Psoriasis- Cause, Immunology, Treatment

Psoriasis is an autoimmune disease that affects the skin. It occurs when the immune system mistakes the skin cells as a pathogen, and sends out faulty signals that speed up the growth cycle of skin cells. Psoriasis is not contagious. However, psoriasis has been linked to an increased risk of stroke, and treating high blood lipid levels may lead to improvement. There are five types of psoriasis: plaque, guttate, inverse, pustular, and erythrodermic. The most common form, plaque psoriasis, is commonly seen as red and white hues of scaly patches appearing on the top first layer of the epidermis (skin). Some patients, though, have no dermatological signs or symptoms.

In plaque psoriasis, skin rapidly accumulates at these sites, which gives it a silvery-white appearance. Plaques frequently occur on the skin of the elbows and knees, but can affect any area, including the scalp, palms of hands and soles of feet, and genitals. In contrast to eczema, psoriasis is more likely to be found on the outer side of the joint.

The disorder is a chronic recurring condition that varies in severity from minor localized patches to complete body coverage. Fingernails are frequently affected (psoriatic nail dystrophy) and can be seen as an isolated sign. Psoriasis can also cause inflammation of the joints, which is known as psoriatic arthiritis. Between 10—30% of all people with psoriasis also have psoriatic arthritis.

The cause of psoriasis is not fully understood, but it is believed to have a genetic component and local psoriatic changes can be triggered by an injury to the skin known as the Koebner phenemenon. Various environmental factors have been suggested as aggravating to psoriasis, including stress, withdrawal of systemic corticosteroids as well as other environmental factors, but few have shown statistical significance. There are many treatments available, but because of its chronic recurrent nature, psoriasis is a challenge to treat. Withdrawal of corticosteroids (topical steroid cream) can aggravate the condition due to the 'rebound effect' of corticosteroids.

Cause

The cause of psoriasis is not fully understood. There are two main hypotheses about the process that occurs in the development of the disease. The first considers psoriasis as primarily a disorder of excessive growth and reproduction of skin cells. The problem is simply seen as a fault of the epidermis and its keratinocyes. The second hypothesis sees the disease as being an immune-mediated disorder in which the excessive reproduction of skin cells is secondary to factors produced by the immune system. T cells (which normally help protect the body against infection) become active, migrate to the dermis and trigger the release of cytokines ( tumour necrosis factor – alpha, TNFα, in particular) which cause inflammation and the rapid production of skin cells. It is not known what initiates the activation of the T cells.

The immune-mediated model of psoriasis has been supported by the observation that immunosupressant medications can clear psoriasis plaques. However, the role of the immune system is not fully understood, and it has recently been reported that an animal model of psoriasis can be triggered in mice lacking T cells. Animal models, however, reveal only a few aspects resembling human psoriasis.

Compromised skin barrier function has a role in psoriasis susceptibility.

Psoriasis is a fairly idiosyncratic disease. The majority of people's experience of psoriasis is one in which it may worsen or improve for no apparent reason. Studies of the factors associated with psoriasis tend to be based on small (usually hospital based) samples of individuals. These studies tend to suffer from representative issues, and an inability to tease out causal associations in the face of other (possibly unknown) intervening factors. Conflicting findings are often reported. Nevertheless, the first outbreak is sometimes reported following stress (physical and mental), skin injury, and stresptococcal infection. Conditions that have been reported as accompanying a worsening of the disease include infections, stress, and changes in season and climate. Certain medicines, including lithium salt, beta blockers and the anti-malarial chloroquine have been reported to trigger or aggravate the disease. Excessive alcohol consumption, smoking and obesity may exacerbate psoriasis or make the management of the condition difficult or perhaps these comorbidities are effects rather than causes.Hairspray, some face creams and hand lotions, can also cause an outbreak of psoriasis.In 1975, Stefania Jablonska and collaborators advanced a new theory that special antibodies tend to break through into the lower layers of the skin and set up a complex series of chemical reactions.

Immunology

In psoriasis, immune cells move from the dermis to the epidermis, where they stimulate skin cells (keratinocytes) to proliferate. Psoriasis does not seem to be a true autoimmune disease.In an autoimmune disease, the immune system confuses an outside antigen with a normal body component, and attacks them both. But in psoriasis, the inflammation does not seem to be caused by outside antigens (although DNA does have an immunostimulatory effect). Researchers have identified many of the immune cells involved in psoriasis, and the chemical signals they send to each other to coordinate inflammation. At the end of this process, immune cells, such as dendritic cells and T cells, move from the dermis to the epidermis, secreting chemical signals, such as tumor necrosis factor-α, interleukin-1β, and interleukin-6, which cause inflammation, and interleukin-22, which causes keratinocytes to proliferate.

The immune system consists of an innate immune system, and an adaptive immune system.

In the innate system, immune cells have receptors that have evolved to target specific proteins and other antigens which are commonly found on pathogens. In the adaptive immune system, immune cells respond to proteins and other antigens that they may never have seen before, which are presented to them by other cells. The innate system often passes antigens on to the adaptive system. When the immune system makes a mistake, and identifies a healthy part of the body as a foreign antigen, the immune system attacks that protein, as it does in autoimmunity.

