The Psoriasis Treatment Pipeline: An Overview and Update.

Significant research advances in our understanding of psoriatic disease have led to the development of several highly selective, effective, and safe topical and systemic treatments. These treatments have led to unprecedented levels of disease clearance and control for most patients with psoriasis with cutaneous disease. However, there remains a need for improved treatments for those patients with recalcitrant disease, psoriatic arthritis, or nonplaque disease variants. Recently approved therapies and investigational products in ongoing clinical development programs that target IL-17A/F, IL-23, TYK2, PDE4, AhR or IL-36 cytokine signaling are improving the clinician's ability to care for a broader range of patients affected by psoriasis.

Biologics for Psoriasis.

Biologic therapies targeting tumor necrosis factor alpha (TNF-α) (infliximab, adalimumab, certolizumab, etanercept), the p40 subunit shared by IL-12 and IL-23 (ustekinumab), the p19 subunit of IL-23 (guselkumab, tildrakizumab, risankizumab), IL-17A (secukinumab, ixekizumab), IL-17-RA (brodalumab) and both IL-17A and IL-17F (bimekizumab) have revolutionized the treatment of psoriasis. In both the short and long term, risankizumab had highest Psoriasis Area and Severity Index 90 scores compared to other oral and injectable biologics. IL-23 inhibitors had lowest rates of short-term and long-term adverse events and most favorable long-term risk-benefit profile compared to IL-17, IL-12/23, and TNF-α inhibitors.

Long-Term Efficacy of Tildrakizumab in the Treatment of Psoriasis.

The pathogenesis of psoriasis has been linked to autoimmune and autoinflammatory traits that result in atypical cytokine and keratinocyte activation and proliferation. Many cytokine pathways are involved in the development of inflammation with interleukin-23 (IL-23) playing a significant role in plaque-type psoriasis. Biologic agents that target specific cytokines have shown to be effective therapies in the treatment of plaque-type psoriasis over other conventional treatments such as systemic retinoids. Tildrakizumab is an immunoglobulin G1-kappa monoclonal antibody that inhibits the IL-23/IL-17 pathway and has demonstrated through two three-part randomized Phase 3 clinical trials (reSURFACE 1 and reSURFACE 2) and their extension trials to be an efficacious and safe therapy for the targeted treatment of moderate-to-severe plaque-type psoriasis.

IL-23 past, present, and future: a roadmap to advancing IL-23 science and therapy.

Interleukin (IL)-23, an IL-12 cytokine family member, is a hierarchically dominant regulatory cytokine in a cluster of immune-mediated inflammatory diseases (IMIDs), including psoriasis, psoriatic arthritis, and inflammatory bowel disease. We review IL-23 biology, IL-23 signaling in IMIDs, and the effect of IL-23 inhibition in treating these diseases. We propose studies to advance IL-23 biology and unravel differences in response to anti-IL-23 therapy. Experimental evidence generated from these investigations could establish a novel molecular ontology centered around IL-23-driven diseases, improve upon current approaches to treating IMIDs with IL-23 inhibition, and ultimately facilitate optimal identification of patients and, thereby, outcomes.

Anti-Interleukin-23 Autoantibodies in Adult-Onset Immunodeficiency.

