Quality of life and patient benefit following transition from methotrexate to ustekinumab in 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.

Tumour necrosis factor-α plays a significant role in the Aldara-induced skin inflammation in mice.

BACKGROUND: 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. OBJECTIVES: To study the impact of constitutive deficiency of tumour necrosis factor (TNF)-α and its upstream regulator mitogen-activated protein kinase-activated protein kinase 2 (MAPKAPK-2, herein MK2) in the Aldara-induced psoriasis-like skin inflammation model. METHODS: TNF-α knockout (KO), MK2 KO and wild-type (WT) mice divided into separate groups received either 45-mg Aldara cream or control cream for 5 consecutive days. The skin inflammation was evaluated clinically, histologically, and by quantitative reverse transcription-polymerase chain reaction. RESULTS: We found that TNF-α KO mice developed significantly less skin inflammation compared with WT mice, as evaluated clinically and histologically. At the molecular level, we demonstrated that the Aldara-induced mRNA expression of the psoriasis-related inflammatory markers interleukin (IL)-17C, IL-23p19, IL-12p40, IL-17A, IL-22 and S100A8 was significantly decreased in TNF-α KO mice compared with WT mice. No significant difference in the mRNA expression of these inflammatory markers between MK2 KO mice and WT mice was found, although Aldara-treated MK2 KO mice showed a tendency towards a lower mRNA expression of IL-17A and IL-22 compared with WT mice. CONCLUSIONS: We were able to demonstrate significantly lower levels of inflammation in TNF-α KO mice compared with WT mice, supporting the use of this model in future studies characterizing the role of TNF-α in psoriasis.

Aldara®-induced skin inflammation: studies of patients with psoriasis.

BACKGROUND: The application of Aldara(®) 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-α, interferon regulatory factor-7 and interleukin (IL)-1ß] were equally expressed in lesional and Aldara-treated skin (n = 6). IL-6 and tumour necrosis factor-α 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.

One-year safety and efficacy of ustekinumab and results of dose adjustment after switching from inadequate methotrexate treatment: the TRANSIT randomized trial in moderate-to-severe plaque psoriasis.

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.

Transition to ustekinumab in patients with moderate-to-severe psoriasis and inadequate response to methotrexate: a randomized clinical trial (TRANSIT).

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.

Pooled safety analysis of calcipotriol plus betamethasone dipropionate gel for the treatment of psoriasis on the body and scalp.

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.

A consensus report on appropriate treatment optimization and transitioning in the management of moderate-to-severe plaque psoriasis.

BACKGROUND: There is limited information on systemic and biological treatment optimization and transitioning in routine clinical practice. OBJECTIVE: To provide practical guidance on treatment optimization and transitioning for moderate-to-severe plaque psoriasis. METHODS: Dermatologists 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. RESULTS: Consensus 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. CONCLUSION: This 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.

Psoriasis beyond the skin: an expert group consensus on the management of psoriatic arthritis and common co-morbidities in patients with moderate-to-severe psoriasis.

BACKGROUND: Psoriatic arthritis (PsA) and co-morbidities of psoriasis represent a significant clinical and economic burden for patients with moderate-to-severe psoriasis. Often these co-morbidities may go unrecognized or undertreated. While published data are available on the incidence and impact of some of them, practical guidance for dermatologists on detection and management of these co-morbidities is lacking. OBJECTIVE: To prepare expert recommendations to improve the detection and management of common co-morbidities in patients with moderate-to-severe psoriasis. METHODS: A systematic literature review was conducted on some common co-morbidities of psoriasis-cardiovascular (CV) diseases (including obesity, hypertension, hyperglycaemia and dyslipidaemia), psychological co-morbidities (including depression, alcohol abuse and smoking) and PsA-to establish the incidence and impact of each. Data gaps were identified and a Delphi survey was carried out to obtain consensus on the detection and management of each co-morbidity. The expert panel members for the Delphi survey comprised 10 dermatologists with substantial clinical expertise in managing moderate-to-severe psoriasis patients, as well as a cardiologist and a psychologist (see appendix) with an interest in dermatology. Agreement was defined using a Likert scale of 1-7. Consensus regarding agreement for each statement was defined as ≥75% of respondents scoring either 1 (strongly agree) or 2 (agree). RESULTS: The expert panel members addressed several topics including screening, intervention, monitoring frequency, and the effects of anti-psoriatic treatment on each co-morbidity. Consensus was achieved on 12 statements out of 22 (3 relating to PsA, 4 relating to psychological factors, 5 relating to CV factors). The panel members felt that dermatologists have an important role in screening their psoriasis patients for PsA and in assessing them for psychological and CV co-morbidities. In most cases, however, patients should be referred for specialist management if other co-morbidities are detected. CONCLUSION: This article provides useful and practical guidance for the detection and management of common co-morbidities in patients with moderate-to-severe psoriasis.

The expression of dual-specificity phosphatase 1 mRNA is downregulated in lesional psoriatic skin.

