BACKGROUND AND AIMS: Recent studies raise concern for increased risk of major adverse cardiovascular events (MACE) with Janus kinase inhibitors (JAKi) used to treat immune-mediated inflammatory disorders (IMIDs). We aimed to examine MACE risk with licensed biologics and small molecules used commonly between IMIDs: inflammatory bowel disease, rheumatoid arthritis, psoriasis/psoriatic arthritis, and ankylosing spondylitis.
METHODS: Data were obtained from systematic searches (from inception to May 31, 2022) in PubMed, Embase, Ovid Medline, Scopus, Cochrane Central, and Clinicaltrials.gov. Studies that assessed a pre-defined MACE (myocardial infarction, cerebrovascular accident, unstable angina, cardiovascular death, or heart failure) risk in those ≥18 years with IMIDs treated with anti-interleukin (IL)-23 antibodies, anti-IL-12/23, anti-tumor necrosis factor-alpha antibodies (anti-TNF-α) or JAKi were included in a network meta-analysis using a random-effects model with pooled odds ratios (ORs) reported with 95% credible intervals (CrIs) by drug class and disease state.
RESULTS: Among 3,528 studies identified, 40 (36 randomized controlled trials [RCTs] and 4 cohort studies) were included in the systematic review, comprising 126,961 patients with IMIDs. Based on network meta-analysis of RCTs, regardless of disease state, anti-TNF-α (OR, 2.49; CrI: 1.14-5.62), JAKi (OR, 2.64; CrI: 1.26-5.99), and anti-IL-12/23 (OR, 3.15; CrI: 1.01-13.35) were associated with increased MACE risk compared with placebo. There was no significant difference in the magnitude of the MACE risk between classes or based on IMID type.
CONCLUSIONS: Anti-IL-12/23, JAKi, and anti-TNF-α were associated with higher risk of MACE compared with placebo. The magnitude of the increased MACE risk was not different by IMID type. These results require confirmation in larger prospective studies.
OBJECTIVES: To evaluate the efficacy and safety of Janus kinase (JAK) inhibitors (Jakinibs) in the treatment of psoriasis and psoriatic arthritis (PsA).
METHODS: Databases including PubMed, Embase, Web of Science, and Cochrane Library were searched for randomized controlled trials on the efficacy and safety of Jakinibs in treating psoriasis and PsA from inception to July 2021. A systematic review and meta-analysis were performed to estimate pooled relative risk (RR) and 95% confidence interval (CI).
RESULTS: Seventeen clinical trials (16 publications) comprising 6802 patients were included. All Jakinibs demonstrated significantly higher response rates compared with placebo (ACR20: RR 2.09, 95% CI 1.90-2.30; PASI75: RR 4.03, 95% CI 3.13-5.18). Within the subgroup analysis, the response rates defined by ACR20 were highest for filgotinib (RR 2.40, 95% CI 1.67-3.45), followed by upadacitinib, tofacitinib, and deucravacitinib. The proportion of patients achieving PASI75 response in the tofacitinib 10 mg twice daily group was significantly higher than that in the tofacitinib 5 mg group. Regarding safety, the incidence of adverse events (AEs) was significantly higher for Jakinibs compared with placebo (RR 1.17, 95% CI 1.11-1.23). Of note, a considerable increase in the risk of infections including upper respiratory tract and herpes zoster infection was observed among patients in the treatment group. For tofacitinib, upadacitinib, and filgotiniband, infection was the most prevalent AE. Moreover, AEs in the 10 mg tofacitinib group were higher than those in the 5 mg tofacitinib group.
CONCLUSION: Jakinibs are efficacious interventions for the treatment of psoriasis and PsA, but they are associated with an increased risk of AEs when compared with placebo. The long-term efficacy and safety data require further evaluation. Key Points • This systematic review investigated and compared the efficacy and safety of different Jakinibs including the novel selective TYK2 inhibitors. • Jakinibs are efficacious interventions for the treatment of psoriasis and PsA. • A relatively higher dosing schedule of Jakinibs is associated with increased toxicity.
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.
INTRODUCTION: The efficacy of guselkumab versus adalimumab for psoriasis remains controversial.
AIM: We conducted a systematic review and meta-analysis to explore the influence of guselkumab versus adalimumab on treatment efficacy for psoriasis.
MATERIAL AND METHODS: We have searched PubMed, Embase, Web of Science, EBSCO, and Cochrane library databases for randomized controlled trials (RCTs) published until March 2021 and assessing the efficacy and safety of guselkumab versus adalimumab for psoriasis. This meta-analysis was performed using the random-effects model.
