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Ustekinumab is a fully human IgG1k monoclonal antibody that binds with high affinity and specificity to the p40 subunit of interleukins (IL-) 12 and 23, inhibiting their activity by preventing binding to their receptors. The European extension of the patent (Supplementary Protection Certificate) of ustekinumab expired on 20 July 2024. Biosimilar alternatives to ustekinumab are now an additional option for treating patients. The efficacy data for this drug in moderate-to-severe psoriasis obtained both from clinical trials and indirect comparisons through meta-analyses, are superior to those of etanercept and adalimumab, and its safety profile is more favorable than that of tumor necrosis factor (TNF) inhibitors. Several ustekinumab biosimilars have already been approved by regulatory agencies: between October 2023 and October 2024, Wezlana® (Amgen ABP 654), Uzpruvo® (Alvotech AVT04) and Pyzchiva® (Samsung/Bioepis SB17) have been approved by both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). SteQeyma® (Celltrion Healthcare CT-P43) was approved by the EMA in August 2024. Otulfi® (Fresenius Kabi/Formycon) was approved by the FDA in October 2024. Several other potential biosimilar candidates are under development, including BAT2206 (Bio-Thera), DMB-3115 (Dong-A ST), QX001S (Qyuns Therapeutic), BFI-751 (BioFactura), NeuLara (Neuclone), ONS3040 (Oncobiologics), and BOW090 (Epirus Biopharmaceuticals). In most cases, these monoclonal antibodies are expressed in cell lines (e.g., Chinese Hamster Ovary, CHO) different from those used for the originator (Sp2/0 spleen cell murine myeloma); of note, the cell line of origin is not a requirement for biosimilarity in the totality-of-evidence comparison exercise and may facilitate the production and reduce the immunogenicity of biosimilars originated in CHO cultures. This narrative review summarizes the available data on characteristics of the full comparability exercises and comparative clinical trials of these drugs.

Background: Inverse psoriasis (IP) is a variant of plaque psoriasis involving flexor surfaces. A clear definition of IP is still lacking. Therapy is based on topical and systemic treatments, including classic systemic drugs and biologic agents, but a well‐defined therapeutic strategy is absent. Materials and methods: This retrospective study investigated the general characteristics of patients with IP or vulgar psoriasis and compared the effectiveness of anti‐interleukin‐17 or anti‐interleukin‐23 agents in the same groups. Second, treatment effectiveness and the demographic characteristics of IP patients treated with IL‐23 and IL‐17 inhibitors were also compared. IP patients were included if they had specific psoriatic involvement of the axillary, inguinal, or submammary lines, breast folds, antecubital and popliteal pits, intergluteal fold, and perianal area. Patients with vulgar plaque psoriasis and concomitant intertriginous involvement were included in the vulgar psoriasis cohort. Results: Patients with IP were prevalently female and treated with IL‐17 inhibitors compared to those with vulgar psoriasis. They also had a greater risk of drug discontinuation and subsequent therapeutical switch (32.1% vs. 18.1%, P = 0.002). At later time points, those with IP showed progressively slower achievement of PASI100 and 90 compared to the cohort with vulgar psoriasis. In the IP cohort, there was greater joint involvement in patients treated with an anti‐IL‐17 agent (P = 0.011), who also had a lower median age of onset (P = 0.011) compared to patients treated with an anti‐IL‐23 agent. Patients with IP treated with an anti‐IL‐23 agent initiated with a lower mean PASI and showed a slower response than patients on an anti‐IL‐17 agent. At later time points, progressively greater effectiveness of IL‐23 inhibitors was observed compared to IL‐17 inhibitors. Conclusions: Patients with IP responded less to biologic agents than those with vulgar psoriasis. In the IP cohort, IL‐17 inhibitors had a faster onset than IL‐23 inhibitors, but long‐term anti‐IL‐23 agents seem to be associated with better outcomes. [ABSTRACT FROM AUTHOR]

Ustekinumab is a fully human IgG1k monoclonal antibody that binds with high affinity and specificity to the p40 subunit of interleukins (IL-) 12 and 23, inhibiting their activity by preventing binding to their receptors. The European extension of the patent (Supplementary Protection Certificate) of ustekinumab expired on 20 July 2024. Biosimilar alternatives to ustekinumab are now an additional option for treating patients. The efficacy data for this drug in moderate-to-severe psoriasis obtained both from clinical trials and indirect comparisons through meta-analyses, are superior to those of etanercept and adalimumab, and its safety profile is more favorable than that of tumor necrosis factor (TNF) inhibitors. Several ustekinumab biosimilars have already been approved by regulatory agencies: between October 2023 and October 2024, Wezlana® (Amgen ABP 654), Uzpruvo® (Alvotech AVT04) and Pyzchiva® (Samsung/Bioepis SB17) have been approved by both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). SteQeyma® (Celltrion Healthcare CT-P43) was approved by the EMA in August 2024. Otulfi® (Fresenius Kabi/Formycon) was approved by the FDA in October 2024. Several other potential biosimilar candidates are under development, including BAT2206 (Bio-Thera), DMB-3115 (Dong-A ST), QX001S (Qyuns Therapeutic), BFI-751 (BioFactura), NeuLara (Neuclone), ONS3040 (Oncobiologics), and BOW090 (Epirus Biopharmaceuticals). In most cases, these monoclonal antibodies are expressed in cell lines (e.g., Chinese Hamster Ovary, CHO) different from those used for the originator (Sp2/0 spleen cell murine myeloma); of note, the cell line of origin is not a requirement for biosimilarity in the totality-of-evidence comparison exercise and may facilitate the production and reduce the immunogenicity of biosimilars originated in CHO cultures. This narrative review summarizes the available data on characteristics of the full comparability exercises and comparative clinical trials of these drugs. [ABSTRACT FROM AUTHOR]

