New Therapies for Psoriasis and Psoriatic Arthritis

Christopher T. Ritchlin; James G. Krueger


Curr Opin Rheumatol. 2016;28(3):204-210. 

In This Article

Psoriasis Vulgaris: Pathobiology and Therapies are Highly Linked

Psoriasis vulgaris is an autoimmune disease of the skin, but it is associated with systemic inflammation and co-morbid conditions that are linked to inflammatory processes, e.g., PsA, cardiovascular disease, and inflammatory bowel disease. In the skin, lesions are created primarily by two immune cell types: myeloid (CD11+) dendritic cells and T-cells that produce 'driver' cytokines of this disease and those cytokines act upon keratinocytes and other skin-resident cell types to create a hyper-proliferative epidermis that is associated with vascular proliferation, vascular dilation, and dermal inflammation. Clinically, these cellular changes produce red, raised plaques that typically have white-to-silver scales on the surface. Usually disease severity is classified by the extent or location of inflammatory lesions, with mild disease defined as <10% affected skin surface and moderate-to-severe disease as >10% skin surface, or affecting critical functional regions such as the hands or feet. New therapies have been developed primarily for moderate-to-severe disease, which is judged to be so extensive that it is beyond treatment with topical agents. In turn, these therapies have been developed with a growing understanding of pathogenic immune cell/cytokine circuits that drive the skin disease and may also contribute to disease co-morbidities.

The central immune axis that drives psoriasis vulgaris is created by at least two endogenous autoantigens [cathelicidin/LL-37 and ADAMTS-like protein 5 (ADAMTSL5)], ensuing T-cell activation, and the production of a Type 17 (Th17/Tc17) polar response that releases interleukin-17 and other associated cytokines.[4,5] The immune response is shaped by antigen presentation by a large number of cutaneous myeloid dendritic cells that produce the cytokine interleukin-23, a key 'driver' cytokine of Type 17 (T17) T-cell activation and polarization. Interleukin-23 production is stimulated in these dermal dendritic cells by TNF, which may be overproduced in psoriasis lesions by a combination of dendritic cells, T-cells, and other cell types. Interleukin-23 also shapes the immune response towards the activation of Th22 T-cells which release the cytokine interleukin-22 when activated. Interleukin-17, interleukin-22, and TNF all act upon keratinocytes, individually and in synergy, to change gene transcription programs in this cell type – the direct response to these cytokines involves hundreds of genes with increased or decreased expression. The induced genes include psoriasin (S100A7), Chemokine Ligand 20 (CCL20), cathelicidin/LL-37, CXCL1, 2, 3 & 8, interleukin-19, and interleukin-36 isoforms. Epidermal hyperplasia occurs in response to interleukin-22, interleukin-19, interleukin-36 and other 'classic' growth factors such as Epidermal Growth Factor (EGF)-family (TGF-α, amphiregulin) and FGF-family (KGF, FGF) that are overproduced in lesions, while vascular proliferation is driven by other keratinocyte-produced cytokines such as Vascular Endothelial-Cell Growth Factor and Platelet Derived Growth Factor. CCL20 is a cytokine that 'feeds forward' to stimulate dendritic cells and T17 T-cell influx, CXCL1, 2, 3 & 8 create neutrophilic influx, and cathelicidin/LL-37 promotes both dendritic cell activation and serves as a probable autoantigen in psoriasis.[6,7] Key therapeutic 'nodes' in this inflammatory reaction include TNF, interleukin-23, and interleukin-17, as biologic antagonists to each of these cytokines can induce high-grade clinical improvements in psoriasis as measured by the PASI score. A desirable outcome from treatment is at least 75% improvement in the PASI score (a PASI75), although the treatment target is moving towards a PASI90 or even a PASI100 (no residual disease).

Several features differentiate psoriatic from rheumatoid synovium including a lesser degree of lining cell hyperplasia, increased vascularity, infiltration of neutrophils, and the absence of a shared epitope.[8] The mechanisms responsible for the divergent histopathologies in PsA and rheumatoid arthritis (RA) were not well understood but reports of an important role for Th17 cells began to emerge.[9,10] Additional studies identified interleukin-17 producing CD4- and CD8+ cells in the synovial fluid of PsA but not rheumatoid joints. Moreover, a subset of innate lymphocytes (ILC-3) were also expanded in psoriatic but not RA synovial fluid and these cells also expressed interleukin-17. These findings in human tissues coupled with mouse models that demonstrated the importance of the interleukin-23-interleukin-17 axis in the development of not only arthritis but also enthesitis, dactylitis, axial disease, and psoriasiform lesions supported the concept that interleukin-23, interleukin-17, interleukin-22, along with TNF, are key cytokines in PsA pathogenesis (reviewed in[11]). In separate studies, the phosphodiesterase inhibitor (PDE4) was shown to raise cAMP levels in immune cells and lessen the release of inflammatory cytokines.[12] Another oral agent, tofacitinib, a Janus kinase (JAK) inhibitor blocks multiple pathways in hematopoietic and immune cells and showed efficacy in RA.[13] Based on the findings related to the pathogenesis of psoriasis and PsA outlined above, clinical trials were initiated to examine if agents that target cAMP or the IL-23-IL-17 or JAK pathways are effective in psoriatic disease.