Aims: A recent guideline presented by the ESC Congress in 2022 had indicated a novel therapy targeted at pulmonary artery hypertension, known as pulmonary artery denervation (PADN), which get inspired from a laboratorial trial that could lowering the pulmonary artery pressure through the intervention on the animals. Our aim is to conduct a network meta-analysis to compare the efficacy and safety of PADN from six aspects with the current conventional therapies. Methods and results: According to the PRISMA guidance, databases including Ovid, ClinicalTrials.gov, Medline, Embase, and PubMed were searched from inception to 22 August 2023, along with a full assessment of the previous five meta-analyses. Data were extracted and curated for Bayesian network meta-analysis. The primary outcome was the change in the 6-min walking distance (6MWD) from baseline with a secondary outcome called change in mean pulmonary artery pressure (mPAP) from baseline. The four safety outcomes included risk of clinical worsening, hospitalization, mortality and severe adverse events (SAEs). The comparison is structured on a contrast model based on 65 randomized controlled trials (RCTs) on PADN and the other conventional mainstream drugs. PADN had a better effect in improving 6MWD than Placebo (−77.76 m, 95% CI: −102.04 to −54.34 m), Macitentan (−65.32 m, 95% CI: −95.34 to −36.1 m), Bosentan (−64.5 m, 95% CI: −94.7 to −35.07 m), Iloprost (−62.66 m, 95% CI: −99.48 to −27.13 m), Oxygen (−62.42 m, 95% CI: −100.01 to −25.78 m), Treprostinil (−62.01 m, 95% CI: −89.04 to −35.61 m), Riociguat (−60.59 m, 95% CI: −86.11 to −35.98 m), Selexipag (−47.2 m, 95% CI: −85.61 to −10.19 m), Sildenafil (−44.92 m, 95% CI: −74.43 to −16.15 m), or Sitaxsentan (−39.53 m, 95% CI: −78.99 to −0.76 m). PADN had a better antihypertensive effect than placebo and showed statistical significant lower risks to induce clinical worsening and re-hospitalization than treprostinil, riociguat, and placebo groups. No statistically significant difference in risk of mortality and severe adverse events was observed between PADN versus the other interventions. Conclusions: Compared with 16 types of conventional therapies and Placebo, PADN has advantage over nine single therapies and Placebo in improving 6MWD and appears to be better than two types of dual-drug combined therapies while with no statistical significance. PADN shows a favourable antihypertensive effect on mPAP and has a lower risk to trigger clinical worsening or hospitalization, while its risk on mortality and severe adverse events is still inconclusive.
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.
OBJECTIVE: To compare the effect of the biological reference agents (infliximab, etanercept, adalimumab) in rheumatoid arthritis (RA) in pivotal superiority placebo-controlled trials (reference agent vs placebo) vs their effect in equivalence active comparator-controlled trials (reference agent vs biosimilar).
METHODS: The PubMed, EMBASE, Cochrane, databases were searched for randomized, double-blind, controlled trials up to March 2020 comparing a biological reference agent vs placebo or biosimilar. The study assessed the American College of Rheumatology (ACR) 20/50/70 responses of the reference agent in these groups (Reference-pbo and Reference-bs, respectively). The effect of the reference agent in both groups was estimated with 95% confidence intervals (95%CI), pooled using random-effects models and then compared using a meta-regression model.
RESULTS: We included 31 trials. The main characteristics of the population (disease duration and activity, % seropositivity and methotrexate dose) of the population in both groups were similar. The meta-analysis found a better ACR20 response to the biological originator in the Reference-bs group with a global rate of 70% (95%CI, 66-74) compared with 59% (95%CI, 55-62) in the reference-pbo group (p= 0.001). A significant difference was also found for ACR 50 [44% (95%CI, 39-50) vs 35% (95%CI, 31-39) respectively, p< 0.01].
CONCLUSION: Effect of the reference biologic agent was better when compared with an active drug to a placebo. This could be linked to an increased placebo effect in active comparator-controlled studies or a nocebo effect in placebo-controlled studies. This effect can be called the Lessebo effect.
