The concept of personalized or “precision” medicine, which has significantly advanced the potential benefits and reduced the risks of therapy in many diseases, is not yet clinically feasible in the treatment of psoriasis.1-3 Instead, a stratified approach to the selection of therapies may offer some of the benefits of personalized medicine while waiting for more substantial evidence to support future clinical decision-making.

Although genetic studies demonstrating a familial link and the identification of the genetic variant of human leukocyte antigen (HLA)-Cw6 have been associated with the development of psoriasis, a clear approach to treatment has not yet been found, mainly because of significant variation among individuals in the responses to all known therapies, including newer biologic agents.

As an immunological disorder, psoriasis has an extremely heterogeneous etiology that develops as a result of unique combinations of genetic, environmental, and immunologic factors that produce highly varied manifestations from 1 patient to the next. The challenge, as recent articles have pointed out,1-3 has been in finding a consistent manner in which to classify patients in a way that can predict responses to different therapies.

Difficulty Measuring Response to Therapy

Similar to many other conditions, psoriasis is currently classified by 3 levels of severity: mild, moderate, and severe, most often measured according to the Psoriasis Area and Severity Index (PASI), the body surface area, and the Physician Global Assessment tools.1 A reduction of PASI score by 75% is widely considered the benchmark for efficacy of a given therapy, with a reduction of PASI score of 90% the goal. Patients with scores lower than 50% are usually considered to be nonresponders.

A baseline score greater than 10 on any of these scales or on the Dermatology Life Quality Index indicates severe disease. However, various presentations of psoriasis in which lesions are extensively present and in difficult-to-manage locations (such as the hands and nails, face, and scalp) do not meet the criteria that would suggest a systemic therapy that contradicts the indicated topical treatment. In cases where active psoriatic arthritis is present, systemic treatment is generally required, regardless of PASI score.1

This conundrum is spelled out in an editorial published in the Journal of Dermatological Treatment by Peter CM van de Kerkhof, MD,3 involving the need for a composite of the simultaneous evaluation of objective severity measures along with subjective measures such as the Dermatology Life Quality Index and clinical judgment, plus history of disease severity. “The difficulty in disease assessment is that each of these three dimensions of disease assessment may be at variance with the others in the individual patient,” he wrote.

In addition to the HLA-Cw6 gene variant, which has been strongly linked to psoriasis, another 50 genetic loci have been identified in genomewide association studies, which explain about 36% of differences in 19 immune-based traits associated with psoriasis.4 Study of these variations has led to biologic therapies that target particular pathways such as interleukin 12 (IL-12), IL-23, and IL-17A (ustekinumab, infliximab, and adalimumab) and ustekinumab, which targets HLA-Cw6 pathways, and produce markedly better responses in patients who carry these variations.1

Because of the chronic, relapsing-remitting nature of psoriasis, patients are likely to be receiving long-term therapy to manage symptoms. Conventional systemic treatments are associated with issues of liver and renal toxicity, whereas phototherapies carry risks for skin carcinomas.1 The newer biologic therapies have better safety and tolerability profiles; however, it is still important to identify patients who are likely to be nonresponders.

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Making Treatment Decisions

The 3 types of treatments currently in use include topical and systemic agents and phototherapy. Topical therapy alone is only indicated for mild disease, so all other patients will be prescribed 1 or more of the other therapies, which, until recently, were applied on what some called a “trial and error” basis.5

Recently, studies have begun to explore the combined effects of biologic therapies to enhance the benefits in specific patients. A 2015 review by Armstrong et al6 found that among carefully selected patient groups, specifically targeted combinations of biologic therapies potentially improved efficacy while reducing toxicity. In moderate to severe psoriasis, the combination of biologics such as etanercept or adalimumab and phototherapy showed greater improvement in disease severity than either therapy alone. Other combinations, such as etanercept or infliximab with methotrexate, also showed superior efficacy to monotherapy with any of those drugs.

Other effects were also demonstrated. The addition of acitretin to etanercept therapy allowed for lower dosing of the latter to reduce adverse effects while maintaining efficacy, whereas the addition of cyclosporine to etanercept or adalimumab therapy improved control of psoriasis flares.6

The current goal in psoriasis is to optimize responses to available therapies through stratification according to disease severity, narrowing down the options according to known genomic factors that influence some responses to therapy. This needs to be coupled with clinical judgment of individual patient factors such as perceived effect of disease on quality of life, the patient’s environment, and the potential adverse effects associated with given therapies. Regular reassessments of therapy are important in light of rapidly emerging evidence on all factors influencing patient responses to therapies, as well as new potential therapies themselves.

References

  1. Gisondi P, Del Giglio M, Girolomoni G. Treatment approaches to moderate to severe psoriasis. Int J Mol Sci. 2017;18:2427.
  2. Wu KC, Reynolds NJ. CARD14 mutations may predict response to antitumour necrosis factor-α therapy in psoriasis: a potential further step towards personalized medicine. Br J Dermatol. 2016;175:17-18.
  3. van de Kerkhof PC. Stratified or personalised medicine in the treatment of psoriasis? J Dermatolog Treat. 2017;28:683.
  4. Alwan W. Nestle FO. Pathogenesis and treatment of psoriasis: exploiting pathophysiological pathways for precision medicine. Clin Exp Rheumatol. 2015;33:S2-S6.
  5. Griffiths CEM, Barnes MR, Burden AD, et al. Establishing an academic-industrial stratified medicine consortium: psoriasis stratification to optimize relevant therapy. J Am Acad Dermatol. 2015;73:829-835.
  6. Armstrong AW, Bagel J, Van Voorhees AS, Robertson AD, Yamauchi PS. Combining biologic therapies with other systemic treatments in psoriasis: evidence-based, best-practice recommendations from the Medical Board of the National Psoriasis Foundation. JAMA Dermatol. 2015;151:432-438.