Peter C.M. van de Kerkhof

Comparison of Ustekinumab and Etanercept for Moderate-to-Severe Psoriasis

BACKGROUND Biologic agents offer a range of new therapeutic options for patients with psoriasis; however, the relative benefit-risk profiles of such therapies are not well known. We compared two biologic agents, ustekinumab (an interleukin-12 and interleukin-23 blocker) and etanercept (an inhibitor of tumor necrosis factor alpha), for the treatment of psoriasis. METHODS We randomly assigned 903 patients with moderate-to-severe psoriasis to receive subcutaneous injections of either 45 or 90 mg of ustekinumab (at weeks 0 and 4) or high-dose etanercept (50 mg twice weekly for 12 weeks). The primary end point was the proportion of patients with at least 75% improvement in the psoriasis area-and-severity index (PASI) at week 12; a secondary end point was the proportion with cleared or minimal disease on the basis of the physicians global assessment. Assessors were unaware of the treatment assignments. The efficacy and safety of a crossover from etanercept to ustekinumab were evaluated after week 12. RESULTS There was at least 75% improvement in the PASI at week 12 in 67.5% of patients who received 45 mg of ustekinumab and 73.8% of patients who received 90 mg, as compared with 56.8% of those who received etanercept (P=0.01 and P<0.001, respectively). Similarly, 65.1% of patients who received 45 mg of ustekinumab and 70.6% of patients who received 90 mg of ustekinumab had cleared or minimal disease according to the physicians global assessment, as compared with 49.0% of those who received etanercept (P<0.001 for both comparisons). Among patients who did not have a response to etanercept, 48.9% had at least 75% improvement in the PASI within 12 weeks after crossover to ustekinumab. One or more adverse events occurred through week 12 in 66.0% of patients who received 45 mg of ustekinumab and 69.2% of patients who received 90 mg of ustekinumab and in 70.0% who received etanercept; 1.9%, 1.2%, and 1.2%, respectively, had serious adverse events. Safety patterns were similar before and after crossover from etanercept to ustekinumab. CONCLUSIONS The efficacy of ustekinumab at a dose of 45 or 90 mg was superior to that of high-dose etanercept over a 12-week period in patients with psoriasis. (ClinicalTrials.gov number, NCT00454584.)

Psoriasis is associated with increased beta-defensin genomic copy number

Psoriasis is a common inflammatory skin disease with a strong genetic component. We analyzed the genomic copy number polymorphism of the β-defensin region on human chromosome 8 in 179 Dutch individuals with psoriasis and 272 controls and in 319 German individuals with psoriasis and 305 controls. Comparisons in both cohorts showed a significant association between higher genomic copy number for β-defensin genes and risk of psoriasis.

Dermatological conditions during TNF-α-blocking therapy in patients with rheumatoid arthritis: a prospective study

Various dermatological conditions have been reported during tumor necrosis factor (TNF)-α-blocking therapy, but until now no prospective studies have been focused on this aspect. The present study was set up to investigate the number and nature of clinically important dermatological conditions during TNF-α-blocking therapy in patients with rheumatoid arthritis (RA). RA patients starting on TNF-α-blocking therapy were prospectively followed up. The numbers and natures of dermatological events giving rise to a dermatological consultation were recorded. The patients with a dermatological event were compared with a group of prospectively followed up RA control patients, naive to TNF-α-blocking therapy and matched for follow-up period. 289 RA patients started TNF-α-blocking therapy. 128 dermatological events were recorded in 72 patients (25%) during 911 patient-years of follow-up. TNF-α-blocking therapy was stopped in 19 (26%) of these 72 patients because of the dermatological event. More of the RA patients given TNF-α-blocking therapy (25%) than of the anti-TNF-α-naive patients (13%) visited a dermatologist during follow-up (P < 0.0005). Events were recorded more often during active treatment (0.16 events per patient-year) than during the period of withdrawal of TNF-α-blocking therapy (0.09 events per patient-year, P < 0.0005). The events recorded most frequently were skin infections (n = 33), eczema (n = 20), and drug-related eruptions (n = 15). Other events with a possible relation to TNF-α-blocking therapy included vasculitis, psoriasis, drug-induced systemic lupus erythematosus, dermatomyositis, and a lymphomatoid-papulosis-like eruption. This study is the first large prospective study focusing on dermatological conditions during TNF-α-blocking therapy. It shows that dermatological conditions are a significant and clinically important problem in RA patients receiving TNF-α-blocking therapy.

