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AIM OF THE STUDY. Several studies have explored cycling versus switching strategies in Psoriatic Arthritis (PsA) when TNF-alpha inhibitors are used as biological DMARD (bDMARD). Conversely, real-world evidence regarding cycling strategies within other bDMARD classes is lacking. In this study, we aimed to evaluate the retention rate of interleukin-17 inhibitors (anti-IL17) in patients with PsA, focusing on the differences between those receiving their first anti-IL17 agent and those previously exposed to anti-IL17 therapy. METHODS This was a multicentre, retrospective, observational study. All consecutive patients with PsA treated with an anti-IL17 bDMARD were included. The baseline assessment encompassed demographic and clinical characteristics, including disease domains and activity scores, IL-17 exposure status, number of prior bDMARD lines, and concomitant therapies. The primary outcomes were: a. the retention rate of anti-IL17 agents in IL-17 naïve versus IL-17 experienced patients; b. predictors of treatment discontinuation. RESULTS. A total of 868 patients were included (59.3% female; median age 56 [48-63] years). The majority were receiving their first anti-IL17 agent (89.3% IL17 naïve vs 10.7% IL17 experienced). Secukinumab was the most frequently prescribed bDMARD (70.8%), followed by Ixekizumab (28.6%), and Bimekizumab (0.6%) (Figure 1.A.). At baseline, IL17 experienced patients more commonly exhibited axial involvement compared to IL17 naïve patients (59.1% vs 35.4%) and had received a higher median number of previous bDMARDs (4 [3-5] vs 2 [1-3] lines, respectively). Secukinumab was more frequently prescribed in IL17 naïve patients (76.9% vs 20.4%), whereas Ixekizumab was preferentially used in IL17 experienced individuals (Figure 1.A.). Median follow-up for the overall cohort was 15.2 [7.0-33.8] months, for a total exposure of 20’014 patient-months. At 12 months, the estimated retention rate was 77.6% vs 77.0% in naïve vs experienced patients respectively, dropping at 61.7% vs 54.0% at 24 months. Although Kaplan–Meier curves suggested a numerically lower persistence among IL17 experienced cases, this difference did not reach statistical significance (log-rank p = 0.068) (Figure 1.B.). In multivariable Cox regression analysis, male gender, a lower number of prior bDMARDs, and treatment with Secukinumab were associated with higher odds of drug survival, whereas axial involvement increased the risk of discontinuation. Prior IL17 exposure was associated with a non-significant trend towards a lower risk of discontinuation (Figure 1.C.). CONCLUSION. Our findings suggest that, in the real-world PsA clinical practice, prior exposure to an IL17 inhibitor may not compromise the retention of a subsequent agent from the same class. Conversely, drug survival was influenced by gender, axial involvement, the specific bDMARD prescribed, and the cumulative number of prior bDMARDs. Recycling within the IL17 inhibitor class may represent an effective strategy. Nevertheless, further studies are warranted to better define the clinical contexts in which this approach could be most appropriate.

Psoriasis is the result of uncontrolled keratinocyte proliferation, and its pathogenesis involves the dysregulation of the immune system. The interplay among cytokines released by dendritic, Th1, Th2, and Th17 cells leads to the phenotypical manifestations seen in psoriasis. Biological therapies target the cytokine-mediated pathogenesis of psoriasis and have improved patient quality of life. This review will describe the underlying molecular pathophysiology and biologics used to treat psoriasis. A review of the literature was conducted using the PubMed and Google Scholar repositories to investigate the molecular pathogenesis, clinical presentation, and current therapeutics in psoriasis. Plaque psoriasis’, the most prevalent subtype of psoriasis, pathogenesis primarily involves cytokines TNF-α, IL-17, and IL-23. Pustular psoriasis’, an uncommon variant, pathogenesis involves a mutation in IL-36RN. Currently, biological therapeutics targeted at TNF-α, IL-12/IL-23, IL-17, and IL-23/IL-39 are approved for the treatment of moderate to severe psoriasis. More studies need to be performed to elucidate the precise molecular pathology and assess efficacy between biological therapies for psoriasis. Psoriasis is a heterogenous, chronic, systemic inflammatory disease that presents in the skin with multiple types. Recognizing and understanding the underlying molecular pathways and biological therapeutics to treat psoriasis is important in treating this common disease.

