INTRODUCTION: Nail changes are frequent clinical findings in patients with cutaneous psoriasis and psoriatic arthritis, often causing significant impairments in quality of life. Numerous targeted therapies have been previously studied for treatment of nail psoriasis, however, newer agents have not been captured in prior systematic reviews. With over 25 new studies published since 2020, the landscape of nail psoriasis systemic treatments is rapidly evolving, warranting analysis of recently approved therapies.
METHODS: An updated systematic review of all PubMed and OVID database studies assessing efficacy and safety of targeted therapies for nail psoriasis was performed, with the goal of incorporating clinical data of recent trials and newer agents, namely brodalumab, risankizumab, and tildrakizumab. Eligibility criteria included clinical human studies reporting at least one of the nail psoriasis clinical appearance outcomes (Nail Psoriasis Severity Index, modified Nail Psoriasis Severity Index).
RESULTS: A total of 68 studies on 15 nail psoriasis targeted therapeutic agents were included. Biological agents and small molecule inhibitors included TNF-alpha inhibitors (adalimumab, infliximab, etanercept, certolizumab, golimumab), IL-17 inhibitors (ixekizumab, brodalumab, secukinumab), IL-12/23 inhibitors (ustekinumab), IL-23 inhibitors (guselkumab, risankizumab, tildrakizumab), PDE-4 inhibitors (apremilast), and JAK inhibitors (tofacitinib). These agents all demonstrated statistically significant improvements in nail outcome scores, compared with placebo or with baseline values, at weeks 10-16 and weeks 20-26, with some studies assessing efficacy up to week 60. Safety data for these agents were acceptable and consistent with known safety profiles within these timepoints, with nasopharyngitis, upper respiratory tract infections, injection site reactions, headache, and diarrhea being the most reported adverse events. Specifically, the newer agents, brodalumab, risankizumab, and tildrakizumab, showed promising outcomes for treatment of nail psoriasis on the basis of current data.
CONCLUSION: Numerous targeted therapies have shown significant efficacy in improving nail findings in patients with psoriasis and psoriatic arthritis. Data from head-to-head trials have shown greater efficacy of ixekizumab over adalimumab and ustekinumab, as well as brodalumab over ustekinumab, while prior meta-analyses have demonstrated superiority of ixekizumab and tofacitinib to other included agents at various assessed timepoints. Further studies on the long-term efficacy and safety of these agents, as well as randomized controlled trials involving comparison with placebo arms, are needed to fully analyze differences in efficacy of newer agents compared with previously established therapies.
OBJECTIVE: To assess the association between the use of biological disease-modifying antirheumatic drugs (bDMARDs) and the risk of cardiovascular events in patients with systemic inflammatory conditions.
METHODS: Eligible cohort studies or randomized controlled trials (RCTs) from inception to January 2021 were included. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) for cardiovascular outcomes were calculated in the fixed- and random-effects model accordingly. Associated factors with risks of cardiovascular events were also studied in sensitivity analyses and metaregression analyses.
RESULTS: Compared with non-bDMARD users, the risks of myocardial infarction (MI) (OR = 0.74, 95% CI, 0.63 to 0.87), heart failure (OR = 0.84, 95% CI, 0.74 to 0.95), cardiovascular (CV) death (OR = 0.62, 95% CI, 0.40 to 0.95), all-cause mortality (OR = 0.64, 95% CI, 0.58 to 0.70), and 3P-MACE (composite endpoint of MI, stroke, and CV death) (OR = 0.69, 95% CI, 0.53 to 0.89) were significantly reduced in bDMARD users, which were mainly driven by the risk reduction in patients with rheumatoid arthritis (RA). TNF-α inhibitors exhibited consistent benefits in reducing the risks of MI, heart failure, CV death, all-cause mortality, and 3P-MACE. Moreover, the risks of heart failure, CV death, all-cause mortality, and 3P-MACE were significantly reduced in bDMARD users with follow-up over one year.
CONCLUSIONS: The use of bDMARDs might be associated with the reduced risks of CV events, especially in patients with RA. The CV events might be less frequent in bDMARD users with TNF-α inhibitors or follow-up over one year. More investigations are needed to validate conclusions.
GOALS AND BACKGROUND: Ustekinumab (UST) is a monoclonal antibody inhibitor of IL-12/IL-23 approved for the treatment of Crohn's disease (CD) and ulcerative colitis (UC). We conducted a meta-analysis to compare rates of adverse events (AEs) in randomized controlled trials (RCTs) of UST for all indications.
STUDY: A systematic search was performed of MEDLINE, Embase, and PubMed databases through November 2019. Study inclusion included RCTs comparing UST to placebo or other biologics in patients aged 18 years or older with a diagnosis of an autoimmune condition.