Patient perspectives in the management of psoriasis: results from the population-based Multinational Assessment of Psoriasis and Psoriatic Arthritis Survey.

BACKGROUND Available psoriasis surveys offer valuable information about psoriasis and psoriatic arthritis (PsA), but are limited by methodology or enrollment requirements. OBJECTIVE To further the understanding of the unmet needs of psoriasis and PsA patients. METHODS This was a large, multinational, population-based survey of psoriasis and/or PsA patients in North America and Europe. Patients were selected by list-assisted random digit dialing and did not have to currently be under the care of a health care provider, a patient organization member, or receiving treatment; 139,948 households were screened and 3426 patients completed the survey. RESULTS The prevalence of psoriasis/PsA ranged from 1.4% to 3.3%; 79% had psoriasis alone and 21% had PsA. When rating disease severity at its worst, 27% (psoriasis) and 53% (PsA ± psoriasis) of patients rated it as severe. Psoriasis patients indicated that their most bothersome signs or symptoms were itching (43%), scales (23%), and flaking (20%). Of psoriasis patients, 45% had not seen a physician in a year; >80% of psoriasis patients with ≥ 4 palms body surface area and 59% of PsA patients were receiving no treatment or topical treatment only. Of patients who had received oral or biologic therapy, 57% and 45%, respectively, discontinued therapy, most often for safety/tolerability reasons and a lack/loss of efficacy. LIMITATIONS The survey lacked a control group, did not account for ethnic and health care system differences across countries, and was limited by factors associated with any patient survey, including accurate recall and interpretation of questions. CONCLUSIONS Several identified unmet needs warrant additional attention and action, including improved severity assessment, PsA screening, patient awareness, and treatment options.

Foxp3+ Regulatory T Cells of Psoriasis Patients Easily Differentiate into IL-17A-Producing Cells and Are Found in Lesional Skin

Psoriasis is an autoimmune-related chronic inflammatory skin disease that is strongly associated with IL-23 and T helper-17 (Th17) effector cytokines. In addition, CD4+CD25(high) regulatory T-cell (Treg) function appeared to be impaired in psoriasis. CD4+CD25(high)Foxp3+ Tregs are typically considered inhibitors of autoimmune responses. However, under proinflammatory conditions, Tregs can differentiate into inflammation-associated Th17 cells--a paradigm shift, with as yet largely unknown consequences for human disease initiation or progression. Th17 cells are highly proinflammatory T cells that are characterized by IL-17A and IL-22 production and expression of the transcription factor retinoic acid-related orphan receptor γt (RORγt). We here show that Tregs of patients with severe psoriasis, as compared with those of healthy controls, have an enhanced propensity to differentiate into IL-17A-producing cells on ex vivo stimulation. This enhanced Treg differentiation was linked to unexpectedly high RORγt levels and enhanced loss of Foxp3. Notably, IL-23 boosted this Treg differentiation process particularly in patients with psoriasis but less so in controls. IL-23 further reduced Foxp3 expression while leaving the high RORγt levels unaffected. The histone/protein deacetylase inhibitor, Trichostatin-A, prevented Th17 differentiation of Tregs in psoriasis patients. Importantly, IL-17A+/Foxp3+/CD4+ triple-positive cells were present in skin lesions of patients with severe psoriasis. These data stress the clinical relevance of Treg differentiation for the perpetuation of chronic inflammatory disease and may pave novel ways for immunotherapy.