BACKGROUND: Autoantibodies against interleukin-12 (anti-interleukin-12) are often identified in patients with thymoma, but opportunistic infections develop in only some of these patients. Interleukin-12 (with subunits p40 and p35) shares a common subunit with interleukin-23 (subunits p40 and p19). In a patient with disseminated Burkholderia gladioli infection, the identification of both anti-interleukin-23 and anti-interleukin-12 prompted further investigation. METHODS: Among the patients (most of whom had thymoma) who were known to have anti-interleukin-12, we screened for autoantibodies against interleukin-23 (anti-interleukin-23). To validate the potential role of anti-interleukin-23 with respect to opportunistic infection, we tested a second cohort of patients with thymoma as well as patients without either thymoma or known anti-interleukin-12 who had unusual infections. RESULTS: Among 30 patients with anti-interleukin-12 who had severe mycobacterial, bacterial, or fungal infections, 15 (50%) also had autoantibodies that neutralized interleukin-23. The potency of such neutralization was correlated with the severity of these infections. The neutralizing activity of anti-interleukin-12 alone was not associated with infection. In the validation cohort of 91 patients with thymoma, the presence of anti-interleukin-23 was associated with infection status in 74 patients (81%). Overall, neutralizing anti-interleukin-23 was detected in 30 of 116 patients (26%) with thymoma and in 30 of 36 patients (83%) with disseminated, cerebral, or pulmonary infections. Anti-interleukin-23 was present in 6 of 32 patients (19%) with severe intracellular infections and in 2 of 16 patients (12%) with unusual intracranial infections, including Cladophialophora bantiana and Mycobacterium avium complex. CONCLUSIONS: Among patients with a variety of mycobacterial, bacterial, or fungal infections, the presence of neutralizing anti-interleukin-23 was associated with severe, persistent opportunistic infections. (Funded by the National Institute of Allergy and Infectious Diseases and others.).

Modulation of Interleukin-23 Signaling With Guselkumab in Biologic-Naive Patients Versus Tumor Necrosis Factor Inhibitor-Inadequate Responders With Active Psoriatic Arthritis.

OBJECTIVE: We assessed and compared immunologic differences and associations with clinical response to guselkumab, a fully human interleukin (IL)-23p19 subunit inhibitor, in participants with active psoriatic arthritis (PsA) who were biologic-naive or had inadequate response to tumor necrosis factor inhibitors (TNFi-IR). METHODS: Serum biomarker levels at baseline and after treatment with guselkumab 100 mg every 8 weeks were compared between biologic-naive (n = 251) and TNFi-IR (n = 93) subgroups identified in the pooled DISCOVER-1/DISCOVER-2/COSMOS data set. Baseline biomarker levels determined by achievement of week 24 clinical responses (≥75%/90% improvement in Psoriasis Area and Severity Index [PASI 75/90], Investigator's Global Assessment [IGA] of psoriasis score 0/1 and ≥2-point improvement], ≥20% improvement in American College of Rheumatology criteria [ACR20]) were compared between prior treatment subgroups. RESULTS: Baseline IL-22, TNFα, and beta defensin-2 (BD-2) levels were significantly lower in biologic-naive than in TNFi-IR participants. With guselkumab, week 24 IL-17A, IL-17F, IL-22, serum amyloid A, C-reactive protein, IL-6, and BD-2 levels were significantly reduced from baseline in biologic-naive and TNFi-IR participants (≥1.4-fold difference, nominal P < 0.05). Clinical responders to guselkumab exhibited significantly higher baseline levels of several biomarkers than nonresponders (IL-17A, IL-17F, BD-2 in biologic-naive PASI 90 responders; IL-17A, BD-2 in TNFi-IR IGA 0/1 responders; IL-22, BD-2 in TNFi-IR PASI 90 responders [nominal P < 0.05]) and trended higher in TNFi-IR ACR20 responders. CONCLUSION: Guselkumab modulates IL-23 signaling and provides consistent pharmacodynamic effects in both biologic-naive and TNFi-IR PsA patients. Significantly elevated baseline IL-22, TNFα, and BD-2 levels and associations between baseline IL-22, IL-17A, and BD-2 levels and skin responses to guselkumab suggest greater dysregulation of IL-23/Th17 signaling in patients with TNFi-IR.

Short-term risk and long-term incidence rate of infection and malignancy with IL-17 and IL-23 inhibitors in adult patients with psoriasis and psoriatic arthritis: a systematic review and meta-analysis.

