Quality of life and patient-perceived symptoms in patients with psoriasis undergoing proactive or reactive management with the fixed-dose combination Cal/BD foam: A post-hoc analysis of PSO-LONG.

BACKGROUND: Psoriasis has important physical and psychosocial effects that extend beyond the skin. Understanding the impact of treatment on health-related quality of life (HRQoL) and patient-perceived symptom severity in psoriasis is key to clinical decision-making. OBJECTIVES: This post hoc analysis of the PSO-LONG trial data assessed the impact of long-term proactive or reactive management with fixed-dose combination calcipotriene 50 µg/g and betamethasone dipropionate 0.5 mg/g (Cal/BD) foam on patient-reported outcomes (PROs) in patients with psoriasis vulgaris. METHODS: Five hundred and twenty-one patients from the Phase 3, randomized, double-blind PSO-LONG trial were included. An initial 4-week, open-label phase of fixed-dose combination Cal/BD foam once daily (QD) was followed by a 52-week maintenance phase, at the start of which patients were randomized to a proactive management arm (Cal/BD foam twice weekly) or reactive management arm (vehicle foam twice weekly). Patient-perceived symptom severity and HRQoL were assessed using the Psoriasis Symptom Inventory (PSI), the Dermatology Life Quality Index (DLQI) and the EuroQol-5D for psoriasis (EQ-5D-5L-PSO). RESULTS: Statistically and clinically significant improvements were observed across all PRO measures. The mean difference (standard deviation) from baseline to Week 4 was -8.97 (6.18) for PSI, -6.02 (5.46) for DLQI and 0.11 (0.15) for EQ-5D-5L-PSO scores. During maintenance, patients receiving reactive management had significantly higher DLQI (15% [p = 0.007]) and PSI (15% [p = 0.0128]) and a numerically lower EQ-5D-5L-PSO mean area under the curve score than patients receiving proactive management (1% [p = 0.0842]). CONCLUSIONS: Cal/BD foam significantly improved DLQI, EQ-5D-5L-PSO and PSI scores during the open-label and maintenance phases. Patients assigned to proactive management had significantly better DLQI and PSI scores and numerically better EQ-5D-5L-PSO versus reactive management. Additionally, baseline flare was associated with worse PROs than the start of a relapse, and patients starting a relapse also had worse PROs than patients in remission.

A Belgian consensus on the definition of a treat-to-target outcome set in psoriasis management.

OBJECTIVE: Treat-to-target (T2T) is an algorithm to reach a predefined outcome. Here, we define a T2T outcome for moderate-to-severe psoriasis vulgaris. METHODS: Briefly, the study included a literature review, discussions with key opinion leaders, recruitment of additional dermatologists with experience in managing moderate-to-severe psoriasis, 3 eDelphi survey rounds and a patient focus group. Relevant topics were selected during discussions prior to the survey for the statements. Surveys were based on the eDelphi methodology for consensus-building using a series of statements. Consensus was defined as at least 80% of participants agreeing. A psoriasis patient focus group provided feedback on topic selection and outcome. RESULTS: A total of 5 discussions were held, and 3 eDelphi rounds were conducted with an average of 19 participants per round. The T2T outcome was set assuming shared decision between patient and dermatologist, awareness and referral for comorbidities by the dermatologist and appropriate treatment adherence by the patient. We defined 'ideal' and 'acceptable' targets; the latter referring to conditions restricting certain drugs. The T2T outcome was multidimensional, including ≥ ΔPASI90/75 or PGA ≤ 1, itch VAS score ≤ 1, absence of disturbing lesions, DLQI ≤ 1/3, incapacity daily functioning VAS score ≤ 1, safety ≤ mild side-effects and full/mild tolerability of treatment for the ideal and acceptable target, respectively. Finally, time to achieve the T2T outcome was set at 12 weeks after initiation for all treatments. At all times, safety should not exceed the presence of mild side-effects. CONCLUSION: With this novel T2T composite outcome for psoriasis, clinicians and patients can make shared decisions on the treatment goals they envisage, as a guidance for future treatment steps - leading to a tight control management of the disease.