Introduction: This study aimed to compare the efficacy and safety of biologics and small molecules for treatment of adults with moderately-to-severely active ulcerative colitis (UC). Methods: A systematic literature review was conducted to identify randomised controlled trials evaluating approved and emerging targeted therapies for patients with UC. A Bayesian network meta-analysis (NMA) approach was applied. Outcomes assessed included clinical response and remission, endoscopic mucosal healing, and safety. Results: Thirty studies were included in the NMA following a feasibility assessment comparing approved induction dosing regimens and 22 studies comparing approved maintenance dosing regimens. In the biologic/Janus kinase inhibitor (JAKi)-naïve population, induction studies showed similar clinical response and remission rates across most interventions, with upadacitinib demonstrating significant improvements versus most other interventions. For maintenance studies, mirikizumab demonstrated significant improvements in clinical response and remission versus most other interventions. In the biologic/JAKi-experienced population, no significant differences were observed between most interventions in induction studies, except for significantly improved clinical response and remission for mirikizumab versus adalimumab, and upadacitinib demonstrated significant improvement versus all other interventions. Few differences between active treatments were observed in maintenance studies. In both populations, all active interventions had similar efficacy in terms of endoscopic mucosal healing in both induction and maintenance studies. Regardless of prior treatment exposure, similar rates of serious adverse events were seen across all active interventions in the induction period. Conclusion: Among the available interventions, owing to its favourable efficacy and safety profile, mirikizumab has a relevant role in the long-term treatment of UC. [ABSTRACT FROM AUTHOR]

Psoriasis is a chronic inflammatory skin condition associated with systemic inflammation and a higher risk of cardiovascular comorbidities. This study retrospectively evaluates coagulation parameters in psoriasis vulgaris patients treated with IL-17 inhibitors (secukinumab, ixekizumab) and IL-23 inhibitors (risankizumab, guselkumab), compared to those untreated systemically. The study reviewed records from 177 patients treated between January 2019 and March 2023. Patients were grouped into control (n = 77), secukinumab (n = 36), ixekizumab (n = 19), guselkumab (n = 24), and risankizumab (n = 21). Coagulation parameters, including PT, aPTT, PLT, MPV, INR, fibrinogen, D-dimer, and B12 levels, were analyzed. The primary endpoint was the comparison of coagulation parameters between groups. Significant differences were found in PT, with secukinumab-treated patients showing a significantly shorter PT compared to controls (p = 0.002). No significant differences were observed in other coagulation parameters across the groups. The study highlights a potential effect of secukinumab on coagulation pathways, possibly related to IL-17’s role in inflammation and endothelial function. Despite current literature suggest a risk of cerebrovascular events with risankizumab, this study did not show any significant changes in coagulation parameters with risankizumab, indicating no hypercoagulability risk associated with this IL-23 inhibitor. Our findings suggest IL-17 and IL-23 inhibitors are generally safe concerning coagulation parameters, but regular monitoring may be warranted for patients on secukinumab due to its effect on PT. Further long-term studies are needed to fully understand the cardiovascular risks associated with these therapies. [ABSTRACT FROM AUTHOR]

Background: Despite extraordinary improvements in the management of psoriasis in recent times, some areas of the body, such as the pretibial area, still show an unsatisfactory response and a more significant impact on patient quality of life. This multicentre study focuses on psoriasis affecting sensitive areas (particularly the pretibial area), its impact on quality of life and the therapeutic response to risankizumab. Methods: This multicentre prospective observational study recruited patients with moderate-to-severe psoriasis with pretibial area involvement. All patients underwent treatment with risankizumab (150 mg every 3 weeks), and efficacy was assessed after 24 weeks. Results: The study included 128 patients with a mean age of 51 years, suffering from moderate-to-severe psoriasis with involvement of the pretibial area with median total Psoriasis Area Severity Index score of 17.05 and Dermatology Life Quality Index of 16.27. The group was further divided into two sub-groups: the ‘mother patch’ group, in whom the very first psoriatic plaque appeared in the pretibial region (45 patients), and the ‘non-mother patch’ group, in whom the psoriatic lesion in the pretibial region was present but not as the first manifestation (83 patients). In order to better assess the involvement of psoriasis in the pretibial area, the pretibial plaque lesion severity index was also calculated at baseline in all patients: extent 2.75, erythema 2.64, infiltration 2.45 and desquamation 2.38. All participants in this study showed a good therapeutic response, with a reduction in all scores. Conclusions: The pretibial area is becoming an object of therapeutic interest due to some resistance to clearance and the consequent impairment of patient quality of life. This study showed that risankizumab can give favourable therapeutic results not only in patients with moderate-to-severe psoriasis with involvement of the difficult-to-treat areas but particularly in patients with recalcitrant plaques in the pretibial area.

Psoriasis is a chronic inflammatory skin disease affecting 2–3% of the global population. Traditional systemic treatments, such as methotrexate, cyclosporine, acitretin and fumaric acid esters, have limited efficacy and are associated with significant adverse effects, necessitating regular monitoring and posing risks of long-term toxicity. Recent advancements have introduced biologic drugs that offer improved efficacy and safety profiles. However, their high cost and the inconvenience of parenteral administration limit their accessibility. Consequently, there is a growing interest in developing new, targeted oral therapies. Small molecules, such as phosphodiesterase 4 inhibitors (e.g. apremilast) and TYK2 inhibitor (e.g. deucravacitinib), have shown promising results with favourable safety profiles. Additionally, other novel oral agents targeting specific pathways, including IL-17, IL-23, TNF, S1PR1 and A3AR, are under investigation. These treatments aim to combine the efficacy of biologics with the convenience and accessibility of oral administration, addressing the limitations of current therapies. This narrative review synthesizes the emerging oral therapeutic agents for psoriasis, focusing on their mechanisms of action, stages of development and clinical trial results.

Psoriasis vulgaris is a systemic, chronic inflammatory disease affecting 2-3% of the population. Recent advances in the understanding of the pathophysiology of psoriatic disease have facilitated the development of novel therapeutic options with improved safety and efficacy. This article is coauthored by a patient with a lifelong history of psoriasis who experienced multiple treatment failures. He details his diagnosis and treatment experiences, as well as the physical, mental, and social ramifications of his skin condition. He then goes on to elaborate how evolutions in the treatment of psoriatic disease have impacted his life. This case is then discussed from the perspective of a dermatologist specializing in inflammatory skin disorders. We highlight the clinical features of psoriasis, its medical and psychosocial comorbidities, and the current landscape of psoriatic disease treatments.

