BACKGROUND: Systemic therapy is an important treatment for psoriasis. Phosphodiesterase 4 (PDE4) inhibitors are new candidates for psoriasis therapy.
OBJECTIVES: To evaluate the efficacy and safety of PDE4 inhibitors in psoriasis.
METHOD: Randomized clinical trials with PDE4 inhibitors vs placebos in patients with psoriasis were identified from MEDLINE, Embase, Cochrane Controlled Register of Trials, ClinicalTrials.gov, from inception to July 14, 2022. The study was registered in PROSPERO (CRD42022345700).
RESULTS: 18 studies were identified, 9 of which included moderate-to-severe plaque psoriasis, 2 mild-to-moderate plaque psoriasis, and 7 psoriatic arthritis. A total of 6036 patients were included. Only one oral PDE4 inhibitor, apremilast, met the inclusion criteria. Overall, compared with the placebo, apremilast was associated with higher response rates in PASI-75 (RR, 3.22; 95% CI, 2.59-4.01), ScPGA of 0 or 1 (RR, 2.21; 95% CI, 1.69-2.91), PPPGA of 0 or 1 (RR 2.33; 95%CI, 1.16-4.66), and a significant decrease in NPASI (SMD, -0.46; 95% CI, -0.58 to -0.33). There were no significant differences in serious adverse events. Subgroup analyses showed that significantly more patients achieved PASI-75 after 16 weeks of therapy with apremilast of 20 mg bid (RR, 2.82; 95% CI, 2.01-3.95) and 30 mg bid (RR, 4.08; 95% CI, 3.12-5.33). Heterogeneity was not significant across studies.
CONCLUSION: Apremilast is a safe and effective treatment for plaque psoriasis and psoriatic arthritis, especially for difficult-to-treat sites.
SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/prospero, identifier (CRD42022345700).
OBJECTIVE: To perform an update of a review of the efficacy and safety of disease-modifying antirheumatic drugs (DMARDs) in psoriatic arthritis (PsA).
METHODS: This is a systematic literature research of 2015-2018 publications on all DMARDs in patients with PsA, searching Medline, Embase and the Cochrane Library. Efficacy was assessed in randomised controlled trials. For safety, cohort studies, case-control studies and long-term extensions (LTEs) were analysed.
RESULTS: 56 publications (efficacy: n=33; safety n=23) were analysed. The articles were on tumour necrosis factor (TNF) inhibitors (n=6; golimumab, etanercept and biosimilars), interleukin (IL)-17A inhibitors (n=10; ixekizumab, secukinumab), IL-23-p19 inhibitors (n=2; guselkumab, risankizumab), clazakizumab (IL-6 inhibitor), abatacept (CD80/86 inhibitor) and ABT-122 (anti-TNF/IL-17A), respectively. One study compared ustekinumab (IL-12/23i) with TNF inhibitor therapy in patients with entheseal disease. Three articles investigated DMARD tapering. Trials on targeted synthetic DMARDs investigated apremilast (phosphodiesterase-4 inhibitor) and Janus kinase inhibitors (JAKi; tofacitinib, filgotinib). Biosimilar comparison with bio-originator showed non-inferiority. Safety was evaluated in 13 LTEs, 9 cohort studies and 1 case-control study investigating malignancies, infections, infusion reactions, multiple sclerosis and major cardiovascular events, as well as efficacy and safety of vaccination. No new safety signals were identified; however, warnings on the risk of venous thromboembolic events including pulmonary embolism when using JAKi were issued by regulators based on other studies.
CONCLUSION: Many drugs in PsA are available and have demonstrated efficacy against placebo. Efficacy varies across PsA manifestations. Safety must also be taken into account. This review informed the development of the European League Against Rheumatism 2019 updated PsA management recommendations.