Practical recommendations for systemic treatment in psoriasis according to age, pregnancy, metabolic syndrome, mental health, psoriasis subtype and treatment history (BETA-PSO: Belgian Evidence-based Treatment Advice in Psoriasis; part 1).

BACKGROUND: Impressive progress in new therapeutic options has been made for psoriasis. Treatments include topical steroids, phototherapy, conventional, synthetic disease-modifying drugs and an expanding list of biologics. OBJECTIVE: The primary objective of this work was to collect evidence for the creation of practice guidelines for systemic treatment of psoriasis (BETA-PSO: Belgian Evidence-based Treatment Advice in Psoriasis). METHODS: Evidence-based recommendations were formulated using a quasi-Delphi methodology after a systematic search of the literature and a consensus procedure involving 8 psoriasis experts. RESULTS: In this part, the use of systemic treatment in different age groups, during pregnancy, in metabolic syndrome, in patients with mental health problems, in different psoriasis subtypes and in previously systemically treated patients treatment is discussed. CONCLUSION: Guidance on therapeutic choice in specific clinical situations in psoriasis is provided in order to facilitate the decision-making in clinical practice.

Practical recommendations for systemic treatment in psoriasis in case of coexisting inflammatory, neurologic, infectious or malignant disorders (BETA-PSO: Belgian Evidence-based Treatment Advice in Psoriasis; part 2).

BACKGROUND: Psoriasis patients carry an increased risk for associated comorbidities. Dermatologists have to be aware of the effects of systemic treatments not only on psoriasis but also on co-occurring diseases. In case of other coexisting inflammatory diseases, the right psoriasis treatment may improve both disorders. For infectious and malignant disorders, some treatments have to be avoided as they may be harmful. OBJECTIVE: The primary objective of this project was to collect evidence for the creation of practice guidelines for systemic treatment of psoriasis (BETA-PSO: Belgian Evidence-based Treatment Advice in Psoriasis). METHODS: Evidence-based recommendations were formulated using a quasi-Delphi methodology after a systematic search of the literature and a consensus procedure involving eight psoriasis experts. RESULTS: Recommendations are given on the use of systemic treatment in psoriatic arthritis, inflammatory bowel disease, demyelinating disorders, hepatitis B and C, HIV and cancer. CONCLUSION: This expert opinion is a practical guide for dermatologists when handling psoriasis patients with these specific conditions.

Rapid onset of action of calcipotriol/betamethasone dipropionate cutaneous foam in psoriasis, even in patients with more severe disease.

BACKGROUND: The effectiveness of topical therapies in psoriasis is dependent on, amongst other factors, patient adherence. Together with treatment effectiveness and reduction of symptoms, speed of onset and health-related quality of life (HRQoL) are important influencers of adherence. METHODS: This pooled analysis of three Phase II/III trials evaluated the efficacy of topical fixed-dose combination calcipotriol 50 µg/g plus betamethasone dipropionate 0.5 mg/g cutaneous foam (Cal/BD foam) vs. foam vehicle at early timepoints in mild-to-severe psoriasis using clinically meaningful modified Psoriasis Area and Severity Index (mPASI) and Dermatology Life Quality Index (DLQI) targets. RESULTS: A greater proportion of Cal/BD-foam- vs. foam-vehicle-treated patients achieved absolute mPASI targets 0 (15.1% vs. 1.0%), ≤1 (41.4% vs. 5.2%), ≤3 (78.5% vs. 29.2%) and ≤5 (90.2% vs. 62.5%) at week 4 (P < 0.001; all targets). Significant differences between Cal/BD-foam- vs. foam-vehicle-treated patients were observed as early as week 1 in those achieving mPASI ≤1 (6.8% vs. 1.5%; P < 0.01), ≤3 (40.4% vs. 22.8%; P < 0.001) and ≤5 (69.7% vs. 50.8%; P < 0.001). In patients with more severe psoriasis (baseline mPASI >10), a greater proportion of Cal/BD-foam- vs. foam-vehicle-treated patients achieved mPASI ≤1 (20.2% vs. 5.9%; P < 0.05), ≤3 (49.2% vs. 8.8%; P < 0.001) and ≤5 (63.7% vs. 26.5%; P < 0.001) at week 4. In patients with severely impaired HRQoL (baseline DLQI >10), a greater proportion of Cal/BD-foam- vs. foam-vehicle-treated patients achieved target DLQI ≤1 or 0 (week 4: DLQI ≤1, 25.0% vs. 4%; P = 0.001; DLQI 0, 17.4% vs. 2.0%; P = 0.006). CONCLUSION: We report rapid onset of action and greater efficacy with Cal/BD foam vs. foam vehicle, even in patients with more severe psoriasis, manageable with topical treatments. This may support physician management of patient expectations and improve patient adherence, translating into overall topical treatment effectiveness.

