Researchers are applying lessons learned in the treatment of psoriasis (above) to other immune-mediated diseases.Credit: Simon Stone / SPL / Alamy
Immune-mediated diseases affect nearly 4% of the global population.1 Although various discoveries have provided insights into the immunopathogenesis of many of these diseases, psoriasis is perhaps the best example of how scientific research at the bench can translate into targeted therapies against disease-driving pathways at the bedside. Combining the learnings from psoriasis with the latest advances in scientific approaches could accelerate breakthroughs in other less well-understood and highly complex immune-mediated diseases.
The vast array of autoimmune and inflammatory skin disorders provides an excellent opportunity to study complex skin diseases beyond psoriasis, such as atopic dermatitis and hidradenitis suppurativa. The skin has the advantage of permitting easily accessible and longitudinal sampling of diseased tissue to study the mechanisms during the course of disease. The advent of ’omics technologies, such as transcriptomics, genomics, proteomics, metabolomics and others, coupled with big data, could drive faster discovery.
Learning from psoriasis
Psoriasis is a common inflammatory skin disease that affects 1–3% of the adult population, and is characterized by scaly patches and plaques on the skin.2 A significant number of patients also suffer from psoriatic arthritis.2 The chronic inflammation of the skin can lead to systemic comorbidities, including metabolic syndrome, diabetes and cardiovascular disease, which increases the risks for myocardial infarctions and stroke.3,4
Decades ago, psoriasis was thought to be driven by the keratinocytes in the epidermis. The discovery that immune cells mediated the disease explained the efficacy of immunosuppressive therapies, such as methotrexate and cyclosporine, and provided the rationale for targeting tumor necrosis factor (TNF), as the first advanced therapy.
By investigating mechanisms that persisted after TNF therapy, researchers identified T helper 17 cells (Th17) as the key cellular drivers. This led to targeting Th17 cell signals, including various interleukin (IL) cytokines: IL-23, IL-17A and IL-17F. The resulting therapies led to a remarkable 85–100% of psoriasis patients achieving durable remissions.5,6
The skin’s window to immune responses
Many immune-mediated diseases include skin manifestations, which allow scientists to study the biology of disease-driving immune responses. For example, atopic dermatitis is a highly prevalent skin disease that affects up to 25% of children and 7–10% of adults.7 This disease is associated with other atopic diseases, such as asthma, allergic rhinoconjunctivitis and food allergies.8 Atopic dermatitis has a complex pathogenesis, involving environmental allergen exposures, an imbalance of the skin microbiome, skin-barrier defects, cytokines from T helper cells type 2 (Th2), as well as contributions of mast cells, eosinophils, basophils, innate lymphoid cells, immunoglobulin E and neurocutaneous responses. In combination, this leads to intensely itchy and inflamed skin.
Like psoriasis, a role of T cells in atopic dermatitis was suggested from the efficacy of cyclosporine. Further, specific inhibition of the Th2 cell cytokines IL-4 and IL-13 by the only approved advanced therapy for atopic dermatitis resulted in approximately 50% of patients achieving 75% control of the disease9. Janus kinase inhibitors inhibit additional cytokine responses and have even greater efficacy in atopic dermatitis.9 Still, more work is needed to understand the specific mechanisms for more targeted therapies with higher efficacy, as seen in psoriasis.
Another skin disease, hidradenitis suppurativa, which is linked to inflammatory bowel diseases (such as ulcerative colitis and Crohn’s disease), has different anatomical features.4 These include inflammatory nodules, abscesses, pus-draining sinus tracts and severe and disfiguring scarring, which mostly occur in skin folds, such as in the underarm and groin.4 Many pathogenic responses have been implicated in this disease, including dysbiosis, hair- and skin-gland abnormalities, neutrophilic inflammation, TNF and interferon responses, and recently a role for autoantibodies and plasma cells.10 Similar to psoriasis, hidradenitis suppurativa is associated with several comorbidities, especially metabolic syndrome, including diabetes mellitus, hypertension, dyslipidemia, and obesity. It is also associated with thyroid disease, psychiatric disorders, joint diseases and cancer.11
So far, the only approved advanced therapy for hidradenitis suppurativa targets TNF inhibition, which results in approximately 50% of patients achieving 50% disease control.10 Additional work is greatly needed to better understand the disease-driving mechanisms to identify specific therapeutic targets with improved efficacy.
Applying advances in scientific approaches
To gain insights into the key pathogenic drivers of immune-mediated diseases, the skin has the advantage of being easy to sample, providing the opportunity to obtain tissue from human subjects taken at different times during the disease pathogenesis. The accessibility of the skin permits the use of many different techniques to study immune responses, including the most recent technologies in next-generation deep transcriptomics sequencing, proteomics, metabolomics, genomics and novel imaging technologies to determine the underlying molecular basis of many diseases. Finally, big data analyses, epidemiologic studies and computational biology will provide real-world evidence to better understand skin and other immune-mediated diseases.
Research progress in psoriasis, combined with all of these technologies, put scientists in a good position to enter into a golden age of immunology research that will accelerate development of targeted therapeutics in complex immune-mediated diseases. This is particularly relevant as many immunologic diseases are highly heterogenous with a variety of clinical features, different genetic associations, racial and ethnic differences, and multiple environmental, microbial, and immune responses, all implicated in their pathogenesis.
Importantly, these approaches could be expanded beyond the skin to better understand other immune-mediated conditions, especially in diseases that also have cutaneous manifestations. For example, systemic lupus erythematosus (SLE) patients often have cutaneous lupus and studying samples of the affected skin could provide insights into SLE pathogenesis. Similarly, different types of vasculitis mediated by autoantibodies, immune complexes and complement activation can also be seen in the skin. Studying longitudinal skin samples from these and other disorders could help facilitate the discovery of overlapping pathways and ultimately the development of new targeted treatments.
Innovative approaches to research are allowing us to delve deeper into the biology of immune-mediated skin diseases, which will afford a greater understanding of mechanisms driving these disorders. As we unravel the disease complexities, this knowledge could be rapidly advanced to other autoimmune and inflammatory diseases beyond the skin, providing key insights for developing better, more-targeted medicines.