Contemporary Pharmacotherapy of Papulopustular Rosacea With Topical Ivermectin and Sub-Antimicrobial Dose Doxycycline: A Comprehensive Systematic Review and Meta-Analysis of Randomized Controlled Trials and Primary Studies

Introduction: Papulopustular rosacea (PPR) is a chronic, relapsing inflammatory dermatosis driven by dysregulated innate immunity, neurovascular hyper-reactivity and Demodex folliculorum overgrowth. Topical ivermectin 1% cream (IVM) and sub-antimicrobial dose doxycycline 40 mg modified-release (DOX-MR; 30 mg immediate-release plus 10 mg delayed-release beads) are the two guideline-endorsed agents that best embody a mechanism-based, antibiotic-sparing strategy. However, no meta-analysis restricted to the last 15 years has jointly quantified their efficacy against inactive control, their position against active comparators (metronidazole and low-dose minocycline), the incremental value of combining them, relapse prevention and safety. We aimed to fill this gap and hypothesised that both agents are superior to inactive control, that their effects are consistent across trials, and that combination therapy confers additional complete clearance without excess harm. Methods: This review followed the PRISMA 2020 statement. PubMed/MEDLINE, Europe PMC, Google Scholar, ClinicalTrials.gov, the Cochrane Library (CDSR and CENTRAL) and Semantic Scholar were searched from 1 January 2011 to 31 October 2026. RCTs, comparative studies, cohorts and case series of adults with PPR treated with IVM and/or DOX-MR were eligible; systematic reviews were excluded from the characteristics tables but retained for the Discussion. Risk of bias was appraised with RoB 2 (RCTs), ROBINS-I (comparative non-randomized studies) and the JBI checklist (case series). Risk ratios (RR), Peto odds ratios and mean differences (MD) were pooled with DerSimonian–Laird random-effects models, with Hartung–Knapp–Sidik–Jonkman (HKSJ) adjustment and prediction intervals; single-arm proportions were pooled on the logit scale. Certainty was rated with GRADE. Results: Of 1,354 records, 26 studies (14 RCTs from 12 publications and 12 non-randomized studies; 41 reports including 12 registry result records) were included, totalling 6,024 participants. Against inactive control, IVM-based regimens increased Investigator's Global Assessment (IGA) success (RR 2.18; 95% CI 1.44–3.30; 3 RCTs; n = 1,561; I² = 79%) and reduced inflammatory lesion counts (MD −8.65 lesions; 95% CI −10.27 to −7.02; I² = 0%), whereas DOX-MR increased IGA success (RR 1.49; 95% CI 1.15–1.94; 4 RCTs; n = 678; I² = 16%) and reduced lesions by 2.98 (95% CI 1.58–4.39). The overall effect versus inactive control was RR 1.84 (95% CI 1.40–2.41; 7 RCTs; n = 2,239), robust to leave-one-out and cumulative analyses. IVM outperformed metronidazole 0.75% (RR 1.13; 95% CI 1.06–1.20; percentage lesion reduction MD −9.3%). DOX-MR was inferior to minocycline formulations (RR 0.54; 95% CI 0.40–0.72; 4 RCTs; n = 672). Adding DOX-MR to IVM in severe PPR doubled complete lesion clearance (RR 2.45; 95% CI 1.22–4.93) and accelerated response. Relapse was numerically lower after IVM induction (RR 0.91; 95% CI 0.83–1.01) and halved with DOX-MR maintenance (RR 0.50; 95% CI 0.24–1.03). Serious adverse events did not differ (Peto OR 1.60; 95% CI 0.88–2.92; 9 RCTs; I² = 0%), and any adverse events with DOX-MR were not increased (RR 0.76; 95% CI 0.51–1.12). Topical IVM eradicated Demodex in 80.9% (95% CI 62.9–91.4) of mite-positive patients. There was no small-study asymmetry within prespecified comparisons (Egger p = 0.97). Discussion: Both agents are effective, well tolerated and complementary: IVM provides the larger topical effect with dual acaricidal and anti-inflammatory activity, whereas DOX-MR provides a modest but consistent systemic anti-inflammatory effect at plasma levels below the antimicrobial threshold. The superiority of extended-release minocycline over DOX-MR in recent phase 3 trials, the high relapse burden after discontinuation and the limited representation of skin of colour qualify current algorithms. Conclusion: Topical ivermectin 1% should be considered first-line therapy for inflammatory lesions of PPR, DOX-MR is an effective antibiotic-stewardship-compatible systemic option and maintenance agent, and their combination is justified in severe disease when complete clearance is the goal. Long-term, head-to-head and skin-of-colour trials are required.