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)-1ß 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.

An assessment of adalimumab efficacy in three Phase III clinical trials using the European Consensus Programme criteria for psoriasis treatment goals.

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.

Comparison of drug survival rates for adalimumab, etanercept and infliximab in patients with psoriasis vulgaris.

BACKGROUND: Adherence to treatment is an indicator of treatment success. Long-term data on adherence to biologic treatment in psoriasis are lacking. OBJECTIVES: To compare the tumour necrosis factor (TNF)-α inhibitors regarding drug survival rate and safety in patients with psoriasis. METHODS: This study is based on data from the Danish nationwide database DERMBIO covering patients with psoriasis treated with a biologic agent. All patients who received anti-TNF-α treatment in academic referral centres were included. Baseline data, adverse events, time on treatment and reason for stopping treatment were recorded. Hazard ratios (HRs) for factors determining drug survival were calculated by logistic regression. RESULTS: In total, 882 treatment series with etanercept (n = 311), adalimumab (n = 427) or infliximab (n = 144) were administered to 747 patients. Significant predictors of drug survival were: sex, the anti-TNF-α agent and the previous response to an anti-TNF-α agent. In the group of anti-TNF-α-naïve patients the longest drug survival was observed for infliximab, followed by adalimumab [HR vs. infliximab 3·70, 95% confidence interval (CI) 1·99-6·89] and etanercept (HR vs. infliximab 3·18, 95% CI 1·72-5·86). The 4-year drug survival is in the range of 40% for etanercept or adalimumab vs. 70% for infliximab. There was no difference in number of adverse events. CONCLUSIONS: The overall efficacy of anti-TNF-α drugs diminishes with time, as envisaged by the progressive loss of patient adherence to treatment. The major reasons for stopping treatment were loss of efficacy, followed by adverse events. Infliximab had the best patient retention ability, with 70% of patients still being on the drug after 4 years of treatment.

Dimethylfumarate inhibits MIF-induced proliferation of keratinocytes by inhibiting MSK1 and RSK1 activation and by inducing nuclear p-c-Jun (S63) and p-p53 (S15) expression.

OBJECTIVE: Dimethylfumarate (DMF) is used in the treatment of psoriasis. Macrophage migration inhibitory factor (MIF) is elevated in patients with severe psoriasis. We studied the effect of DMF on the MIF-induced activation of the mitogen- and stress-activated kinase 1 (MSK1) and p90 kDa ribosomal S6 kinase (RSK1) signaling pathways which regulate the proliferation of human keratinocytes via transcription factors. METHODS: The effects of DMF on the MIF-induced activation of MSK1, RSK1, cAMP-responsive element-binding protein (CREB), Cox-2 and c-Jun, JunB and p53 were studied by Western blotting using phospho-specific antibodies. RESULTS: DMF inhibited the MIF-induced phosphorylation of MSK1, RSK1, CREB and JunB, and reduced Cox-2 expression and the proliferation of cultured human keratinocytes. The expression of p-p53 (S15) was induced simultaneously with the inhibition of Cox-2. Addition of DMF before MIF induced nuclear expression of p-c-Jun (S63) and c-Jun. Transfection with small interfering MSK1 and RSK1 RNA before MIF incubation stimulated p-p53 (S15) and nuclear p-c-Jun (S63) similarly to DMF. CONCLUSION: Our results indicate that the specific inhibitory effects of DMF on RSK1 and MSK1 activation together with the induction of p-c-Jun (S63) and p-p53 (S15) lead to the inhibition of keratinocyte proliferation, partly explaining the anti-psoriatic effect of DMF.

Strategies for improving the quality of care in psoriasis with the use of treatment goals--a report on an implementation meeting.

Targeted treatment, early intervention and the use of treatment goals is a new approach in medicine that has been implemented across several disciplines (e.g. diabetes, pulmonary arterial hypertension and rheumatoid arthritis) over the last 5-10 years. As in other chronic diseases, well-defined treatment goals may be helpful in guiding physicians in their care of patients with psoriasis, thereby obviating poor outcomes. Individual treatment goals were recently developed for the first time in psoriasis by a European Consensus group of experts from 19 European countries to supplement guidelines and promote the consistent use of available therapies to improve patient care. Goal-oriented therapy involves treating according to a treatment algorithm, regularly monitoring therapeutic response and prompt modification of therapy if goals are not met. In the absence of hard outcomes in psoriasis (e.g. biomarkers or biomedical predictors of clinical response), the European Consensus group based their treatment goals on changes in Psoriasis Area Severity Index and Dermatology Life Quality Index scores. Further evidence generation is important to determine whether surrogate markers for disease progression (e.g. co-morbidities) or predictors of clinical response can be identified for psoriasis. Furthermore, psoriasis may have a potential cumulative effect on the life course of patients, the understanding of which is likely to provide the rationale for earlier treatment strategies in psoriasis. For the work of the European Consensus group to have an impact on clinical care, transmission of treatment goals into guidelines, along with implementation of treatment goals at both the regional and national level is needed. Thus, dermatology experts from Europe, the Middle East, Australia and Canada gathered in Frankfurt, 2010, for a 1.5 day educational meeting run by the Progressive Psoriasis Initiative to discuss how treatment goals in psoriasis might best be implemented in clinical practice. The meeting conclusions are presented here.