Background: Inflammatory bowel disease (IBD), encompassing Crohn's disease (CD) and ulcerative colitis (UC), continues to challenge treatment paradigms. Advancements in therapeutic options have been have been driven by Phase 2 and 3 clinical trials of new drug classes, particularly sphingosine-1-phosphate (S1P) modulators and interleukin-23 (IL-23) inhibitors. Methods: This review synthesizes findings from Phase 2 and 3 clinical trials conducted up to early 2024, focusing on the impact of S1P modulators and IL-23 inhibitors on IBD management. Drugs such as ozanimod, etrasimod, risankizumab, mirikizumab, guselkumab, and brasikumab were evaluated for their efficacy and safety profiles. Results: S1P modulators, such as ozanimod and etrasimod, effectively regulate immune cell trafficking to reduce inflammation and several trials highlight their clinical effectiveness in both inducing and maintaining remission in IBD, highlighting its long-term safety and sustained therapeutic effects. Additionally, IL-23 inhibitors including risankizumab, mirikizumab, and guselkumab, which disrupt key inflammatory cytokine pathways, have already shown significant effectiveness in inducing and maintaining remission in both CD and UC, with favorable safety profiles across multiple studies, suggesting their potential as critical components in managing IBD. Conclusions: The clinical trials indicate that both S1P modulators and IL-23 inhibitors offer promising therapeutic benefits and maintain strong safety profiles, positioning them as potential cornerstone treatments for IBD. Despite these advancements, further exploration into long-term safety and the development of personalized treatment strategies is essential for maximizing clinical outcomes. [ABSTRACT FROM AUTHOR]

Introduction: Primary sclerosing cholangitis (PSC) is the most specific hepatobiliary extraintestinal manifestation in inflammatory bowel disease (IBD). PSC ultimately has a poor prognosis, with disease progression resulting in liver cirrhosis and subsequent liver failure. While there is current data for the medical management of IBD, the optimal approach for concurrent PSC-IBD is unclear. Areas Covered: This review focuses on the current literature of pharmacotherapy in the PSC-IBD population including anti-tumor necrosis factor agents, vedolizumab, JAK inhibitors, IL-12/23 inhibitors, and thiopurines. Regarding PSC-IBD, it focuses on effectiveness of IBD therapies on liver biochemistry and IBD activity as well as the advent of clinically relevant liver outcomes and safety. The authors also address the need for further advances in research. Expert Opinion: The longer-term data for pharmacological management for IBD is well established. In the concomitant PSC-IBD population there is no drug to date that has effectively reduced disease related morbidity and mortality outcomes. There are limitations in the current, mostly retrospective data on IBD drugs in PSC-IBD with respect to samples sizes, heterogenous outcomes, and lack of a high-quality surrogate endpoint in PSC. However, current data for adalimumab offers encouraging results which require further exploration with larger prospective studies. [ABSTRACT FROM AUTHOR]

The advent of biologic and targeted synthetic disease-modifying anti-rheumatic drugs (b/tsDMARDs) have transformed the management of immune-mediated rheumatic diseases, including spondylarthritis (SpA). However, the data about combining b/ts DMARDs in the treatment of SpA are scarce. The study objectives were to assess the efficacy and safety of combination b/tsDMARD in SpA. We conducted systematic literature review (PubMed and Medline) with two independent reviewers, one adjudicator, exploring the efficacy and safety of combination b/tsDMARDs in the treatment of SpA. Inclusion criteria were studies published in last 20 years, English language, interventions included use of two b/tsDMARDs, and minimal three-month follow-up. Out of 1936 initial hits, 28 manuscripts fulfilled the inclusion criteria. Two were randomized controlled trials, and the remaining were retrospective cohort studies or case series. Combination of apremilast with bDMARD, or TNF inhibitor plus IL12/23 inhibitor were the commonest and reported good efficacy with no increased safety signal. There is not enough data to fully evaluate efficacy and safety of combination b/tsDMARDs in SpA treatment. Limited information shows apremilast plus bDMARD, or TNF inhibitor plus IL12/23 inhibitor combination to be efficacious and safe. Randomized controlled trials and larger cohort with a longer follow-up are required. [ABSTRACT FROM AUTHOR]

Acne inversa is a chronic, progressive inflammatory skin disease. It is characterized by the occurrence of relapsing, painful, deep-seated nodules, abscesses, fistulae, sinus tracts, and scars in the axilla, inguinal area, submammary folds, and perianal area. The disease significantly affects patients’ quality of life and is often associated with severe, debilitating pain and depression. Pro-inflammatory cytokines such as TNF-α, interleukin 17 (IL-17), IL-23, IL-12, IL-1α, and IL-1β play a significant role in the pathogenesis of hidradenitis suppurativa. Treatment is difficult and often ineffective, based on both surgical and pharmacological methods. Biologic drugs in hidradenitis suppurativa are the subject of many clinical trials and may be effective in patients for whom other therapies have failed. The first biological drug approved by the Food and Drug Administration for the treatment of hidradenitis suppurativa was the TNF-α inhibitor — adalimumab. The advancement of knowledge of immune mechanisms in the pathogenesis of hidradenitis suppurativa has allowed the development of clinical trials of new therapeutic targets. In 2023, the Food and Drug Administration (FDA) approved the IL-17 inhibitor — secukinumab as the second biological drug in hidradenitis suppurativa. The aim of this review is an update of the biological treatment and its effectiveness in hidradenitis suppurativa. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Promoting a Th17 pathogenic response, the interleukin (IL)-23 pathway is crucial in the pathophysiology of inflammatory bowel disease (IBD). With a favorable safety profile, ustekinumab, a monoclonal antibody targeting the shared p40 component of IL-12/23, is currently approved for the treatment of IBD in patients with disease refractory to corticosteroids and biologic drugs. Risankizumab, mirikizumab, and guselkumab are specific IL-23p19 antagonists tested for the treatment of Crohn's disease (CD). However, only risankizumab currently has been approved for its treatment. Trials with guselkumab and mirikizumab are currently ongoing, with promising preliminary efficacy and safety results. In this review, we provide a summary of the current knowledge about selective IL-23 inhibitors, focusing on their positioning in the therapeutic algorithm of patients with moderate to severe CD. [ABSTRACT FROM AUTHOR]

