Dr. Marlis Sarkany

	Of all the stunning advances medical science has made over the past few decades, perhaps few are more pronounced than the treatment of psoriasis. In the 1950s, common remedies included arsenic, ammoniated mercury, and coal tar. In the ‘60s and ‘70s, heavy advertising promoted a “new healing discovery” called Tegrin, a coal tar product promising relief from “the heartbreak of psoriasis.” Methotrexate, the first breakthrough in systemic treatment, became common in the 1970s.

	It’s just in the past two decades that advances in psoriasis therapy have greatly accelerated. Growing understanding of the genetic, immunological, and environmental factors that contribute to the condition’s pathogenesis have led to development of targeted, precision therapies that alleviate patient morbidity and improve quality of life, especially in patients with moderate to severe symptoms. These developments have produced life-changing results for those afflicted with this widely debilitating condition.

	Psoriasis is a chronic skin disorder and the most prevalent autoimmune disease in the United States, affecting as many as 7.5 million Americans-and at least 100 million worldwide. A recent study of the disease’s burden estimated the annual direct and indirect costs of psoriasis as high as $25,796 per person, or about $135 billion annually.

The disease is characterized by exaggerated and disordered epidermal cell proliferation and keratinization. Despite advances in our understanding of the disease, the precise chain of events that culminates in this aberrant keratinization remains unclear.

	Although psoriasis itself does not often affect survival, it is associated with a variety of comorbidities that include psoriatic arthritis, metabolic syndrome, cardiovascular disease, Type 2 diabetes, inflammatory bowel disease, and depression.

It also can seriously diminish patients’ quality of life. In fact, patients with psoriasis have a reduction in their quality of life similar to, or worse than, patients with other chronic diseases such as heart disease and diabetes.

	The disease is primarily seen in adults, but approximately 10-15 percent of psoriasis presents in childhood. About eight in 10 of those diagnosed have mild to moderate disease, while the remaining 20 percent have moderate to severe affliction that affects more than 5 percent of their body surface area.

Up to 40 percent of people with psoriasis-generally the more severely affected-have a concomitant destructive arthritis called psoriatic arthritis.

For these patients, skin and joint symptoms tend to flare and remit simultaneously.

	Psoriasis is a complex, multifactorial condition related to a combination of genetic, immunological, and environmental factors. While it is a genetic disease, the mechanisms of inheritance are complex and involve at least nine distinct genes.

It arises as a result of dysregulated interactions of the innate and adaptive immune system in the context of skin epithelium and connective tissue.

The pathophysiology of psoriasis involves the activation and proliferation of T helper cells, in particular Th-17 cells. These activated Th-17 cells produce the clinical characteristics of psoriatic lesions: 

	· Scaling, from abnormal epidermal differentiation, histologically called parakeratosis.

	· Induration, from epidermal hyperproliferation.

	Several environmental triggers are known to exacerbate psoriasis-among them, emotional stress, injury to the skin (Koebner phenomenon), some types of infection (especially streptococcus), and reactions to certain drugs, including lithium, beta-blockers, anti-malarials, non-steroidal anti-inflammatory drugs, and tetracyclines.

	Psoriasis is a clinically heterogenous disease with several clearly defined subtypes: 

is by far the most common, comprising 80-90 percent of cases. Chronic plaque psoriasis is characterized by erythema, scaling, and induration of silvery plaques. 

also known as flexural psoriasis, is concentrated in the flexural folds, including the axillae, groin, inframammary areas, gluteal cleft, and skin folds.

is characterized by small, sterile, pus-filled vesicles that are surrounded by erythema, and can be either generalized or localized to the hands and feet.

typically presents with small, coin-shaped lesions diffusely distributed on the trunk and extremities, and is often preceded by streptococcus infection. 

most often represents a severe exacerbation of chronic plaque psoriasis, with total-body erythema and scaling. 

is limited to the hands and feet and may occur without pustules.

	Clinical studies of psoriasis treatments generally involve two major efficacy endpoints: the Investigator’s Global Assessment scale and the Psoriasis Area and Severity Index.

	The Investigator’s Global Assessment, or IGA scale, is the most common clinical study endpoint for many dermatology indications, including psoriasis, acne, and atopic dermatitis.

IGA is typically the primary endpoint in clinical studies of topical psoriasis treatments. The IGA scale preferred by the FDA’s Dermatology Division has five increments ranging from 0 (clear) to 4 (severe).

	The Psoriasis Area and Severity Index, or PASI is used to evaluate systemic therapies. PASI is a complex assessment that divides the body into four regions: head/neck, upper extremities, lower extremities, and trunk. Each body region is assessed for percentage area of disease involvement and severity of the pathognomonic signs of psoriasis: erythema, scaling, and induration, or lesion thickness. 

	Patients with mild to moderate psoriasis often respond well to topical corticosteroids and vitamin D derivatives, and these remain the mainstays of treatment. Other topical treatments include anthralin, coal tar, emollients, salicylic acid, and tazarotene. These topical medications may be used alone or in combination with other medications.

	Moderate to severe psoriasis often necessitates treatment with phototherapy, the use of ultraviolet light to slow the growth of new skin cells. Phototherapy treatment includes narrow- and broadband ultraviolet B (UVB) and UVA treatment. UVB light may be used alone or in combination with topical treatments.

	The most recent oral medication to receive FDA approval is apremilast (brand name Otezla), which has been on the market since 2014. Apremilast is an oral phosphodiesterase (PDE)-4 inhibitor for treatment of active psoriatic arthritis.

