Psoriasis and lasting implications

Abstract

Psoriasis is a chronic immunological disorder that affects the joints and skin. The disease is strongly correlated with genetic predisposition and environmental factors that can act as triggers of the innate and adaptive immune response. Once this immune response has begun many different signaling factors lead to inflammation and plaques which are visible throughout the body. As psoriasis progresses, it strongly affects the mental and physical health of the individual. This article reviews the different types of psoriasis, genetic and environmental triggers of psoriasis, the molecular progression of psoriasis, and current and future therapies.

Keywords::

• epidermal hyperplasia
• monoclonal antibodies
• NK lymphocytes
• plaques
• psoriasis
• PSORS
• TNF-α

Prevalence & characteristics of psoriasis

Psoriasis is a chronic inflammatory skin disorder that affects approximately 2% of the human population around the world [1]. Plaque psoriasis, affecting >80% of psoriasis patients, is the most common type, and it is characterized by irregular, red, scaly patches distributed over the body, but mostly appearing around the elbows, knees, scalp and lower back [2]. These plaques grow at an abnormal rate as a result of epidermal hyper proliferation and dermal inflammation. The degree to which the plaques spread throughout the skin and the length of the condition are highly variable, depending on the individual patient. Relapses of plaque psoriasis are known to occur, and it appears to be a lifelong condition, although not fatal.

Other forms of psoriasis such as guttate, inverse and pustular mostly appear in children, overweight individuals and adults, respectively [3]. Guttate psoriasis in children is usually triggered by an upper respiratory infection and is associated with small, pink–red dots around the arms and thighs [4]. These usually leave after a few weeks; however, more persistent cases may require treatment. Inverse psoriasis is accompanied by bright red, smooth, shiny lesions around the armpits and private regions in overweight individuals [5]. Pustular psoriasis, although uncommon, creates pus-filled bumps (pustules) that lead to serious complications such as fevers, chills, nausea, increased heart rate and muscle weakness [6]. Although the causes of psoriasis are not fully understood, there are two main hypotheses about the process and development of the disease: genetic predisposition and environmental triggers for an inflammatory cascade.

Relationship between genetics & the onset of psoriasis

Plaque psoriasis is a multifaceted disease, a large component of which is hereditary. Most of the genes associated with psoriasis involve T cells and the major histocompatibility complex [7]. Mutations within these genes and specifically PSORS1–PSORS9 lead to inflammation, a critical component of psoriasis [7]. For instance, HLSA-Cw6 encodes for a major histocompatibility complex Class I protein, and CDSM variant 5 encodes for corneodesmosin, which is found upregulated in the epidermis of psoriasis patients [8]. In addition, IL-12B of chromosome 5q and IL-23R of chromosome 1p express IL-12B and IL-23 receptors, respectively [9]. These interleukins are involved in T-cell differentiation, which play a critical role within the inflammatory cascade. In the same gene pathways are TNF-α and NFκB, both of which are involved in inflammation [10]. In addition, recent evidence has shown that individuals with IL36RN mutations develop general guttate psoriasis [11].

Antigen exposure & the molecular progression of psoriasis

Even though genetics play a prominent, albeit not fully understood, role in psoriasis, oftentimes, an environmental trigger is needed to begin the inflammatory cascade. In the adaptive immune response, an unknown antigen triggers antigen-presenting skin cells to enter the lymphatic system. These cells travel through the lymphatic system to activate T cells [12]. Upon activation, T cells begin to secrete cytokines (proteins), which lead to an inflammatory cascade and eventually psoriatic skin plaques.

In contrast to the adaptive immune response, the mechanisms of the innate immune system in the pathogenesis of psoriasis are identified by more discernible characteristics. Toll-like receptors are type 1 membrane glycoproteins that are able to detect pathogen-associated molecular patterns, which then lead to downstream signaling pathways and an inflammatory cascade [13]. In the inflammatory cascade, the keratinocyte barrier can be disrupted and lead to activated natural killer (NK) lymphocytes, which express natural killer receptors. NK lymphocytes produce high levels of IFN-γ, which work cooperatively with TNF-α, which are produced by keratinocytes and other types of immune cells. The IFN-γ along with TNF-α leads to inflammation, which is the physical demarcation of plaque psoriasis [14].

After their initial activation, the NK lymphocytes escape the lymphatic system and spread to the epidermal layer. Within this layer, the NK lymphocytes lead to excessive epidermal growth thereby inducing greater inflammation. This inflammation is mediated via cytokines, but not limited to TNF-α [15]. The cytokines engender additional cytokines by inducing other immune cells via an auto-feedback mechanism. This mechanism works with immune and nonimmune cells within the local environment for a greater perpetuation of the inflammatory response.

