Novel systemic drugs under investigation for the treatment of psoriasis.

In the last few years, there has been progress in identifying some of the risk genes for psoriasis. This has resulted in a major impetus toward drug development as many of the same pathways and processes identified in psoriasis have been shown to have major roles in other chronic inflammatory diseases, suggesting that psoriasis can be used as a treatment model for many other diseases. This has resulted in a shift in research toward a select number of biological processes and has been accompanied by a surge in drug development with over 20 systemic agents currently in clinical testing for psoriasis, many of which target the pathways identified through genetic and basic research. Although it is too early to tell for many of these agents how effective and safe they will be, and where they will fit into treatment algorithms, it is evident that our range of options in treating this often perplexing disease will greatly increase in the future.

Ustekinumab: a new option in psoriasis therapy.

Psoriasis is a chronic inflammatory disease that affects a significant portion of the population. Aside from the well known cutaneous and joint involvements, psoriasis is associated with a host of systemic ailments and risk factors. Thus, psoriasis can diminish a patient's quality and even length of life. Various systemic agents have been developed to control this condition, including the more recent introduction of biological agents. As the pathogenesis of psoriasis becomes better understood, a new class of biological drug is being studied and shows promise in long-term disease control for psoriasis patients, namely anti-interleukin-12/interleukin-23p40 monoclonal antibodies. The new biological agent, ustekinumab, has been shown to improve moderate to severe psoriasis in patients who cannot tolerate other treatment modalities with ease or in whom these modalities have failed. A favourable side effect profile has also been shown for this agent.

Placebo response in two long-term randomized psoriasis studies that were negative for rosiglitazone.

BACKGROUND: Previous research has suggested that the thiazolidinedione rosiglitazone may possess anti-psoriatic activity. OBJECTIVE: To compare the efficacy and safety of rosiglitazone with that of placebo in the treatment of chronic plaque psoriasis. METHODS: Two large-scale, randomized, double-blind, multicenter studies (study A, n = 1563; study B, n = 1032) were conducted over 52 weeks (plus optional 44 weeks safety extension) in an outpatient setting. The subjects (aged 18-75 years) had moderate-to-severe chronic plaque psoriasis affecting >or=10% body surface area (BSA) with plaques of any elevation above normal-appearing skin (or >or=6% BSA involvement with marked elevation) and had not used phototherapy during the previous month or thiazolidinediones within the previous 3 months. Rosiglitazone was administered as 2, 4, or 8 mg tablets once daily. The main outcome measure was the proportion of subjects achieving >or=75% improvement from baseline in the Psoriasis Area and Severity Index (PASI 75) at week 26. RESULTS: Rosiglitazone was well tolerated but no more effective than placebo for moderate-to-severe chronic plaque psoriasis. However, there was a large placebo response unrelated to concomitant rescue medication. Interestingly, subjects had been advised to expect a long period before onset of action. At week 26 and across both studies for subjects receiving placebo, the PASI 75 was 9% (48/506) and the PASI 50 (proportion of subjects who achieved at least 50% improvement from baseline) was 27% (135/506). In addition, few subjects withdrew from placebo or rosiglitazone treatment because of 'lack of efficacy' and the majority persisted in the year-long study. CONCLUSION: While these large-scale, robust studies demonstrated that rosiglitazone is not active in psoriasis, they also showed that for a large proportion of subjects receiving placebo, the expectation of a successful treatment, the favorable adverse effect profile of the drug, and the supportive environment of a clinical study conferred beneficial effects. These results may have implications for the design of future placebo-controlled studies in patients with psoriasis.

Psoriasis--recent advances in understanding its pathogenesis and treatment.

Although not completely understood, there is clearly a genetic component in the development of psoriasis. Twin studies show a 67% concordance for monozygotic twins versus 18% for dizygotic twins. This lack of complete concordance in monozygotic twins suggests multifactorial inheritance and interaction between genetic predisposition and the environment. At present, 8 different psoriasis susceptibility loci have been identified in genome-wide linkage scans, including locations on 15 different chromosomes. Genetic connections have been made between psoriasis and other diseases, including atopic dermatitis, rheumatoid arthritis, and Crohn's disease. A variety of approaches are available for the treatment of psoriasis, ranging from topical agents for milder forms of the disease to phototherapy and systemic agents for severe psoriasis. Despite the importance of systemic therapies and recent advances represented by biologic agents, topical treatments will probably remain the mainstay of psoriasis therapy for most patients. The advent of new, cosmetically attractive vehicles may enhance compliance, add to the use of topical agents, and potentially improve patient outcomes.

A randomized, double-blind, placebo-controlled phase III study evaluating efficacy and tolerability of 2 courses of alefacept in patients with chronic plaque psoriasis.

BACKGROUND: In previous phase II studies, alefacept significantly improved psoriasis and was well tolerated. The clinical response to alefacept was durable. OBJECTIVE: Our purpose was to further evaluate efficacy and tolerability of alefacept in a phase III study of patients (n = 553) with chronic plaque psoriasis. METHODS: Two 12-week courses of once-weekly intravenous alefacept 7.5 mg or placebo were given in a randomized double-blind study; patients were followed up for 12 weeks after each course. RESULTS: During treatment and follow-up of course 1, a 75% or greater reduction in the Psoriasis Area Severity Index (PASI) was achieved by 28% of alefacept-treated and 8% of placebo-treated patients (P <.001). Patients who received a single course of alefacept and achieved a 75% or greater reduction from baseline PASI during or after treatment, without the use of phototherapy or systemic therapies, maintained a 50% or greater reduction in PASI for a median duration of more than 7 months. Among patients who received 2 courses of alefacept, 40% and 71% of patients achieved a 75% or greater and 50% or greater reduction in PASI, respectively, during the study period. Alefacept was well tolerated over both courses. In course 1, the incidence of transient chills was higher in the alefacept group compared with the placebo group; more than 90% of cases occurred within 24 hours after the first few doses. CONCLUSION: Alefacept significantly improved psoriasis and produced durable clinical improvements among patients who responded. A second course of alefacept increased efficacy and was equally well tolerated.