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      Therapeutic agents affecting the immune system and drug-induced inflammatory bowel disease (IBD): A review on etiological and pathogenetic aspects

      , , , ,
      Clinical Immunology
      Elsevier BV

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          Immune-Related Adverse Events Associated with Immune Checkpoint Blockade

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            Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn's disease: unexpected results of a randomised, double-blind placebo-controlled trial.

            The authors tested whether the anti-interleukin (IL)-17A monoclonal antibody secukinumab was safe and effective for the treatment of active Crohn's disease. In a double-blind, randomised, placebo-controlled proof-of-concept study, 59 patients with moderate to severe Crohn's disease (Crohn's Disease Activity Index (CDAI) ≥220 to ≤450) were assigned in a 2:1 ratio to 2×10 mg/kg intravenous secukinumab or placebo. The primary end point, addressed by bayesian statistics augmented with historical placebo information, was the probability that secukinumab reduces the CDAI by ≥50 points more than placebo at week 6. Ancillary analyses explored associations of 35 candidate genetic polymorphisms and faecal calprotectin response. 59 patients (39 secukinumab, 20 placebo, mean baseline CDAI 307 and 301, respectively) were recruited. 18/59 (31%) patients discontinued prematurely (12/39 (31%) secukinumab, 6/20 (30%) placebo), 10/59 (17%) due to insufficient therapeutic effect (8/39 (21%) secukinumab, 2/20 (10%) placebo). Fourteen serious adverse events occurred in 10 patients (seven secukinumab, three placebo); 20 infections, including four local fungal infections, were seen on secukinumab versus none on placebo. Primary end point analysis estimated <0.1% probability (CDAI (SD) =33.9 (19.7), 95% credible interval -4.9 to 72.9) that secukinumab reduces CDAI by ≥50 points more than placebo. Secondary area under the curve analysis (weeks 4-10) showed a significant difference (mean ΔCDAI=49; 95% CI (2 to 96), p=0.043) in favour of placebo. Post hoc subgroup analysis showed that unfavourable responses on secukinumab were driven by patients with elevated inflammatory markers (CRP≥10 mg/l and/or faecal calprotectin≥200 ng/ml; mean ΔCDAI=62; 95% CI (-1 to 125), p=0.054 in favour of placebo). Absence of the minor allele of tumour necrosis factor-like ligand 1A was strongly associated with lack of response measured by baseline-adjusted changes in calprotectin at week 6 (p=0.00035 Bonferroni-corrected). Blockade of IL-17A was ineffective and higher rates of adverse events were noted compared with placebo. This trial was registered at ClinicalTrial.gov with the number NCT01009281.
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              IL-6 signaling in autoimmunity, chronic inflammation and inflammation-associated cancer.

              IL-6 activates various cell types carrying the membrane bound IL-6R (classical IL-6 signaling) as well as IL-6R(-) gp130(+) cells via the soluble IL-6R (IL-6 trans-signaling). IL-6 signaling plays a pivotal role in controlling the differentiation and activation of T lymphocytes by inducing the Jak/STAT-3 and the Ras/Erk/C/EBP pathways. In particular, IL-6 modulates the resistance of T cells against apoptosis, induces activation of T helper cells and controls the balance between regulatory T cells and Th17 cells. Importantly, recent findings suggest that blockade of IL-6 signaling is effective in treating experimental models of autoimmune and chronic inflammatory diseases such as inflammatory bowel diseases, diabetes, multiple sclerosis, asthma and rheumatoid arthritis as well as models of inflammation-associated cancer. Thus, anti-IL-6/anti-IL-6R strategies emerge as promising novel approaches for therapy of inflammatory diseases in humans. In this review article, we discuss the latest findings on the role of IL-6 in experimental models of autoimmunity and cancer, as well as clinical perspectives. Copyright © 2011 Elsevier Ltd. All rights reserved.
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                Author and article information

                Journal
                Clinical Immunology
                Clinical Immunology
                Elsevier BV
                15216616
                January 2022
                January 2022
                : 234
                : 108916
                Article
                10.1016/j.clim.2021.108916
                34971840
                f6d07452-3761-4207-82d5-af790f0a4650
                © 2022

                https://www.elsevier.com/tdm/userlicense/1.0/

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