BACKGROUND: The objective of our systematic review and meta-analysis was to evaluate the effectiveness and safety of tofacitinib in the treatment of moderate-severe ulcerative colitis (UC).
METHODS: We searched Medline, Embase, Web of Science, and Cochrane Central to identify articles and abstracts reporting efficacy or safety data on tofacitinib use in UC. Primary outcome assessed was remission. Secondary outcomes included clinical response, steroid free remission, and adverse events (AEs).
RESULTS: A total of 26 studies were included. The rates of remission were 29.81% [95% confidence interval (CI): 22.37%-37.25%, I2: 90%] at week 8, 32.27% (95% CI: 27.67%-36.88%, I2: 42%) at 6 months and 38.03% (95% CI: 33.59%-42.48%, I2: 0%) at 1-year. Clinical response rates were 59.41% (95% CI: 55.03%-63.94%, I2: 61%) at week 8, 48.99% (95% CI: 36.92%-61.06%, I2: 91%) at 6 months and 50.87% (95% CI: 42.16%-59.58%, I2: 67%) at 1-year. Odds ratio of clinical response at week 8 in biologic naive versus biologic experienced patients was 1.59 (95% CI: 0.54-4.63). Pooled incidence rate for serious infections, major adverse cardiovascular events, and nonmelanotic squamous cell malignancies across all doses was 4.41 per 100-patient years (PYs) (95% CI: 2.32-8.38 per 100-PY, I2: 78%), 0.91 per 100-PY (95% CI: 0.43-1.93 per 100-PY, I2: 37%) and 0.91 per 100-PY (95% CI: 0.61-1.34 per 100-PY, I2: 0%), respectively. Higher dose was associated with an increased frequency of AEs.
CONCLUSIONS: While the overall efficacy and safety of tofacitinib in moderate-severe UC is consistent with clinical trial data, the dose dependent increase in AEs highlights the significance of early dose de-escalation. Rate of clinical response after tofacitinb induction was similar in biologic naive and biologic experienced patients.
WHAT IS KNOWN AND OBJECTIVE: In the absence of head-to-head comparisons, the objective of this study was to conduct a network meta-analysis (NMA) to indirectly compare the relative efficacy and safety of Janus kinase (JAK) inhibitors for ulcerative colitis (UC).
METHODS: We searched PubMed, EMBASE, Web of Science and Cochrane Library from the database inception until 13 August 2021. No randomized controlled trials (RCTs) that directly compared these interventions were identified. Therefore, a fixed-effects Bayesian NMA was conducted by identifying a connected (via comparison to placebo) network of RCTs. Ranking was assessed using surface under the cumulative ranking (SUCRA) probabilities.
RESULTS AND DISCUSSION: Seven RCTs including 3190 patients met the inclusion criteria. Filgotinib 100 mg was ranked highest for induction of endoscopic remission (SUCRA, 0.67) whereas peficitinib 75 mg BID was ranked highest for induction of clinical response (SUCRA, 0.72). Peficitinib 75 mg was ranked highest for induction of mucosal healing (SUCRA, 0.71), whereas peficitinib 150 mg was ranked highest for clinical remission (SUCRA, 0.74). Tofacitinib 3 mg had the highest probability of being the best treatment in terms of change from baseline in Mayo score (SUCRA, 0.78). Adverse events (AEs) and treatment discontinuations or withdrawals from the study due to AEs did not differ between JAK inhibitors and placebo groups.
WHAT IS NEW AND CONCLUSION: Based on indirect comparisons, peficitinib 75 mg/75 mg BID/150 mg, tofacitinib 3 mg and filgotinib 100mg were the most efficacious JAK inhibitor interventions in patients with UC. However, head-to-head trials are warranted to inform clinical decision-making with greater confidence.