The safety and efficacy of apremilast were evaluated in three clinical trials involving nearly 1,500 patients with active psoriatic arthritis.

The drug also was approved for patients with moderate to severe plaque psoriasis for whom systemic therapy or phototherapy is appropriate.

	· Methotrexate, used to treat psoriasis for more than half a century despite the paucity of clinical data characterizing its efficacy and safety.

	· Cyclosporine, first used to help prevent rejection in organ transplant patients, was approved in 1997 for patients with severe psoriasis and otherwise normal immune systems. Cyclosporine has a quick onset of effect in psoriasis, but relapse after the drug is withdrawn is almost universal.

	· Acitretin, a vitamin A derivative, is the only oral retinoid approved by the FDA specifically for treating psoriasis. Unlike methotrexate and cyclosporine, acitretin is not immunosuppressive.

	The greatest advances of the past two decades have occurred in biologic medicines. Advances in our understanding of disease pathogenesis had led to targeted therapies that act on the cytokine pathways that are upregulated in psoriasis. 

	The revolution began with the tumor necrosis factor (TNF) inhibitors in the form of:

	· Etanercept, sold under the brand name Enbrel. In a Phase III study, nearly half of patients treated with etanercept achieved PASI 75 after 12 weeks, compared to 4 percent in the placebo group.

Etanercept is self-injected once or twice weekly.

	· In a Phase III study, nearly 80 percent of patients randomized to infliximab (brand name Remicade) achieved PASI 75 through 23 weeks of therapy.

Infliximab’s use is limited by an intravenous route of administration.

	· Adalimumab (brand name Humira) showed significantly greater efficacy than methotrexate in a Phase III trial, with 80 percent of patients achieving PASI 75 after 16 weeks.

Adalimumab is self-administered via biweekly subcutaneous injection.

	The TNF inhibitors were followed by the IL-12/23 inhibitor ustekinumab (brand name Stelara), a monoclonal antibody that targets the p40 subunit shared by IL-12 and IL-23 (IL-12/23).

The importance of the IL-23/Th17 axis in the development of psoriasis is underscored by the relatively superior efficacy of ustekinumab compared to the TNF inhibitors. About 70 percent of treated subjects showed a PASI 75 response after 12 weeks of dosing. An important advantage of ustekinumab is that maintenance therapy requires injections only every three months.

	In July 2017, the IL-23 monoclonal antibody Guselkumab was approved to treat psoriasis. Guselkumab selectively binds to the p19 subunit of IL-23 and inhibits its interaction with the IL-23 receptor. After 16 weeks of treatment, 70 to 75 percent of patients experienced a 90 percent improvement in their psoriasis, reaching the PASI-90 response endpoint.

Such efficacy in the treatment of psoriasis is truly astonishing.

	Also very recently, IL-17 inhibitors have been changing the psoriasis treatment landscape.

	· Secukinumab (brand name Cosentyx) is approved for adults with moderate to severe plaque psoriasis that involves large areas or many areas of the body, and who may benefit from taking systemic therapy or phototherapy, alone or with systemic therapy. It also is approved for active psoriatic arthritis and active ankylosing spondylitis.

Secukinumab acts on the Th17 pathway by blocking cytokine IL-17A. PASI 75 responses approaching 80 percent are observed after 12 weeks of treatment, and PASI 90 improvements of 70 percent are reported after 16 weeks of treatment.

	· Ixekizumab (brand name Taltz) is a humanized anti-IL-17 monoclonal antibody approved for adults with moderate to severe plaque psoriasis who may benefit from taking systemic therapy or phototherapy. In Phase III studies, ixekizumab resulted in PASI-90 improvements in 71 percent of subjects after 12 weeks of treatment.

Notably, ixekizumab showed efficacy in difficult-to-treat areas, such as the scalp and nails.

	· Brodalumab (brand name Siliq) received FDA approval in February 2017. Brodalumab is a human monoclonal antibody directed against IL-17RA, the receptor of IL-17A.

	· Brodalumab is indicated for the treatment of moderate to severe plaque psoriasis in adult patients who are candidates for systemic therapy or phototherapy and who have not responded to-or have lost response to-other systemic therapies. Findings from a Phase III trial showed that, after three months of treatment, up to 83 percent of people achieved PASI 75 and up to 76 percent experienced IGA success.

	Advances in our understanding of the genetic, immunological, and environmental factors that contribute to the pathogenesis of psoriasis have led to the development of very effective precision therapies that alleviate patient morbidity and improve quality of life, especially for patients with moderate to severe disease. However, we have observed considerable variability in individual response to biologics, and studies are needed to characterize patient- and disease-specific immune and molecular features that help predict response to therapy. In addition, further characterization of the pathways that underlie the disease will help identify novel disease mechanisms and, potentially, new therapeutic targets.

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https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm390091.htm

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http://ir.celgene.com/releasedetail.cfm?releaseid=872240

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September 2017;7(3):281-292. doi: 10.1007/s13555-017-0187-0. Epub 2017 Jun 21. Guselkumab for the Treatment of Psoriasis: A Review of Phase III Trials. 

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http://www.nejm.org/doi/full/10.1056/NEJMoa1512711#t=article

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, Medical Director for Dermatology, Premier Research

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Advances in our understanding of the genetic, immunological, and environmental factors that contribute to the pathogenesis of psoriasis have led to the development of very effective precision therapies that alleviate patient morbidity and improve quality of life, especially for patients with moderate to severe disease.

Dr. Marlis Sarkany

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