A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes.

We performed a multitiered, case-control association study of psoriasis in three independent sample sets of white North American individuals (1,446 cases and 1,432 controls) with 25,215 genecentric single-nucleotide polymorphisms (SNPs) and found a highly significant association with an IL12B 3'-untranslated-region SNP (rs3212227), confirming the results of a small Japanese study. This SNP was significant in all three sample sets (odds ratio [OR](common) 0.64, combined P [Pcomb]=7.85x10(-10)). A Monte Carlo simulation to address multiple testing suggests that this association is not a type I error. The coding regions of IL12B were resequenced in 96 individuals with psoriasis, and 30 additional IL12B-region SNPs were genotyped. Haplotypes were estimated, and genotype-conditioned analyses identified a second risk allele (rs6887695) located approximately 60 kb upstream of the IL12B coding region that exhibited association with psoriasis after adjustment for rs3212227. Together, these two SNPs mark a common IL12B risk haplotype (OR(common) 1.40, Pcomb=8.11x10(-9)) and a less frequent protective haplotype (OR(common) 0.58, Pcomb=5.65x10(-12)), which were statistically significant in all three studies. Since IL12B encodes the common IL-12p40 subunit of IL-12 and IL-23, we individually genotyped 17 SNPs in the genes encoding the other chains of these cytokines (IL12A and IL23A) and their receptors (IL12RB1, IL12RB2, and IL23R). Haplotype analyses identified two IL23R missense SNPs that together mark a common psoriasis-associated haplotype in all three studies (OR(common) 1.44, Pcomb=3.13x10(-6)). Individuals homozygous for both the IL12B and the IL23R predisposing haplotypes have an increased risk of disease (OR(common) 1.66, Pcomb=1.33x10(-8)). These data, and the previous observation that administration of an antibody specific for the IL-12p40 subunit to patients with psoriasis is highly efficacious, suggest that these genes play a fundamental role in psoriasis pathogenesis.

Observations of psoriasis in the absence of therapeutic intervention identifies two unappreciated morphologic variants, thin-plaque and thick-plaque psoriasis, and their associated phenotypes.

Psoriatic plaque thickness is a clinical measure of psoriasis severity. We have observed that patients tend to revert to a baseline thickness of psoriatic plaques when in an untreated state, and hypothesized that other features of psoriasis could associate with this trait. Data prospectively collected on 500 participants in the Utah Psoriasis Initiative were used for the study. In response to a question assessing plaque thickness when disease was at its worst, 144 (28.8%) reported thick plaques, 123 (24.6%) reported thin plaques, and 233 (46.6%) reported intermediate thickness. For patients with "worst-ever" disease at enrollment (n=122), there was significant correlation of thickness between assessment by the patient and the physician (r=0.448, P-value 0.01). Thick plaques associated with male gender, increased body mass index, nail disease, psoriatic arthritis, larger plaques, more body sites, and greater total body surface area affected. Thin plaques associated with eczema, guttate psoriasis, and skin cancer. We suggest that this is preliminary evidence that plaque thickness is an easily measured trait that associates with other clinical features of psoriasis, and that stratification on this phenotype may be useful in further defining the genetic basis of this disease.

Impact of obesity and smoking on psoriasis presentation and management.