The risk of infection and malignancy may be a concern for patients with psoriasis receiving interleukin (IL)-17 and IL-23 inhibitors, particularly with long-term treatments. We aimed to estimate the short-term risks and long-term incidence rates of infection and malignancy with IL-17 or IL-23 antagonists in adult patients with psoriasis and psoriatic arthritis through this comprehensive meta-analysis (PROSPERO registration number: CRD42022363127). We searched PubMed, MEDLINE, Web of Science and ClinicalTrials.gov until May 17, 2023 for randomized placebo-controlled trials and long-term (≥ 52 weeks) open-label extension studies. The estimates of short-term risk ratios (RRs) and long-term exposure-adjusted incidence rates (EAIRs) were pooled using R software 4.1.1 and STATA 16.0. This review included 45 randomized placebo-controlled studies and 27 open-label extension studies. Short-term RRs of serious infection, overall infection and malignancy were 1.45 (95% confidence intervals, 95% CI: 0.81-2.59), 1.20 (95% CI: 1.06-1.35), 0.83 (95% CI: 0.41-1.71) with IL-17 inhibitors; and 0.68 (95% CI: 0.38-1.22), 1.13 (95% CI: 1.00-1.28), 0.87 (95% CI: 0.37-2.04) with IL-23 inhibitors. Increased short-term risks of nasopharyngitis and Candida infection with IL-17 inhibitors were found. Long-term EAIRs of serious infection, overall infection, nonmelanoma skin cancer (NMSC), malignancies excluding NMSC, nasopharyngitis and upper respiratory tract infection were 1.11/100 patient-years (PYs), 57.78/100PYs, 0.47/100PYs, 0.24/100PYs, 15.07/100PYs, 8.52/100PYs, 3.41/100PYs with IL-17 inhibitors; and 1.09/100PYs, 48.50/100PYs, 0.40/100PYs, 0.43/100PYs, 10.75/100PYs, 5.84/100PYs with IL-23 inhibitors. Long-term EAIR of Candida infection was 3.41/100PYs with IL-17 inhibitors. No active or reactivated tuberculosis was ever reported in all the trials, and only a few cases of latent tuberculosis, hepatitis, and herpes zoster were reported during the long-term extension periods. No evidence of increased EAIRs of infection and malignancy with longer durations was found. Our study suggested that short-term risk and long-term incidence of infections and malignancies in psoriasis patients receiving IL-17 inhibitors and IL-23 inhibitors are generally low. However, close monitoring is required for nasopharyngitis and Candida infection with IL-17 inhibitors. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022363127.

Efficacy of anti-IL-23 and anti-IL-17 after adalimumab failure in psoriatic patients.

BACKGROUND: Many national guidelines at the European level recommend first-line therapy based on the anti-TNF-alpha adalimumab for treatment of psoriasis and psoriatic arthritis, mainly for economic reasons. Consequently, patients being treated with newer IL-17 and IL-23 inhibitors underwent previous unsuccessful first-line adalimumab-based therapy. OBJECTIVES: Evaluate the efficacy and safety of IL-17 and IL-23 inhibitors after treatment with adalimumab compared to adalimumab-naive psoriatic patients. METHODS: We retrospectively analysed 1053 psoriatic patients treated with anti-IL17 and anti-IL23 agents, which included 68 and 24 adalimumab-experienced and 399 and 260 bio-naive patients. Efficacy was assessed with mean PASI, PASI90, PASI100, and <3. RESULTS: Concerning the achieving of PASI100, PASI90 and PASI < 3 in patients treated with anti-IL17 agents, no significant differences were observed between adalimumab-experienced and bio-naive patients. In patients treated with an anti-IL-23 agent, a faster response was observed in bio-naive patients, with PASI < 3 significantly higher than ADA-experienced patients at 16 weeks (77% vs. 58% p = 0.048). In a sub-analysis that evaluated the performance of anti-IL17 and anti-IL23 agents in adalimumab-experienced patients with a history of secondary failure, no significant differences were found. In multivariate analysis of PASI100, only anti-IL-17 therapy appeared to have a negative impact at 52 weeks (OR: 0.54 p = 0.04) independently of previous treatment. For PASI90, type of treatment and bio-naïve status did not seem to have an impact at any time point. CONCLUSIONS: Anti-IL 23 and anti-IL 17 agents are not significantly different in terms of efficacy in bio-naive patients or as second-line therapy after failure with a biosimilar or originator adalimumab.

Effectiveness of anti-interleukin-23 therapy in psoriatic arthritis: A pilot prospective real-world study.