BACKGROUND: Biologic drugs such as adalimumab, etanercept, and infliximab represent major first-line and second-line treatments for rheumatoid arthritis (RA) patients. However, their high cost poses a massive burden on healthcare systems worldwide. The expiration of patents for these biologics has driven the production of biosimilar drugs, which are potentially less costly and remarkably similar, albeit not identical to the reference molecules. This paper aims to outline the protocol of a systematic review that will investigate the efficacy and safety profile of biosimilars compared to biologics (objective 1) and the impact of switching between biosimilar drugs and reference biologics on the management of RA patients (objective 2).
METHODS: We will investigate the effects of any biosimilars of adalimumab, etanercept, and infliximab on RA patients. We will include randomized controlled trials (RCTs) or quasi-RCTs to assess efficacy and safety outcomes and RCTs with two- or multiple-part designs to evaluate the consequences of switching from reference biologics to biosimilar drugs (and vice-versa). Electronic searches will be performed through MEDLINE (via PubMed), EMBASE, LILACS, and CENTRAL (from inception to April 2021). Two independent reviewers will screen studies, extract data, and evaluate the risk of bias. The latter will be carried out considering specific domains from equivalence trials and switching studies. Random-effects models will be fitted to obtain summary estimates using either relative risk or standardized mean difference as a metric. The primary outcome will be the rate of treatment success according to the American College of Rheumatology 20 (ACR20), and the co-primary outcome will be the Health Assessment Questionnaire-Disability Index (HAQ-DI). Conclusions will be based on equivalence hypothesis testing using predefined margins of equivalence elicited from a group of experienced rheumatologists and prior studies. The overall certainty of the evidence will be assessed based on the GRADE system.
DISCUSSION: The present investigation proposes a comprehensive, clinician-oriented approach to assess the equivalence and the impact of switching between biosimilars and biologics on the management of patients with RA. Our results will elucidate the efficacy, safety, immunogenicity of biosimilars, and the clinical consequences of substituting biologics with biosimilars in the management of RA.
SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42019137152 and CRD42019137155.
BACKGROUND: Biological agents are commonly used for the treatment of ulcerative colitis (UC). As new treatments, tofacitinib, and fecal microbiota transplantation (FMT) have demonstrated efficacy in treating UC. This network meta-analysis aims to determine the efficacy and safety of biological agents, tofacitinib, and FMT.
METHODS: A network meta-analysis was conducted by systematically searching the PubMed, Embase, and Cochrane Libraries. According to strict inclusion and exclusion criteria, we included randomized controlled trials (RCTs) of biological agents, tofacitinib, and FMT in UC. A random-effect model was chosen by the network meta-analysis and sensitivity analysis. Heterogeneity test and publication bias test were performed to determine the efficacy of treatments.
RESULTS: Data were extracted from 16 RCTs and we found that all treatments were more effective than the placebos. A total of 21 comparisons were made to determine efficiency. We found that infliximab, vedolizumab, and FMT performed better curative effect in terms of absolute effects and relative ranks. Furthermore, there was no statistical difference in the efficacy of biological agents, tofacitinib, and FMT. Moreover, no treatments were found to increase the occurrence of adverse events when compared with placebos, except infliximab. However, vedolizumab seemed to reduce the occurrence of adverse events compared with infliximab.
CONCLUSION: Of the biological agents, vedolizumab and infliximab were the most effective, suggesting that biological agents are still a better choice. Nevertheless, tofacitinib and FMT may be promising alternatives with high efficacies. However, more safety and maintenance studies need to be conducted in future for the acquisition of more accurate results.Abbreviations: FMT: Fecal microbiota transplantation; UC: Ulcerative colitis; RCTs: Randomized controlled trials; IBD: Inflammatory bowel disease; CD: Crohn's disease; IBS: Irritable bowel syndrome; CDI: Clostridium difficile infections; ITT: Intention-to-treat; RR: Relative risk; CI: Confidence interval; CrI: Credible intervals; IFX: Infliximab; ADA: Adalimumab; TFB: Tofacitinib; GLM: Golimumab; VDZ: Vedolizumab; PBO: Placebo; wk: week; F: Female; M: Male; AEs: Adverse events; SAEs: Serious adverse events; anti-TNF: Anti-tumor necrosis factors.
