Combination Therapy for Plaque Psoriasis: A Reappraisal of Cyclosporine and Acitretin

Despite the widespread adoption of biologics in psoriasis management, traditional systemic therapies remain essential for many patients—particularly those with contraindications to immunomodulatory biologics or limited access due to cost or comorbidities. A randomized controlled trial published in Frontiers in Medicine, provides timely evidence supporting a combination strategy using cyclosporine A (CsA) and acitretin for moderate-to-severe plaque psoriasis.

This multicenter, open-label trial randomized 345 adults with moderate-to-severe plaque psoriasis to receive CsA plus acitretin, CsA alone, or acitretin alone. Inclusion criteria reflected clinical practice: PASI ≥12 or BSA ≥10%, and insufficient response to topical or phototherapy without recent biologic use. Treatment lasted 12 to 16 weeks, with follow-up through week 24. Although not blinded due to differing dosing and monitoring requirements, efficacy was assessed by independent, blinded dermatologists—a key design strength.

Faster onset, deeper response with combination therapy

The combination therapy group consistently outperformed monotherapies across all key efficacy metrics:

• By week 4, 64% achieved PASI75 and 22% achieved PASI90, compared with <21% and <3%, respectively, in either monotherapy arm (p < .001).
• At week 12, PASI75 and PASI90 were achieved in 89% and 67% of the combination group, versus 71–84% and 16–30% with monotherapies.
• These differences persisted through week 24, with PASI90 response in 77% of the combination group compared to 34% for acitretin and 59% with CsA.

Importantly, these outcomes were achieved with lower average doses, suggesting dose-sparing synergy without compromising efficacy.

Tolerability profile supports feasibility

Adverse events (AEs) were largely mild and manageable. Acitretin-related dryness and dyslipidemia were significantly reduced in the combination group, while CsA-related hypertension remained the most frequent serious AE, albeit occurring less often in combination users. Hepatic enzyme elevations were numerically higher in the combination arm but not statistically significant, and all resolved with dose adjustment or discontinuation.

DLQI scores and BSA involvement improved across all groups, but the combination arm showed earlier improvement in both measures. These gains leveled off after week 12, reflecting real-world patterns where medication tapering often occurs with symptom control.

While the study offers compelling efficacy data, several limitations temper generalizability. Patients with psoriatic arthritis, erythrodermic, or pustular subtypes were excluded. The open-label design introduces performance bias in patient-reported outcomes, although objective endpoints were blinded. Slight baseline imbalances in BSA may have influenced early outcome differences, despite the use of relative PASI reductions as endpoints.

For patients with moderate-to-severe plaque psoriasis who are ineligible for biologics—or require rapid control with oral agents—combining CsA and acitretin may offer enhanced efficacy with reduced exposure to each drug. This approach could be especially valuable in resource-limited settings or where long-term monotherapy is poorly tolerated.

Further research should explore optimal dosing windows, long-term safety, and comparative effectiveness versus newer oral agents. But for now, this trial reaffirms the enduring relevance of traditional systemic agents when used strategically.

Reference:

Xu K, Yuan P, Jia S, et al. Efficacy and safety of cyclosporine a combined with acitretin in moderate-to-severe plaque psoriasis: a randomized controlled trial. Front Med (Lausanne). 2025;12:1667058. Published 2025 Sep 26. doi:10.3389/fmed.2025.1667058