AIM: This study aimed to show the effectiveness of interleukin (IL)-23 inhibitors in psoriatic arthritis (PsA) at weeks 12 and 24 in a real-world setting. MATERIALS AND METHODS: Forty-three patients with active PsA were enrolled in this study. These patients were treated with either guselkumab (n = 20) or risankizumab (n = 23). Treatment responses at the 12th and 24th weeks were evaluated with the parameters of the number of joints with active arthritis, Psoriasis Area Severity Index (PASI) response rate, Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score, Disease Activity Index for Psoriatic Arthritis (DAPSA) score, and C-reactive protein (CRP) value. The study's primary endpoint was BASDAI ≤ 4 and DAPSA ≤ 14 at week 24, and the secondary endpoint was the absence of joints with clinically active arthritis signs at week 24. RESULTS: IL-23 inhibition significantly improved all treatment response parameters at the 12th and 24th weeks (P < 0.001). While 90% of patients reached the primary endpoint with anti-IL23 therapy, 74% achieved the secondary endpoint. Both biologic-naïve and biologic-experienced patients responded significantly to anti-IL-23 therapy. Also, no adverse events related to anti-IL-23 agents were observed. CONCLUSIONS: The response parameters indicating the severity of PsA (the number of joints with active arthritis, BASDAI score, DAPSA score, and CRP value) and a parameter indicating the severity of skin involvement, that is, PASI score, significantly improved with anti-IL-23 therapy at weeks 12 and 24. Moreover, significant improvement was achieved at week 24 compared to week 12 in all response parameters.

Eficacia y seguridad de guselkumab y secukinumab en pacientes adultos con psoriasis vulgar severa, no respondedores a terapia tópica y sistémica convencional y no tributario a terapia biológica antagonista al factor de necrosis tumoral por antecedente de neoplasia maligna / Efficacy and safety of guselkumab and secukinumab in adult patients with severe psoriasis vulgaris, non-responsive to conventional topical and systemic therapy and not amenable to biological therapy antagonistic to tumor necrosis factor due to a history of malignancy