Objective: Few real-world studies have shown clear association between interleukin (IL)-17 inhibitors and inflammatory bowel disease (IBD) onset. This study investigated the reporting prevalence and evaluated the clinical features and management of IL-17 inhibitor-related IBD events. Methods: We used the US FDA Adverse Event Reporting System database and retrieved data, from 2015 to 2022, on IL-17 inhibitors to identify gastrointestinal inflammatory events and conduct disproportionality analyses by estimating the reporting odds ratios (RORs) and corresponding 95% confidence intervals (CIs). Furthermore, case reports and case series, from 2015 to 30 November 2022, on IBD induced by IL-17 inhibitors were collected for retrospective analysis. Results: A total of 388 cases of primary suspected IL-17 inhibitor-associated gastrointestinal events were reported (268 IBD and 120 colitis), including 348 cases involving secukinumab (SEC), 36 cases involving ixekizumab (IXE), and 4 cases involving brodalumab (BRO). Statistically significant reporting rates of total IBD events were observed for SEC and IXE (ROR = 2.13, 95% CI [1.96-2.30] and ROR = 2.79, 95% CI [2.39-3.27], respectively), whereas BRO did not trigger a safety signal. Twenty-nine studies, which included 34 cases, showed evidence of IBD, following SEC (79.4%) and IXE (20.6%) treatment. The median age was 42 years; typical initial symptoms included diarrhea (90.9%), abdominal pain (57.6%), bloody diarrhea (51.5%), and fever (36.4%). The median time to onset of IBD symptoms was 2.9 months. Some cases were accompanied by elevated white blood cell (WBC) count (87.5%), erythrocyte sedimentation rate (ESR; 85.7%), C-reactive protein (CRP; 100%), and fecal calprotectin (FC; 100%). Cessation of IL-17 inhibitors plus treatment with corticosteroids and TNF antagonists, as either monotherapy or in combination, could lead to complete clinical remission. The median time to remission after IL-17 inhibitor discontinuation was 4 weeks. Conclusion: IL-17 inhibitor treatment is associated with exacerbation and new onset of IBD and colitis. Obtaining a detailed patient history before initiation of treatment and monitoring gastrointestinal symptoms and intestinal inflammatory biomarkers during IL-17 inhibitor treatment is important for safe use of these drugs.

Hidradenitis suppurativa (HS) is a chronic, recurrent, inflammatory skin disease deriving from the hair follicles. The formation of inflammatory nodules, abscesses, fistulas, and sinus tracts is characterized by a large inflow of key pro-inflammatory mediators, such as IFN-γ, TNF-α, IL-1, IL-17, and IL-12/23. Adalimumab is currently the only Food and Drug Administration (FDA)- and European Medicines Agency (EMA)-approved biologic therapy for moderate to severe HS in adults and adolescents. However, the long-term effectiveness of this TNF-α inhibitor in HS patients has shown to be highly variable. This review aims to review the evidence for emerging therapies that target the main pro-inflammatory cytokines in HS pathogenesis. A review of the literature was conducted, using the PubMed and Google Scholar repositories, as well as Clinicaltrials.gov. Presently, the most promising biologics in phase III trials are anti-IL-17 antibodies, secukinumab, and bimekizumab. Furthermore, an anti-IL-1 biologic, bermekimab, is currently in phase II trials, and shows encouraging results. Overall, the clinical efficacies of all new targeted therapies published up to this point are limited. More studies need to be performed to clarify the precise molecular pathology, and assess the efficacy of biological therapies for HS.

The introduction of biologic therapies has led to dramatic improvements in the management of moderate-to-severe psoriasis. Even though the efficacy and safety of the newer biologic agents are difficult to match, oral administration is considered an important advantage by many patients. Current research is focused on the development of oral therapies with improved efficacy and safety compared with available alternatives, as exemplified by deucravacitinib, the first oral allosteric Tyk2 inhibitor approved for the treatment of moderate to severe psoriasis in adults. Recent advances in our knowledge of psoriasis pathogenesis have also led to the development of targeted topical molecules, mostly focused on intracellular signaling pathways such as AhR, PDE-4, and Jak-STAT. Tapinarof (an AhR modulator) and roflumilast (a PDE-4 inhibitor) have exhibited favorable efficacy and safety outcomes and have been approved by the FDA for the topical treatment of plaque psoriasis. This revision focuses on the most recent oral and topical therapies available for psoriasis, especially those that are currently under evaluation and development for the treatment of psoriasis.

Background For patients with ankylosing spondylitis (AS) who experience inefficacy or adverse events with biologics, no recommendations exist regarding the preference for class cycling or switching as a second- or higher-line biologics. Previous studies on the drug retention of TNF and IL-17 inhibitors in AS patients with prior biologics exposure have limitations, including relatively short follow-up periods, exclusion of patients with extra-articular manifestations, and a primary focus on second-line treatment. This study aimed to compare the retention rates of TNF and IL-17 inhibitors in AS patients with prior biologics experience, over a relatively longer follow-up period in real clinical practice. Methods A total of 148 AS cases receiving either a TNF or IL-17 inhibitor as a second- or higher-line biologic were retrospectively analyzed after propensity score matching. Patient characteristics at the time of cycling or switching and drug retention were compared between the two groups. Subgroup analyses were conducted based on the reasons for drug discontinuation. Cox regression analyses were used to identify the factors associated with drug discontinuation. Results The median follow-up period was 31.4 months, and drug survival tended to be lower for IL-17 inhibitors than for TNF inhibitors in the Kaplan–Meier analysis ( P  = 0.134). The lower retention of IL-17 inhibitors was more pronounced when discontinuations unrelated to treatment failure were censored ( P  = 0.034) or when used for reasons other than psoriasis aggravation ( P  = 0.028). However, in multivariable Cox regression, the number of previous biologics (HR: 1.62, 95% CI: 1.17–2.23, P  = 0.003) and BASDAI (HR: 1.3, 95% CI: 1.03–1.65, P  = 0.030) were significantly associated with drug discontinuation, whereas the class of biologics did not reach statistical significance (HR: 2.11, 95% CI: 0.96–4.63, P  = 0.064). Conclusion In patients with AS who had prior experience with biologics, the drug retention of TNF inhibitors tended to be higher compared to IL-17 inhibitors in real-world clinical practice. However, the factors significantly associated with higher drug survival were a lower number of previously exposed biologics and a lower BASDAI.