RESULTS: Three RCTs were included in the meta-analysis. Overall, compared with adalimumab for psoriasis, guselkumab was associated with improved PASI 100 (OR = 2.18; 95% CI: 1.47 to 3.23; p = 0.0001), PASI 90 (OR = 2.63; 95% CI: 2.11 to 3.27; p < 0.00001), PASI 75 (OR = 3.10; 95% CI: 2.35 to 4.08; p < 0.00001) and PGA 0/1 (OR = 2.04; 95% CI: 1.26 to 3.31; p = 0.004), as well as decreased DLQI (SMD = -0.24; 95% CI: -0.34 to -0.13; p < 0.00001). In addition, guselkumab resulted in higher DLQI score 0/1 (OR = 1.88; 95% CI: 1.51 to 2.33; p < 0.00001) than adalimumab.
CONCLUSIONS: Guselkumab showed better efficacy than adalimumab for psoriasis.
BACKGROUND: The long-term use of anti-TNF-α agents can lead to adverse effects, such as infections and immune-mediated cutaneous reactions. Whether de-escalation by dose reduction or interval lengthening reduces these adverse effects is uncertain. This systematic review aims to compare the incidence of infections and skin manifestations after anti-TNF-α dose de-escalation with standard dosing.
METHODS: MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched from inception to 14 January 2022. Randomized controlled trials (RCTs) and observational studies comparing anti-TNF-α de-escalation strategies with standard dosing among patients with inflammatory conditions, that report on infections, skin manifestations, or both, were included. The risk of bias was assessed with the revised Cochrane risk-of bias tool (RCTs) or the Newcastle-Ottawa scale (non-RCTs).
RESULTS: Fourteen RCTs and six observational studies (or 2706 patients) were included. Eight RCTs had low risk of bias or some concerns. Four non-RCTs were of good methodological quality. The studies described patients with axial spondyloarthritis (8 studies, 780 patients), rheumatoid arthritis (7 studies, 1458 patients), psoriasis (3 studies, 332 patients), or inflammatory bowel disease (2 studies, 136 patients). De-escalation strategies included interval lengthening (12 studies, 1317 patients), dose reduction (6 studies, 1130 patients), or both (2 studies, 259 patients). Overall, the occurrence of infections and skin manifestations did not differ between standard treatment and de-escalation. The disappearance of infections or skin manifestations after de-escalation was only reported in two studies. The majority of studies focused on etanercept and adalimumab. Heterogeneity in reporting of infections and skin manifestations precluded meta-analysis.
CONCLUSION: We found that anti-TNF-α de-escalation does not reduce infections or skin reactions. A de-escalation strategy should not be recommended for the sole purpose of reducing drug-related adverse effects. The meticulous documentation of adverse effects is recommended to further address this question.
REGISTRATION: PROSPERO CRD42021252977.
The objective of our study was to compare a potent drug of the anti-TNF class family, infliximab, with a potent drug of the IL-inhibitors family, risankizumab, in terms of efficacy and safety endpoints. Online databases were searched for relevant placebo-controlled, randomized trials. The following efficacy outcomes were included: PASI-75, PASI-90, and sPGA, as well as the incidence of any adverse events and serious adverse events. The risk ratios (RR) with the respective 95% confidence intervals (CIs) of different psoriasis scores were pooled in a meta-analysis model, using the Mantel-Haenszel method. The combined risk ratios (RR) showed that infliximab and risankizumab are effective in increasing the number of patients with more than 75% improvement in the PASI (RR= 26.68, 95% CI [14.98, 47.51] p<0.001) and (RR= 10.17, 95% CI [7.24, 14.30] p<0.001), respectively. Test for subgroup differences showed that risankizumab is more effective. Regarding PASI-90 outcome, risankizumab and infliximab are more effective than placebo (RR= 26.22, 95% CI [14.20, 48.41], p<0.001), and (RR= 15.18, 95% CI [8.72, 26.45], p<0.001) respectively. The results showed that risankizumab does not cause significant serious adverse events (RR = 0.59, 95% CI [0.31, 1.13], p=0.12) while, on the other hand, infliximab causes significant serious adverse events (RR = 2.30, 95% CI [1.08, 4.88], p=0.03). The test of subgroup difference showed that risankizumab is safer (p<0.001). Analysis of the incidence of any adverse events showed that risankizumab is safer as well (p=0.007). Infection rates were similar among both drugs (p=0.05). In conclusion, risankizumab is preferred for the treatment of psoriasis than infliximab, and is significantly more effective and safe.
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.
