Efficacy and Safety of Dual Targeted Therapy Using Biologics and Small Molecules for Psoriasis and Comorbidities: A Systematic Review

To the Editor,

Psoriasis is a T-helper 17 (Th17) driven chronic immune-mediated inflammatory skin disease that may co-exist with other inflammatory skin conditions, with increasing reports of dual targeted therapy usage targeting the Th17 pathway in addition to other immunologic pathways.^1,2 This systematic review summarizes the evidence on the efficacy and safety of dual targeted therapies in patients with psoriasis.

Following Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines, MEDLINE and Embase were searched using specific keywords (Supplemental Table 1). Evidence quality was assessed using the Oxford Centre for Evidence-Based Medicine 2011 Levels of Evidence. Articles were independently screened by 2 reviewers, resulting in 39 articles reporting on 125 patients (Supplemental Figure 1 and Supplemental Table 2). Mean age was 48.6 years (range: 17-78) with 59.6% (68/114) being male.

Of the 125 patients, 72.8% (91/125) received dual targeted therapy for psoriasis only, 16.0% (20/125) for psoriasis with atopic dermatitis (AD), 3.2% (4/125) for psoriasis with psoriatic arthritis, 2.4% (3/125) for psoriasis with bullous pemphigoid, 1.6% (2/125) for psoriasis with prurigo nodularis, 1.6% (2/125) for psoriasis with asthma, 0.8% (1/125) for psoriasis with multiple sclerosis, 0.8% (1/125) for psoriasis with chronic spontaneous urticaria, and 0.8% (1/125) for psoriasis with ulcerative colitis. Mean follow-up duration was 11.7 months (range: 1.5-132.9).

Among 91 patients with only psoriasis, the most commonly reported dual targeted therapies included apremilast with ustekinumab (33.0%, 30/91) and apremilast with secukinumab (8.8%, 20/91; Supplemental Table 3). All patients achieved improvement except 2 (2.2%) patients (apremilast with ustekinumab [n = 1], adalimumab with infliximab [n = 1]). The greatest reductions in Psoriasis Area and Severity Index (PASI) were achieved by apremilast with infliximab (−96.6%, n = 1; 24.0 weeks) and apremilast with secukinumab (−91.4%, n = 6; 29.0 weeks).

Among 20 patients with psoriasis and AD, the most common dual targeted therapies included dupilumab with guselkumab (60.0%, 12/20) and dupilumab with risankizumab (20.0%, 4/20). All patients achieved improvement except 1 (5.0%) patient receiving dupilumab with guselkumab. The greatest reductions in PASI were achieved by dupilumab with risankizumab (−100%, n = 1; 66.5 weeks) and dupilumab with secukinumab (−80.0%, n = 1; 40.0 weeks). The greatest reduction in Eczema Area and Severity Index was achieved by dupilumab with risankizumab (−100%, n = 1; 66.5 weeks).

Adverse events (AEs) were reported in 23.2% (29/125) patients, most commonly diarrhea (27.6%, 8/29; apremilast with ustekinumab [n = 3], apremilast with secukinumab [n = 2], apremilast with ixekizumab [n = 2], apremilast with adalimumab [n = 1]) and nausea (20.7%, 6/29; apremilast with ustekinumab [n = 4], apremilast with ixekizumab [n = 2]). Three (2.4%) patients discontinued treatment due to treatment-related AEs.

Psoriasis pathogenesis is primarily driven by the Th17 pathway, explaining the efficacy of phosphodiesterase-4 inhibitors, Janus kinase inhibitors, and biologic agents with anti-Th17/IL-23 properties.^{3 -5} While this study is limited by small sample size and reporting bias due to reliance on small case reports/series, our results demonstrate that biologic and small molecule therapies were safe when used in combination, with no reports of serious infection even when combined with biologics targeting other immune pathways (ie, Th2 in AD). Dual targeted therapies may be safe and efficacious as add-on therapy for patients with psoriasis refractory to monotherapy and for those with comorbidities that also warrant targeted therapy. Large, prospective studies are warranted.