Itch relief in patients with psoriasis: effectiveness of calcipotriol plus betamethasone dipropionate foam.

BACKGROUND: Itch is common in psoriasis, adversely affecting health-related quality of life (HRQoL) and sleep. OBJECTIVE: We evaluated the efficacy of topical fixed-dose combination calcipotriol 50 µg/g plus betamethasone dipropionate 0.5 mg/g cutaneous foam (Cal/BD foam) on itch, itch-related sleep loss and HRQoL vs. foam vehicle. METHODS: We pooled data from three Phase II/III trials (NCT01536886/NCT01866163/NCT02132936) of Cal/BD foam vs. foam vehicle in adults with mild-severe psoriasis. For itch-related analyses, patients with baseline itch visual analogue scale (VAS) >40 (range 0-100) were analysed. Outcomes included the following: itch VAS reduction >40, ≥70% improvement in itch (Itch70) or itch-related sleep loss, 75% improvement in modified Psoriasis Area and Severity Index (excluding head; mPASI75) and Dermatology Life Quality Index (DLQI) scores 0/1 through 4 weeks. RESULTS: Of 837 patients, 800 had baseline itch VAS >0 (Cal/BD foam, n = 610; foam vehicle, n = 190); 484 had baseline itch VAS >40. There was no correlation between itch VAS score and mPASI at baseline (R2  = 0.021). In patients with baseline itch VAS >40, more patients achieved itch VAS reduction >40 in the active vs. vehicle group from Day 5 onwards (Day 5: 57.5% vs. 40.2% [P < 0.05]; Week 4: 83.0% vs. 45.8% [P < 0.001]). More Cal/BD-foam-treated patients achieved Itch70 at Day 3 (34.2% vs. 22.5%; P < 0.05) through to Week 4 (79.3% vs. 38.1%; P < 0.001). In patients with baseline itch VAS >40 and sleep loss >20, improvements in itch-related sleep loss occurred at Week 1 and continued through 4 weeks. Itch-related improvements occurred before improvements in mPASI75. There were significant differences in the proportion of Cal/BD-foam- vs. foam-vehicle-treated patients with baseline DLQI >10 (n = 172 vs. n = 50) achieving DLQI ≤1 (25.0% vs. 4.0%; P = 0.001) and DLQI 0 (17.4% vs. 2.0%; P = 0.006) at Week 4. CONCLUSION: Compared with foam vehicle, Cal/BD foam offers more rapid and effective itch relief, with associated significant improvements in sleep and DLQI.

Reformulations of well-known active ingredients in the topical treatment of psoriasis vulgaris can improve clinical outcomes for patients.

Although the majority of patients with psoriasis vulgaris are treated exclusively with topical therapies, research to develop more effective topical therapies that are associated with higher patient satisfaction has lagged behind the development of systemic agents. The aim of this literature review was to determine whether there is documented evidence that applying an innovative approach to improving the formulation of active ingredients commonly used in the topical treatment of psoriasis can have a positive effect on clinical outcomes and patient-reported outcomes (PROs). The Embase and PubMed databases were searched for articles published between 2001 and 2016 that made direct head-to-head comparisons of different formulations of an active pharmaceutical ingredient (API), focusing on clinical outcomes and PROs. In total, 22 publications on APIs or API combinations met the eligibility criteria (19 head-to-head clinical trials, one pooled analysis, one health-economic modelling study and one systematic review). Significant clinical benefit associated with the use of a reformulated API over an older formulation was reported in three trials of clobetasol propionate, one trial of calcipotriol, three trials of betamethasone and five trials/pooled analyses of calcipotriol/calcipotriene + betamethasone dipropionate (Cal/BD) formulations. Significantly improved PROs associated with the use of a reformulated API over an older formulation were reported in three trials of clobetasol propionate, one trial of betamethasone valerate and two trials of Cal/BD formulations. These results demonstrate that the innovative reformulation of APIs used in the treatment of psoriasis can produce therapies that attain significantly improved clinical outcomes and PROs. This suggests that improvement in topical therapy for psoriasis need not only to be achieved by the identification of new targets and the development of new APIs, but that improvement in the vehicle used to deliver existing APIs has the potential to result in significant clinical and patient benefits.