BACKGROUND: Biological therapy is effective for the treatment of psoriasis and psoriatic arthritis; however, adverse effects related to immunosuppression, such as viral infections, have been reported. Amongst these infections, herpes zoster (HZ) is common.
OBJECTIVE: To evaluate the risk of HZ in psoriasis and psoriatic arthritis patients treated with biological therapy.
DATA SOURCES: A comprehensive literature search of PubMed, Embase, and Web of Science was performed using certain keywords until October 9, 2020. Nine studies were included after a detailed assessment.
STUDY ELIGIBILITY CRITERIA: The eligibility criteria included randomized controlled trials (RCTs) and observational studies of patients with psoriasis or psoriatic arthritis treated with biological therapies; compared with non-biological therapies, non-biological systemic therapies, or controls; with the incidence of HZ reported in case and control groups. The Cochrane risk of bias tool and Newcastle-Ottawa scale were used to assess the quality of the RCTs and observational studies, respectively. Data were extracted from 9 eligible studies and then analyzed using Stata software (Version 12.0).
RESULTS: The risk of HZ in biological therapies was higher than that in non-biological (odds ratios [OR]: 1.48; 95% confidence interval [CI]: 1.18-1.86; I2 = 0%) and non-biological systemic (OR: 1.32; 95% CI: 1.02-1.71; I2 = 0%) therapies. Furthermore, the risk of HZ associated with tumor necrosis factor-α inhibitors increased significantly (OR: 1.50; 95% CI: 1.11-2.02; I2 = 0%). Notably, infliximab (OR: 2.43; 95% CI: 1.31-4.50; I2 = 0%) and etanercept (OR: 1.65; 95% CI: 1.07-2.56; I2 = 0%) increased the risk of HZ, while adalimumab (OR: 1.21; 95% CI: 0.64-2.30; I2 = 0%), ustekinumab (OR: 2.20; 95% CI: 0.89-5.44; I2 = 0%), alefacept (OR: 1.46; 95% CI: 0.20-10.47; I2 = 0%), and efalizumab (OR: 1.58; 95% CI: 0.22-11.34; I2 = 0%) did not.
LIMITATIONS: Few RCTs have reported HZ incidents; thus, our results require confirmation via large-scale RCTs.
CONCLUSIONS AND IMPLICATIONS OF KEY FINDINGS: Biological therapies, especially tumor necrosis factor-α inhibitors, may lead to the risk of HZ in psoriasis and psoriatic arthritis patients. Amongst these agents, infliximab and etanercept have been shown to significantly increase the risk of HZ. Additionally, younger age and female sex may be risk factors.
SYSTEMATIC REVIEW REGISTRATION NUMBER: INPLASY202110027.
Recent studies raise concern for increased risk of major adverse cardiovascular events (MACE) with Janus kinase inhibitors (JAKi) used to treat immune-mediated inflammatory disorders (IMIDs). We aimed to examine MACE risk with licensed biologics and small molecules used commonly between IMIDs: inflammatory bowel disease, rheumatoid arthritis, psoriasis/psoriatic arthritis, and ankylosing spondylitis.
METHODS:
Data were obtained from systematic searches (from inception to May 31, 2022) in PubMed, Embase, Ovid Medline, Scopus, Cochrane Central, and Clinicaltrials.gov. Studies that assessed a pre-defined MACE (myocardial infarction, cerebrovascular accident, unstable angina, cardiovascular death, or heart failure) risk in those ≥18 years with IMIDs treated with anti-interleukin (IL)-23 antibodies, anti-IL-12/23, anti-tumor necrosis factor-alpha antibodies (anti-TNF-α) or JAKi were included in a network meta-analysis using a random-effects model with pooled odds ratios (ORs) reported with 95% credible intervals (CrIs) by drug class and disease state.
RESULTS:
Among 3,528 studies identified, 40 (36 randomized controlled trials [RCTs] and 4 cohort studies) were included in the systematic review, comprising 126,961 patients with IMIDs. Based on network meta-analysis of RCTs, regardless of disease state, anti-TNF-α (OR, 2.49; CrI: 1.14-5.62), JAKi (OR, 2.64; CrI: 1.26-5.99), and anti-IL-12/23 (OR, 3.15; CrI: 1.01-13.35) were associated with increased MACE risk compared with placebo. There was no significant difference in the magnitude of the MACE risk between classes or based on IMID type.
CONCLUSIONS:
Anti-IL-12/23, JAKi, and anti-TNF-α were associated with higher risk of MACE compared with placebo. The magnitude of the increased MACE risk was not different by IMID type. These results require confirmation in larger prospective studies.
