria for lectures, presentations: Boehringer Ingelheim, UCB Pharma, Eli Lilly and AbbVie; support for attending meetings and/or travel: AbbVie, Gilead, Sandoz, Pfizer, AstraZeneca and Bristol-Myers Squibb. DA: grants: AbbVie, Amgen, Lilly, Novartis, Roche, SoBi and Sanofi; consulting/lecture fees: AbbVie, Amgen, Lilly, Merck, Novartis, Pfizer, Roche and Sandoz. GRB: consulting fees: AbbVie, Galapagos, Lilly, Pfizer, Roche and Sanofi; honoraria for lectures, presentations: AbbVie, Galapagos, Lilly, Pfizer, Roche and Sanofi. EC: has no financial relationship to disclose. CD: grants: FWF Austria and Celgene; consulting fees and honoraria for lectures/presentations: AbbVie, MSD, Pfizer, Roche, Sanofi, Janssen, Novartis, Lilly and Galapagos; support for attending meetings and/or travel: AbbVie, MSD, Pfizer, Roche, Sanofi, Janssen, Novartis, Lilly and Galapagos; receipt of equipment, materials, drugs, medical writing, gifts or other services: MSD. MD: consulting fees: Roche, Sanofi, Pfizer, AbbVie, Lilly, BMS, Merck, Galapagos and UCB; honoraria fees for participations at symposia and advisory boards: Roche, Sanofi, AbbVie, Pfizer, Lilly, UCB, Merck, Galapagos and Novartis; his department received grants from: Roche, Sanofi, Pfizer, AbbVie, Lilly, BMS, Merck, Galapagos and UCB. IBM: grants: AbbVie, BMS, Eli Lilly, Janssen, Pfizer, UCB Pharma, Amgen and Novartis; consulting fees: AbbVie, BMS, Eli Lilly, Janssen, Pfizer, Sanofi Regeneron, Novartis, Gilead, Amgen, UCB, GSK and Moonlake; honoraria for lectures, presentations: AbbVie; IBM is also vice principal and head of MVLS College of University of Glasgow and board member of NHS Greater Glasgow & Clyde and Evelo; stock: Causeway Therapeutics, Compugen, Cabaletta and EveloBio. AR: grants: Pfizer and Novartis; speaker fees/advisory boards: AbbVie, Angelini, BMS, Centocor, Pfizer, Roche, Novartis and Reckitt Benckiser; AR is also president of the Pediatric Rheumatology European Society (PReS). NS: consulting fees: Amgen, AstraZeneca, Affimune, Boehringer Ingelheim, Eli-Lilly, Hanmi Pharmaceuticals, Janssen, Novartis, Novo Nordisk and Sanofi and his University has received grant funds for research from AstraZeneca, Boehringer Ingelheim, Novartis and Roche Diagnostics. TAS: grant/research support: AbbVie and Roche; consulting fees: AbbVie and Sanofi Genzyme; speaker fees: AbbVie, Roche, Sanofi and Takeda. TT: grants: Asahi Kasei Pharma, Chugai Pharmaceutical; speaking and consulting fees: Bristol Myers K.K., Chugai Pharmaceutical, Janssen Pharmaceutical K.K., R-Pharma, Sanofi.K.K. MT: grants/ research support: Albireo, Cymabay, Falk, Gilead, Intercept, MSD, Takeda, Alnylam, Ultragenyx; speaker and/or consultant and/or advisory board member: Albireo, BioMX, Boehringer Ingelheim, Falk, Genfit, Gilead, Intercept, Jansen, MSD, Novartis, Phenex, Regulus and Shire; travel support: AbbVie, Falk, Gilead and Intercept; MT is also coinventor of patents on the medical use of 24-norursodeoxycholic acid. DvdH: consulting fees: AbbVie, Bayer, BMS, Cyxone, Eisai, Galapagos, Gilead, Glaxo-Smith-Kline, Janssen, Lilly, Novartis, Pfizer and UCB Pharma; DvdH is also director of Imaging Rheumatology bv. MJHV: has no financial relationship to disclose. KW: research funding: BMS and Pfizer; consulting fees: Pfizer, AbbVie, UCB, Eli Lilly & Company, Galapagos, GlaxoSmithKline (GSK), Roche, Gilead, BMS, Regeneron, Sanofi, AstraZeneca and Novartis. JSS: grants/consulting and personal fees: AbbVie, AstraZeneca, Lilly, Novartis, Amgen, Astro, Bristol-Myers Squibb, Celgene, Celltrion, Chugai, Gilead, ILTOO, Janssen, Merck Sharp & Dohme, Novartis-Sandoz, Pfizer, Roche, Samsung and UCB. AK: honoraria from AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Gilead, Janssen, Merck Sharp & Dohme, Novartis, UCB and Pfizer.

Figures

Figure 1
Figure 1
Flowchart describing the study selection process.
Figure 2
Figure 2
Efficacy of biological disease modifying antirheumatic drugs targeting the IL-6 receptor or ligand and their relative efficacy and/or regulatory approvals across immune-mediated inflammatory diseases (based on available data at end of December 2020). aNCT02991469 (recruiting); bNCT02776735 (recruiting); cNCT03600805 (study terminated, results are awaited); d trial terminated early due to sponsor decision. For colorblind readers, figure 2 is provided in the online supplemental appendix (section 7: S7.1). EU, European Union; JPN, Japan; RU: Russian Federation; US: United Stated of America.
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