Proposed model of psoriasis pathogenesis highlighting the role of IFN-α-primed moDCs, TLR stimulation and T lymphocytes.Under inflammatory conditions, blood-derived monocytes are potential precursors of skin DCs. GM-CSF necessary for DC development is produced by a variety of cell types in skin (neutrophils, keratinocytes, macrophages, mast cells, lymphocytes and fibroblasts). IFN-α (a physiological factor for DC development) is mainly produced by pDCs. Stressed keratinocytes (through environmental factors including viral infections) release self-DNA and self-RNA that form complexes with the cathelicidin antimicrobial peptide LL37. Self-DNA-LL37 and self-RNA-LL37 complexes activate pDCs to produce IFN-α. Self-RNA-LL37 complexes and viral ssRNA directly promote the phenotypical and functional maturation of IFN-α-primed moDCs. Other factors released by stressed keratinocytes include IL-1β, IL-6 and TNF-α, which very likely influence IFN-α-primed moDC development. Furthermore IFN-α-primed moDCs produce IFN-α and IFN-γ themselves further contributing to their own maturation. In vivo under inflammatory conditions other cytokines such as IL-1β, IL-6 and TNF-α and IFN-γ are also present in the psoriatic inflammatory infiltrate produced by lymphocytes, macrophages, fibroblasts, NK T cells and keratinocytes therefore IFN-α-primed moDCs are influenced by a variety of proinflammatory cytokines. Mature IFN-α-primed moDCs then possibly migrate to the skin-draining lymph nodes where they promote naive T cell differentiation into Th1 and/or Th17 cells through IL-12 and IL-23. These T cells migrate via lymphatic and blood vessels into psoriatic dermis and contribute to the formation of a psoriatic plaque. Th1 cells produce TNF-α and IFN-γ, which also stimulate keratinocyte proliferation. Th17 cells secrete IL-17A, IL-17F and IL-22, which stimulate keratinocyte proliferation and the release of proinflammatory cytokines, antimicrobial peptides and chemokines. Th1 and Th17 cells can directly interact with monocytes by producing GM-CSF, TNF-α and IFN-γ and instruct these cells to differentiate into specialized moDC subsets. Figure is modified from Ref. 7. Reproduced with permission from John Wiley & Sons, Inc. All rights reserved. Abbreviations: moDC, monocyte-derived dendritic cell; GM-CSF, granulocyte/macrophage colony-stimulating factor; IFN, interferon; IL, interleukin; LL37, cathelicidin antimicrobial peptide; NK, natural killer; pDC, plasmacytoid dendritic cell; ssRNA, single-stranded RNA; Th, T-helper; TNF, tumour necrosis factor.

In psoriasis, DNA is an inflammatory stimulus. DNA stimulates the receptors on plasmacytoid dendritic cells, which produce interferon-α, an immune stimulatory signal (cytokine). In psoriasis, keratinocytes produce antimicrobial peptides. In response to dendritic cells and T cells, they also produce cytokines, such as interleukin-1, interleukin-6, and tumor necrosis factor-α, which signals more inflammatory cells to arrive and produces further inflammation.

Dendritic cells bridge the innate and adaptive immune system. They are increased in psoriatic lesions and induce the proliferation of T cells and type 1 helper T cells. Certain dendritic cells can produce tumor necrosis factor-α, which calls more immune cells and stimulates more inflammation. Targeted immunotherapy, and psoralen and ultraviolet A (PUVA) therapy, reduces the number of dendritic cells.

T cells move from the dermis into the epidermis. They are attracted to the epidermis by alpha-1 beta-1 integrin, a signalling molecule on the collagen in the epidermis. Psoriatic T cells secrete interferon-γ and interleukin-17. Interleukin-17 is also associated with interleukin-22. Interleukin-22 induces keratocytes to proliferate.

One hypothesis is that psoriasis involves a defect in regulatory T cells, and in the regulatory cytokine interleukin-10.

Is psoriasis curable?

No, psoriasis is not currently curable. However, it can go into remission and show no signs of disease. Ongoing research is actively making progress on finding better treatments and a possible cure in the future.

What is the treatment for psoriasis?

There are many effective treatment choices for psoriasis. The best treatment is individually determined by the treating physician and depends, in part, on the type of disease, the severity, and the total body area involved.

For mild disease that involves only small areas of the body (like less than 10% of the total skin surface), topical (skin applied) creams, lotions, and sprays may be very effective and safe to use. Occasionally, a small local injection of steroids directly into a tough or resistant isolated psoriasis plaque may be helpful.

For moderate to severe disease that involves much larger areas of the body (like 20% or more of the total skin surface), topical products may not be effective or practical to apply. These cases may require ultra-violet light treatments or systemic (total body treatments such as pills or injections) medications. Internal medications usually have greater risks.

For psoriatic arthritis, systemic medications are generally required to stop the progression of permanent joint destruction. Topical therapies are not effective.

It is important to keep in mind that as with any medical condition, all medications carry possible side effects. No medication is 100% effective for everyone, and no medication is 100% safe. The decision to use any medication requires thorough consideration and discussion with your physician. The risks and potential benefit of medications have to be considered for each type of psoriasis and the individual patient. Some patients are not bothered at all by their skin symptoms and may not want any treatment. Other patients are bothered by even small patches of psoriasis and want to keep their skin clear. Everyone is different and, therefore, treatment choices also vary depending on the patient's goals and expressed wishes.

An approach to minimize the toxicity of some of these medicines has been commonly called "rotational" therapy. The idea is to change the antipsoriasis drug every six to 24 months in order to minimize the possible side effects from any one type of therapy or medication.

In another example, a patient who has been using strong topical steroids over large areas of their body for prolonged periods may benefit from stopping the steroids for a while and rotating onto a different therapy like calcitriol (Vectical), light therapy, or an injectable biologic.