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Summary: Background: Biologics targeting IL‐23 and IL‐17 show efficacy and safety in the treatment of moderate‐to‐severe psoriasis. Objective: To investigate drug survival in patients with psoriasis treated with biologics. Patients and methods: We performed a comparative evaluation of the achievement of PASI 90 and PASI ≤ 3 at 16, 28, and 52 weeks along with a DS (drug survival) analysis with IL‐17 and IL‐23 inhibitors brodalumab, ixekizumab, secukinumab, risankizumab, tildrakizumab, and guselkumab on 1,057 patients. Results: IL‐17 inhibitors showed a faster achievement of PASI 90 and PASI ≤ 3 with significant superiority over IL‐23 inhibitors at week 16 (p < 0.001; 56% vs. 42% and 70% vs. 59%, respectively). A difference was shown in favor of IL‐23 inhibitors regarding DS (p < 0.001), which was 88% at 24 months vs. 75% for IL‐17 inhibitors. In multivariate analysis, IL‐23 inhibitors (HR 0.54 CI 0.37–0.78, p = 0.001), and male sex (HR 0.57 CI 0.42–0.76, p < 0.001) were all associated with a lower probability of drug interruption. Risankizumab (HR 0.42 CI 0.26‐0.69, p = 0.001), guselkumab (HR 0.49 CI 0.24–0.99, p = 0.046), and male sex (HR 0.57 CI 0.43–0.77, p < 0.001) were associated with a lower probability of drug interruption than secukinumab. Conclusions: IL‐23 inhibitors showed the best performance on DS. Overall, the most effective class was IL‐17 inhibitors considering the short‐term effectiveness, but long‐term effectiveness is in favor of anti‐IL‐23. [ABSTRACT FROM AUTHOR]

Psoriasis is a chronic inflammatory skin disease characterized by plaque formation. Interleukin (IL)‐23 is upregulated in psoriatic lesions and is thought to be a major regulator of the Th17 pathway in psoriasis pathogenesis. Three monoclonal antibodies targeting the IL‐23p19 subunit, guselkumab, tildrakizumab, and risankizumab, have been approved for psoriasis therapy. The balance between cytokines IL‐23 and IL‐12 can affect antitumor and pro‐tumor immune activities, and patients with psoriasis may have higher rates of cancer than the general population. Moreover, a chronic inflammatory state typical of psoriasis may induce protumorigenic effects, however, the potential risk of malignancy in patients taking these drugs remains largely unknown. This study investigated the occurrence of malignancies as suspected adverse reactions (SARs) potentially associated with IL‐23 inhibitors by analyzing real‐world data from the European EudraVigilance database. Although indicatory, these real‐world data seem to confirm the potential association between the IL‐23 inhibitors risankizumab and tildrakizumab, and the occurrence of SARs linked to cancer in patients with psoriasis and, according to a gender perspective, they show that this relationship is asymmetrically distributed between women and men, with a clear prevalence of oncologic SARs in men. [ABSTRACT FROM AUTHOR]

Abstract Psoriasis vulgaris is a systemic, chronic inflammatory disease affecting 2–3% of the population. Recent advances in the understanding of the pathophysiology of psoriatic disease have facilitated the development of novel therapeutic options with improved safety and efficacy. This article is coauthored by a patient with a lifelong history of psoriasis who experienced multiple treatment failures. He details his diagnosis and treatment experiences, as well as the physical, mental, and social ramifications of his skin condition. He then goes on to elaborate how evolutions in the treatment of psoriatic disease have impacted his life. This case is then discussed from the perspective of a dermatologist specializing in inflammatory skin disorders. We highlight the clinical features of psoriasis, its medical and psychosocial comorbidities, and the current landscape of psoriatic disease treatments.

In recent years, the use of interleukin (IL) 23 inhibitors in the treatment of psoriatic arthritis (PsA) has been the subject of much research. By specifically binding to the p19 subunit of IL-23, IL-23 inhibitors block downstream signaling pathways and inhibit inflammatory responses. The objective of this study was to assess the clinical efficacy and safety of IL-23 inhibitors in the treatment of PsA. PubMed, Web of Science, Cochrane Library, and EMBASE databases were searched from the time of conception to June 2022 for randomized controlled trials (RCTs) investigating the use of IL-23 in PsA therapy. The main outcome of interest was the American College of Rheumatology 20 (ACR20) response rate at week 24. We included six RCTs (3 studies on guselkumab, 2 on risankizumab, and 1 on tildrakizumab) with a total of 2971 PsA patients in our meta-analysis. We found that the IL-23 inhibitor group showed a significantly higher ACR20 response rate compared to the placebo group (relative risk = 1.74, 95% confidence interval: 1.57–1.92; P < 0.001; I2 = 40%). There was no statistical difference in the risk of adverse events (P = 0.07) and serious adverse events (P = 0.20) between the IL-23 inhibitor and placebo groups. Notably, the rate of elevated transaminases in the IL-23 inhibitor group was higher than the placebo group (relative risk = 1.69; 95%CI 1.29–2.23; P < 0.001; I2 = 24%). In the treatment of PsA, IL-23 inhibitors significantly outperform placebo intervention while maintaining a favorable safety profile. [ABSTRACT FROM AUTHOR]

The article discusses the importance of a comorbidity-centered approach to managing psoriasis, highlighting the connection between psoriasis and systemic conditions like cardiovascular disease and autoimmune disorders. It emphasizes the need for personalized treatment plans that consider both medical factors and practical concerns, such as cost and patient preferences. The text also points out research gaps in psoriasis management, including the long-term safety of newer biologics and the lack of head-to-head studies comparing treatments in patients with comorbidities. Additionally, it suggests holistic interventions like relaxation therapy and exercise as beneficial complements to medical treatments. [Extracted from the article]

The possibility of modulating the treatment regimen regarding dose reduction (de-escalation) or dose augmentation (escalation) in psoriasis biological treatment has been of increasing interest. De-escalation strategies include reducing the single therapeutic dose, the mg/kg ratio or the number of injections, or dose-spacing (D-S), that is, extending the interval between administrations. Data regarding dose de-escalation, in particular D-S, on IL-23, are lacking to date. The present pilot study is a cohort study with a retrospective analysis of the general characteristics and effectiveness outcomes of psoriatic patients undergoing therapeutic biologic D-S of risankizumab and guselkumab. Ninety-four patients, 32 (34.04%) treated with guselkumab and 62 (65.96%) treated with risankizumab, underwent dose modulation by D-S of 50% of the approved range. The mean PASI decreased from 12.15 (5.43 SD) to 0.15 (0.46 SD) at D-S time. Attainment of PASI100 was rapid: 88.3% at the D-S date, remaining stable over the following year, reaching 100% of patients observed 12 months after D-S. Similar is the trend for PASI 90 and PASI <=1 with 91.49% and 97.87% of achievement at D-S date, and all patients observed at 12 months post-D-S. The 12-month drug survival of the D-S regimen was 89.4%. Guselkumab showed a D-S drug survival of 93.3% versus 89.5% of risankizumab. No differences in mean PASIs at each time point were found between guselkumab and risankizumab. To conclude therapeutic modulation of IL-23 inhibitors in psoriatic patients who have achieved response stability seems a legitimate therapeutic strategy to maintain efficacy and safety., (© 2025 The Author(s). Experimental Dermatology published by John Wiley & Sons Ltd.)