Regorafenib-associated hand-foot skin reaction: practical advice on diagnosis, prevention, and management.

BACKGROUND: Regorafenib is an orally available, small-molecule multikinase inhibitor with international marketing authorizations for use in colorectal cancer and gastrointestinal stromal tumors. In clinical trials, regorafenib showed a consistent and predictable adverse-event profile, with hand-foot skin reaction (HFSR) among the most clinically significant toxicities. This review summarizes the clinical characteristics of regorafenib-related HFSR and provides practical advice on HFSR management to enable health care professionals to recognize, pre-empt, and effectively manage the symptoms, thereby allowing patients to remain on active therapy for as long as possible. DESIGN: This review is based on a systematic literature search of the PubMed database (using synonyms of HFSR, regorafenib, and skin toxicities associated with targeted therapies or cytotoxic chemotherapy). However, as this search identified very few articles, the authors also use their clinical experience as oncologists and dermatologists managing patients with treatment-related HFSR to provide recommendations on recognition and management of HFSR in regorafenib-treated patients. RESULTS: Regorafenib-related HFSR is similar to that seen with other multikinase inhibitors (e.g. sorafenib, sunitinib, cabozantinib, axitinib, and pazopanib) but differs from the hand-foot syndrome seen with cytotoxic chemotherapies (e.g. fluoropyrimidines, anthracyclines, and taxanes). There have been no controlled trials of symptomatic management of regorafenib-related HFSR, and limited good-quality evidence from randomized clinical trials of effective interventions for HFSR associated with other targeted therapies. Recommendations on prevention and management of regorafenib-related HFSR in this review are therefore based on the expert opinion of the authors (dermatologists and oncologists with expertise in the management of treatment-related skin toxicities and oncologists involved in clinical trials of regorafenib) and tried-and-tested empirical experience with other multikinase inhibitors and cytotoxic chemotherapies. CONCLUSIONS: As recommended in this review, treatment modifications and supportive measures to prevent, reduce, and manage HFSR can allow patients to continue regorafenib at the optimal dose to derive benefit from treatment.

Factors impacting the combination of topical corticosteroid therapies for psoriasis: perspectives from the International Psoriasis Council.

Corticosteroids are the mainstay of topical therapies for the treatment of mild to moderate psoriasis. Selection of vehicle, concentrations of corticosteroid and coadministered medications, and frequency of administration are critical factors that enhance bioavailability of topical corticosteroids. Topical corticosteroids are commonly used as polytherapy and combination therapy with other agents, such as salicylic acid, vitamin D analogues and tazarotene. Combinations are selected for the ability to enhance efficacy while minimizing corticosteroid-related side-effects, such as cutaneous atrophy. New, innovative products such as sprays, foams and nail lacquers provide opportunities to tailor treatment for individuals, which promotes patient adherence to medications. This review covers features of topical corticosteroid formulations that affect bioavailability, efficacy and safety when used as monotherapy and in combination with other agents for the treatment of mild to moderate psoriasis.

Long-term safety of infliximab for the treatment of inflammatory bowel disease: a single-centre cohort study.

