BACKGROUND:Cutaneous leishmaniasis (CL) is increasingly reported in previously non-endemic European countries. Although often self-limiting or amenable to topical therapy, systemic treatment is indicated in specific situations. Evidence guiding systemic therapies remains limited and heterogeneous. OBJECTIVES:This systematic review and meta-analysis aimed to synthesize available evidence on systemic treatment regimens for CL. METHODS:MEDLINE/PubMed and Embase were searched for clinically and/or parasitologically confirmed CL receiving systemic monotherapy with meglumine antimoniate (MA), miltefosine, azoles, pentamidine, or liposomal amphotericin B (L-AmB) until February 2026. Primary outcome was clinical cure assessed 2-7.5 months after treatment initiation. Pooled cure rates were estimated using random-effects meta-analysis. Subgroup analyses were performed for Old World (OWCL) and New World (NWCL) CL, and by Leishmania species. RESULTS:Eighty-three studies comprising 96 treatment arms and 4603 patients with OWCL and NWCL were included. Overall, study quality was moderate (per JBI checklist). MA, long regarded as standard of care in many countries, had a pooled cure rate of 59% (95% CI 52%-66%). Higher rates were observed with L-AmB (77%; 95% CI 56%-90%), followed by miltefosine (75%; 95% CI 69%-81%), itraconazole (70%; 95% CI 65%-76%), and fluconazole (62%; 95% CI 16%-93%). Lower rates were obtained with pentamidine (55%; 95% CI 42%-67%) and ketoconazole (36%; 95% CI 7%-82%). Species- and region-specific sub-analyses indicated miltefosine highly effective for OWCL (particularly L. major) and NWCL (L. braziliensis, L. guyanensis, L. panamensis). Head-to-head comparisons of miltefosine and MA showed no statistically significant difference. L-AmB was similarly effective in NWCL (particularly L. braziliensis), with lack of evidence for other species. CONCLUSIONS:Systemic treatment options for CL show variable efficacy. Despite the promising cure rates for miltefosine and L-AmB, comparative evidence remains insufficient to support therapy recommendations. Confirmation in adequately powered, high-quality RCTs, ideally stratified by species, is warranted to strengthen the evidence base.
BACKGROUND:Ivarmacitinib, an oral JAK1 inhibitor, improved efficacy outcomes versus placebo at Week 16 in a phase 3 trial in patients with moderate-to-severe atopic dermatitis (AD). OBJECTIVES:To describe efficacy and safety outcomes through Week 52. METHODS:In this multicentre, double-blind, phase 3 trial (NCT04875169), patients aged 12-75 years were randomized 1:1:1 to receive once-daily oral ivarmacitinib 4 mg, ivarmacitinib 8 mg, or placebo for 16 weeks, followed by a 36-week double-blind extension. At Week 16, placebo-treated patients who continued in the study were re-randomized to ivarmacitinib 4 mg or 8 mg. Key Week 52 endpoints included Investigator's Global Assessment (IGA) 0/1 with at least a 2-grade improvement, Eczema Area and Severity Index 75 (EASI-75), and Worst Itch Numeric Rating Scale (WI-NRS) response. RESULTS:Of 336 randomized patients, 258 completed 52 weeks of treatment. Among patients initially randomized to ivarmacitinib, Week 52 IGA responses were achieved by 42.3% and 40.2% of patients in the 4 mg and 8 mg groups, respectively. EASI-75 responses were achieved by 60.6% and 55.9%, and WI-NRS responses by 59.6% and 45.1%, respectively. During the active-treatment period, treatment-emergent adverse events (TEAEs) occurred in 87.5% and 85.5% of patients in the 4 mg and 8 mg groups, respectively. The most frequent TEAEs were upper respiratory tract infection, COVID-19, SARS-CoV-2 test positive, and increased blood creatine phosphokinase. Serious TEAEs occurred in 5.6% and 4.4% of patients, respectively. CONCLUSION:Ivarmacitinib was associated with generally maintained improvement through Week 52, with a safety profile generally consistent with that observed during the placebo-controlled period. Because the extension phase had no placebo control after Week 16, long-term efficacy findings should be interpreted as descriptive.
BACKGROUND:Adjuvant anti-PD-1 therapy improves recurrence-free survival in resected stage III melanoma, but its impact on survival remains uncertain. OBJECTIVE:To evaluate the association of adjuvant anti-PD-1 therapy with overall survival (OS) and melanoma-specific mortality (MSM) in patients with stage III melanoma. METHODS:Five-year OS and MSM were compared between stage III melanoma patients diagnosed before (pre-cohort: June 2016-May 2018, n = 450) and after (post-cohort: January 2019-December 2020, n = 552) implementation of adjuvant anti-PD-1 in Denmark. Post-cohort patients receiving adjuvant anti-PD-1 were propensity score-matched to pre-cohort patients. RESULTS:Median follow-up exceeded 5 years in both cohorts. At the population level, no difference in 5-year OS or MSM was demonstrated between the total cohorts. In the post-cohort, 297 patients (53.8%) received adjuvant anti-PD-1. After matching (n = 279 per group), adjuvant anti-PD-1 was associated with higher 5-year OS (80.3% vs. 71.7%; HR 0.67, 95% CI 0.47-0.95; p = 0.022). 5-year MSM estimates were inconclusive (16.6% vs. 20.8%, HR 0.77, 95% CI 0.52-1.14; p = 0.24). Among matched patients with occult nodal disease, results were also inconclusive (OS HR 0.70, 95% CI 0.46-1.06). Sensitivity power analyses indicated that only large effects were detectable given the available events. CONCLUSIONS:We were unable to demonstrate an improved survival at the population level after adjuvant anti-PD-1 introduction, but matched analysis showed higher OS in treated patients. However, uncertainty in disease-specific outcomes and limited power preclude firm conclusions. Mature trial data are essential for defining the role of adjuvant therapy alongside emerging neoadjuvant strategies. Until then, carefully individualized adjuvant treatment decisions are of particular importance.