Psoriasis of the Scalp

Coal tar shampoos, containing 2 to 10% coal tar solution, are effective in scalp psoriasis. However, no double-blind studies are available to support such an assumption. Salicylic acid 5 to 10% has a pronounced keratolytic effect. Salicylic acid should be formulated in an ointment, which can be washed off easily. Crude coal tar is the most effective tar available for the treatment of psoriasis. An important feature of coal tar is its potent efficacy against pruritus. At the scalp, the application of crude coal tar is difficult. Therefore coal tar solution is the most frequently applied tar preparation in scalp psoriasis.Dithranol 0.1 to 3% is manufactured in various formulations. Treatment is initiated at a low concentration and the concentration is increased stepwise until a slight irritation, the feeling of warmth, is reached. In the treatment of scalp psoriasis, cream formulations are used. Imidazole antifungals have been used with success in scalp psoriasis. Overgrowth of the scalp with pityrosporon is a well-known feature of scalp psoriasis and seborrheic dermatitis. In case of resistance to other topical treatments use of a topical or systemic imidazole derivative might be helpful.So far, topical corticosteroids are the most frequently used treatments for psoriasis of the scalp. Corticosteroids inhibit epidermal proliferation, inhibit inflammation and modulate immune functions. Topical corticosteroids are fast acting: within 3 to 4 weeks maximal efficacy is reached. No data are available to support the efficacy and safety of topical corticosteroids during long term use. However, from epidemiologic surveys we know that these treatments are used by the majority of patients for more than 8 weeks. Since 1992 vitamin D3 formulations have been developed for the treatment of psoriasis. Calcipotriol is available in most countries. Tacalcitol is available in Japan and several other countries. Vitamin D3 analogues inhibit epidermal proliferation, enhance cornification and inhibit inflammation. Therefore, vitamin D3 analogues have a substantial antipsoriatic effect. Systemic treatments such as methotrexate, cyclosporine and acitretin are indicated in patients with recalcitrant disease.Management of scalp psoriasis requires long term strategies in order to reach an optimal improvement of the condition, while avoiding the adverse effects associated with the long term use of treatments.

Induction of nocebo and placebo effects on itch and pain by verbal suggestions

&NA; Physical complaints, such as pain, can be effectively reduced by placebo effects through induction of positive expectations, or increased by nocebo effects through induction of negative expectations. In the present study, verbally induced nocebo and placebo effects on itch were experimentally investigated for the first time. In part 1, the role of verbal suggestions in inducing nocebo effects on itch and pain was investigated. All subjects received the same somatosensory quantitative sensory testing stimuli, that is, mechanical and electrical stimuli and application of histamine, and verbal suggestions to manipulate expectations regarding the stimuli. The suggestions were designed to produce either high expectations for itch (itch nocebo) or pain (pain nocebo) or low expectations for itch (itch nocebo control) or pain (pain nocebo control). Results showed that high itch and pain expectations resulted in higher levels of itch and pain, respectively. When comparing nocebo effects, induced by verbal suggestions, results were more pronounced for itch than for pain. In part 2, verbal suggestions designed to produce a placebo effect on itch (itch placebo) or pain (pain placebo), or neutral suggestions (itch placebo control and pain placebo control) were given regarding a second application of histamine and compared with the first application applied in part 1. Results of placebo effects only showed a significantly larger decrease in itch in the itch placebo condition than in the pain placebo condition. In conclusion, we showed for the first time that nocebo and possibly placebo responses can be induced on itch by verbal suggestions. Experiments of nocebo and placebo effects on itch and pain demonstrated that particularly nocebo effects can be induced on itch and pain by verbal suggestions.

Biochemical and biophysical assessment of MTX-induced liver fibrosis in psoriasis patients: Fibrotest predicts the presence and Fibroscan predicts the absence of significant liver fibrosis.

Background: Methotrexate (MTX) use is associated with hepatic fibrosis in psoriasis patients. To monitor this serial liver biopsies were performed. The Fibroscan® and the Fibrotest are two novel, non‐invasive methods that might be able to assess MTX‐induced hepatic fibrosis.

Clinical and histological effects of blue light on normal skin.

Introduction: Phototherapy with visible light is gaining interest in dermatological practice. Theoretically, blue light could induce biological effects comparable to ultraviolet A (UVA) radiation.

No increased risk of cancer after coal tar treatment in patients with psoriasis or eczema.

Coal tar is an effective treatment for psoriasis and eczema, but it contains several carcinogenic compounds. Occupational and animal studies have shown an increased risk of cancer after exposure to coal tar. Many dermatologists have abandoned this treatment for safety reasons, although the risk of cancer after coal tar in dermatological practice is unclear. This large cohort study included 13,200 patients with psoriasis and eczema. Information on skin disease and treatment, risk factors, and cancer occurrence was retrieved from medical files, questionnaires, and medical registries. Proportional hazards regression was used to evaluate differences in cancer risk by treatment modality. Patients treated with coal tar were compared with a reference category of patients treated with dermatocorticosteroids (assumed to carry no increased cancer risk). The median exposure to coal tar ointments was 6 months (range 1-300 months). Coal tar did not increase the risk of non-skin malignancies (hazard ratio (HR) 0.92; 95% confidence interval (CI) 0.78-1.09), or the risk of skin cancer (HR 1.09; 95% CI 0.69-1.72). This study has sufficient power to show that coal tar treatment is not associated with an increased risk of cancer. These results indicate that coal tar can be maintained as a safe treatment in dermatological practice.