RESULTS: Thirty RCTs with 16,068 patients were included in our analysis. Nine thousand six hundred and twenty-six subjects were included in the UST vs placebo analysis. There was no significant difference in serious or mild/moderate AEs between UST and placebo with an OR of 0.83 (95% CI 0.66, 1.05) and 1.08 (95% CI 0.99, 1.18), respectively, over a median follow-up time of 16 weeks. In a sub-analysis of CD and UC trials, no difference in serious or mild/moderate AEs in UST versus placebo was seen.
CONCLUSIONS: UST was not associated with an increase in short-term risk of AEs.
There is a rapidly increasing number of novel biologic therapies for psoriasis targeting interleukin-23 (IL-23) and interleukin-17 (IL-17). This systematic review and meta-analysis evaluated the efficacy and safety of induction therapy (12-16 weeks) with biologic therapies targeting the IL-23/IL-17 immune axis for the treatment of moderate-to-severe plaque psoriasis. Twenty-seven randomized controlled trials met the specified inclusion criteria. The results showed that ixekizumab q2w had the greatest efficacy in terms of achieving PASI90 when compared to placebo (RR 65.01, 95% CI 13.97-302.56, p < 0.00001), etanercept (RR 3.14, 95% CI 2.22-4.45), and ustekinumab (RR 1.73, 95% CI 1.41-2.12). The IL-17 inhibitors were overall shown to have a higher efficacy than the IL-23 inhibitors during induction therapy. However, the IL-17 inhibitors had an increased risk of adverse events when compared to placebo, while there was no increased risk with any of the IL-23 inhibitors. In conclusion, induction therapy with IL-17 inhibitors is highly efficacious but carries a higher risk of adverse events than induction therapy with IL-23 inhibitors. This article is protected by copyright. All rights reserved.
Introduction: Several new treatments have been developed for psoriatic disease, an inflammatory condition that involves skin and joints. Notwithstanding, few studies have made direct comparisons between treatments and therefore it is difficult to select the ideal treatment for an individual patient. The aim of this systematic review with network meta-analysis (NMA) was to analyze available and approved biologic therapies for each domain of psoriatic disease: skin, peripheral arthritis, axial arthritis, enthesitis, dactylitis, and nail involvement. Methods: Data from randomized clinical trials (RCTs) were included. A systematic review was performed using the MEDLINE database (July 2020) using PICO criteria. Bayesian NMA was conducted to compare the clinical efficacy of biological therapy in terms of the American College of Rheumatology criteria (ACR, 24 weeks) and Psoriasis Area and Severity Index (PASI, 10–16 weeks). Results: Fifty-four RCTs were included in the systematic review. Due to the design of the RCTs, namely, outcomes and time points, network meta-analysis was performed for skin and peripheral arthritis domains. For the skin domain, 30 studies reporting PASI100 were included. The peripheral arthritis domain was analyzed through ACR70 in 12 studies. From the therapies approved for both domains, secukinumab and ixekizumab were the ones with the highest probability of reaching the proposed outcomes. There is a lack of outcome uniformization in the dactylitis, enthesitis, and nail domains, and therefore, an objective comparison of the studies was not feasible. Nevertheless, secukinumab was the treatment with the best compromise between the number of studies in each domain and the results obtained in the different outcomes. Conclusion: Secukinumab and ixekizumab were the treatments with the highest probability of reaching both PASI100 and ACR70 outcomes. Due to the lack of a standard evaluation of outcomes of the other psoriatic disease domains, a network meta-analysis for all the domains was not possible to perform.
BACKGROUND: The comparative effectiveness of available targeted immunomodulators for moderate-to-severe psoriasis has not been evaluated.
OBJECTIVE: To evaluate the comparative effectiveness of targeted immunomodulators for adults with moderate-to-severe plaque psoriasis.
METHODS: Systematic literature review of placebo-controlled and head-to-head randomized trials of eight targeted immunomodulators that evaluated clinical benefits or harms. The primary outcome was a 75% improvement on the Psoriasis Area and Severity Index ("PASI 75"). We also conducted a network meta-analysis (NMA) adjusted for placebo response to perform indirect comparisons between agents.
RESULTS: In the NMA, the targeted immunomodulators ordered by an increasing relative risk (demonstrating greater likelihood) of achieving PASI 75 relative to placebo were: apremilast (6.2), etanercept (9.6), adalimumab (13.0), ustekinumab (14.0), secukinumab (15.4), infliximab (16.2), brodalumab (17.3), and ixekizumab (17.9). Ixekizumab, brodalumab, and infliximab were all statistically superior to ustekinumab, adalimumab, etanercept, and apremilast; results were similar to head-to-head studies where data were available.