Methods Following PRISMA guidelines, we conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) and observational studies. Results A systematic review and meta-analysis evaluated the efficacy and safety of IL-17 inhibitors for treating Hidradenitis Suppurativa, based on a selection of 271 articles that led to the inclusion of four studies (six RCTs) involving 2232 participants [1, 2, 3–4] (Table 1). Subgroup analysis indicated Bimekizumab had no significant effect on flare reduction, while Secukinumab demonstrated significant reduction (RR = 0.66).

The involvement of IL-17A in autoimmune and inflammatory diseases has prompted the development of therapeutic strategies to block the Th17 pathway. Promising results came from their use in psoriasis and in ankylosing spondylitis. IL-17A acts on various cell types and has both local and systemic effects. Considering the premature mortality observed during chronic inflammatory diseases, IL-17A action on vascular cells was studied. Both in vitro and in vivo results suggest that this cytokine favors inflammation, coagulation and thrombosis and promotes the occurrence of cardiovascular events. These observations led to study the role of IL-17A in diseases characterized by vascular inflammation, namely allograft rejection and vasculitis. Increased circulating levels of IL-17A and histological staining reveal that the Th17 pathway is involved in the pathogenesis of these diseases. Vasculitis treatment faces challenges while the use of steroids has many side effects. Regarding results obtained in giant cell arteritis with IL-6 inhibitors, a cytokine involved in Th17 differentiation, the use of anti-IL-17 is a promising strategy. However, lessons from rheumatoid arthritis and multiple sclerosis must be learnt before targeting IL-17 in vasculitis, which may be culprit, consort or both of them.

The spondyloarthritides (SpA) are a group of chronic inflammatory diseases that affect the axial skeleton (ax-SpA), peripheral joints and entheses (p-SpA) and are expressed with several clinical phenotypes such as psoriasis, psoriatic arthritis (PsA), inflammatory bowel disease (IBD), and uveitis. The pathogenesis of SpA involves the pivotal role of tumour necrosis factor alpha (TNFα) and the interleukins (IL) IL-17/IL-23. Their distribution and hierarchy in the affected organs and tissues is differently expressed in SpA. TNFα is expressed in all tissues and organs, while IL-17 and IL-12/IL-23 is lacking from the gut and the axial skeleton respectively. This knowledge is a dilemma for physicians when they must choose a biological therapy. Nowadays, the armamentarium of SpA treatment has been expanded comprising biological therapies such as TNFα inhibitors (TNFαi), IL-17 inhibitors (IL-17i), IL-12/IL-23 inhibitors (IL-12/IL-23i), as well as the Janus Kinase inhibitors (JAKi). Several studies have shown that IL-12/IL-23i are very effective to treat psoriasis, PsA and IBD, but are ineffective in treating ax-SpA. IL-17i are very effective in patients with ax-SpA, psoriasis and PsA, but seem ineffective in IBD. Finally, TNFαi have shown to be effective in all SpA phenotypes with an acceptable toxicity profile. On the other hand, JAKi are also effective in almost all SpA phenotypes, but caution is required for elderly patients who may develop Herpes-Zoster infection, thromboembolic events and malignancies. However, the treatment of SpA is individualised according to the clinical phenotype and after shared decision between patients and physicians.

The application of interleukin-17 (IL-17) inhibitors, including secukinumab, ixekizumab, brodalumab, and bimekizumab, are associated with elevated risk of candidiasis. These medications interfere with the IL-17 pathway, which is essential for maintaining mucosal barriers and coordinating the immune response against Candida species. The observational data and clinical trials demonstrate the increased incidence of candidiasis in individuals treated with IL-17 inhibitors. Brodalumab and bimekizumab pose a greater risk than secukinumab in eliciting candidiasis, whereas the data regarding ixekizumab are equivocal. Higher doses and prolonged treatment duration of IL-17 inhibitors increase the risk of candidiasis by compromising the immune response against Candida species. Prior to prescribing IL-17 inhibitors, healthcare professionals should comprehensively evaluate patients' medical histories and assess their risk factors. Patients should be educated on the signs and symptoms of candidiasis to facilitate early detection and intervention. Future research should focus on identifying the risk factors associated with candidiasis in patients receiving IL-17 inhibitors. Prospective studies and long-term surveillance are required to explore the impact of specific inhibitors on the incidence and severity of candidiasis and to evaluate the effectiveness of combination therapies, such as concurrent use of IL-17 inhibitors and prophylactic antifungal agents.