BACKGROUND AND AIMS: This study evaluates the long-term safety of infliximab in patients with inflammatory bowel disease (IBD) treated with the drug over a 14-year period. METHODS: The medical records of 734 patients with IBD treated with infliximab and 666 control patients not treated with infliximab were reviewed for adverse events. The time of onset and outcome, severity and concomitant medication were recorded. RESULTS: Patients and controls were followed up for serious adverse events for a median time of 58 months (IQR 33-88) and 144 months (IQR 83-163), respectively. 112 severe adverse events occurred in 93 patients (13%) treated with infliximab and 157 occurred in 126 (19%) control patients (OR 1.33 (95% CI 0.56 to 3.00, p = 0.45). There was no difference between the two groups in mortality, malignancies and infection rate. Tuberculosis was diagnosed in two patients receiving infliximab who had negative skin tests at baseline whereas none of 16 patients with positive skin tests who received prophylaxis developed tuberculosis. Concomitant treatment with steroids was the only independent risk factor for infections in patients treated with infliximab (OR 2.69 (95% CI 1.18 to 6.12), p = 0.018). The most commonly observed systemic side effects were skin eruptions including psoriasiform eruptions in 150 patients (20%). CONCLUSIONS: Long-term infliximab treatment had a good overall safety profile in the patient cohort studied.

Efficacy and safety of calcipotriol plus betamethasone dipropionate scalp formulation compared with calcipotriol scalp solution in the treatment of scalp psoriasis: a randomized controlled trial.

BACKGROUND: Current topical therapies for scalp psoriasis are difficult or unpleasant to apply, resulting in decreased adherence and efficacy. OBJECTIVES: To compare the efficacy and safety of once-daily treatment with a combination of calcipotriol 50 microg g(-1) plus betamethasone 0.5 mg g(-1) (as dipropionate) (Xamiol; LEO Pharma A/S, Ballerup, Denmark) and twice-daily calcipotriol 50 microg mL(-1) scalp solution in patients with scalp psoriasis. METHODS: This 8-week, multicentre, randomized, investigator-blind, parallel-group study compared two-compound calcipotriol/betamethasone scalp formulation with calcipotriol scalp solution in patients with moderately severe scalp psoriasis. Primary efficacy outcome was the proportion of patients who achieved 'clear' or 'minimal' disease severity according to investigator's global assessment of disease severity at week 8. Secondary efficacy outcomes and adverse events were also evaluated. Relapse and rebound were assessed in an 8-week, post-treatment observation phase. RESULTS: In total, 207 patients received the two-compound scalp formulation and 105 patients received calcipotriol scalp solution. The proportion of patients with 'clear' or 'minimal' disease at week 8 was significantly greater in the two-compound scalp formulation group (68.6%) than in the calcipotriol scalp solution group (31.4%; P < 0.001). Improvement was more rapid with the two-compound scalp formulation than with calcipotriol scalp solution. Further evidence of the superiority of the two-compound scalp formulation over the scalp solution was demonstrated through greater improvements in clinical signs and fewer adverse events. CONCLUSIONS: A once-daily combination of calcipotriol plus betamethasone dipropionate was significantly more effective and better tolerated than twice-daily calcipotriol scalp solution in the treatment of scalp psoriasis.

A new scalp formulation of calcipotriol plus betamethasone dipropionate compared with each of its active ingredients in the same vehicle for the treatment of scalp psoriasis: a randomized, double-blind, controlled trial.

BACKGROUND: There is a need for new treatments for scalp psoriasis, as many topical treatments are cosmetically unacceptable and difficult to apply, resulting in poor compliance. OBJECTIVES: To compare the efficacy and safety of a new, once-daily, two-compound scalp formulation (Xamiol; LEO Pharma A/S, Ballerup, Denmark) containing calcipotriol 50 microg g(-1) plus betamethasone 0.5 mg g(-1) (as dipropionate), with the active ingredients as single compounds in the same vehicle. METHODS: This 8-week, multicentre, double-blind, parallel-group study, randomized adult patients with scalp psoriasis involving > 10% of the scalp to the two-compound scalp formulation (n = 568), betamethasone dipropionate 0.5 mg g(-1) (n = 563), or calcipotriol 50 microg g(-1) (n = 286). The primary efficacy measure was the proportion of patients with 'absence of disease' or 'very mild disease' according to investigators' assessments at week 8. RESULTS: The proportion of patients with 'absence of disease' or 'very mild disease' at week 8 was significantly higher in the two-compound group (68.4%) than the betamethasone dipropionate (61.0%, P = 0.0079) or calcipotriol (43.4%, P < 0.0001) groups. The proportion of patients rating their scalp psoriasis as 'clear' or 'almost clear' was significantly higher for the two-compound scalp formulation (69.6%) than for betamethasone dipropionate (59.9%, P = 0.0006) or calcipotriol (44.7%, P < 0.0001). The incidence of lesional/perilesional adverse events was lower in the two-compound and betamethasone dipropionate groups than the calcipotriol group. CONCLUSIONS: The two-compound scalp formulation was well tolerated and more effective in the treatment of scalp psoriasis than either of its individual components in the same vehicle.