Introduction: Peficitinib, a Janus kinase (JAK) inhibitor, is approved for clinical use in Japan, Korea, and Taiwan, but head-to-head comparisons versus other JAK inhibitors are lacking. We indirectly compared peficitinib, tofacitinib, and baricitinib for rheumatoid arthritis treatment. Methods: We searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and congress archives up until February 12, 2019, for randomized controlled trials of peficitinib, tofacitinib, and baricitinib. Efficacy (American College of Rheumatology responses, disease activity scores, modified total Sharp score, Simplified Disease Activity Index [SDAI]) and safety outcomes were compared using a Bayesian network meta-analysis. The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) consensus was followed for reporting results. A network meta-regression assessed the impact on outcomes of proportions of patients receiving concomitant methotrexate or of Asian ethnicity. Results: The network meta-analysis included 21 randomized controlled trials. At 12 weeks, all evaluable efficacy outcomes were comparable or improved with peficitinib 150 mg and 100 mg once daily, versus baricitinib 2 and 4 mg once daily and tofacitinib 5 mg twice daily. At 24 weeks, efficacy outcomes were comparable or improved for each peficitinib dose versus baricitinib and tofacitinib. Risk of adverse events and serious adverse events at 12 weeks were similar with peficitinib 100 and 150 mg versus baricitinib and tofacitinib. The proportion of patients receiving concomitant methotrexate had no effect on any outcome analyzed, but Asian ethnicity had a positive effect on multiple efficacy outcomes. Conclusions: Peficitinib had comparable efficacy versus tofacitinib and baricitinib for reduction in disease activity as measured by SDAI, and for reduction in progression of joint damage as measured radiographically. No notable differences in safety outcomes were observed. Further studies are required to better characterize the impact of ethnicity on the efficacy of JAK inhibitors.
Objective: To evaluate the comparative efficacy and safety of Janus kinase (JAK) inhibitors and biological disease-modifying antirheumatic drugs (bDMARDs) in patients with rheumatoid arthritis (RA) and an inadequate response to at least one disease-modifying antirheumatic drug (DMARD). Methods: PubMed, Embase, Cochrane library and ClinicalTrials.gov were searched for relevant randomized controlled trials (RCTs) from inception to April 2020. The active drugs included three JAK inhibitors and eight bDMARDs while the control drugs included placebo or conventional synthetic disease-modifying antirheumatic drugs (csDMARDs). Outcomes include American College of Rheumatology 20% response (ACR20), Disease Activity Score in 28 joints (DAS28), Health Assessment Questionnaire–Disability Index (HAQ-DI) and discontinuations for adverse events (AEs). We estimated summary odds ratios (ORs) and weighted mean differences (WMDs) using network meta-analysis with random effects. Results: Eighty-eight RCTs with 31,566 patients were included. All JAK inhibitors and bDMARDs were more effective than placebo in ACR20 (ORs ranging between 3.05 and 5.61), DAS28 (WMDs ranging between −1.91 and −0.80) and HAQ-DI (WMDs ranging between −0.34 and −0.21). Tocilizumab, certolizumab pegol and upadacitinib showed relatively good efficacy in these three outcomes according to their relative ranking. Notably, tocilizumab was more effective than other active drugs in DAS28 (WMDs ranging between −1.11 and −0.49). Compared with the lower recommended doses, increasing the doses of JAK inhibitors (baricitinib 4 mg versus 2 mg, tofacitinib 10 mg versus 5 mg and upadacitinib 30 mg versus 15 mg) cannot provide significant additional benefits. In terms of discontinuations for AEs, all active drugs showed no significant difference compared with placebo except certolizumab pegol [OR 1.65, 95% credible interval (CrI) 1.06–2.61] and rituximab (3.17, 1.11–10.80). Conclusions: Tocilizumab, certolizumab pegol and upadacitinib may have relatively good efficacy in patients with RA after treatment failure with csDMARDs. RA patients taking a JAK inhibitor may have a preference for a lower recommended dose.
