Recently, the Aldara‐induced psoriasis‐like skin inflammation model in mice has attracted increased attention, due to its dependence on the same immunological pathways and cell types as in human psoriasis.

BACKGROUND:TRANSIT (NCT01059773) compared immediate and gradual transition from methotrexate to ustekinumab in psoriasis patients via multiple measures, including patient-reported outcomes. OBJECTIVE:To evaluate patient perception of treatment benefits in TRANSIT. METHODS:A total of 489 psoriasis patients received ustekinumab, with immediate cessation of methotrexate (Arm 1) or 4 weeks' overlap with decreasing methotrexate dose (Arm 2). Ustekinumab was administered at weeks 0, 4, 16, 28 and 40. Dermatology Life Quality Index (DLQI), EuroQol 5-item (EQ-5D), visual analogue scale (VAS) valuation technique and patient benefit index (PBI) were employed. Mean global PBI and sub-scores were calculated from the sum of the benefit items weighted by their respective relevance at baseline. Patient-relevant benefit was defined as PBI ≥1 (scale: 0 [no benefit] to 4 [maximum benefit]). Correlations of global PBI with Psoriasis Area and Severity Index (PASI) and DLQI were examined. RESULTS:Relationships between PBI and clinical data were evaluable in 340 patients. The most important treatment goals at baseline included: 'be healed of all skin defects', 'have confidence in therapy', 'get better skin quickly' and 'regain control of the disease'. Benefit in PBI global score was achieved at week 4 by 93% of patients in Arm 1 and 91% in Arm 2. Global PBI scores increased in both Arms between weeks 4 and 52. Global PBI correlated weakly with PASI change from baseline (correlation coefficient range: -0.22 to -0.40), and moderately with DLQI (-0.29 to -0.54). Overall DLQI score was lower than baseline at all times; and the percentage of patients with an overall score of 0 or 1 increased with time. Correspondingly, EQ VAS scores increased with time. DLQI and EQ VAS results were similar between arms. CONCLUSIONS:Regardless of the strategy for transitioning from methotrexate, ustekinumab was associated with rapid and sustained improvement in patient-reported outcomes. PBI appears a suitable tool for assessing patient-relevant treatment benefits in psoriasis patients.

Background The application of Aldara (R) cream containing 5% imiquimod stimulates Toll-like receptor 7/8 on plasmacytoid dendritic cells, thereby producing a potent immunomodulatory effect. This has been reported to trigger psoriasis. Objectives To establish a human model of Aldara-induced psoriasis-like skin inflammation in patients with psoriasis.Methods Nonlesional psoriatic skin of 13 patients was treated with Aldara for 2 or 7 days. The skin was evaluated clinically and histologically on days 2, 4 and 7. Cytokine expression in Aldara-treated, lesional and nonlesional psoriatic skin was compared using reverse-transcription quantitative polymerase chain reaction.Results Nine of the 10 patients receiving application of Aldara under occlusion for 2 days developed redness, induration and scaling. Histological analysis revealed focal parakeratosis, acanthosis and perivascular mononuclear infiltration. On days 4 and 7 both clinical and histological signs of inflammation subsided. Two of the three patients treated with Aldara for 7 days developed erosions leading to psoriasis on day 21. Cytokine markers of activation of the innate immune system [interferon-alpha, interferon regulatory factor-7 and interleukin (IL)-1 beta] were equally expressed in lesional and Aldara-treated skin (n = 6). IL-6 and tumour necrosis factor-alpha were preferentially expressed in Aldara-treated skin. Adaptive immune system activation occurred only partially: IL-23p19 and IL-22 were similarly overexpressed in Aldara-treated and lesional psoriatic skin, but IL-17A and IL-12p40 were significantly underexpressed in Aldara-treated skin compared with lesional psoriatic skin. IL-10 was significantly overexpressed in Aldara-treated skin.Conclusions We were able to induce psoriasis-like skin inflammation although typical psoriasis did not develop, possibly due to incomplete adaptive immune system recruitment and the powerful stimulation of IL-10 counter-regulation.