Quality of life in patients with scalp psoriasis treated with calcipotriol/betamethasone dipropionate scalp formulation: a randomized controlled trial.

BACKGROUND: Psoriasis vulgaris of the scalp has a significant psychosocial impact on individuals affecting their quality of life (QoL). A combination of calcipotriol and betamethasone dipropionate in a formulation suitable for treatment of scalp psoriasis has been developed. OBJECTIVE: To assess the impact of treatment with either calcipotriol plus betamethasone dipropionate scalp formulation or calcipotriol scalp solution on QoL in patients with scalp psoriasis (both within and between treatment groups). METHODS: This 8-week, randomized, investigator-blind study, compared the once-daily, two-compound scalp formulation (calcipotriol 50 microg/g plus betamethasone 0.5 mg/g as dipropionate; Xamiol, LEO Pharma A/S, Ballerup, Denmark) with twice-daily calcipotriol scalp solution (50 microg/mL; Daivonex, LEO Pharma A/S) in patients with scalp psoriasis of at least moderate severity covering > or = 10% of the scalp. QoL was assessed (weeks 0, 2, 4, 8) using the 36-item Short Form Health Survey (version 2; SF-36v2) and Skindex-16. RESULTS: Treatment with the two-compound scalp formulation (n = 207) resulted in significant improvements from baseline on the SF-36v2 (Physical Component Summary, P = 0.005, week 8; Mental Component Summary, P < 0.05, weeks 2, 4, 8). A significant change from baseline in the calcipotriol scalp solution group (n = 105) was seen only on the Mental Component Summary (P = 0.04, week 8). Change from baseline in Skindex-16 was significantly in favour of the two-compound scalp formulation. Change was significant on both total score and individual scales. CONCLUSION: The two-compound scalp formulation was superior to calcipotriol scalp solution in improving QoL in patients with scalp psoriasis.

Consensus guidelines for the management of radiation dermatitis and coexisting acne-like rash in patients receiving radiotherapy plus EGFR inhibitors for the treatment of squamous cell carcinoma of the head and neck.

BACKGROUND: Radiation dermatitis occurs to some degree in most patients receiving radiotherapy, with or without chemotherapy. Patients with squamous cell carcinoma of the head and neck (SCCHN) who receive radiotherapy in combination with epidermal growth factor receptor (EGFR) inhibitors, such as cetuximab, may develop a characteristic acne-like rash in addition to dermatitis. DESIGN: An advisory board of 11 experienced radiation oncologists, medical oncologists and dermatologists discussed the management options for skin reactions in patients receiving EGFR inhibitors and radiotherapy for SCCHN. Skin toxicity was categorised according to the National Cancer Institute-Common Terminology Criteria for Adverse Events (version 3) grading. RESULTS: Both general and grade-specific approaches for the management of dermatitis in this patient group are presented. It was concluded that where EGFR inhibitor-related acne-like rash and dermatitis coexist within irradiated fields, management should be based on the grade of dermatitis: for grade 1 (or no dermatitis), treatment recommendations for EGFR-related acne-like rash outside irradiated fields should be followed; for grades 2 and above, treatment recommendations for dermatitis were proposed. CONCLUSIONS: This paper presents comprehensive consensus guidelines for the treatment of dermatitis in patients with SCCHN receiving EGFR inhibitors in combination with radiotherapy.

