Paradoxical adverse events (PAEs) have been reported during biological treatment for chronic immune-mediated diseases. PAEs are defined as the occurrence during biological agent therapy of a pathological condition that usually responds to this class of drug. A wide range of PAEs have been reported including dermatological, intestinal and ophthalmic conditions, mainly with antitumour necrosis factor α (TNF-α) agents. True PAEs include psoriasis, Crohn's disease and hidradenitis suppurativa. Other PAEs may be qualified as borderline and include uveitis, scleritis, sarcoidosis and other granulomatous diseases (granuloma annulare, interstitial granulomatous dermatitis), vasculitis, vitiligo and alopecia areata. Proposed hypotheses to explain these PAEs include an imbalance in cytokine production, the differential immunological properties between the monoclonal antibodies and TNF-α soluble receptor, an unopposed type I interferon production and a shift towards a Th1/Th2 profile. Data from registries suggest that the risk for paradoxical psoriasis is low and non-significant. We discuss management of these PAEs, which depends on the type and severity of the adverse events, pre-existing treated conditions and the possibility of alternative therapeutic options for the underlying disease. Paradoxical adverse events are not restricted to anti-TNF-α agents and close surveillance of new available biological drugs (anti-interleukin-17/23, anti-integrin) is warranted in order to detect the occurrence of new or as yet undescribed events.

IL-23 is a pro-inflammatory cytokine belonging to the IL-12 cytokine family. IL-23 is essential for the differentiation of Th17 lymphocytes, a subtype of T lymphocyte implicated in chronic inflammatory/autoimmune mediated diseases. IL-23 and Th17 correspond to a new axis that drives immune activation and chronic inflammation through the differentiation and activation of Th17 cells. Animal models of chronic inflammatory diseases such as chronic joint diseases, inflammatory bowel diseases and demyelinating diseases strongly suggest the involvement of this cytokine pathway. Thus, IL-23/Th17 is considered as a relevant therapeutic target in autoimmune driven diseases, and biological agents blocking IL-23 or IL-17 are currently being developed. Ustekinumab is a monoclonal antibody targeting the common p40 subunit of IL-12 and IL-23. This treatment has demonstrated its efficacy over placebo in randomized placebo controlled trials and is currently licensed for the treatment of psoriasis. It has also demonstrated its efficacy in psoriatic arthritis. Results for Crohns disease were less evident, while ustekinumab was ineffective in multiple sclerosis. Secukinumab is an IL-17A monoclonal antibody that is under development and preliminary results have suggested its efficacy in inflammatory mediated diseases such as psoriasis and ankylosing spondylitis. Several other IL-23 or IL-17 neutralizing agents are being evaluated in clinical trials. The biological properties of the IL-23/Th17/IL-17 axis and the clinical applications of the drugs that aim to block its functions are reviewed here. Targeting the IL-23/Th17 axis seems to be a relevant and realistic therapeutic approach and these new agents pave the way for additive and alternative treatments to currently available biologics in chronic inflammatory diseases.

The IL-23/T helper 17 (Th17) axis plays an important role in joint inflammation in ankylosing spondylitis (AS). Conventional CD4⁺ Th17 cells are a major source of IL-17A. IL-22 is another cytokine implicated in AS pathophysiology and is produced by Th17 and Th22 cells. In this study, we aimed to analyze conventional and non-conventional T cell subsets producing IL-17A and IL-22 in patients with AS. We thus evaluated the intracellular staining for IL-17A, IL-22, and IFN-γ in peripheral blood mononuclear cells of 36 patients with AS and 55 age- and sex-matched healthy controls (HC). Conventional CD4⁺ and CD8⁺ T cells, γδ T cells, and mucosal-associated invariant T (MAIT) cells were evaluated. In patients with AS, we found a decreased frequency and number of γδ T cells, of MAIT cells and of IFN-γ⁺ CD4⁺ and CD8⁺ T cells. Th17-related IL-17A⁺/IFN-γ⁻ CD4⁺ T cells were decreased in AS. The number of IL-22⁺ MAIT cells was higher in AS compared with HC, as well as the number of IFN-γ⁺/IL-17A⁺ MAIT cells. The number of IFN-γ⁻/IL-17A⁺ MAIT cells was higher only in female patients with AS compared with female HC. The cellular source of IL-17A was thus not restricted to conventional Th17 CD4⁺ T cells and might involve innate-like T cells, such as MAIT cells. Circulating MAIT cells producing IL-22 were increased in AS. These results strengthen the importance of innate and innate-like sources of IL-17A and/or IL-22.