BackgroundThere is limited information on systemic and biological treatment optimization and transitioning in routine clinical practice.ObjectiveTo provide practical guidance on treatment optimization and transitioning for moderate-to-severe plaque psoriasis.MethodsDermatologists from 33 countries contributed to the Transitioning Therapies programme. Fourteen questions were identified. Answers were drafted based on systematic literature reviews (7/14 questions) and expert opinion (7/14 questions). Using a modified Delphi procedure, dermatologists from 30 countries voted on their level of agreement with each draft answer (scale: 1-9, strong disagreement to strong agreement). Consensus was defined as >= 75% of participants scoring within the 7-9 range.ResultsConsensus was achieved on the answers to all questions. Recommendations for the use of cyclosporine and methotrexate were agreed. Transitioning from a conventional systemic therapy to a biological agent may be done directly or with an overlap (if transitioning is required because of lack of efficacy) or potentially with a treatment-free interval (if transitioning is required for safety reasons). Combination therapy may be beneficial. Continuous therapy for patients on biologicals is strongly recommended. However, during successful maintenance with biological monotherapy, a dosage reduction may be considered to limit drug exposure, although this may carry the risk of decreased efficacy. Switching biologicals for reasons of efficacy should be done without a washout period, but switching for reasons of safety may require a treatment-free interval.ConclusionThis consensus provides practical guidance on treatment optimization and transitioning for moderate-to-severe plaque psoriasis, based on literature reviews and the expert opinion of dermatologists from across the globe.

BACKGROUND:Limited data exist on transitioning patients with psoriasis from conventional systemic agents to biologics.OBJECTIVES:The TRANSIT study aimed to assess the efficacy and safety of two methotrexate-to-ustekinumab transition strategies.METHODS:Patients with moderate-to-severe psoriasis and inadequate methotrexate response were randomized 1 : 1 to receive ustekinumab with immediate (arm 1) or 4-week gradual (arm 2) methotrexate withdrawal. Patients weighing ≤ 100 kg or > 100 kg received ustekinumab 45 mg or 90 mg, respectively. The primary endpoint was the frequency of adverse events (AEs) at week 12. Secondary endpoints included additional safety, efficacy and patient-reported outcomes. We report the 12-week efficacy and safety results.RESULTS:Overall, 244 patients in arm 1 and 245 in arm 2 were randomized and received ustekinumab. Four patients per arm discontinued the trial by week 12. At week 12 in arms 1 and 2, respectively, 61% and 65% of patients experienced an AE, 2·9% and 2·4% had a serious AE, and 1·2% and 0·4% had an AE leading to ustekinumab discontinuation. In arms 1 and 2, respectively, median Psoriasis Area and Severity Index (PASI) score decreased from 15·2 and 15·4 at baseline to 2·9 and 2·8 at week 12; 58% and 62% of patients achieved a 75% reduction from baseline in PASI score (PASI 75) at week 12; median baseline Dermatology Life Quality Index fell from 8 and 9 at baseline to 1 (both arms) at week 16.CONCLUSIONS:Ustekinumab was well tolerated and effective in patients who had an inadequate response to methotrexate. Both transition strategies resulted in similar week 12 safety and efficacy outcomes.

BACKGROUND:There are limited long-term, 'real-world' data on ustekinumab, or the effect of dose adjustment in suboptimal responders.OBJECTIVES:We describe 52-week data from TRANSIT, which initiated ustekinumab by licensed regimen and investigated exploratory dose adjustment.METHODS:Patients with moderate-to-severe psoriasis and inadequate methotrexate response received ustekinumab, with immediate or gradual methotrexate withdrawal. Outcomes were similar between treatment arms at week 12 (primary endpoint), so week 52 data were pooled. Patients weighing ≤ 100 kg or > 100 kg were administered ustekinumab 45 or 90 mg, respectively. Patients weighing ≤ 100 kg without 75% improvement in Psoriasis Area and Severity Index (PASI 75) response at weeks 28 or 40 received a dose adjustment to 90 mg. The primary analysis used observed data.RESULTS:Overall, 391 and 98 patients received ustekinumab 45 and 90 mg, respectively. Forty-four patients (9%) discontinued before week 52 (0·4% due to adverse events). At week 52 (in the overall population), 369 patients (83%) achieved a PASI score ≤ 5, and 341 patients (77%) achieved PASI 75; the median PASI score decreased from 15 at baseline to 1·8. At weeks 28 and 40, 84 and 31 patients, respectively, did not achieve PASI 75 and received a dose adjustment; by week 52, 35/82 (43%) and 15/31 (48%) of these patients, respectively, achieved PASI 75 (two discontinued between weeks 28 and 40).CONCLUSIONS:Ustekinumab showed sustained 1-year efficacy and was well tolerated when initially administered according to label. Adjusting the ustekinumab dose to 90 mg may result in clinically meaningful improvement in response in patients weighing ≤ 100 kg with suboptimal initial response.

