Comparative Efficacy of Advanced Therapies in the Treatment of Radiographic Axial Spondyloarthritis or Ankylosing Spondylitis as Evaluated by the ASDAS Low Disease Activity Criteria.

INTRODUCTION: With an increasing number of biologic/targeted synthetic disease-modifying antirheumatic drug options available for the treatment of active ankylosing spondylitis (AS), also known as radiographic axial spondyloarthritis, it is of clinical interest to determine the comparative efficacy of these advanced therapies among populations with differing prior advanced therapy exposure. This study aimed to assess the comparative efficacy of approved advanced therapies for AS in tumor necrosis factor inhibitor (TNFi)-naïve and, separately, in TNFi inadequate responder/intolerant (-IR) populations. METHODS: A systematic literature review was conducted to identify randomized clinical trials for TNFis, interleukin-17A inhibitors, and Janus kinase inhibitors used as advanced therapies for active AS. Clinical efficacy was considered by the Ankylosing Spondylitis Disease Activity Score low disease activity (ASDAS LDA) criteria, defined as ASDAS score less than 2.1, among approved therapies. Comparative efficacy in the TNFi-naïve population was assessed utilizing network meta-analysis, while comparative efficacy in the TNFi-IR population was assessed utilizing matching-adjusted indirect comparison. Odds ratios were calculated, from which absolute rates and numbers needed to treat were calculated. Safety in the form of trial-reported and placebo-adjusted rates of discontinuation due to adverse events (AEs) was reviewed. RESULTS: Among the TNFi-naïve population, the estimated ASDAS LDA rate between week 12 and 16 was highest for patients treated with upadacitinib (52.8%) and lowest for patients treated with placebo (11.6%). Among the TNFi-IR population, the estimated ASDAS LDA rate was 41.3% for patients treated with upadacitinib and 17.5% for patients treated with ixekizumab. The trial-reported and placebo-adjusted rates of discontinuation due to AEs were generally low across included advanced therapies. CONCLUSIONS: Relative to other assessed therapies, upadacitinib demonstrated greater clinical efficacy per ASDAS LDA in the treatment of active AS in both TNFi-naïve and TNFi-IR populations. Head-to-head and real-world data comparisons are warranted to both validate these findings and aid medical decision makers.

Comparative Efficacy of Targeted Systemic Therapies for Moderate-to-Severe Atopic Dermatitis without Topical Corticosteroids: An Updated Network Meta-analysis.

INTRODUCTION: The treatment landscape for moderate-to-severe atopic dermatitis (AD) continues to expand. This network meta-analysis (NMA) updates a previously conducted NMA to include data from the most recent phase 3 trials to assess the comparative efficacy of targeted systemic therapies without the addition of topical corticosteroids (TCS) and/or topical calcineurin inhibitors (TCI) in adults with moderate-to-severe AD. METHODS: Data from recent phase 3 monotherapy trials of lebrikizumab, ADvocate1 (NCT04146363) and ADvocate2 (NCT04178967), were included in the analyses, along with other eligible phase 3/4 randomized placebo-controlled trials for abrocitinib, baricitinib, dupilumab, tralokinumab, and upadacitinib identified through a systemic literature review in Silverberg et al. (Dermatol Ther (Heidelb) 12(5):1181-1196, 2022). The proportion of patients achieving Eczema Area and Severity Index (EASI) improvement ≥ 90% from baseline (EASI-90), EASI improvement ≥ 75% from baseline (EASI-75), ≥ 4-point improvement on Pruritus Numerical Rating Scale from baseline (ΔNRS ≥ 4), and Investigator Global Assessment (IGA) score of 0 or 1 (clear or almost clear) and reduction of ≥ 2 points from baseline (IGA 0/1) were evaluated using a Bayesian network meta-analysis. RESULTS: The updated NMA analyzed 13 unique placebo-controlled trials involving 7105 patients in 32 arms across 6 targeted therapies. Upadacitinib 30 mg was the most efficacious therapy across all endpoints at the primary timepoint (week 12 or 16) and at earlier timepoints, generally followed by abrocitinib 200 mg, upadacitinib 15 mg, dupilumab 300 mg, and lebrikizumab 250 mg or abrocitinib 100 mg. Baricitinib 2 mg and tralokinumab were generally ranked lower across outcomes. CONCLUSIONS: Many factors need to be considered for treatment selection for AD, especially as new treatments continue to emerge. After incorporating recent placebo-controlled phase 3 data of lebrikizumab, upadacitinib 30 mg, upadacitinib 15 mg, and abrocitinib 200 mg remain the most efficacious targeted systemic therapies over 12-16 weeks of therapy in AD. These updated findings can help healthcare providers when creating a patient's personalized treatment plan.