LIMITATIONS: Much of the evidence is short-term (10-16 weeks); limited direct comparisons.
CONCLUSIONS: The Interleukin-17A inhibitors are more effective in achieving clearance than ustekinumab, which are, in turn, generally more effective than etanercept, adalimumab, and apremilast.
PURPOSE: To evaluate the relative efficacy of brodalumab compared with approved biologic therapies and apremilast for moderate-to-severe psoriasis.
METHODS: We searched MEDLINE, Embase and Cochrane for randomized controlled trials reporting induction phase responses. The primary analysis examined the proportion of patients achieving Psoriasis Area Severity Index (PASI) 50, 75, 90 or 100 responses using a random-effects Bayesian multinomial likelihood model with probit link, with and without adjustment for variation in study-level placebo responses.
RESULTS: A total of 54 studies were included. Based on PASI 100 response, the most efficacious therapies were brodalumab 210mg every two weeks (Q2W) and ixekizumab. Brodalumab 210mg Q2W was significantly more efficacious than adalimumab, apremilast, brodalumab 140mg Q2W, etanercept, infliximab, secukinumab and ustekinumab. Results were consistent for PASI 50, 75 and 90 outcomes and all sensitivity analyses.
CONCLUSIONS: Our findings are consistent with pivotal trials which indicate that high levels of complete clearance can be achieved with brodalumab. Based on existing evidence, induction-phase efficacy of brodalumab is similar to ixekizumab and superior to other approved therapies, including anti-TNFs, apremilast, secukinumab and ustekinumab.
BACKGROUND: The clinical benefits of biologic therapies for moderate-to-severe psoriasis are well established, but wide variations exist in patient response.
OBJECTIVES: To determine the number needed to treat (NNT) to achieve a 75% and 90% reduction in the Psoriasis Area and Severity Index (PASI-75/90) with FDA-approved agents and evaluate the incremental cost per PASI-75 or PASI-90 responder.
METHODS: The relative probabilities of achieving PASI-75 and PASI-90, as well as NNTs were estimated using a network meta-analysis. Costs (2017 USD) included drug acquisition and administration. The incremental cost per PASI-75 or PASI-90 responder for each treatment was estimated for the clinical trial period, and annually.
RESULTS: Compared with supportive care, the NNT to achieve PASI-75 was 1.18 for ixekizumab, 1.29 for secukinumab 300 mg, 1.37 for infliximab, 1.48 for adalimumab, 1.53 for secukinumab 150 mg, 1.58 for ustekinumab, 2.25 for etanercept, and 3.71 for apremilast. The one-year incremental cost per PASI-75 responder relative to supportive care was $59,830 for infliximab, $88,775 for secukinumab 300 mg, $91,837 for adalimumab, $95,898 for ixekizumab, $97,363 for ustekinumab, $105,131 for secukinumab 150 mg, $129,665 for apremilast, and $159,328 for etanercept. Results were similar for PASI-90.
CONCLUSION: The NNT and incremental cost per responder are meaningful ways to assess comparative effectiveness and cost effectiveness among psoriasis treatments.
Antecedentes: Se han planteado preocupaciones en relación con un mayor riesgo de eventos cardiovasculares adversos mayores (MACE) (infarto de miocardio, accidente cerebrovascular o muerte cardiovascular) en pacientes tratados con agentes anti-interleucina (IL) -12 / 23 para moderados a severos psoriasis. OBJETIVO: Examinar el riesgo de MACE en pacientes adultos con psoriasis en placas expuestos a terapias biológicas mediante un metanálisis de ensayos controlados aleatorios (ECA). MÉTODOS: i) Fuentes de datos: Se realizaron búsquedas sistemáticas en la Biblioteca Cochrane, MEDLINE y EMBASE, Administración de Alimentos y Medicamentos de los Estados Unidos, Agencia Europea de Medicamentos, plataformas de búsqueda en línea de compañías farmacéuticas individuales y 5 registros de ensayos (hasta el 31 de marzo de 2016). Ii) Selección de estudios: ECA que informan sobre eventos adversos en adultos con psoriasis en placas que reciben al menos una dosis autorizada de terapia biológica, terapia sistemática convencional o placebo. Iii) Síntesis de datos: odds ratios de ORP con intervalos de confianza del 95% Y se utilizaron estadísticas I (2) para evaluar la heterogeneidad utilizando RevMan5.3. RESULTADOS: En total, se incluyeron 38 ECA con 18.024 pacientes. No MACEs se observaron en 29 estudios, mientras que 9 ECA informó de 10 pacientes que experimentan MACEs. No hubo diferencias estadísticamente significativas en el riesgo de MACE asociados con el uso de terapias biológicas en general (OR 1,45; IC del 95%: 0,34-6,24); Inhibidores del factor de necrosis tumoral α (adalimumab, etanercept e infliximab) (OR 0,67; IC del 95%: 0,10-4,63); Agentes anti - IL - 17A (secukinumab y ixekizumab) (OR1.00, 95CI% 0,09 - 11,09) o ustekinumab (OR4,48, 95% CI 0,24 - 84,77). No se observó heterogeneidad en estas comparaciones. CONCLUSIONES: La limitada evidencia existente sugiere que las terapias biológicas con licencia no están asociadas con MACE durante los cortos períodos controlados aleatorios en ensayos clínicos. Este artículo está protegido por derechos de autor. Todos los derechos reservados.
