Psoriasis: Evolving treatment for a complex disease
ABSTRACTThe cutaneous manifestations of psoriasis can vary in morphology and severity, and therapy should be tailored accordingly. Biologic agents are important new options for treating patients with the most severe forms of the disease. All physicians should be aware that severe psoriasis may increase cardiovascular morbidity and the risk of death, and preventive strategies for patients with severe disease should be considered.
KEY POINTS
- Studies in the past 10 years have uncovered a link between psoriasis, metabolic syndrome, and cardiovascular disease. Interestingly, the risk grows less with age; patients at greatest risk are young men with severe psoriasis.
- The most common presentation of psoriasis is plaque psoriasis. However, there are several other clinical variations of psoriasis, each of which has a distinct response to treatment and may be associated with significant systemic symptoms.
- Tumor necrosis factor inhibitors should be considered first-line in the treatment of psoriatic arthritis.
- Phototherapy and systemic medications including methotrexate, acitretin (Soriatane), cyclosporine (Gengraf, Neoral, Sandimmune), and biologic agents are the most effective treatments for moderate-to-severe psoriasis.
Much has changed in our understanding of psoriasis over the past decade, which is having a major effect on its treatment.
Although topical corticosteroids and phototherapy remain mainstays of treatment, a variety of biologic agents have given new hope to those with the most severe forms of the disease. We are also beginning to understand that patients with psoriasis are at greater risk of cardiovascular disease, though the exact nature of that risk and how we should respond remains unclear. Finally, genome-wide association studies are just beginning to unravel the genetic basis of psoriasis.
In this paper, we review the epidemiology and impact of psoriasis, current views of its pathogenesis, its varied clinical forms, and its treatment.
PSORIASIS IMPOSES A GREAT BURDEN
Psoriasis is common, with a reported prevalence ranging from approximately 2%1 to 4.7%.2 It can manifest at any age, but it is most common in two age groups, ie, 20 to 30 years and 50 to 60 years.
For the patient, the burden is great, affecting physical, psychological, and occupational well-being. In fact, patients with psoriasis report quality-of-life impairment equal to or worse than that in patients with cancer or heart disease.3,4 Notably, functional disability secondary to psoriatic arthritis has been reported in up to 19% of psoriatic arthritis patients, and this negatively affects quality of life.5
In 2004, the annual direct medical costs of psoriasis in the United States were estimated to exceed $1 billion. Its indirect costs, measured as missed days and loss of productivity at work, are estimated to exceed the direct costs by $15 billion annually.6,7
Linked to cardiovascular and other diseases
Studies in the past 10 years have uncovered a link between psoriasis, metabolic syndrome, and cardiovascular disease.8–13 Specifically, patients with severe psoriasis are at higher risk of myocardial infarction and cardiovascular death than control patients. Interestingly, the risk decreases with age; patients at greatest risk are young men with severe psoriasis.8–10
In a large cohort study in the United Kingdom7 comparing patients with and without psoriasis, the hazard ratio for cardiovascular death in patients with severe psoriasis was 1.57 (95% confidence interval 1.26–1.96). This translated to 3.5 excess deaths per 1,000 patient-years. These patients were also at higher risk of death from malignancies, chronic lower respiratory disease, diabetes, dementia, infection, kidney disease, and unknown causes.
How much of the risk is due to psoriasis itself, its treatments, associated behaviors, or other factors requires more study. However, some evidence points to the dysregulation of the immune system, notably chronic elevation of pro-inflammatory cytokines.
Psoriasis and its comorbid conditions are thought to arise from chronically elevated levels of cytokines such as tumor necrosis factor alpha (TNF-alpha), interleukin 1 beta (IL-1 beta), and IL-17. These cytokines impair insulin signaling, deregulate lipid metabolism, and increase atherosclerotic changes in the coronary, cerebral, and peripheral arteries. In addition, several other diseases that involve the immune system occur more frequently with psoriasis, including Crohn disease, ulcerative colitis, lymphoma, obesity, and type 2 diabetes.1,8,14–18
In view of the prevalence of these comorbid conditions and the risks they pose, primary care physicians should consider screening patients with severe psoriasis for metabolic disorders and cardiovascular risk factors and promptly begin preventive therapies.19 Unfortunately, to date, there are no consensus guidelines as to the appropriate screening tests or secondary cardiovascular preventive measures for patients with severe psoriasis.
A VICIOUS CIRCLE OF INFLAMMATION AND KERATINOCYTE PROLIFERATION
The hallmark of plaque psoriasis is chronic inflammation in the skin, leading to keratinocyte proliferation.
External and internal triggers that have been identified include cutaneous injury (eg, sunburn, drug rash, viral exanthems), infections (eg, streptococcal), hypocalcemia, pregnancy, psychogenic stress, drugs (eg, lithium, interferon, beta-blockers, and antimalarials), alcohol, smoking, and obesity.20–23
As reviewed by Nestle et al,24 the initiation of lesion formation is still poorly understood but is thought to occur when a trigger (physical trauma, bacterial product, cellular stress) causes DNA to be released from keratinocytes. DNA forms a complex with the antimicrobial protein LL-37 and activates plasmacytoid dendritic cells (PDCs) via toll-like receptor 9. Activated PDCs release type I interferons, which in turn activate myeloid dendritic cells. Myeloid dendritic cells release IL-20 locally, which speeds keratinocyte proliferation.
A subset of myeloid dendritic cells leaves the dermis and migrates to local lymph nodes, where they release IL-23 and activate naive T cells. T helper 1 (Th1) and Th17 cells are recruited to the lesions and begin producing numerous cytokines, including interferon gamma, IL-17, and IL-22. This cytokine milieu increases keratinocyte proliferation and causes the keratinocytes to secrete antimicrobial proteins (LL-37, beta defensins), chemokines, and S100 proteins. These soluble factors have three main functions: stimulation of dendritic cells to release more IL-23, recruitment of neutrophils to the epidermis, and activation of dermal fibroblasts.
This cycle of keratinocytes activating dendritic cells, dendritic cells activating T cells, and T cells activating keratinocytes appears to be the main force maintaining the disease.24 It is unclear, however, whether this applies to all forms of psoriasis or only to plaque psoriasis.
Genetic factors discovered
In recent years, genome-wide association studies have identified at least 10 psoriasis-susceptibility loci that involve functioning of the immune system.25 These genes include those of the major histocompatibility complex, cytokines, receptors, and beta-defensins.
Of specific interest, polymorphisms in the IL-12/IL-13 receptor, the p40 subunit of IL-12 and IL-23, and the p19 subunit of IL-23 strongly associate with psoriasis, supporting their critical role in the disease process and providing targets for medical therapy.26