Abstract Background Psoriasis is a chronic immune-mediated inflammatory skin disease for which biologics are effective treatments. Dose reduction (DR) of the first generation biologics seems a promising way for more efficient use of expensive biologics. A substantial part of patients on tumor necrosis factor (TNF)-alfa inhibitors and ustekinumab could successfully lower their dose, after following a tightly controlled DR strategy. The objective of this study is to assess whether controlled DR of interleukin (IL)-17 and IL-23 inhibitors in psoriasis patients with low disease activity is non-inferior (NI) to usual care (UC). Methods This is an international, prospective, multicenter, pragmatic, randomized, non-inferiority trial. A total of 244 patients with stable low disease activity (Psoriasis Area and Severity Index (PASI) ≤ 5) for at least 6 months and using secukinumab, ixekizumab, brodalumab, guselkumab, risankizumab, or tildrakizumab in the standard dose, together with stable low disease activity, defined as a PASI ≤ 5 and Dermatology Life Quality Index (DLQI) ≤ 5 at the moment of inclusion, will be randomized 2:1 to DR or UC. In the DR group, dosing intervals will be prolonged stepwise to achieve 66% and 50% of the original dose. Disease activity is monitored every 3 months by PASI and DLQI. In case of disease flare (i.e., PASI and/or DLQI increase), treatment is adjusted to the previous effective dose. The primary outcome is the incidence proportion of persistent flares (PASI > 5 for ≥ 3 months), which will be compared between arms. Secondary outcomes include proportion of patients with successful DR, (course of) PASI and DLQI, serious adverse events (SAEs), health-related quality of life, costs, and pharmacokinetic profile. Outcomes of DR will be compared to UC. Discussion With this study, we aim to assess whether DR of IL-17 and IL-23 inhibiting biologics can be achieved for psoriasis patients with low disease activity, without losing disease control. Reducing the dose may lead to more efficient use of biologics. Trial registration ClinicalTrials.gov NCT04340076 . Registered on April 9 2020.

During the placebo-controlled periods of these trials, for both PsO and CD there were no reported events of stroke for risankizumab compared to one nonfatal stroke event in placebo; while in PsA, one event of nonfatal stroke was reported for risankizumab and none for placebo. AbbVie undertook a review of the post-marketing data comprising >585 000 patient-treatment years of exposure yielding a reporting rate for central nervous system haemorrhages and cerebrovascular accidents of <1/1000 which is rare,[7] despite the known association of CVA with inflammatory conditions such as psoriasis in the background population. Keywords: IL-23 inhibitors; monoclonal antibodies; pharmacovigilance; psoriasis; risankizumab; stroke; systematic review EN IL-23 inhibitors monoclonal antibodies pharmacovigilance psoriasis risankizumab stroke systematic review 2639 2641 3 07/21/23 20230801 NES 230801 Woods recently published an article regarding a potential signal for cerebrovascular accident (CVA) in psoriasis (PsO) patients treated with risankizumab based on disproportionality of drug-event pairs in the publicly available FDA adverse event reporting system (FAERS).[1] As stated by the author, this is a hypothesis-generating exercise. [Extracted from the article]

This review article aims to compare global dermatologic organizations and the clinical practice guidelines available for the use of interleukin (IL)-23 inhibitors in the treatment of psoriasis. A literature review encompassing systemic therapies for the treatment of psoriasis was conducted. Guidelines from the American Academy of Dermatology (AAD)-National Psoriasis Foundation (NPF), the National Institute for Health and Care Excellence (NICE), and the British Association of Dermatologists (BAD) served as the main comparators in this review. Of the American and European guidelines available for use of IL-23 inhibitors, several organizations are in agreement regarding the dosage and indications of guselkumab, tildrakizumab, and risankizumab. However, there are differences as well as insufficient recommendations concerning laboratory monitoring and screenings as well as contraindications to therapy. IL-23 inhibitors are safe and efficacious therapeutic options for patients with psoriasis and should be considered as a potential first-line therapy alone or in combination with topical medications, phototherapy, and other systemic non-biologic agents. Consideration should be given to the evidence-based guidelines of global dermatologic organizations to help guide therapeutic decisions. [ABSTRACT FROM AUTHOR]

Luca Navarini,1,* Damiano Currado,1,* Luisa Costa,2 Marco Tasso,2 Maria Sole Chimenti,3 Francesco Caso2 1Unit of Rheumatology, Immunology and Clinical Medicine, Università Campus Bio-Medico Di Roma, Rome, Italy; 2Rheumatology Unit, Department of Clinical Medicine and Surgery, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy; 3Rheumatology, Allergology and Clinical Immunology, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy*These authors contributed equally to this workCorrespondence: Francesco CasoRheumatology Unit, Department of Clinical Medicine and Surgery, School of Medicine and Surgery, University of Naples Federico II, Via Pansini 5, Naples 80131, ItalyTel +39 081 7463773Fax +39 081 5463445Email francescocaso1@yahoo.itAbstract: In recent years, different studies have shown in psoriatic arthritis (PsA), the pathogenetic role of multiple cytokines other than tumor necrosis factor-α, such as interleukin-17 (IL-17), and IL-23 and dysfunction of Janus kinase (JAK)-signal family pathway. These molecules also represent the target of recently developed biologic (bDMARDs) and targeted synthetic disease modifying antirheumatic drugs (DMARDs) (tsDMARDs) currently investigated in several Phase II and III randomized controlled trials (RCTs). This review examines the therapeutic efficacy and safety of most recent developed IL-17, IL-23 and JAK inhibitors and highlights how these new PsA therapies are going to revolutionize the management of PsA in the next few years. Ongoing RCTs of these molecules in PsA are also described. Available literature on new anti-IL-17 and anti-IL-23 agents and JAK inhibitors demonstrates the potential role of these molecules as effective therapeutic strategies across multiple PsA clinical domains, along with an acceptable tolerability and safety profile, thus expanding the treatment options available for PsA patients. Of note, other molecules are under investigation, and among those, potential therapeutic strategies seem to be represented by single antibodies blocking simultaneously two cytokines, the agents inhibiting mammalian target of rapamycin (mTOR), receptor retinoic acid receptor-related orphan receptor gamma (RORγt), A3 adenosine receptor (A3 AR), and K+ channel voltage channel inhibitors. Remarkable progress has been made in PsA pharmacotherapy, and novel bDMARDs targeting IL17A and tsDMARDs (JAK-inhibitors) represent promising therapies. More clinical trials are needed to better characterize the efficacy and safety profile of these therapeutic agents in PsA treatment.Keywords: bDMARDs, filgotinib, IL-17 inhibitors, IL-23 inhibitors, JAK-inhibitors, psoriatic arthritis, tofacitinib, tsDMARDs, upadacitinib