A new generation of biologics targeting IL-23/Th17 pathway has been developed. This study aimed to assess the short-term effectiveness and safety of these new agents using a network meta-analysis. Twenty seven randomized clinical trials (n=10,629) were identified by a comprehensive systematic literature review (PROSPERO 2015:CRD42015025472). Quality of evidence was assessed following Cochrane compliant rules and GRADE approach. Efficacy and safety outcomes at weeks 10-16 were compared using a random-effects network meta-analysis within a frequentist framework to estimate pooled odds ratios (OR) of direct and indirect comparisons among the therapeutic options. There were 6 direct drug-to-drug comparisons in the network, with a high degree of consistency between the direct and the indirect evidence. From the available evidence, infliximab 5mg.kg-1 every eight weeks (OR: 118.89; 95%CI: 60.91-232.04) and secukinumab 300mg every four weeks (OR: 87.07;95%CI: 55.01-137.82) are shown as among the most effective short-term treatment, but are ranked as the biologic most likely to produce any adverse event (AE) or an infectious AE, respectively. Ustekinumab 90mg every twelve weeks, the third most efficacious (OR: 73.67; 95%CI: 46.97-115.56), was the only agent that did not show increased risk of adverse events when compared with placebo. Treatment recommendations should also consider long term outcomes and costs. This article is protected by copyright. All rights reserved.
Nail changes are frequent clinical findings in patients with cutaneous psoriasis and psoriatic arthritis, often causing significant impairments in quality of life. Numerous targeted therapies have been previously studied for treatment of nail psoriasis, however, newer agents have not been captured in prior systematic reviews. With over 25 new studies published since 2020, the landscape of nail psoriasis systemic treatments is rapidly evolving, warranting analysis of recently approved therapies.
METHODS:
An updated systematic review of all PubMed and OVID database studies assessing efficacy and safety of targeted therapies for nail psoriasis was performed, with the goal of incorporating clinical data of recent trials and newer agents, namely brodalumab, risankizumab, and tildrakizumab. Eligibility criteria included clinical human studies reporting at least one of the nail psoriasis clinical appearance outcomes (Nail Psoriasis Severity Index, modified Nail Psoriasis Severity Index).
RESULTS:
A total of 68 studies on 15 nail psoriasis targeted therapeutic agents were included. Biological agents and small molecule inhibitors included TNF-alpha inhibitors (adalimumab, infliximab, etanercept, certolizumab, golimumab), IL-17 inhibitors (ixekizumab, brodalumab, secukinumab), IL-12/23 inhibitors (ustekinumab), IL-23 inhibitors (guselkumab, risankizumab, tildrakizumab), PDE-4 inhibitors (apremilast), and JAK inhibitors (tofacitinib). These agents all demonstrated statistically significant improvements in nail outcome scores, compared with placebo or with baseline values, at weeks 10-16 and weeks 20-26, with some studies assessing efficacy up to week 60. Safety data for these agents were acceptable and consistent with known safety profiles within these timepoints, with nasopharyngitis, upper respiratory tract infections, injection site reactions, headache, and diarrhea being the most reported adverse events. Specifically, the newer agents, brodalumab, risankizumab, and tildrakizumab, showed promising outcomes for treatment of nail psoriasis on the basis of current data.
CONCLUSION:
Numerous targeted therapies have shown significant efficacy in improving nail findings in patients with psoriasis and psoriatic arthritis. Data from head-to-head trials have shown greater efficacy of ixekizumab over adalimumab and ustekinumab, as well as brodalumab over ustekinumab, while prior meta-analyses have demonstrated superiority of ixekizumab and tofacitinib to other included agents at various assessed timepoints. Further studies on the long-term efficacy and safety of these agents, as well as randomized controlled trials involving comparison with placebo arms, are needed to fully analyze differences in efficacy of newer agents compared with previously established therapies.