Objectives: Because only one head-to-head randomized trial of biologics for moderate-to-severe ulcerative colitis (UC) has been performed, indirect treatment comparisons remain important. This systematic review and network meta-analysis examined efficacy and safety of biologics and tofacitinib for moderate-to-severe UC, using values for vedolizumab as a reference. Methods: Relevant studies (N=19) of vedolizumab, adalimumab, infliximab, golimumab, ustekinumab, and tofacitinib were identified. Study design differences were addressed by assessing efficacy outcomes conditional on response at maintenance initiation. Primary analysis used fixed-effect models to estimate odds ratios for efficacy and safety endpoints. Results: Compared with vedolizumab 300 mg, adalimumab 160/80 mg was associated with less clinical remission (odds ratio, 0.69 [95% credible interval, 0.54-0.88]), and infliximab 5 mg/kg was associated with more clinical remission (1.67 [1.16-2.42]) and response (1.63 [1.15-2.30]). Adalimumab 40 mg, golimumab 50 mg, and ustekinumab 90 mg Q12W had significantly lower clinical remission rates during maintenance (0.62 [0.45-0.86], 0.55 [0.32-0.95], and 0.59 [0.35-0.99]) versus vedolizumab 300 mg Q8W. Response results were similar. Tofacitinib 10 mg had the highest maintenance treatment efficacy estimates and highest infection risk. Conclusion: Network meta-analysis and novel integrated benefit-risk analysis suggest a potentially favorable efficacy-safety balance for vedolizumab compared with adalimumab and other advanced UC therapies.
Aims: A recent guideline presented by the ESC Congress in 2022 had indicated a novel therapy targeted at pulmonary artery hypertension, known as pulmonary artery denervation (PADN), which get inspired from a laboratorial trial that could lowering the pulmonary artery pressure through the intervention on the animals. Our aim is to conduct a network meta-analysis to compare the efficacy and safety of PADN from six aspects with the current conventional therapies. Methods and results: According to the PRISMA guidance, databases including Ovid, ClinicalTrials.gov, Medline, Embase, and PubMed were searched from inception to 22 August 2023, along with a full assessment of the previous five meta-analyses. Data were extracted and curated for Bayesian network meta-analysis. The primary outcome was the change in the 6-min walking distance (6MWD) from baseline with a secondary outcome called change in mean pulmonary artery pressure (mPAP) from baseline. The four safety outcomes included risk of clinical worsening, hospitalization, mortality and severe adverse events (SAEs). The comparison is structured on a contrast model based on 65 randomized controlled trials (RCTs) on PADN and the other conventional mainstream drugs. PADN had a better effect in improving 6MWD than Placebo (−77.76 m, 95% CI.: −102.04 to −54.34 m), Macitentan (−65.32 m, 95% CI.: −95.34 to −36.1 m), Bosentan (−64.5 m, 95% CI.: −94.7 to −35.07 m), Iloprost (−62.66 m, 95% CI.: −99.48 to −27.13 m), Oxygen (−62.42 m, 95% CI.: −100.01 to −25.78 m), Treprostinil (−62.01 m, 95% CI.: −89.04 to −35.61 m), Riociguat (−60.59 m, 95% CI.: −86.11 to −35.98 m), Selexipag (−47.2 m, 95% CI.: −85.61 to −10.19 m), Sildenafil (−44.92 m, 95% CI.: −74.43 to −16.15 m), or Sitaxsentan (−39.53 m, 95% CI.: −78.99 to −0.76 m). PADN had a better antihypertensive effect than placebo and showed statistical significant lower risks to induce clinical worsening and re-hospitalization than treprostinil, riociguat, and placebo groups. No statistically significant difference in risk of mortality and severe adverse events was observed between PADN versus the other interventions. Conclusions: Compared with 16 types of conventional therapies and Placebo, PADN has advantage over nine single therapies and Placebo in improving 6MWD and appears to be better than two types of dual-drug combined therapies while with no statistical significance. PADN shows a favourable antihypertensive effect on mPAP and has a lower risk to trigger clinical worsening or hospitalization, while its risk on mortality and severe adverse events is still inconclusive.