Introduction: Psoriatic arthritis (PsA) is a debilitating chronic condition characterized by inflammation of the joints, bones, enthesis, and skin. The pivotal role of interleukin-23 (IL-23) in the pathogenesis of PsA has become increasingly evident. This proinflammatory cytokine is markedly elevated in patients with PsA, suggesting its potential as a therapeutic target. Consequently, IL-23 inhibitors have emerged as promising first-line biologic treatments for PsA., Areas Covered: This review delves into the immunopathogenic mechanisms of IL-23 at the cellular and molecular levels in PsA. Furthermore, it provides the recent efficacy and safety profiles of IL-23 inhibitors. We conducted a literature search in PubMed for the following terms: 'IL-23 and psoriatic arthritis,' 'Ustekinumab,' 'Guselkumab,' 'Risankizumab,' and 'Tildrakizumab.' In addition, we retrieved clinical trials involving IL-23 inhibitors registered in ClinicalTrials.gov, EudraCT, and ICTRP., Expert Opinion: Despite the promising outcomes observed with IL-23 inhibitors, several challenges persist. The long-term effects of these agents require further investigation through prospective studies, and their limited accessibility worldwide necessitates urgent attention. Additionally, ongoing research is warranted to explore other potential drug targets within the IL-23/IL-23 R axis. The development of reliable biomarkers could greatly enhance early detection, tailored management strategies, and personalized treatment approaches for patients with PsA.

Axial spondyloarthritis (axSpA) is comprised of ankylosing spondylitis (AS) and non-radiographic axSpA. In recent years, the involvement of the interleukin (IL)-23/IL-17 axis in the pathophysiology of axSpA has been widely proposed. Since IL-23 is an upstream activating cytokine of IL-17, theoretically targeting IL-23 should be effective in axSpA, especially after the success of the treatment with IL-17 blockers in the disorder. Unfortunately, IL-23 blockade did not show meaningful efficacy in clinical trials of AS. In this review, we analyzed the possible causes of the failure of IL-23 blockers in AS: 1) the available data from an animal model is not able to support that IL-23 is involved in a preclinical rather than clinical phase of axSpA; 2) Th17 cells are not principal inflammatory cells in the pathogenesis of axSpA; 3) IL-17 may be produced independently of IL-23 in several immune cell types other than Th17 cells in axSpA; 4) no solid evidence supports IL-23 as a pathogenic factor to induce enthesitis and bone formation. Taken together, IL-23 is not a principal proinflammatory cytokine in the pathogenesis of axSpA.

Purpose of review: Significant advances in the discovery of novel therapeutic targets for inflammatory bowel disease address a crucial need for patients refractory to available treatment options. We will review the recent literature and data available for novel therapies for adult patients with Crohn's disease (CD) and ulcerative colitis (UC), limited to those currently in phase III trials with a focus on clinical endpoints and safety. Recent findings: Emerging therapeutic agents currently in phase III trials including IL-23 inhibitors (risankizumab, guselkumab, and mirikizumab), JAK inhibitors (filgotinib and upadacitinib), and S1P1 modulators (ozanimod and etrasimod) are effective in the treatment of patients with moderate to severe CD and UC. Therapies with greater selectivity, including IL-23 inhibitors, have favorable safety profiles. Small molecules including JAK inhibitors and S1P receptor modulators are both orally administered and non-immunogenic. Emerging novel agents recently approved or currently in phase III trials appear to be effective and safe for the treatment of CD and UC and will expand options for medically refractory patients. Future comparative effectiveness studies and progress in precision medicine may influence therapy selection. [ABSTRACT FROM AUTHOR]

Axial spondyloarthritis (axSpA) is comprised of ankylosing spondylitis (AS) and non-radiographic axSpA. In recent years, the involvement of the interleukin (IL)-23/IL-17 axis in the pathophysiology of axSpA has been widely proposed. Since IL-23 is an upstream activating cytokine of IL-17, theoretically targeting IL-23 should be effective in axSpA, especially after the success of the treatment with IL-17 blockers in the disorder. Unfortunately, IL-23 blockade did not show meaningful efficacy in clinical trials of AS. In this review, we analyzed the possible causes of the failure of IL-23 blockers in AS: 1) the available data from an animal model is not able to support that IL-23 is involved in a preclinical rather than clinical phase of axSpA; 2) Th17 cells are not principal inflammatory cells in the pathogenesis of axSpA; 3) IL-17 may be produced independently of IL-23 in several immune cell types other than Th17 cells in axSpA; 4) no solid evidence supports IL-23 as a pathogenic factor to induce enthesitis and bone formation. Taken together, IL-23 is not a principal proinflammatory cytokine in the pathogenesis of axSpA. [ABSTRACT FROM AUTHOR]

Background: Psoriasis is a chronic immune-mediated inflammatory skin disease for which biologics are effective treatments. Dose reduction (DR) of the first generation biologics seems a promising way for more efficient use of expensive biologics. A substantial part of patients on tumor necrosis factor (TNF)-alfa inhibitors and ustekinumab could successfully lower their dose, after following a tightly controlled DR strategy. The objective of this study is to assess whether controlled DR of interleukin (IL)-17 and IL-23 inhibitors in psoriasis patients with low disease activity is non-inferior (NI) to usual care (UC).Methods: This is an international, prospective, multicenter, pragmatic, randomized, non-inferiority trial. A total of 244 patients with stable low disease activity (Psoriasis Area and Severity Index (PASI) ≤ 5) for at least 6 months and using secukinumab, ixekizumab, brodalumab, guselkumab, risankizumab, or tildrakizumab in the standard dose, together with stable low disease activity, defined as a PASI ≤ 5 and Dermatology Life Quality Index (DLQI) ≤ 5 at the moment of inclusion, will be randomized 2:1 to DR or UC. In the DR group, dosing intervals will be prolonged stepwise to achieve 66% and 50% of the original dose. Disease activity is monitored every 3 months by PASI and DLQI. In case of disease flare (i.e., PASI and/or DLQI increase), treatment is adjusted to the previous effective dose. The primary outcome is the incidence proportion of persistent flares (PASI > 5 for ≥ 3 months), which will be compared between arms. Secondary outcomes include proportion of patients with successful DR, (course of) PASI and DLQI, serious adverse events (SAEs), health-related quality of life, costs, and pharmacokinetic profile. Outcomes of DR will be compared to UC.Discussion: With this study, we aim to assess whether DR of IL-17 and IL-23 inhibiting biologics can be achieved for psoriasis patients with low disease activity, without losing disease control. Reducing the dose may lead to more efficient use of biologics.Trial Registration: ClinicalTrials.gov NCT04340076 . Registered on April 9 2020. [ABSTRACT FROM AUTHOR]

