Recent research has focused on multiple pathogenic mechanisms involved in the development of psoriasis, including genetic factors, changes to the gut microbiome and various pathways such as the hypothalamic-pituitary-adrenal axis, sympathetic-adrenal-medullary axis, peripheral nervous system and immune system. The multifactorial etiology of psoriasis seems to be linked to both genetic susceptibility and the presence of comorbid conditions. Currently, no treatments exist that are consistently effective in all patients with psoriasis. Hence, the most recent reviews have focused on the convergence of decades of data collected on these multiple etiologies to identify targeted therapies that are highly individualized.

A Systemic Disorder

Understandably, because of its many skin manifestations, psoriasis was for a long time categorized as a purely dermatologic disorder–in fact, until 1841 it was considered a variation of leprosy.1  Research during the past 3 decades, however, has revealed it to be a systemic disease with multiple underlying immunologic pathogenetic mechanisms that are primarily genetic and triggered by environmental factors.1,2 Pathogenesis is predominantly marked by chronic inflammation that produces widespread keratinocyte hyperproliferation with poor cell differentiation.3

Of the several types of psoriasis–pustular, erythrodermic, guttate, inverse, and even scalp and nail psoriasis–plaque psoriasis is the most common.3,4 Plaques form as a result of inflammatory processes within the epidermal layers triggered by the sudden and over-abundant infiltration of keratinocytes interacting with other types of skin cells already present. This causes massive local disruption of the normal skin turnover cycles, producing areas of profound acanthosis (thickening),  hyperkeratosis, or parakeratosis, which can be identified on histological studies.1


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Genetic Prevalence and Susceptibility

The worldwide prevalence of psoriasis is approximately 2% to3%; it can be as high as 11% among Caucasian and Scandinavian populations, and considerably lower in Asia and Africa.1-3 In Japan, for instance, the prevalence ranges from 0.3% to 0.4%.5 These demographic patterns are an intense area of study for the purposes of identifying targeted treatments in genetic subpopulations with psoriasis.5

Genetic susceptibility to psoriasis can be identified in an estimated 70% of patients, and the disorder tends to run in families.5 Although the predominance in northern European populations is well recognized, large-scale genome-wide association studies (GWASs) have been conducted during the past decade to explore genetic patterns among other ethnic populations.5

Psoriasis becomes symptomatic when a response is triggered in a susceptible individual. Known triggers include streptococcal infection, localized physical traumas ranging from tattoos to surgical procedures, the use of antidepressants, antihypertensives, or anti-cytokine therapies, as well as smoking and abuse of alcohol.1

Comorbidities and the Gut Microbiome

Psoriasis frequently affects both skin and joints, as well as other organ systems.3 Patients with psoriasis often have comorbid conditions such as hypertension, hyperlipidemia, coronary artery disease, type 2 diabetes, and tend to have greater than average body mass.3,6

Of the more recent developments in understanding the pathogenesis of psoriasis is research pointing to origins in the gut, and more specifically, to dysregulation of the gut microbiome related the same comorbid conditions seen with psoriasis. Trimethylamine-N-oxide (TMAO) is a known contributor to cardiovascular diseases and possibly to the development of metabolic disorders such as diabetes mellitus.7 Recent research indicates that the production of its precursor molecule, Trimethylamine, may result from disruption of the gut microbiota.7

Factors such as increased gut permeability and an imbalance of gut bacteria lead to increased liposaccharide levels in the blood that contribute to inflammation and set the stage for metabolic issues such as type 2 diabetes and obesity.7 On an immune level, dysbiosis of gut bacteria exerts a powerful influence on T-cell responses to immune triggers, and can affect basic cell differentiation to promote inflammatory conditions such as colitis. Although these mechanisms are not yet well understood, further investigation is highly promising.

Immunology

Psoriasis is now recognized as a collective of maladaptive inflammatory responses occurring in the skin and other organs that signal significant disruption of the innate and adaptive immune systems.3 The keratinocytes throughout the dermal layers proliferate unchecked, and then interact other cells via multiple pathways. Although many of these remain unknown, the TNF-alpha-IL-23-Th17 pathway has been identified in plaque psoriasis, opening the door to therapies designed to act via this pathway.3 Likewise, T-cell suppression therapies (such a cyclosporin) have demonstrated a key function to T cells in the initiation of psoriasis. 3 B-cell mechanisms have also been implicated in supporting continued T-cell dysfunction, and therapies that act to reduce B-cell production (such as anti-CD20 monoclonal antibodies) have shown promising effects in early trials.3

Once the inflammatory process has been triggered, activation of the adaptive immune response becomes a primary mechanism driving continued proliferation of TH17 cytokines that makes psoriasis a sustained and chronic condition.3 This mechanism is also undergoing investigation.

Influence of Stress

Physical and psychological stress have long been closely associated with the development of psoriasis. Sleep deprivation is a well-recognized trigger.6 More recently, the dual role of psychological stress as both a cause and a consequence of psoriasis have been examined. Stress is mediated via both the hypothalamic-pituitary-adrenal axis and the sympathetic-adrenal medullary axis to have effects on the peripheral nervous system and the immune system, which helps to explain the wide range of potential comorbidities to psoriasis.6

Effective, Targeted Therapies

Exploration of immunologic mechanisms in psoriasis are in early stages of study, but promise to yield important clues to its pathogenesis, and more importantly, to direct the continued search for effective targeted drug therapies.

References

1. Grän F, Kerstan A, Serfling E, Goebeler M, Muhammad K. Current Developments in the Immunology of Psoriasis. Yale J Biol Med. 2020 Mar 27;93(1):97-110.

2. Hugh JM, Weinberg JM. Update on the pathophysiology of psoriasis. Cutis. 2018 Nov;102(5S):6-12.

3. Rendon A, Schäkel K. Psoriasis Pathogenesis and Treatment. Int J Mol Sci. 2019 Mar 23;20(6):1475.

4. Rajguru JP, Maya D, Kumar D, Suri P, Bhardwaj S, Patel ND. Update on psoriasis: A review. J Family Med Prim Care. 2020;9(1):20-24.

5. Ogawa K, Okada Y. The current landscape of psoriasis genetics in 2020. J Dermatol Sci. 2020 Jul;99(1):2-8. doi: 10.1016/j.jdermsci.2020.05.008

6. Yang H, Zheng J. Influence of stress on the development of psoriasis. Clin Exp Dermatol. 2020 Apr;45(3):284-288. doi: 10.1111/ced.14105

7. Komine M. Recent Advances in Psoriasis Research; the Clue to Mysterious Relation to Gut Microbiome. Int J Mol Sci. 2020;21(7):2582.