Pathogenesis of Plaque Psoriasis

Copyright not intended.

Psoriasis is an inflammatory skin disease that affects ~125 million individuals worldwide. The condition is genetic: there is a 10% chance of developing psoriasis if one parent has this disease. Recent evidence shows that psoriasis may also have an epigenetic component, studies have found dysregulated DNA methylation levels in psoriasis patients (to learn more about epigenetics, read my previous article).

Symptoms of psoriasis include red dry patchy skin with a silvery appearance on the surface. These lesions are also called plaques and can be very itchy and sore. Plaques around joints can be uncomfortable and often bleed more. Symptoms usually appear during early teens to mid-twenties, but can show up at any age. Triggers include sunburn, medications, infections, and stress.

Many celebrities have opened up about their personal experience with psoriasis, including Kim Kardashian and supermodel Cara Delevingne, and how it has affected their confidence.

Not only does psoriasis affect mental health and self-esteem but also the quality of life (QOL) with 60% of sufferers saying it affects their QOL.

Pathogenesis & Physiology

Diagram showing the differences in the layers of skin in normal skin vs psoriasis. In psoriasis, the skin is inflamed with red plaques and scales (copyright not intended).

The skin is divided into 3 main layers: epidermis, dermis, and the subcutaneous layer. The epidermis itself is made up of developing skin cells called keratinocytes, which have coined the name due to being full of the protein: Keratin. The thickness of the uppermost layer is usually regulated, however, in psoriasis, the skin cells are replaced faster than normal.

In psoriasis, the keratinocytes are abnormal in shape, development, and structure. Due to their abnormality in maturation, these keratinocytes which are usually flattened in shape, have retained their nuclei causing a bumpier appearance.

Further to this, the cells do not adhere properly as they are producing less adhering molecules and do not fit together as well as usual, so this causes breaks in the skin, giving rise to the scaly appearance.

Inflammation & Immune Response

We all have small microbes living on the surface of our skin. When we get a cut in our skin, these microbes may be able to enter and cause an infection. Dendritic cells (a type of immune cell) help to break down the invading microbe. The fragments of the microbe are passed onto T-cells that release small proteins called cytokines i.e. interleukins (IL-12, IL-23, IL-17) and TNF-alpha.

This process results in increased proliferation of keratinocytes and recruits other immune cells to the site of infection. The diagram below demonstrates the complex immune response seen when there is trauma to the skin and how inflammation is kept going in a loop.

The diagram shows the pathogenesis of psoriasis and how the inflammatory response is kept going. Stress or damage to the skin i.e. infection can trigger the inflammatory response. Stressed keratinocytes activate dendritic cells that pass on the fragments of the microbe to the T-cells, which in turn results in releasing cytokines that play a part in keratinocyte activation and the ongoing inflammation. (Young, Aldredge and Parker, 2020)

Once the microbe has been destroyed in normal skin, proliferation eventually returns to normal. However, in psoriasis, this immune response is not turned off and cells continue to proliferate which leads to a thicker layer of cells, this explains the red bumpy lesions. Once psoriasis is triggered there is no going back, and there is also no cure for this skin disease.

Treatment & Trials

There are 3 main types of treatment for psoriasis: topical, phototherapy, and systemic. Topical treatment involves treating the affected area with special creams i.e. aqueous cream or ointments. Some creams can be brought without a prescription, whilst others have to be prescribed by the GP. Phototherapy, a method used by Kim Kardashian herself, involves treating the skin lesions with specific UV light. Finally, systemic treatment can be the use of medication, both orally and via injection. Most patients try different types of treatment options to see what works for them and often use a combination of these methods.

Scientists have a better understanding of the immune response and the role it plays in psoriasis than they did decades ago. This new perception has helped launch research into better more targetted drug therapy. A placebo double-blind clinical trial in 2015 by Papp looked at the effect of the monoclonal antibody as an inhibitor of Interleukin-23 (IL-23).

The study involved 355 patients with chronic plaque psoriasis. The results were promising as there was a significant improvement in plaque psoriasis in individuals given compared to those given the placebo. Further to this, there were no severe side effects reported by individuals. This shows that there is potential in treating psoriasis by inhibiting the cytokines that are released as part of the immune response and thus stopping keratinocyte proliferation.

Drugs take a very long time, often up to 10–15 years, to end up on our shelves or behind the counter. Clinical trials have many phases from phase 0 to phase IV, drugs can get all the way to phase III and fail. Hence why it is important studies are repeated on large cohorts, side effects closely observed, and approval from larger regulatory bodies received.

By understanding the mechanism at work behind psoriasis, this can help scientists improve their drug design and target molecules more precisely. There are several drugs in the pipeline for this condition already, and as we’ve observed from Papp some of these show promising results! Hopefully, in a decade or two, we’ll be able to treat psoriasis more effectively and fewer people will suffer from this painful plaque disease.

A writer of science, health, and anything that interests me.

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