TNF-α, which stimulates the production of chemokines, is a chemoattractant protein that mediates the stimulation and activation of lymphocytes. TNF-α upregulates adhesion molecules and then facilitates lymphocytes to the skin. It also increases the VEGF that increases capillary permeability in angiogenesis. This increase in capillary density, recruitment of immune cells to the epidermis and accumulation of keratinocytes and additional mediators within the inflammatory cascade, all lead to erythema and psoriatic plaques [16].

The most prevalent feature of psoriasis is epidermal hyperplasia, in which epidermal layers increase the proliferation of keratinocytes with notable abnormalities in the inflammatory process. Within the focal skin regions, which are mediated by CD8⁺ and CD4⁺ T lymphocytes, the type 1 effectors accumulate and cause epidermal changes created by additional cytokines such as IL-12 and IL-23 along with IFN-γ and TNF-α [17]. The IL-12 and IL-23 cytokines connect the CD4⁺ T-cell differentiation and activation to the T helper 1 cell phenotype. Hence, targeting the cytokines are an effective therapeutic goals.

Mental health of individuals

Psoriatic patients have physical plaques that can cover nearly the entire human body. Chronic relapses of these plaques are known to occur and cause significant psychological distress upon these individuals [18]. Notably, the stress produced is connected to the inflammatory cascade by the neuroendocrine system, which shows a mechanism by which plaque psoriasis can progress [19]. Psoriatic patients experience episodes of intense stress that leads to changes in the serum cortisol levels and the pituitary–adrenocortical axis; such changes affect the regulatory mechanisms within the neuroendocrine system that leads to further progression of plaque psoriasis [19].

Current & future therapies

Currently, there are a wide range of therapies to combat plaque psoriasis. These therapies include topical agents, systemic therapies and biological drugs to combat the key agents within the inflammatory cascade. In the past 25 years, significant research has been done on using biological immunosuppressant therapies, and it has been shown to be effective within late phase clinical trials [20]. Specifically, anti-TNF-α monoclonal antibodies (mAbs) target cytokines, the p40 shared domain of IL-12 and IL-23 and the anti-inflammatory pathway. Abbott Laboratories has developed adalimumab, which is a fully human anti-TNFα mAb, as a therapeutic drug that has been approved by US FDA to treat plaque psoriasis [20]. Similarly, Amgen has developed etanercept, an anti-TNF-α dimeric fusion protein to treat moderate-to-severe psoriasis [20]. In addition, Janseen Biotech has developed infliximab, which is a mouse–human chimeric anti-TNF-α mAb-based drug to treat psoriasis and psoriatic arthritis [20].

These biological immunosuppressant therapies incorporate anti-TNF-α agents to neutralize soluble TNF-α, which then leads to a variety of effects within TNF-α cells. The therapies introduced by Abbott, Amgen and Janssen are clinically effective and have side effects that do not lead to significant risk of infections [20]. However, current approaches can be improved by better understanding the molecular progression of plaque psoriasis and developing future therapies to target immune cell receptors, chemokines and additional agents within the inflammatory cascade.

Expert commentary

Psoriasis is a disease that, although not fatal, ranks with chronic lung failure, congestive heart disease and Type 2 diabetes as a disease that most greatly affect the mental and physical health of patients. Currently, roughly 2% of people in the world are living with some form of psoriasis, and this number is expected to rise by the end of the decade. Although there are many different forms of psoriasis that has different risk factors and slightly different environmental triggers and genetic predisposition, there are a wide range of therapies to combat this disease. Phototherapy can lead to keratinocyte apoptosis, cortical steroids can be applied as topical agents, and systemic agents work throughout the body. The most effective therapy, currently, is biological drugs; one type is the TNF-α blocker, which inhibits TNF-α to prevent inflammation, a significant factor in plaque psoriasis. Future therapies will become more encompassing and not only better deal with TNF-α but also with other cytokines and cells involved within the inflammatory cascade.

Five-year view

In the next 5 years, additional psoriasis research will allow for greater understanding of the molecular progression of psoriasis. This research, in conjunction with the new knowledge developed from research of autoimmune diseases, will allow for a more comprehensive treatment of plaque psoriasis. More specifically, we will see a significant growth in biological therapies to target T cells, TNF-α and interleukins. There are many new psoriasis drugs in the market and in late phase clinical trials. Some of these biological drugs include AMB 827 (which inhibits IL-17 receptor), briakinumab (which blocks IL-12 and IL-23) and voclosporin (which blocks calcineurin, a protein phosphatase that is involved in T-cell activation). These and many more biological therapies, including ustekinumab and golimumab, which were recently marketed by Janssen Pharmaceuticals, show much promise in treating plaque psoriasis.

Financial & competing interests disclosure

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.