ANTECEDENTES: En el marco de la metodología ad hoc para evaluar solicitudes de tecnologías sanitarias, aprobada mediante Resolución de Instituto de Evaluación de Tecnologías en Salud e Investigación N° 111-IETSI-ESSALUD-2021 y ampliada mediante Resolución de Instituto de Evaluación de Tecnologías en Salud e Investigación N° 97-IETSI-ESSALUD2022, se ha elaborado el presente dictamen, el cual expone la evaluación de la eficacia y seguridad de guselkumab y secukinumab en pacientes adultos con psoriasis vulgar severa, no respondedores a terapia tópica y sistémica convencional y no tributario a terapia biológica antagonista al factor de necrosis tumoral disponible en EsSalud por antecedente de neoplasia maligna, en comparación de la mejor terapia de soporte. Así, la médica Evelyn Giuliana Castro Vargas, especialista en dermatología, a través del Comité Farmacoterapéutico del Hospital Nacional Alberto Sabogal Sologuren y siguiendo la Directiva N° 003-IETSI-ESSALUD-2016, envía al Instituto de Evaluación de Tecnologías en Salud e Investigación - IETSI la solicitud de autorización de uso del producto farmacéutico guselkumab no incluido en el Petitorio Farmacológico de EsSalud. ASPECTOS GENERALES La psoriasis es una enfermedad dermatológica inflamatoria crónica no transmisible que afecta aproximadamente del 1 % al 3 % de la población mundial (Augustin et al., 2010) con una prevalencia de alrededor del 2.5 % en el Perú (Rodríguez-Zúñiga, 2016). Esta enfermedad es considerada como un problema de salud pública y de elevada carga para la sociedad (Parisi et al., 2013), lo que se explica por su alto riesgo de morbilidad y porque deteriora la calidad de vida y la salud mental de las personas que lo padecen (Boehnoke & Schón, 2015). El fenotipo de psoriasis más común es la psoriasis vulgar, que se caracteriza por la presencia de placas eritematosas, gruesas y escamosas que se presentan mayormente en cuero cabelludo, glúteos, tronco y extremidades (codos y rodillas). La psoriasis suele clasificarse en leve, moderada y severa, según la clinimetría de las mediciones del Psoriasis Area and Severity Index (PASI), la Body surface area (BSA) y la calidad de vida medida a partir del Dermatology Life Quality Index (DLQI) (Finlay, 2015; Robinson et al., 2012). Es decir, la enfermedad severa se define por tener más de 10 puntos en el PASI, más del 10 % de la superficie corporal (BSA) afectada por la enfermedad, o más de 10 puntos en el DLQI (Strober et al., 2019). Los tratamientos para los pacientes con psoriasis vulgar severa tienen como objetivo lograr una reducción de por lo menos el 75 % o 90 % de la severidad de enfermedad inicial medida por la escala PASI (i.e. PASI75 o PASI90, respectivamente) luego de al menos tres meses de tratamiento efectivo (Belinchón Romero et al., 2021). Asimismo, se considera que, si después de 16 a 24 semanas de la aplicación de un esquema terapéutico efectivo no se ha logrado por lo menos alcanzar el PASI75 con DLQI < 5 o un PASI90, se considera que el paciente no ha respondido al tratamiento (i.e. falla terapéutica) (Aschoff et al., 2021). Así, entre los tratamientos disponibles para la psoriasis tenemos la terapia tópica que se utiliza en los casos de psoriasis leve a moderada', y la terapia sistémica, en casos de psoriasis de moderada a severa2. Dentro de la terapia sistémica, tenemos a los agentes sistémicos convencionales (metotrexato, ciclosporina o acitretina) y la terapia biológica. Ésta última se utiliza generalmente en los casos de falla al tratamiento con agentes sistémicos convencionales (Gisondi et al., 2017). Las terapias biológicas se clasifican según el mecanismo de acción, es decir, según la inhibición dirigida a citoquinas específicas del sistema inmune, tales como el factor de necrosis tumoral alfa (TNF), la interleucina (IL) 17 (IL17) y la IL23 (Fellner, 2016). METODOLOGIA: Se realizó una búsqueda bibliográfica exhaustiva con el objetivo de identificar la mejor evidencia sobre la eficacia y seguridad de guselkumab y secukinumab en pacientes adultos con psoriasis vulgar severa no respondedores a terapia tópica y sistémica convencional y no tributario a terapia biológica anti TNF disponibles en EsSalud por antecedente de neoplasia maligna. La búsqueda se realizó en las bases de datos bibliográficas de PubMed, The Cochrane Library, Web of Science y LILACS (Literatura Latinoamericana y del Caribe en Ciencias 'de la Salud). Asimismo, se realizó una búsqueda dentro de la información generada en las páginas web de grupos o instituciones que realizan revisiones sistemáticas (RS), evaluación de tecnologías sanitarias (ETS) y guías de práctica clínica (GPC), tales como: el National Institute for Health and Care Excellence (NICE), la Agency for Healthcare Research and Quality's (AHRQ), la Scottish Intercollegiate Guidelines Network (SIGN), la New Zealand Guidelines Group (NZGG), la National Health and Medical Research Council (NHMRC), el Instituto de Evaluación de Tecnologías en Salud e Investigación (IETSI), el Centro Nacional de Excelencia Tecnológica en Salud (CENETEC), la Canadian Agency for Drugs and Technologies in Health (CADTH), el Scottish Medicines Consortium (SMC), la Haute Authorité de Santé (HAS), el Institute for Quality and Efficiency in Health Care (IQWiG), la Comissáo Nacional de lncorporagáo de Tecnologías no Sistema Único de Saúde (CONITEC), el Institute for Clinical and Economic Review (ICER) y en la Base Regional de Informes de Evaluación de Tecnologías en Salud de las Américas (BRISA). Además, se realizó una búsqueda de las guías en las principales instituciones o sociedades especializadas en dermatología y en psoriasis, tales como la American Academy of Dermatology (AAD), la British Association of Dermatologists (BAD), la European Academy of Dermatology and Venereology (EADV), y la International Psoriasis Council (IPC). Adicionalmente, se llevó a cabo una búsqueda manual en el motor de búsqueda Google utilizando los términos: "Psoriasis guidelines"; revisando documentos de interés en las diez primeras páginas. Finalmente, se realizó una búsqueda adicional en la página web de registro de ensayos clínicos (EC) www.clinicaltrials.gov, para identificar EC en curso o aún no publicados. RESULTADOS: Luego de la búsqueda bibliográfica hasta diciembre de 2022, se identificaron: una GPC de la BAD publicada en el 2020 (Smith et al., 2020); y una RS con MA en red (Sbidian et al., 2022) publicada en el 2022 que fue seleccionada como evidencia indirecta para responder a la pregunta PICO del presente dictamen. CONCLUSIÓN: Por lo expuesto, el Instituto de Evaluación de Tecnologías en Salud e Investigación aprueba el uso de guselkumab en pacientes adultos con psoriasis vulgar severa, no respondedores a terapia tópica y sistémica convencional y no tributario a terapia biológica anti TNF antecedente de neoplasia maligna, como producto farmacéutico no incluido en el Petitorio Farmacológico de EsSalud, según lo establecido en el Anexo N° 1. La vigencia del presente informe preliminar es de un año a partir de la fecha de publicación. Así, la continuación de dicha aprobación estará sujeta a la evaluación de los resultados obtenidos y de mayor evidencia que pueda surgir en el tempo.