Once weekly administration of etanercept 50 mg is efficacious and well tolerated in patients with moderate-to-severe plaque psoriasis: a randomized controlled trial with open-label extension.

BACKGROUND: In previous studies, etanercept 25 mg twice weekly (BIW) or 50 mg BIW significantly reduced disease severity in patients with plaque psoriasis and demonstrated a favourable safety profile. OBJECTIVES: To assess the efficacy and safety of etanercept 50 mg administered once weekly (QW) compared with placebo in patients with moderate-to-severe plaque psoriasis over 24 weeks. METHODS: This study was conducted in two parts: (i) a 12-week, double-blind, placebo-controlled phase, in which patients received etanercept 50 mg QW or placebo QW; and (ii) a 12-week, open-label extension phase, in which all patients received etanercept 50 mg QW. Primary endpoint was a 75% or greater improvement from baseline in the Psoriasis Area and Severity Index (PASI 75) at week 12. Secondary endpoints included percentage PASI improvement and Physician's Global Assessment (PGA). RESULTS: One hundred and forty-two patients were analysed in the double-blind phase; 126 patients entered the open-label phase. At week 12, significantly more patients receiving etanercept 50 mg QW (37.5%) achieved PASI 75 response than patients receiving placebo (2.2%; P < 0.0001). At week 24, 71.1% in the etanercept-etanercept group and 44.4% in the placebo-etanercept group achieved PASI 75. Mean percentage of PASI improvement from baseline was 55.4% with etanercept vs. 9.4% worsening with placebo at week 12 (P < 0.0001), with 77.4% and 57.7% improvement in the etanercept-etanercept and placebo-etanercept groups at week 24. A PGA score of 0-1 (clear-almost clear) was achieved by 64% and 42% in the etanercept-etanercept and placebo-etanercept groups at week 24, respectively. Etanercept 50 mg QW was well tolerated. No deaths, serious infections, opportunistic infections (including tuberculosis), demyelinating disorders, malignancies or new safety signals were reported. CONCLUSIONS: Nearly three-quarters of patients with moderate-to-severe psoriasis receiving etanercept 50 mg QW achieved significant improvement in disease severity over 24 weeks. This study also showed a favourable tolerability and safety profile with etanercept 50 mg QW.

Anchorage-dependent expression of the vitamin D receptor in normal human keratinocytes.

Although the nuclear vitamin D receptor (VDR) is involved in the control of keratinocyte proliferation and differentiation by its ligand 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], its role in epidermal physiology remains poorly understood. Because VDR abundance reflects cellular responsiveness to 1,25(OH)2D3, we investigated VDR expression in cultured human keratinocytes and identified cell anchorage and cytoskeletal integrity as essential requirements for the maintenance of VDR levels. Suspension culture rapidly suppressed VDR expression and 1,25(OH)2D3 responsiveness (as estimated by induction of 24-hydroxylase mRNA), due to decreased transcription of the VDR gene. Concomitantly, overt growth arrest with p21WAF1 induction and cyclin D1 and c-myc suppression occurred, together with induction of differentiation markers and retinoid X receptor alpha, the heterodimeric partner for VDR. Reattachment of suspended keratinocytes to fibronectin led to a rapid restoration of VDR expression, which could be blocked by RGD peptides or a blocking anti-beta1 integrin antibody. VDR expression was also reduced by disruption of the actin cytoskeleton with cytochalasin D. Malignant keratinocytes (SCC12B2 and A431), characterized by, anchorage-independent growth, displayed a profound resistance to suspension-induced suppression of VDR, cyclin D1, and c-myc. Taken together, our results associate VDR expression [and 1,25(OH)2D3 responsiveness] with cell adhesion and an organized cytoskeleton, which are also required for cell growth of primary cells.

Retinoic acid modulates the anti-proliferative effect of 1,25-dihydroxyvitamin D3 in cultured human epidermal keratinocytes.

