Psoriatic arthritis (PsA) occurs in approximately 30% of patients with psoriasis.1 Although most cases of PsA are linked to underlying cutaneous psoriasis, a direct correlation has not been established. Even though they are clinically linked, the features of PsA and cutaneous psoriasis are distinct. Cutaneous psoriasis commonly presents as chronic, symmetrical, erythematous, scaling papules and plaques, but PsA presents with a diverse combination of musculoskeletal manifestations that can progress to joint or bone lysis, with the most severe form being the telescoping of digits.2,3 Both diseases are associated with a broad range of comorbidities, including cardiovascular disease, osteoporosis, depression, and cancer.4 Among patients with cutaneous psoriasis who develop PsA, the musculoskeletal manifestations of PsA can be disabling, particularly at the advanced stages because of peripheral joint and axial deformities that can result in dramatic joint fusion.3 Understanding the differences in the pathophysiologic mechanisms of these related diseases can help researchers identify pathways that may allow risk prediction and improved treatment.
The treatment of inflammatory skin and joint diseases have advanced significantly in the past decade as improved understanding of the cellular machinery of inflammation has translated to an increasing armamentarium of targeted therapies. These include tumor necrosis factor-α (TNF-α) inhibitors, an array of interleukin (IL) inhibitors (IL-6, IL-12/23, IL-17/23, and IL-17A), Janus kinase inhibitors, and phosphodiesterase 4 (PDE4) inhibitors.5 The classification of PsA as a spondyloarthropathy has informed its treatment focused on agents approved for the treatment of various inflammatory skin and joint diseases. Although these agents have been shown to inhibit PsA radiographic progression, their efficacy is only modest. The reported response rate of 20% improvement in American College of Rheumatology criteria to TNF-α inhibitors ranges between 51% and 65%, whereas the 70% improvement in American College of Rheumatology criteria response ranges only between 10% and 29%.6
The reason why 30% to 60% of patients with PsA do not respond sufficiently to treatment with TNF-α inhibitors is largely unknown. The speculation, however, is that different combinations of genetic factors are thought to play a role.7 Similarly, other agents approved for the treatment of PsA, including IL-12/23 inhibitors, IL-17A inhibitors, PDE4 inhibitors, JAK inhibitors, and T-cell signaling inhibitors, also have a modest to low efficacy.6 Furthermore, the serious adverse events associated with the currently approved agents, including serious infections, heart failure, malignancies, and depression, limit their long-term use.6 The suboptimal or lack of response to agents currently used to treat PsA suggests the involvement of other pathways or drivers of inflammation.
Genome-wide association studies reveal differences in the genetic architecture of PsA and cutaneous psoriasis and provide insight into the pathogenetic similarities and differences between them.1 This is corroborated in a comprehensive review by Furst et al that provides evidence for genetic association with inflammatory markers in PsA pathogenesis and explores the potential application of genes and biomarker proteins in predicting onset and severity of PsA.6 As the pathogenesis of PsA slowly unravels, it is becoming clear that the unique influences of specific genes, epigenetic factors, and cellular inflammation driving disease pathogenesis differ between cutaneous psoriasis and PsA.
It has been postulated that variants of these genes determine the downstream events that distinguish PsA from cutaneous psoriasis.6 For example, among the human leukocyte antigen (HLA) class I genes, HLA-B genes contribute to the musculoskeletal manifestations of PsA, whereas HLA-C genes predominantly contribute to the skin manifestation of PsA. Furthermore, specific combinations of HLA alleles have been associated with specific clinical manifestations that can distinguish different diseases. For example, the B*27:05-C*01:02 haplotype is preferentially associated with enthesitis in spondyloarthropathy, including PsA, but not with rheumatoid arthritis.6 Other HLA-associated genes (major histocompatibility genes, nonmajor histocompatibility susceptibility genes, and epigenetic mechanism) all play a role in the unique pathologic mechanism of PsA that distinguishes it from other inflammatory joint diseases such as rheumatoid arthritis.6,8 These differences offer a potential target for the development of therapeutics specific to PsA and the development of biomarkers as diagnostic prognostic indicators.
Unraveling the unique genetic blueprint of inflammatory joint diseases can, in theory, help identify patients with cutaneous psoriasis who are predisposed to develop PsA. It may also result in the development of targeted therapies that are more efficacious, have more favorable adverse effects, and offer a potential for personalized disease management assisted by biomarkers. Genome-wide association studies can contribute to this effort, suggest Daniel Furst, MD, Carl M. Pearson Professor of Medicine at the David Geffen School of Medicine, Division of Rheumatology, University of California, Los Angeles, Medical Center, and colleagues. “[Genome-wide association studies] will assume greater meaning when communities of dedicated clinicians record clinical data and collaborate with skilled molecular investigators,” wrote Furst and colleagues.6
Dr Furst told Rheumatology Advisor that the application of genetics to answer important clinical questions related to psoriatic diseases is “not ready for prime time,” emphasizing that, “this is work in progress. More work is needed to see if, and how, much of it is valuable.” The evidence to date support potential clinical application of genetic and inflammatory factors associated with PsA. Improved patient stratification to identify which patients with cutaneous psoriasis will develop PsA, and the development of more targeted therapies for PsA, are current challenges that may be addressed.
1. Stuart PE, Nair RP, Tsoi LC, et al. Genome-wide association analysis of psoriatic arthritis and cutaneous psoriasis reveals differences in their genetic architecture. Am J Hum Genet. 2015;97(6):816-836.
2. Langley RG, Krueger GG, Griffiths CE. Psoriasis: epidemiology, clinical features, and quality of life. Ann Rheum Dis. 2005;64(Suppl 2):ii18-ii23.
3. Gladman DD, Antoni C, Mease P, Clegg DO, Nash P. Psoriatic arthritis: epidemiology, clinical features, course, and outcome. Ann Rheum Dis. 2005;64(Suppl 2):ii14-ii17.
4. National Psoriasis Foundation. Comorbidities associated with arthritic diseases. https://www.psoriasis.org/about-psoriasis/related-conditions. Accessed March 15, 2019.
5. Braun J. New targets in psoriatic arthritis. Rheumatology (Oxford). 2016;55(Suppl 2):ii30-ii37.
6. Furst DE, Belasco J, Louie JS. Genetic and inflammatory factors associated with psoriatic arthritis: Relevance to diagnosis and management [published online February 6, 2019]. Clin Immunol. doi:10.1016/j.clim.2019.02.001
7. Hüffmeier U, Mössner R. Complex role of TNF variants in psoriatic arthritis and treatment response to anti-TNF therapy: evidence and concepts. J Invest Dermatol. 2014;134(10):2483-2485.
8. FitzGerald O, Haroon M, Giles JT, Winchester R. Concepts of pathogenesis in psoriatic arthritis: genotype determines clinical phenotype. Arthritis Res Ther. 2015;17:115.