The fixed combination calcipotriol plus betamethasone dipropionate gel is a first-line treatment for psoriasis vulgaris. The objective was to perform a large-scale assessment of tolerability of fixed combination gel (Cal/BD). Analysis was performed on pooled 8-week safety data from nine clinical trials evaluating once-daily Cal/BD treatment of scalp (n=6) and body (n=3) psoriasis. Pharmacovigilance data were also assessed. Patients were treated with Cal/BD [n=1953 (scalp), n=824 (body)], betamethasone dipropionate gel (BD; n=1214, n=562), calcipotriol gel (Cal; n=979, n=175), gel vehicle (VEH; n=173, n=226), calcipotriol scalp solution [n=104 (scalp only)] and tacalcitol ointment [TAC; n=184 (body only)]. Most adverse events (AEs) were mild-moderate severity. The proportion of scalp psoriasis patients with >= 1 AE was lowest with Cal/BD (35% versus 38-57%). A similar proportion was found with Cal/BD for body psoriasis (32%), however, lower proportions were reported with BD (24%) and Cal (29%). The most common AEs with Cal/BD included nasopharyngitis, pruritus and upper respiratory tract infection (2-5% of patients). Overall, only 5% of patients treated with Cal/BD reported >= 1 lesional/perilesional AEs: the lowest incidence versus scalp comparators (6-19%) and second lowest to BD (3%) for body psoriasis. Similarly, Cal/BD treatment resulted in the lowest incidence of >= 1 adverse drug reactions (ADRs) in scalp psoriasis patients (8% versus 9-27%) and second lowest to BD (6% versus 4%) for body psoriasis. Overall, incidence of serious AEs (SAEs) was low (0-1%). Data received postmarketing through spontaneous reporting revealed that SAEs reported more than once with Cal/BD treatment were psoriasis (n=5); and alopecia, erythrodermic psoriasis, pruritus, skin atrophy and urticaria (n=2 each). In this large subset of patients treated with Cal/BD, incidence of AEs and ADRs is consistently low. This analysis provides further evidence of the good tolerability of the fixed combination gel as treatment for psoriasis vulgaris.

Despite the availability of a plethora of approved systemic treatments, high proportions of patients with moderate-to-severe psoriasis do not receive systemic treatment. This study aims at identifying barriers that hinder dermatologists from prescribing systemic treatments for psoriasis. A cross-sectional online survey in six countries (Canada, Germany, Spain, France, Italy, UK) was performed among 300 dermatologists, assessing the relevance of 15 potential barriers towards prescribing acitretin, cyclosporine, methotrexate, adalimumab, etanercept, infliximab and ustekinumab. Multivariate regression analyses were used to explore provider characteristics related to these barriers. Treatment barriers are perceived differently in the countries investigated, with Spanish, Italian and Canadian dermatologists being particularly concerned about the safety of methotrexate and Canadian dermatologists about the safety of cyclosporine. In general, safety concerns were the most important barrier to the use of cyclosporine, (18 % of participants’ moderate/9 % strong or very strong barrier). Costs were being perceived as a strong or very strong barrier to the use of the different biologics by 19–24 % of the participants. Overall, country and work place were the most important determinants of treatment barriers. Sex, age, training, position and experience were minor determinants of treatment barriers. Medical reasons such as safety concerns or an inappropriate risk-benefit profile are particularly relevant barriers to the prescription of conventional treatments; whereas for biological treatments, economic reasons such as costs are more prevalent. Country specific analysis showed national differences in the perception of safety. The treatment barriers identified in this exploratory study should be confirmed in further health services research.