Anti-IL 23 biologics for the treatment of plaque psoriasis.

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.

Biological treatment for erythrodermic psoriasis.

INTRODUCTION: Erythrodermic psoriasis (EP) is an extreme and potentially life-threatening form of psoriasis in which most or all of the body surface area is affected by psoriasis. It occurs in 1-2% of patients with psoriasis and is less responsive to conventional therapies. Biologics have shown promise in the management of EP. AREAS COVERED: This review briefly discusses the pathophysiology of EP. Current evidence on established and emerging targeted therapies for EP is covered, including anti-TNF-α biologics, IL-12/23, IL-17, and IL-23 inhibitors. EXPERT OPINION: The need for rapidly acting, safe, and efficacious agents in EP has been met with advent of newer biologics, particularly IL-17 and IL-23 inhibitors. These targeted approaches warrant consideration as first-line management option for the management of EP; however, high-quality evidence regarding their long-term efficacy and safety in EP is lacking. Novel biologics such as bimekizumab and mirikizumab, and nanobodies such as netakimab and sonelokimab have shown promise in the management of plaque psoriasis, and potential of these molecules in management of EP should be explored. Management of patients with prior biologic failure remains a challenge. Guidelines for the management of EP need to be revisited in light of the recent advances.

Personalised Medicine with IL-23 Blockers: Myth or Reality?

BACKGROUND AND AIMS: The medical management of inflammatory bowel disease [IBD] has become increasingly targeted, through the identification of specific immune mediators involved in its pathogenesis. IL-23 is an inflammatory cytokine involved in both innate and adaptive immunity, which has been identified as a therapeutic target in Crohn's disease [CD] and ulcerative colitis [UC] through its upstream inhibition of the T helper 17 [Th17] pathway. We sought to review available data on the efficacy of IL-23 inhibitors in the treatment of IBD and the potential for clinical and molecular predictors of response to facilitate a personalised medicine approach with these agents. METHODS: We reviewed and summarised available clinical trial data on the use of the IL-23 inhibitors risankizumab, brazikumab, mirikizumab, and guselkumab in the treatment of IBD, as well as the evidence from studies of these agents in IBD and other immune-mediated conditions which might inform prediction of response to IL-23 inhibition. RESULTS: Early clinical trials have demonstrated promising results following both induction and maintenance therapy with IL-23 inhibitors in CD and UC. Pre- and post-treatment levels of IL-22 and post-treatment levels of IL-17 have been identified as potential molecular predictors of response to therapy, in several studies. No significant clinical predictors of response have been identified thus far. CONCLUSIONS: IL-23 antagonism is a promising therapeutic approach in IBD. Further exploration of molecular and clinical predictors of response may identify patients most likely to benefit from these medications.