Psoriasis is a chronic, immune-mediated skin condition with systemic involvement, frequently requiring long-term treatment. At present, there are 11 biologic agents available for the treatment of moderate-to-severe psoriasis, which target specific inflammatory cytokines involved in the immunopathogenesis of the disease. Among these, three monoclonal antibodies specifically inhibit the p19 subunit of IL-23. IL-23 is a heterodimeric cytokine consisting of two subunits: IL-23p19 and IL-23p40. IL-23 plays a key role in the immunopathogenesis of psoriasis by activating Th17 cells, leading to stimulation of downstream cytokines involved in the systemic inflammation and keratinocyte hyperproliferation observed in psoriasis. Overall, the anti-IL-23 agents demonstrate rapid clinical improvement along with a favourable safety profile. This review has analysed data on the clinical efficacy, safety, and tolerability of the three IL-23 agents (tildrakizumab, guselkumab, and risankizumab) in the treatment of moderate-to-severe plaque psoriasis.

Tildrakizumab is an IL-23-inhibitor that has been approved to treat plaque psoriasis. However, few reports have become available on its efficacy profile in the real-world. Our objective was to study the mid-term efficacy of tildrakizumab in patients with moderate-to-severe psoriasis in the Spanish routine clinical practice setting. This was a retrospective multicenter study that included a total of 91 psoriatic patients on tildrakizumab. The mean Psoriasis Area and Severity Index (PASI) was 9.09 (SD, 5.30). The overall tildrakizumab survival rate was 93.47% for a mean treatment exposure of 30.18 weeks (SD, 16.57). No drug discontinuation was associated with drug tolerability, or adverse reactions. Absolute PASI ≤3 was reached by 91.3% and 96.5% of the patients on weeks 28 and 52, respectively. Response was not impacted by weight, age (>65), metabolic syndrome, presence of arthritis, or previous number of biological therapies used. Based on our own experience tildrakizumab is an effective strategy to treat plaque psoriasis and difficult-to-treat-areas., (Copyright © 2024 AEDV. Publicado por Elsevier España, S.L.U. All rights reserved.)

Clinical trials and prospective registry studies are currently not supportive of an increased risk of malignancy with IL-23 blockade.[[8]] AUTHOR CONTRIBUTIONS Katie Lovell completed the preliminary research and wrote the manuscript. In general, IL-23 inhibitors are safe drugs typically well tolerated by patients. Keywords: adverse events; drug safety; IL-23 inhibitors; spontaneous reporting database EN adverse events drug safety IL-23 inhibitors spontaneous reporting database 1 2 2 10/19/23 20231001 NES 231001 Abbreviations IL-23 interleukin-23 In this issue, Calapai et al. reported a potential association between oncologic adverse reactions and interleukin-23 (IL-23)[1] inhibitor use in psoriasis patients using the EudraVigilance database for spontaneous adverse event reports.[2] The study evaluated suspected adverse events from 2020 to 2022 with a reported 53 events related to oncologic disease development following the use of IL-23 blockers: guselkumab, risankizumab, or tildrakizumab.[2] The reporting odds ratio (ROR) for risankizumab and tildrakizumab was >1 when comparing each drug to the other two, concluding a potential association between IL-23 inhibitors and the occurrence of oncologic adverse events.[2] While adverse event reporting databases can be valuable resources to monitor drug safety, there are major limitations to drawing definite conclusions. [Extracted from the article]

Introduction: Biologic drugs have revolutionized the treatment of moderate to severe psoriasis in recent years because of their high efficacy and low risk of toxicity. However, even within the group of biologic therapies, there are differences related to the different mechanisms of action. Areas covered: We review the main adverse events associated with the biologic agents currently available for the treatment of psoriasis and the new inhibitors targeting the p19 subunit of interleukin (IL) 23 and the IL-17A receptor. This review covers injection site reactions, infections, cardiovascular events, demyelinating disorders, tumours, class effects secondary adverse events, immunogenicity, safety in pregnancy and vaccines efficacy. Expert commentary: More than a decade after the first approval of biologic drugs for use in psoriasis, the good safety profile of these drugs is one of the main justifications and incentives for their long-term use. The emergence of new pharmacological groups has made it possible to avoid some of the class effects of first-generation biologic agents and the new therapies appear to pose less risk of reactivation of latent infections, such as hepatitis B virus and tuberculosis. However, they are associated with new adverse effects related to their mechanism of action, including candidiasis and the risk of exacerbation or onset of inflammatory bowel disease. [ABSTRACT FROM AUTHOR]

The rapid progress of genetic engineering furthermore opens up new prospects in the therapy of this difficult-to-treat disease. IL-23 inhibitors, phosphodiesterase 4 (PDE4) inhibitors, and Janus kinase (JAK) inhibitors are currently encouraging further research. Two drugs which are IL-23 inhibitors are now in phase III of clinical trials. The aim of the action of both drugs is selective IL-23 inhibition by targeting the p19 subunit. Guselkumab is a fully human monoclonal antibody. Tildrakizumab is a humanized monoclonal antibody, which also belongs to IgG class and is targeted to subunit p19 of interleukin 23 (IL-23). Phosphodiesterase inhibitors exert an anti-inflammatory action and their most common group is the PDE4 family. PDE4 inhibits cAMP, which reduces the inflammatory response of the pathway of Th helper lymphocytes, Th17, and type 1 interferon which modulates the production of anti-inflammatory cytokines such as IL-10 interleukins. The Janus kinase (JAK) signaling pathway plays an important role in the immunopathogenesis of psoriasis. Tofacitinib suppresses the expression of IL-23, IL-17A, IL-17F, and IL-22 receptors during the stimulation of lymphocytes. Ruxolitinib is a selective inhibitor of JAK1 and JAK2 kinases and the JAK-STAT signaling pathway. This article is a review of the aforementioned drugs as described in the latest available literature. [ABSTRACT FROM AUTHOR]