Background: Tofacitinib and other new treatments approved for use in psoriatic arthritis have only recently been included in psoriatic arthritis treatment guidelines, and studies evaluating the relative efficacy of available therapies are important to inform treatment decisions by healthcare professionals. Objective: To perform a network meta-analysis to evaluate the efficacy and safety profiles of tofacitinib, biologic disease-modifying antirheumatic drugs (bDMARDs), and apremilast in patients with psoriatic arthritis naïve to tumor necrosis factor inhibitor therapy (TNFi-naïve) or with an inadequate response (TNFi-IR). Methods: A systematic literature review used searches of MEDLINE, Embase, and The Cochrane Library on October 9, 2017. Randomized controlled trials including adult patients with psoriatic arthritis receiving treatment administered as monotherapy or with conventional synthetic DMARDs were selected. Efficacy outcomes included American College of Rheumatology 20 response, change from baseline in Health Assessment Questionnaire-Disability Index, ≥75% improvement in Psoriasis Area and Severity Index, and change from baseline in Dactylitis Severity Score and Leeds Enthesitis Index. Treatment effects were evaluated during placebo-controlled phases, using a binomial logit model for binary outcomes and a normal identify link model for other outcomes. Discontinuations due to adverse events and serious infection events were assessed as safety outcomes. Results: The network meta-analysis included 24 published randomized controlled trials, of which 13 enrolled TNFi-naïve patients only, 3 enrolled TNFi-IR patients only, and 8 enrolled both TNFi-naïve and TNFi-IR patients. Placebo-controlled treatment durations ranged from 12 to 24 weeks. Indirect comparisons showed tofacitinib 5 and 10 mg BID to have similar efficacy compared with most bDMARDs and apremilast in improving joint symptoms (based on American College of Rheumatology 20 response), and with some bDMARDs in improving skin symptoms (based on Psoriasis Area and Severity Index) (tofacitinib 10 mg BID only in TNFi-IR) in patients with psoriatic arthritis who were TNFi-naïve or TNFi-IR. Results also showed that, compared with placebo, the improvement in physical functioning (based on Health Assessment Questionnaire-Disability Index) with tofacitinib 5 and 10 mg BID was similar to that observed with most bDMARDs and apremilast in TNFi-naïve patients, and similar to that observed with all bDMARDs with available data in the TNFi-IR population. Improvements in Dactylitis Severity Score and Leeds Enthesitis Index scores were comparable between treatments. Tofacitinib 5 and 10 mg BID were median-ranked 8 and 15, respectively, for discontinuation due to any adverse events, and 5 and 16, respectively, for a serious infection event out of a total of 20 treatments in the network (lower numbers are more favorable). Conclusions: Tofacitinib provides an additional treatment option for patients with psoriatic arthritis, both in patients naïve to TNFi and in those with TNFi-IR. (Curr Ther Res Clin Exp. 2020; 81:XXX–XXX)
BACKGROUND: The comparative efficacy and safety of small molecule and biological agents in the treatment of psoriatic arthritis (PsA) remain unknown.
OBJECTIVES: To compare the efficacy and safety of 14 small molecule and biological agents by network meta-analysis (NMA).
METHODS: Relevant randomized controlled trials involving biological treatments for PsA were identified by searching PubMed, Cochrane Library, EMBASE, Web of Science, and Clinicaltrials.gov and by manual retrieval, up to June 2018. NMA was conducted with Stata 14.0 based on the frequentist method. Effect measures were odds ratios (ORs) with 95% confidence intervals (CIs). Intervention efficacy and safety were ranked according to the surface under the cumulative ranking curve (SUCRA).
RESULTS: A total of 30 studies involving 10,191 adult subjects were included. According to NMA, ≥ 20% improvement in modifed American College of Rheumatology response criteria (ACR20) response, Psoriasis Area and Severity Index 75 (PASI75) response, and serious adverse events rate (SAEs) were observed. In direct comparisons, most of the biologics performed better than placebo in terms of ACR20 response rate and PASI75 response rate. Additionally, all medicines were comparable to placebo in terms of SAEs except secukinumab. In terms of mixed comparisons, with regard to the ACR20 response, etanercept (ETN) and infliximab (IFX) were more effective than golimumab (GOL), with ORs of 3.33 (95% CI: 1.17-9.48) and 1.24 (95% CI: 0.61-2.52), respectively. For PASI75 response, IFX was superior to certolizumab pegol (OR = 10.08, 95% CI: 1.54-75.48). In addition, these medicines were comparable to each other in terms of SAEs. ETN and IFX were shown to have the most favorable SUCRA for achieving improved ACR20 and PASI75 responses, respectively, while ABT-122 exhibited the best safety according to the SUCRA for SAEs. Considering both the efficacy (ACR20, PASI75) and safety (SAEs), GOL, ETN, and IFX are the top 3 treatments.
CONCLUSIONS AND IMPLICATIONS: Direct and indirect comparisons and integrated results suggested that the 3 anti- tumor necrosis factor -α biologics (GOL, ETN, and IFX) can be considered the best treatments for PsA after comprehensive consideration of efficacy and safety.