OBJECTIVE: To study the impact of obesity and smoking on psoriasis. DESIGN: Cross-sectional study. SETTING: University of Utah Department of Dermatology clinics. PATIENTS: A case series of patients with psoriasis enrolled in the prospective Utah Psoriasis Initiative (UPI) (which carefully performs phenotyping of patients with psoriasis) was compared with 3 population databases: the Behavioral Risk Factor Surveillance System of the Utah population, the 1998 patient-member survey from the National Psoriasis Foundation, and 500 adult patients who attend our clinics and do not have psoriasis (non-psoriatic population). RESULTS: The prevalence of obesity in patients within the UPI population was higher than that in the general Utah population (34% vs 18%; P<.001) and higher than that in the non-psoriatic population attending our clinics. Assessment of body image perception with a standardized diagram in the UPI group resulted in the median body image score of normal weight at 18 years of age and the onset of psoriasis, but it changed to overweight at the time of enrollment in the UPI. Thus, obesity appears to be the consequence of psoriasis and not a risk factor for onset of disease. We did not observe an increased risk for psoriatic arthritis in patients with obesity; furthermore, obesity did not positively or negatively affect the response or the adverse effects of topical corticosteroids, light-based treatments, and systemic medications. The prevalence of smoking in the UPI population was higher than in the general Utah population (37% vs 13%; P<.001) and higher than in the non-psoriatic population (37% vs 25%; P<.001). We found a higher prevalence of smokers in the obese population within the UPI than in the obese population within the Utah population (25% vs 9%; P<.001). CONCLUSIONS: Patients with psoriasis attending the University of Utah Dermatology Clinics were more likely to be obese and to smoke compared with non-psoriatic patients and more likely to be obese compared with other large cohorts with psoriasis. Smoking appears to have a role in the onset of psoriasis, but obesity does not. The high prevalence of obesity and smoking in a psoriasis cohort has not been previously noted; if confirmed, it supports the prediction that a significant portion of patients with psoriasis will have the comorbid conditions and public health issues of those with obesity and smoke.

Development and use of alefacept to treat psoriasis.

Activated memory T cells, expressing CD2, are key components in the pathogenesis of psoriasis. Alefacept binds to CD2, blocks co-stimulatory signaling, and selectively induces apoptosis of pathogenic T cells. Our objective is to present safety and efficacy results which lead to the new drug application (NDA) of alefacept for the treatment of psoriasis. We reviewed the key phase II and III trials in over 1300 patients and found that during treatment and follow-up of patients receiving 12 weekly intramuscular or intravenous injections of alefacept, about 1/3 will achieve a reduction in psoriasis area and severity index (PASI) of > or =75% and nearly 2/3 a reduction in PASI of > or =50%. Patients who achieved a > or =75% reduction from baseline PASI during or after a single course maintained a > or =50% reduction in PASI for a median duration of >7 months. Among patients who received 2 courses of alefacept, 40% and 71% of patients achieved a > or =75% and > or =50% reduction in PASI, respectively and duration of effect was prolonged. Adverse events in the placebo and active treatment arms did not differ. We conclude that alefacept significantly improves psoriasis and produces durable clinical improvement with a very favorable safety profile.

Efficacy of acitretin and commercial tanning bed therapy for psoriasis.

OBJECTIVE: To assess the efficacy of acitretin and commercial tanning bed therapy for the treatment of moderate to severe chronic plaque-type psoriasis. DESIGN: Retrospective medical record review and telephone survey of subjects and prospective open-label trial. SETTING: University dermatology clinic. PATIENTS: The study population comprised 26 subjects in the retrospective study and 17 subjects in the prospective study, all with moderate to severe plaque-type psoriasis. INTERVENTION: Twelve weeks of daily oral acitretin (25 mg) therapy and commercial tanning bed UV exposure (mean UV-B output of 4.7%) for 4 to 5 days per week. RESULTS: In the retrospective review, 19 (83%) of 23 subjects had clearance or near clearance, 2 (9%) of 23 had moderate improvement, and 2 (9%) of 23 had no improvement. Patients reported a high degree of satisfaction with the treatment. In the prospective trial, the Psoriasis Area and Severity Index (PASI) and National Psoriasis Foundation scores decreased an average of 78.6% and 79.0% from baseline, respectively. A reduction from baseline in the PASI score of 50% and 75% (PASI 50 and PASI 75) was achieved by 13 (76%) and 10 (59%) patients, respectively. Adverse events were generally mild to moderate. CONCLUSIONS: Acitretin use in combination with commercial tanning bed therapy appears to be effective and useful for psoriasis in areas without access to physician-directed phototherapy. The variability of tanning salon light and quality mandates caution when using this therapy.