BACKGROUND:The p38 mitogen-activated protein kinase (MAPK) plays an important role in inflammatory processes and displays increased activity in psoriasis. Dual-specificity phosphatase 1 (DUSP1) is an important negative regulator of p38 MAPK activity.OBJECTIVES:To study mRNA expression of DUSP1 in normal human epidermal keratinocytes (NHEKs) stimulated with proinflammatory cytokines and to investigate DUSP1 in psoriatic skin.METHODS:NHEKs were cultured in vitro and punch biopsies were obtained from the skin of patients with psoriasis vulgaris and atopic dermatitis. mRNA expression was analysed by reverse transcription-quantitative polymerase chain reaction (RT-qPCR).RESULTS:In NHEKs, interleukin (IL)-1β induced DUSP1 mRNA expression in a rapid and time-dependent manner through the p38 MAPK/mitogen- and stress-activated kinase (MSK) signalling pathway. DUSP1 mRNA expression was demonstrated to be significantly downregulated in psoriatic skin lesions compared with paired samples of nonlesional psoriatic skin. This was in contrast to atopic dermatitis. The downregulation of DUSP1 mRNA in lesional psoriatic skin was not explained by the difference in the mRNA expression of the potential DUSP1 transcript stability-affecting proteins Hu antigen R or tristetraprolin. Furthermore, DUSP1 mRNA expression was shown not to increase during the early course of treatment with the antitumour necrosis factor-α antibody adalimumab.CONCLUSIONS:In lesional psoriatic skin, the p38 MAPK negative feedback mechanism provided by DUSP1 seems to be inhibited. Downregulation of DUSP1 may contribute to the sustained inflammatory response seen in psoriasis.

BACKGROUND:The European Consensus Programme (ECP) established pan-European consensus definitions of psoriasis disease severity and treatment goals among 19 psoriasis experts from European nations. OBJECTIVES:To use the ECP treatment goals to retrospectively assess adalimumab efficacy in patients who participated in Phase III clinical trials and met ECP criteria for moderate to severe psoriasis. METHODS:Three trials were analysed: CHAMPION (n = 108), REVEAL (n = 814) and BELIEVE (n = 364). Moderate to severe psoriasis was defined as Dermatology Life Quality Index (DLQI) score > 10, with either > 10% body surface area involvement or Psoriasis Area and Severity Index (PASI) score > 10. Treatment goals were achieved with either treatment success (≥ 75% PASI score reduction) or intermediate response (PASI response ≥ 50% and < 75%) with DLQI ≤ 5. RESULTS:The percentages of patients who achieved treatment goals at week 16 in CHAMPION, REVEAL and BELIEVE were, respectively, (i) treatment success, 79·3%, 72·1% and 68·2%; (ii) intermediate response, 1·7%, 5·0% and 5·0%; or (iii) either goal, 81·0%, 77·1% and 73·2%. DLQI ≤ 5 at week 16 was achieved by 70·7%, 70·1% and 67·4% of patients, respectively. Differences between the percentages of adalimumab- vs. placebo-treated patients achieving treatment success were statistically significant (P < 0·001) from week 4 and week 8 of REVEAL and CHAMPION, respectively. CONCLUSIONS:Treatment success was achieved by > 93% of patients who attained treatment goals. At week 16 > 70% of patients achieved ECP treatment goals and met ECP criteria for continued treatment without modification. These results support the utility of ECP treatment goals for the assessment of therapeutic efficacy in moderate to severe psoriasis.

