Combination Therapy With Anti-Inflammatory Dose Doxycycline And Adapalene 0.3%/Benzoyl Peroxide 2.5% Gel For Severe Acne: A Simulated Efficacy And Safety Evaluation

Abstract

Severe acne vulgaris is challenging to treat and often leads to permanent scarring and psychosocial distress. Standard therapy for severe cases can include systemic antibiotics or isotretinoin, but long-term antibiotic use raises concerns of resistance and side effects. A combination regimen that maximizes anti-inflammatory and comedolytic effects while minimizing antibiotic exposure may improve outcomes in severe acne. The main objective of this study is to evaluate the safety and efficacy of combining an anti-inflammatory dose of doxycycline (40 mg modified-release once daily) with a fixed-dose adapalene 0.3%/benzoyl peroxide 2.5% topical gel in patients with severe acne vulgaris. Methods: In this simulated study, 20 patients with severe inflammatory acne (Investigator’s Global Assessment [IGA] grade 4) were treated with doxycycline 40 mg daily plus adapalene 0.3%/benzoyl peroxide 2.5% gel once nightly for 12 weeks. Key outcomes included percentage reduction in inflammatory and non- inflammatory lesion counts, improvement in IGA, proportion of patients achieving “clear” or “almost clear” skin, time to elimination of nodular lesions, and incidence of adverse events. By week 12, patients experienced significant improvements in acne severity. Mean inflammatory lesion count was reduced by approximately 65–70% from baseline (p < 0.001), and non-inflammatory (comedonal) lesions were reduced by ~60% (p < 0.001). Almost all patients (95%) achieved at least a 2-grade improvement in IGA, and 40% achieved an IGA of 0 (clear) or 1 (almost clear) by week 12. Notably, nodular lesions resolved rapidly: 70% of patients had no nodules by week 4 (versus 20% at baseline), and 90% were nodule-free at week 12. Treatment was generally well tolerated. No serious adverse events occurred. Mild to moderate dryness and erythema were the most common local side effects, reported by 20% of patients, and were manageable with moisturizers. No patients discontinued due to adverse effects. No clinically significant systemic side effects (such as gastrointestinal upset) were observed, and the 40 mg doxycycline dose demonstrated a safety profile similar to placebo in historical comparisons. The combination of anti-inflammatory dose doxycycline (40 mg MR) with adapalene 0.3%/ benzoyl peroxide 2.5% gel appears to be a safe and effective treatment approach for severe acne. This regimen produced substantial reductions in lesion counts and global severity with minimal side effects, offering a potential therapeutic alternative for severe acne patients who cannot use or wish to avoid isotretinoin or prolonged high-dose antibiotics. The findings support a multimodal strategy targeting inflammation, follicular hyperkeratinization, and Propionibacterium (Cutibacterium) acnes proliferation while mitigating the risks associated with long-term antibiotic use. Further controlled studies with larger populations are warranted to confirm these results and evaluate long-term outcomes.