Time to Relapse After Discontinuing Systemic Treatment for Psoriasis: A Systematic Review.

BACKGROUND: The decision of when to discontinue systemic treatment after achieving remission in psoriasis is an important question. In this systematic review, we sought to evaluate time to relapse after the discontinuation of systemic treatment in psoriasis patients. METHODS: Systematic searches of PubMed, Cochrane Library, and Embase databases were performed for randomized controlled studies reporting time to relapse after discontinuation of systemic drugs in psoriasis patients. In addition, pharmaceutical companies were contacted by the authors regarding missing data from the identified publications. In each publication, the time to psoriasis relapse and the timing of drug discontinuation were carefully assessed. The level of psoriasis control at the time of drug discontinuation and the definition used for psoriasis relapse were taken into account. RESULTS: Thirty articles published before April 2021 were included in the systematic review. Four articles focused on conventional systemic treatments with methotrexate and/or cyclosporine, nine focused on tumor necrosis factor (TNF) antagonists, eight focused on interleukin-17 (IL-17) antagonists, eight focused on IL-12/23 or IL-23 antagonists, and one focused on tofacitinib and apremilast. Different definitions were used to define psoriasis treatment success at the time of drug discontinuation. Similarly, heterogeneous criteria were used to define psoriasis relapse. Comparison between drugs was performed indirectly (i.e. across studies) for most drugs. Considering time of 50% loss of maximum Psoriasis Area Severity Index (PASI) improvement, a shorter median time to psoriasis relapse was observed with traditional systemic treatment (~ 4 weeks) compared to biological agents (from 12 to ~ 34 weeks). When using stringent relapse criteria, such as loss of PASI 90, a longer time to relapse after treatment cessation was observed with IL-23 antagonists (21-42 weeks) versus IL-17 antagonists (7-24 weeks). CONCLUSION: Biological agents are associated with a longer time to relapse than oral systemic agents after drug discontinuation. Among biologicals, IL-23 antagonists are associated with the longest time to relapse. These findings may have clinical consequences for the selection of systemic agents when intermittent treatment is necessary.

Treatment Options and Goals for Patients with Generalized Pustular Psoriasis.

Generalized pustular psoriasis (GPP) is a rare, severe neutrophilic skin disorder characterized by sudden widespread eruption of superficial sterile pustules with or without systemic inflammation. GPP flares can be life-threatening if untreated due to potential severe complications such as cardiovascular failure and serious infections. Currently, there are no GPP-specific therapies approved in the USA or Europe. Retinoids, cyclosporine, and methotrexate are the most commonly used non-biologic therapies for GPP. The evidence that supports the currently available treatment options is mainly based on case reports and small, open-label, single-arm studies. However, recent advances in our understanding of the pathogenic mechanisms of GPP and the identification of gene mutations linked to the disease have paved the way for the development of specific targeted therapies that selectively suppress the autoinflammatory and autoimmune mechanisms induced during GPP flares. Several biologic agents that target key cytokines involved in the activation of inflammatory pathways, such as tumor necrosis factor-α blockers and interleukin (IL)-17, IL-23, and IL-12 inhibitors, have emerged as potential treatments for GPP, with several being approved in Japan. The evidence supporting the efficacy of these agents is mainly derived from small, uncontrolled trials. A notable recent advance is the discovery of IL36RN mutations and the central role of IL-36 receptor ligands in the pathogenesis of GPP, which has defined key therapeutic targets for the disease. Biologic agents that target the IL-36 pathway have demonstrated promising efficacy in patients with GPP, marking the beginning of a new era of targeted therapy for GPP.

Non-immune functions of inflammatory cytokines targeted by anti-psoriatic biologics: a review.

