Introduction
The Current Understanding of Psoriasis Pathogenesis
Corticosteroid and Vitamin D Analog Combination Therapy Results in Increased Effectiveness Versus Monotherapy in the Treatment of Psoriasis
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Dendritic cell cytokine release Corticosteroids and vitamin D analogs both inhibit the release of cytokines, such as IL-23, which are known to stimulate the innate and adaptive immune systems. Furthermore, studies with combination treatment in in vitro cultured dendritic cells have shown additive effects, leading to greater inhibition compared with monotherapies of the active ingredients (Fig. 2, adapted from Lovato et al. [27]).×
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Th17-cell cytokine release Data have shown that pro-inflammatory cytokines (e.g., IL-17A) were inhibited significantly more with combination treatment than monotherapies of the active ingredients in cultured and activated cytotoxic and helper T-cells (Figs. 2, 3) [17, 27]. Reduction of these pro-inflammatory cytokines can inhibit keratinocyte hyperproliferation and abnormal differentiation.
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Keratinocyte pro-inflammatory mediator release Keratinocytes in psoriatic plaques release inflammatory mediators, such as IL-6, IL-8, IL-17C, IL-20, IFN-γ, and AMPs, which leads to the initiation of the pro-inflammatory feedback loop. Combination of corticosteroids and vitamin D analogs inhibits all of the aforementioned pro-inflammatory cytokines more than monotherapies of the active ingredients (Fig. 2) [27].
Corticosteroid and Vitamin D Analog Combination Topical Treatment May Be Able to Provide Long-Term Management of Psoriasis
Summary: Combination Therapy has Complementary Effects on the Underlying Pathophysiology of Psoriasis, Resulting in Increased Therapeutic Response
Corticosteroid and Vitamin D Analog Combination Therapy Attenuates Side Effects Associated with their Individual Monotherapies
Mechanism | Effect of corticosteroids | Effect of vitamin D analogs | Overall clinical effect of combination treatment |
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Lipid synthesis | ⇩ | ⇧ | Prevents skin barrier and water loss impairment caused by corticosteroids |
AMPs, e.g., LL-37 | ⇩ | ⇧ | |
KC proliferation* | ⇩ | = | Attenuates epidermal thinning by corticosteroid-induced reduction of epidermal cells |
Change in tissue modeling and structure: –Hyaluronic acid –Matrix metalloproteinases | ⇩ | ⇧ | Limits epidermal thinning from corticosteroid-induced loss of cellular volume |
Collagen synthesis and turnover | ⇩ | ⇧ | Reduces dermal thinning caused by corticosteroid induced decrease in matrix network |
Glycosamine synthesis | ⇩ | ⇧ | Increases water-binding capacity of the skin, decreasing corticosteroid-induced dermal thinning |
Elastic fiber synthesis | ⇩ | ⇧ | Attenuates reduced skin flexibility/elasticity observed in topical steroidal monotherapy |
Summary: Combination Treatment Minimizes Skin Atrophy and Decreases Other Monotherapy-Related Risks
Challenges of Drug Delivery in Topical Formulations
Summary: Challenges in Drug Delivery
Clinical Benefits of Corticosteroid and Vitamin D Analog Fixed-Dose Combination Treatment
Corticosteroid and Vitamin D Analog Fixed-Dose Combination Treatment is More Efficacious than Monotherapies in Treating the Underlying Psoriasis
An Innovative Drug Delivery Formulation Results in Improved Efficacy
References | Study identifier | Design | Duration (weeks) |
N
| Comparator(s) | Outcomes |
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Queille-Roussel [49] | NCT01347255 | Phase IIa, exploratory, single-center, intra-individual comparison | 4 | 24 | Cal/BD foam vs. Cal/BD ointment vs. BD foam vs. foam vehicle (all n = 24) | TCS decrease: −6.00 vs. −5.25 (Cal/BD ointment; P = 0.038), vs. −4.96 (BD foam; P = 0.005) |
Koo et al. [51] | NCT01536886 | Phase II, randomized, multicenter | 4 | 376 | Cal/BD foam (n = 141) vs. Cal/BD ointment (n = 135) vs. foam (n = 49) and ointment (n = 51) vehicle | Treatment success rates: 54.6% vs. 43.0% (Cal/BD ointment; P = 0.025); mPASI mean difference: −0.6 vs. Cal/BD ointment (P = 0.005) |
Paul et al. [52] | NCT02132936 | Phase III, randomized, parallel-group (PSO-ABLE) | 12 | 463 | Cal/BD foam (n = 185) vs. Cal/BD gel (n = 188) vs. foam (n = 47) and gel (n = 43) vehicle | Treatment success rates: 38% vs. 22% (Cal/BD gel; P < 0.001); mPASI mean difference: −0.6 vs. Cal/BD gel (P = 0.028) |
Paul et al. [53] | NCT02132936 | Phase III, randomized, parallel-group (PSO-ABLE secondary, HRQoL analysis) | 12 | 463 | Cal/BD foam (n = 185) vs. Cal/BD gel (n = 188) | DLQI scores of 0/1: 61% vs. 44% (Cal/BD gel; P = 0.003); EQ-5D utility index: 0.09 vs. 0.03 (Cal/BD gel; P < 0.001) |