Prevalence and Overlap of Cardiac, Renal, and Metabolic Conditions in US Adults, 1999-2020.

Importance: Individually, cardiac, renal, and metabolic (CRM) conditions are common and leading causes of death, disability, and health care-associated costs. However, the frequency with which CRM conditions coexist has not been comprehensively characterized to date. Objective: To examine the prevalence and overlap of CRM conditions among US adults currently and over time. Design, Setting, and Participants: To establish prevalence of CRM conditions, nationally representative, serial cross-sectional data included in the January 2015 through March 2020 National Health and Nutrition Examination Survey (NHANES) were evaluated in this cohort study. To assess temporal trends in CRM overlap, NHANES data between 1999-2002 and 2015-2020 were compared. Data on 11 607 nonpregnant US adults (≥20 years) were included. Data analysis occurred between November 10, 2020, and November 23, 2022. Main Outcomes and Measures: Proportion of participants with CRM conditions, overall and stratified by age, defined as cardiovascular disease (CVD), chronic kidney disease (CKD), type 2 diabetes (T2D), or all 3. Results: From 2015 through March 2020, of 11 607 US adults included in the analysis (mean [SE] age, 48.5 [0.4] years; 51.0% women), 26.3% had at least 1 CRM condition, 8.0% had at least 2 CRM conditions, and 1.5% had 3 CRM conditions. Overall, CKD plus T2D was the most common CRM dyad (3.2%), followed by CVD plus T2D (1.7%) and CVD plus CKD (1.6%). Participants with higher CRM comorbidity burden were more likely to be older and male. Among participants aged 65 years or older, 33.6% had 1 CRM condition, 17.1% had 2 CRM conditions, and 5.0% had 3 CRM conditions. Within this subset, CKD plus T2D (7.3%) was most common, followed by CVD plus CKD (6.0%) and CVD plus T2D (3.8%). The CRM comorbidity burden was disproportionately high among participants reporting non-Hispanic Black race or ethnicity, unemployment, low socioeconomic status, and no high school degree. Among participants with 3 CRM conditions, nearly one-third (30.5%) did not report statin use, and only 4.8% and 3.0% used glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter 2 inhibitors, respectively. Between 1999 and 2020, the proportion of US adults with multiple CRM conditions increased significantly (from 5.3% to 8.0%; P < .001 for trend), as did the proportion having all 3 CRM conditions (0.7% to 1.5%; P < .001 for trend). Conclusions and Relevance: This cohort study found that CRM multimorbidity is increasingly common and undertreated among US adults, highlighting the importance of collaborative and comprehensive management strategies.

Clinical and Economic Benefit of Advanced Therapies for the Treatment of Active Ankylosing Spondylitis.

INTRODUCTION: Recent changes to treatment guidelines for ankylosing spondylitis (AS) have listed first-line advanced therapies as tumor necrosis factor (TNF), interleukin (IL)-17, and Janus kinase (JAK) inhibitors. This study sought to assess the comparative clinical and economic benefit of advanced therapies approved for AS. METHODS: A systematic literature review was conducted to identify randomized clinical trials for JAK inhibitors (upadacitinib [UPA], tofacitinib [TOF]), anti-IL-17 therapies (secukinumab [SEC], ixekizumab [IXE]), and TNF inhibitors (adalimumab [ADA], etanercept [ETN], golimumab [GOL]) used for the treatment of active AS. Clinical efficacy was evaluated by Assessment of Spondyloarthritis International Society 40 (ASAS40) criteria and treatment discontinuation due to adverse events (AEs) was used to generate response rates synthesized via a Bayesian network meta-analysis. Number needed to treat (NNT) was calculated as the reciprocal of incremental response rate of each treatment versus placebo. Cost per ASAS40 responder (CPR) was calculated as the 12-week treatment costs divided by ASAS40 response rates. Data were stratified by biologic treatment status (i.e., biologic naïve [bio-naïve] or inadequate response or intolerance to biologics [bio-IR]) for efficacy and CPR analyses. RESULTS: Among bio-naïve patients, the response rate for ASAS40 was 53.6% for UPA-treated patients, whereas most other treatments had response rates between 41% and 49%. NNTs were lowest for UPA-treated patients at 2.8 (other therapies 3.2-4.8). Estimated CPR among UPA-treated patients was lowest (UPA $39.5k vs others $44.2k-102.5k). Efficacy and CPR trends were similar among bio-IR and TNF-IR patients. Among bio-naïve and bio-IR patients, the rate of AEs leading to discontinuation was lowest among UPA and SEC-treated patients (0.0, others 0.6-3.7%). CONCLUSIONS: Relative to other treatments assessed in this study, UPA demonstrated numerically greater clinical and economic benefit for the treatment of AS. Head-to-head or real-world comparisons of these therapies are warranted and may inform clinical decision-making.