PURPOSE: Psoriasis is an inflammatory disease characterized by skin thickening with silvery white desquamation due to dysregulated inflammatory pathways and elevated levels of inflammatory cytokines. Biologic agents targeting these inflammatory cytokines have brought about significant improvement in clearing psoriatic lesions in patients with moderate-to-severe psoriasis. Moreover, biologics exert both beneficial and detrimental effects on comorbidities in psoriasis, which include increased risk of cardiovascular events, metabolic syndrome, among other conditions. However, non-immune functions of cytokines targeted by biologics, and, hence, the potential risks and benefits of biologics for psoriasis to different organs/systems and comorbidities, have not been well elucidated. RESULTS: This review summarizes current understanding of the pathogenesis of psoriasis-related comorbidities and emerging discoveries of roles of cytokines targeted in psoriasis treatment, including tumor necrosis factor α and interleukins 12, 23, and 17, aiming to complete the safety profile of each biologics and provide therapeutic implications on psoriasis-related comorbidities, and on diseases involving other organs or systems.

Comparison of psoriasis guidelines for use of IL-23 inhibitors in the United States and United Kingdom: a critical appraisal and comprehensive review.

PURPOSE: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Effects of TNF inhibitors and an IL12/23 inhibitor on changes in body weight and adipokine levels in psoriasis patients: a 48-week comparative study.

BACKGROUND: Psoriasis is a chronic inflammatory disease associated with obesity and metabolic syndrome. Adipokines are thought to be a link between psoriasis and obesity. Leptin, adiponectin, and omentin are bioactive adipokines thought to play a role in both metabolic comorbidities and inflammation. Anti-tumour necrosis factor alfa (anti-TNF-α) agents are effective for psoriasis treatment, although significant weight gain has been reported during anti-TNF-α therapy. The interleukin 12/23 (IL 12/23) inhibitor ustekinumab is also effective for psoriasis treatment. We compared the effects of three anti-TNF-α drugs and an IL-12/23 inhibitor on adipokines and weight gain during treatment. PATIENTS AND METHODS: This prospective study included 80 patients (37 women, 43 men) with moderate to severe plaque psoriasis whose age and weight were matched. The patients were divided into four equal groups: etanercept, infliximab, adalimumab, and ustekinumab treatment groups. Psoriasis Area Severity Index (PASI) score, body weight (muscle and fat compartments), and leptin, adiponectin, and omentin levels were evaluated at baseline and weeks 4, 12, 24, and 48 of treatment. RESULTS: There were no differences between drug groups in terms of weight parameters or biochemical parameters at baseline. At the end of 48 weeks, there was significant weight gain in the adalimumab group. Patients who received infliximab showed significant weight gain by week 12, but in the following weeks they returned to their initial weight. Body weight reached a maximum level by week 12 in patients using etanercept, but they lost weight in the following weeks and finished the study below their initial weight. Patients using ustekinumab did not demonstrate significant weight change during the 48 weeks except at week 12. At the end of week 48, PASI75 (improvement in PASI ≥75%) response rates were approximately 85% for the ustekinumab group, 80% for the adalimumab group, 75% for the infliximab group, and 50% for the etanercept group. Leptin, adiponectin, and omentin levels were higher in the ustekinumab group at all weeks except baseline. The lowest levels were observed in the etanercept group. The treatment response rate was also lower in the etanercept group. LIMITATIONS: We did not evaluate visfatin and resistin levels, insulin sensitivity, and cardiovascular risk that may be associated with weight gain and adipokine levels. CONCLUSIONS: Unlike TNF inhibitors, ustekinumab does not cause significant weight changes and it increases adipokine levels more than TNF inhibitors. Adipokine levels seem to be related to the treatment response.

No efficacy of anti-IL-23 therapy for axial spondyloarthritis in randomised controlled trials but in post-hoc analyses of psoriatic arthritis-related 'physician-reported spondylitis'?

The three monoclonal antibodies ustekinumab, guselkumab and risankizumab targeting the p 40 or the 19 subunit of interleukin -23 have now been approved for the indication psoriasis and the former two also for psoriatic arthritis (PsA). Ustekinumab and risankizumab have appeared ineffective in randomised controlled trials with patients with axial spondyloarthritis (axSpA), but post-hoc analyses of PsA trials have now suggested that they may improve back pain symptoms potentially induced by axial inflammation based on PsA. Here we argue that, based on the absence of efficacy in axSpA, this is unlikely and more probably due to generic, non-specific effects, which are not adequately covered by the tools developed for the assessment of inflammation in axSpA.