Both 1,25-dihydroxyvitamin D3 (VD) and retinoids have potent effects on keratinocyte proliferation. Parallelism in their action as steroid hormones, which involves interaction of their receptors, and in their therapeutic efficacy for hyper-proliferative skin diseases provides a rationale to investigate their combined action on proliferation in pre-confluent human epidermal keratinocyte cultures. As shown by [3H]thymidine incorporation, all-trans retinoic acid (atRA) at subpharmacologic concentrations and 9-cis retinoic acid (9cRA) diminished the anti-proliferative effect of VD. Pre-incubation of the cells with the retinoids clearly enhanced this effect. Cell-cycle analysis revealed G1 arrest upon VD treatment that was attenuated by retinoic acid (RA). Moreover, Northern and Western blot analysis demonstrated that retinoic acid opposed VD-induced accumulation of transforming growth factor-beta1, p21WAF1, and p27KIP1. Finally, retinoic acid reduced VD-elicited hypophosphorylation of the retinoblastoma protein. AtRA at micromolar concentrations conversely potentiated most of the aforementioned VD-dependent actions. In addition, atRA and 9cRA (but not VD) caused a rapid, sustained reduction of RXR alpha protein. VD receptor protein was induced by VD regardless of the presence of RA. In conclusion, RA modulates VD-dependent effects at different levels of keratinocyte proliferation. This could have implications for the use of combinations of both drugs for skin diseases.

Suppression of vitamin D receptor and induction of retinoid X receptor alpha expression during squamous differentiation of cultured keratinocytes.

To gain more insight in the role of the vitamin D system in epidermal differentiation, we studied the expression of the vitamin D receptor and its heterodimeric partner retinoid X receptor alpha in cultured normal human keratinocytes during squamous differentiation, as triggered by different approaches. Northern and western blot analysis allowed us to investigate mRNA and protein levels of these nuclear receptors and of markers for growth control (c-myc, cyclin D1, p21WAF1) and differentiation (keratinocyte transglutaminase, small proline rich proteins). Growing cells to postconfluence was a potent stimulus for growth arrest and differentiation with concomitant suppression of vitamin D receptor and induction of retinoid X receptor alpha, at both the mRNA and the protein level. These changes could be prevented by concomitant treatment with epidermal growth factor or keratinocyte growth factor. Subjecting the cells to a calcium switch leading to stratification and differentiation lowered vitamin D receptor protein levels without affecting vitamin D receptor mRNA and induced both retinoid X receptor alpha mRNA and protein. Interferon-gamma and the phorbolester 12-O-tetradecanoyl phorbol 13-acetate, two well-known inducers of keratinocyte differentiation, both inhibited vitamin D receptor expression but only interferon-gamma induced retinoid X receptor alpha. The decreased vitamin D receptor expression was accompanied by reduced vitamin D responsiveness (as assessed by 24-hydroxylase mRNA induction) in postconfluent, high calcium, and 12-O-tetradecanoyl phorbol 13-acetate treated keratinocytes but not with interferon-gamma treatment. Taken together, our results associate vitamin D receptor expression with undifferentiated, proliferating keratinocytes, whereas retinoid X receptor alpha expression appears to be related to the differentiated phenotype. Therefore, proliferating and differentiating keratinocytes may be differentially targeted by active vitamin D metabolites.

Recent developments in the use of vitamin D analogues.

The non-classical effects of 1alpha,25-dihydroxyvitamin D(3) (1alpha, 25(OH)(2)D(3)) create possible therapeutic applications for immune modulation (e.g., autoimmune diseases and graft rejection), inhibition of cell proliferation (e.g., psoriasis, cancer) and induction of cell differentiation (e.g., cancer). The major drawback related to the use of 1alpha,25(OH)(2)D(3) is its calcaemic effect, which prevents the application of pharmacological concentrations. Intensive research has led to the development of analogues of 1(2)D(3) characterised by a clear dissociation of the antiproliferative and prodifferentiating capacity from the calcaemic effects. Due to this dissociation, these analogues can be used not only for the treatment of bone disorders but also for non-classical applications. In the present review, a summary is given on the use of the 1alpha,25(OH)(2)D(3) analogues for the treatment of cancer, skin and immune disorders and for the prevention of graft rejection. Moreover a brief overview is given on the use of analogues for secondary hyperparathyroidism.