Efficacy and Safety of Advanced Therapies for Moderately to Severely Active Ulcerative Colitis at Induction and Maintenance: An Indirect Treatment Comparison Using Bayesian Network Meta-analysis.

Background: Given rapid innovation in advanced therapies for moderately to severely active ulcerative colitis (UC), we investigated their comparative efficacy and safety during induction and maintenance through network meta-analysis. Methods: Using Bayesian methods, endpoints of clinical remission and clinical response per Full Mayo score, and endoscopic improvement were assessed in bio-naive and -exposed populations. Safety was assessed in overall populations by all adverse events (AEs), serious AEs, discontinuation due to AEs, and serious infections. Phase 3 randomized controlled trials were identified via systematic literature review, including the following advanced therapies: infliximab, adalimumab, vedolizumab, golimumab, tofacitinib, ustekinumab, filgotinib, ozanimod, and upadacitinib. Random effects models were used to address between-study heterogeneity. Intent-to-treat (ITT) efficacy rates were calculated by adjusting maintenance outcomes by likelihood of induction response. Results: Out of 48 trials identified, 23 were included. Across all outcomes and regardless of prior biologic exposure, ITT efficacy rates were highest for upadacitinib, owing to its highest ranking for all efficacy outcomes in induction and for all but clinical remission during maintenance among bio-naive induction responders. For all advanced therapies versus placebo, there were no significant differences in serious AEs or serious infections across therapies. For all AEs, golimumab had higher odds versus placebo during maintenance; for discontinuation due to AEs, upadacitinib had lower odds versus placebo during induction, while ustekinumab and vedolizumab had lower odds versus placebo during maintenance. Conclusions: Upadacitinib may be the most efficacious therapy for moderately to severely active UC based on ITT analyses, with similar safety across advanced therapies.

Comparative Efficacy of Targeted Systemic Therapies for Moderate to Severe Atopic Dermatitis without Topical Corticosteroids: Systematic Review and Network Meta-analysis.

INTRODUCTION: The comparative efficacy of targeted systemic therapies for moderate to severe atopic dermatitis (AD) has not been systematically assessed using recent phase 3 data. This network meta-analysis assesses the comparative efficacy of targeted systemic therapies without the addition of topical corticosteroids (TCS) and/or topical calcineurin inhibitors (TCI) in adults with moderate to severe AD. METHODS: The systematic literature review searched through 17 May 2021 for phase 3/4 trials with upadacitinib, interleukin-4 (IL-4), interleukin-13 (IL-13), or JAK inhibitors compared with placebo or active intervention for adults and adolescents with moderate to severe AD with inadequate response to TCS/TCI or for whom TCS/TCI was medically inadvisable, without restrictions on year or region. Researchers assessed data using PRISMA guidelines. The proportion of patients achieving trial co-primary endpoints [Investigator Global Assessment (IGA) score of 0 or 1 (clear or almost clear) and reduction of ≥ 2 points from baseline; proportion of patients achieving Eczema Area and Severity Index (EASI) improvement ≥ 75% from baseline (EASI-75)]; EASI improvement ≥ 90% from baseline (EASI-90); and ≥ 4-point improvement on Pruritus Numerical Rating Scale from baseline (ΔNRS ≥ 4) were evaluated using Bayesian network meta-analysis. RESULTS: Of 3415 initially identified records, network meta-analysis (NMA) ultimately included 6 records representing 9 unique studies. Two upadacitinib trials were also included. Eleven clinical trials including 6254 patients were analyzed. Upadacitinib 30 mg daily was the most efficacious therapy across all endpoints at the primary endpoint (week 12 or 16) and at earlier timepoints, followed by upadacitinib 15 mg daily and abrocitinib 200 mg daily. DISCUSSION: Many factors need to be considered for treatment selection for AD. These findings can help healthcare providers when personalizing a patient's treatment. CONCLUSION: Upadacitinib 30 mg daily, upadacitinib 15 mg daily, and abrocitinib 200 mg daily may be the most efficacious targeted systemic therapies over 12-16 weeks of therapy in AD.