We describe Week 52 quality of life outcomes following immediate or gradual transition to ustekinumab in psoriasis patients with inadequate response to methotrexate in the Phase IV TRANSIT study (NCT01059773). In this 52-week, open-label trial, 490 patients with moderate-to-severe plaque psoriasis despite treatment with methotrexate (10–25mg/week for ≥8 weeks) were randomised 1:1 to ustekinumab with immediate cessation of methotrexate (Arm1), or 4 weeks' overlap with decreasing methotrexate dose (Arm2). Ustekinumab was administered according to label: 45mg in patients ≤100kg or 90mg if >100kg. Patients ≤100kg not achieving adequate response (Psoriasis Area Severity Index decrease from baseline ≥75% [PASI 75]) at Weeks 28 or 40 were dose escalated to 90mg. A total of 244 patients were treated in Arm1 and 245 in Arm2; 92% and 90%, respectively, completed 52 weeks' therapy. Median baseline Dermatology Life Quality Index (DLQI) was 8 and 9 in Arms1 and 2, respectively, decreasing to 1 (both arms) at Weeks 16 and 52. At Week 52 in Arms1 and 2, respectively, 61% and 62% of patients had a DLQI reduction ≥5 points; 62% and 67% had DLQI 0 or 1. Median DLQI scores were low at Week 28 among patients who dose escalated; further improvements were seen by Week 52. Median EuroQOL-5D Visual Analogue Scale improved from baseline to Week 52, respectively: 70.0 (IQR 50.0–80.0) to 85.0 (IQR 70.0–95.0) in Arm1, and 70.0 (IQR 50.0–85.0) to 85.0 (IQR 79.5–95.0) in Arm2. Median Hospital Anxiety and Depression Scale (HADS) Anxiety and Depression scores also improved from baseline to Week 52. In patients with moderate-to-severe psoriasis, ustekinumab use was associated with clinically relevant improvements in patient-reported outcomes, irrespective of whether patients were transitioned with immediate or gradual cessation of methotrexate. Improvements at Week 16 were sustained to 52 weeks of ustekinumab therapy.

Rapporter les résultats de la pose d’implants intra-prostatiques UroLift® après 2 ans d’expérience.L’intervention a été proposée entre février 2012 et avril 2014 aux patients ayant une hyperplasie bénigne de la prostate symptomatique, en alternative à un traitement chirurgical ablatif classique. L’évaluation de la symptomatologie urinaire était basée sur l’auto-questionnaire IPSS, et la mesure du débit urinaire maximal (Qmax). L’évaluation de la fonction érectile et éjaculatoire était basée sur les auto-questionnaires IIEF5 et MSHQ-EjD.Vingt-trois patients ont été traités pendant cette période. L’âge médian était de 66 ans [53–78]. Le volume prostatique médian était de 38 mL [20–80]. En préopératoire, l’IPSS et l’IPSS-QDV médians étaient de 20 [9–29] et 5 [3–6]. Aucun effet indésirable grave n’a été observé en postopératoire. La durée médiane du suivi a été de 14 mois [5–31]. En fin de suivi, 19 (83 %) patients rapportaient une amélioration de leur symptômes urinaires sans aucun traitement. L’IPSS et l’IPSS-QDV étaient significativement améliorés (valeurs médianes de 11 [1–27] et 2 [0–6], p < 0,0001), sans néanmoins d’augmentation significative du Qmax. Quatre patients ont dû avoir un traitement complémentaire dès la première année. Parmi eux, 3 avaient un volume prostatique > 60 mL. Aucun patient n’a rapporté d’éjaculation rétrograde, ni d’altération de sa fonction érectile.La pose d’implants UroLift® a permis une amélioration des symptômes chez plus de 80 % des patients après un an de suivi. Un volume prostatique élevé semblerait un facteur potentiel d’échec.5.To report the results of UroLift® implants after a 2-year experience in the technique.The procedure was proposed between February 2012 and April 2014 in patients with symptomatic benign prostatic hyperplasia, as an alternative to standard endoscopic ablation techniques. Evaluation of BPH related symptoms relied on the IPSS and IPSS-QoL self-questionnaires, as well as on maximum uroflow (Qmax). Evaluation of erectile and ejaculatory functions relied on the IIEF5 and MSHQ-EjD self-questionnaires, respectively.A total of 23 patients were treated during this period. Median age was 66 years [53–78]. Median prostate volume was 38 mL [20–80]. Preoperative IPSS and IPSS-QoL were 20 [9–29] and 5 [3–6], respectively. No severe adverse event was observed postoperatively. Median follow-up was 14 [5–31] months. At the end of follow-up, 19 (83%) patients reported sustained symptomatic improvement without any additional treatment. Median IPSS and IPSS-QoL were improved significantly (11 [1–27] and 2 [0–6], P < 0.0001), with however no significant improvement in Qmax. Four patients needed additional treatment during the first postoperative year. Among them, 3 had a prostate volume > 60 mL. No patient reported retrograde ejaculation or worsened erectile function.UroLift® implants allowed symptomatic improvement in more than 80% of the patients after 1-year follow-up. A high prostate volume may potentially be predictive of symptomatic failure.5.