Psoriatic arthritis (PsA) is associated with progressive joint destruction and reduced quality of life. The time until a drug treatment starts to show an effect (TOA) is important for preventing joint destruction. The objective was to assess the time until onset of action of drugs when treating PsA. A systematic review of PsA drug trials was performed. Outcomes were: time until 25% of patients (TOA) reached (1) ≥ 20%, (2) ≥ 50% improvement in modified American College of Rheumatology response criteria (ACR), (3) ≥ 75% reduction in Psoriasis Area and Severity Index (PASI75). 95% confidence intervals were calculated extracting data from graphs using a novel method. Meta-analysis was conducted. Two head-to-head trials show no difference between ixekizumab and adalimumab or adalimumab and tofacitinib for TOA-ACR outcomes. For PASI75, ixekizumab had a faster onset than adalimumab. Infliximab plus MTX was faster than MTX alone. Pooled results from 32 study arms for TOA-ACR20 (week [95% CI]) are: < 2 weeks: infliximab (1.18 [0.72-1.65]), ixekizumab (1.04 [0.80-1.28]), tofacitinib (10 mg 1.56 [1.14-1.98]); ≤ 4 weeks: adalimumab (1.95 [1.35-2.55]), secukinumab (75 mg 1.89 [0.16-3.62], 150 mg 2.13 [1.34-2.91], 300 mg 2.26 [1.75-2.76]), tofacitinib (5 mg 2.20 [1.41-2.99]); 4 + weeks: apremilast, ustekinumab. For TOA-ACR50, all pooled point estimates are > 4 weeks. For TOA-PASI75, the range is between 2.24 [1.65-2.84] for ixekizumab and 6.03 [3.76-8.29] for adalimumab. Indirect, mixed comparison suggest a faster onset of infliximab, ixekizumab and tofacitinib compared to apremilast, methotrexate and ustekinumab for ACR20, not ACR50. For PASI75, ixekizumab is faster than adalimumab.
BACKGROUND: Tofacitinib and apremilast have shown considerable efficacy in placebo-controlled trials of active psoriatic arthritis, but the relative efficacy and safety remain unclear because of a lack of head-to-head comparisons.
OBJECTIVE: The aim of this study was to assess the relative efficacy and safety of tofacitinib and apremilast at different doses in patients with active psoriatic arthritis.
METHOD: We performed a Bayesian network meta-analysis to combine evidence from randomized controlled trials for examination of the efficacy and safety of tofacitinib 10 mg, tofacitinib 5 mg, apremilast 30 mg, and apremilast 20 mg in psoriatic arthritis.
RESULTS: Eight randomized controlled trials including 3086 patients met the inclusion criteria. There were ten pairwise comparisons including six direct comparisons of five interventions. All the interventions achieved a significant American College of Rheumatology 20 response compared with placebo. Tofacitinib 10 mg and apremilast 30 mg were among the most effective treatments for active psoriatic arthritis, followed by tofacitinib 5 mg, and apremilast 20 mg. The ranking probability based on the surface under the cumulative ranking curve (SUCRA) indicated that tofacitinib 10 mg had the highest probability of being the best treatment in terms of the American College of Rheumatology 20 response rate (SUCRA = 0.785). This was followed by apremilast 30 mg (SUCRA = 0.670), tofacitinib 5 mg (SUCRA = 0.596), apremilast 20 mg (SUCRA = 0.448), and placebo (SUCRA = 0.001). We observed no significant differences in the incidence of serious adverse events after treatment with tofacitinib 10 mg, apremilast 30 mg, tofacitinib 5 mg, apremilast 20 mg, or placebo.
CONCLUSIONS: In patients with active psoriatic arthritis, tofacitinib 10 mg and apremilast 30 mg were the most efficacious interventions and were not associated with a significant risk of serious adverse events.
Systemic therapy is an important treatment for psoriasis. Phosphodiesterase 4 (PDE4) inhibitors are new candidates for psoriasis therapy.
OBJECTIVES:
To evaluate the efficacy and safety of PDE4 inhibitors in psoriasis.
METHOD:
Randomized clinical trials with PDE4 inhibitors vs placebos in patients with psoriasis were identified from MEDLINE, Embase, Cochrane Controlled Register of Trials, ClinicalTrials.gov, from inception to July 14, 2022. The study was registered in PROSPERO (CRD42022345700).
RESULTS:
18 studies were identified, 9 of which included moderate-to-severe plaque psoriasis, 2 mild-to-moderate plaque psoriasis, and 7 psoriatic arthritis. A total of 6036 patients were included. Only one oral PDE4 inhibitor, apremilast, met the inclusion criteria. Overall, compared with the placebo, apremilast was associated with higher response rates in PASI-75 (RR, 3.22; 95% CI, 2.59-4.01), ScPGA of 0 or 1 (RR, 2.21; 95% CI, 1.69-2.91), PPPGA of 0 or 1 (RR 2.33; 95%CI, 1.16-4.66), and a significant decrease in NPASI (SMD, -0.46; 95% CI, -0.58 to -0.33). There were no significant differences in serious adverse events. Subgroup analyses showed that significantly more patients achieved PASI-75 after 16 weeks of therapy with apremilast of 20 mg bid (RR, 2.82; 95% CI, 2.01-3.95) and 30 mg bid (RR, 4.08; 95% CI, 3.12-5.33). Heterogeneity was not significant across studies.
CONCLUSION:
Apremilast is a safe and effective treatment for plaque psoriasis and psoriatic arthritis, especially for difficult-to-treat sites.