Introduction: Psoriasis affecting the genital, palmoplantar, and scalp regions is recognized as difficult-to-treat, and data on the efficacy of biologics in these areas remains limited., Research Design and Methods: This single-center study evaluated the effectiveness of anti-IL-17 and anti-IL-23 agents on scalp, genital, and palmoplantar psoriasis. We retrospectively analyzed data from all patients with psoriasis being treated with IL inhibitors at our clinic. Effectiveness was evaluated at 16, 28, and 52 weeks, according to the achievement of relative and mean PSSI, PGA-G, and ppPASI., Results: In all, 308 patients showed involvement of the scalp, 136 in the genital area, and 94 in the palmoplantar regions. On scalp psoriasis, anti-IL-17 agents demonstrated superiority in disease control compared to anti-IL-23 agents. PSSI100 at week 16 was reached by 59% of patients on an anti-IL17 vs 39.8% on an anti-IL-23 ( p  < 0.003). At genital sites, no significant differences between anti-IL-17 and anti-IL-23 agents were observed, and all classes achieved PGA-G 0/1. No significant differences between anti-IL-17 and anti-IL-23 agents were observed in palmoplantar areas., Conclusions: The present data support the utility of both anti-IL-17 and anti-IL-23 agents for the treatment of difficult-to-treat areas in patients with psoriasis. Anti-IL-17 agents achieved better control of scalp psoriasis.

Introduction: Targeted therapies have greatly improved the quality of life of patients with psoriasis. Despite the extensive list of treatments available, multiple new drugs are being developed, especially oral therapies with potential advantages as regards comfort of administration. However, the efficacy and safety of these new oral therapies need to be improved to match those of novel biologics., Areas Covered: We provide a narrative review of the oral therapies for psoriasis that are currently under development, from Jak inhibitors to oral IL-17 and IL-23 inhibitors, among others. A literature search was performed for articles published from 1 January 2020, to 6 June 2023., Expert Opinion: The approval of deucravacitinib, the first Jak inhibitor for the treatment of moderate-to-severe plaque psoriasis, heralds a bright therapeutic future with multiple new oral formulations. A great number of oral treatments with singular mechanism of action, like A3AR agonists, HSP90 inhibitors, ROCK-2 inhibitors, oral TNF inhibitors, oral IL-23 inhibitors, oral IL-17 inhibitors, PD4 inhibitors (orismilast) and several Tyk2 inhibitors, are currently being evaluated in clinical trials and could be suitable for approval in the future. Growing variation in treatment modes of administration will allow dermatologists to better integrate patient preferences in the therapeutic decision process.

Introduction: Psoriasis is a chronic inflammatory disease that can drastically affect a patient's quality-of-life and is associated with multiple comorbid conditions. The most common form of psoriasis is plaque psoriasis, commonly presenting as sharply demarcated, erythematous plaques with overlying silvery scale on the trunk, extensor surfaces, limbs, and scalp. Although initially limited to oral therapies, the choices in systemic therapies for moderate-to-severe plaque psoriasis have evolved with biologic immunotherapies being the main focus., Areas Covered: In this review, we describe the IL-23/Th17 axis and IL-23 inhibitors as targets for a growing family of biologics. This family includes the FDA-approved medications ustekinumab, guselkumab, tildrakizumab, and risankizumab. We will review the safety and efficacy of these medications throughout various Phase 1,2, and 3, trials for moderate-to-severe psoriasis. A literature search of PubMed was utilized for the following terms: 'psoriasis and IL-23,' 'ustekinumab,' 'guselkumab,' 'tildrakizumab,' and 'risankizumab.' We also searched for clinical trials involving IL-23 inhibitors registered at ClinicalTrials.gov., Expert Opinion: Anti-IL 23 therapy, especially anti-p19 monoclonal antibodies, should be considered first-line therapy for moderate-to-severe plaque psoriasis due to their efficacy and relative safety. More research is required to expand the scope of anti-p19 therapy to pediatric populations and additional indications such as psoriatic arthritis.

Competing Interests: None disclosed.

Novel biologic therapies have revolutionized the treatment of psoriasis and atopic dermatitis. Although they are generally safe, they are immunomodulatory and therefore unique considerations apply in regards to infections and vaccine administration. This review aims to provide a clear and practical guide for dermatologists or other healthcare providers to reference when caring for psoriasis or atopic dermatitis patients being treated with biologic therapies using currently available guidelines and clinical data. Vaccinations for approved biologics including TNFα, IL-12/23, IL-23, IL-17, and IL-4/13 inhibitors will be discussed, with a special note on current COVID-19 vaccination recommendations., (Copyright ©2022, Yale Journal of Biology and Medicine.)

Increasing insights into the immunopathogenesis of inflammatory bowel diseases [IBD] have led to the advent of targeted therapies that inhibit crucial mediators of the inflammatory process, thereby widening our available therapeutic armamentarium. Anti-tumour necrosis factor [anti-TNF] agents are still a mainstay of our therapeutic endeavours and the introduction of corresponding biosimilars has further widened their use. Nevertheless, only a subgroup of treated patients benefit from the initiated treatment and there is secondary non-response in the course of therapy. Initiation of subsequent therapy often poses a challenge to the treating physician, as non-response to primary anti-TNF treatment generally characterizes a patient group that is more treatment-resistant, which may be due to the immunological impregnation by prior anti-TNF exposure. At present, there is currently no guidance for the most appropriate second-line therapy after anti-TNF failure. Here, we review the efficacy of secondary biological therapy in anti-TNF-treated patients. We focus on and assess available clinical trial data of the emerging substance class of IL-23p19 inhibitors, which have demonstrated remarkable efficacy not only in anti-TNF-naïve but also refractory patients. We present molecular mechanisms that drive IL-23-mediated resistance to ongoing anti-TNF therapy and discuss the dynamic fluidity of the mucosal cytokine network in the course of therapy that perpetuates the mucosal inflammatory reaction. Translation of these findings into clinical practice might finally lead to initiation of the most appropriate therapy at the right time of the individual disease course, which would have important implications for the patient's probability of response to treatment., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.)