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.

Adalimumab therapy rapidly inhibits p38 mitogen-activated protein kinase activity in lesional psoriatic skin preceding clinical improvement.

BACKGROUND: The pathogenesis of psoriasis and the mechanisms of action of antitumour necrosis factor (TNF)-α therapies are incompletely understood. OBJECTIVES: To investigate the early molecular effects of adalimumab in psoriatic skin. METHODS: Biopsies taken from patients with psoriasis were examined before and after the onset of adalimumab therapy. TNF-α protein level and mRNA expression were measured by enzyme-linked immunosorbent assay and quantitative reverse transcription-polymerase chain reaction, respectively. The activities of p38 mitogen-activated protein kinase (MAPK) and extracellular regulated kinase 1 and 2 (ERK1/2) as well as the downstream kinases MAPK-activated protein kinase 2 (MK2) and mitogen- and stress-activated protein kinase 1 and 2 (MSK1/2) were measured by Western blot analyses. RESULTS: We demonstrated that clinical and histological improvements were detected from day 14. The increased activity of p38 MAPK in lesional psoriatic skin was significantly inhibited by adalimumab already at day 4. The activities of ERK1/2, MSK1/2 and MK2 were reduced at the end of study (day 84) when the level of TNF-α in lesional psoriatic skin reached the nonlesional level, and the Psoriasis Area and Severity Index score was reduced. CONCLUSIONS: The rapid inhibition of p38 MAPK by adalimumab in lesional psoriatic skin preceded clinical and histological improvements, demonstrating an association between TNF-α neutralization and p38 MAPK inhibition. Thus, inhibition of p38 MAPK may be a novel mechanism by which adalimumab mediates its antipsoriatic effect.

Preferential inhibition of the mRNA expression of p38 mitogen-activated protein kinase regulated cytokines in psoriatic skin by anti-TNFα therapy.

BACKGROUND: Anti-TNFα therapies are well established for severe psoriasis; however, their mechanism of action in disease resolution is not fully understood. p38 mitogen-activated protein kinase (MAPK) is a kinase known to play a key role in the pathogenesis of psoriasis. OBJECTIVES: To elucidate the early effects of adalimumab, a human monoclonal anti-TNFα antibody, on the expression of interleukins in psoriatic skin. PATIENTS AND METHODS: Biopsies from patients with psoriasis were examined before and after the start of adalimumab therapy. mRNA expression of cytokines were measured with quantitative polymerase chain reaction. p38 MAPK and signal transducer and activator of transcription 3 (STAT3) were analysed by Western blotting and immunofluorescence analyses, and IL-17A and IL-17C were examined with immunohistochemistry. RESULTS: The increased mRNA level of IL-1ß, IL-8, IL-17C and IL-20 in lesional psoriatic skin was already significantly reduced 4 days after the start of adalimumab treatment, i.e. before clinical and histological improvement was detectable. The mRNA expression of the Th17-derived cytokines IL-17A, IL-17F and IL-22 as well as the dendritic cell product IL-23/IL-12 (p40) were not significantly reduced until 2 weeks after the start of treatment, whereas the mRNA expression of IL-23 (p19) and the Th1 cytokines IFN-γ and IL-2 were reduced late in disease resolution. IL-1ß, IL-8 and IL-20 are all known to be regulated by p38 MAPK. IL-17C was produced by cultured human keratinocytes and this production was also mediated by a p38 MAPK dependent mechanism. Moreover, the early effects of adalimumab included the phosphorylation of p38 MAPK, but not STAT3 phosphorylation. CONCLUSIONS: This study indicates that an important mechanism of action of anti-TNFα therapy in psoriasis is a reduction in p38 MAPK phosphorylation and a subsequent decrease in the expression of p38 MAPK regulated genes.

A phase IIIb, multicentre, randomized, double-blind, vehicle-controlled study of the efficacy and safety of adalimumab with and without calcipotriol/betamethasone topical treatment in patients with moderate to severe psoriasis: the BELIEVE study.

BACKGROUND: Data are lacking on the use of topical therapies in combination with tumour necrosis factor blockers for the treatment of psoriasis. OBJECTIVES: To assess the efficacy and safety of adalimumab (ADA) with topical calcipotriol/betamethasone (C/B) in patients with psoriasis resembling those treated in routine clinical practice. METHODS: A 16-week, randomized, vehicle-controlled trial was conducted in patients with moderate to severe psoriasis and previous failure, intolerance or contraindications to two or more systemic treatments. All patients received ADA (80 mg, week 0; 40 mg every other week, weeks 1-15) in addition to either topical C/B or drug-free vehicle applied once daily for 4 weeks, and as needed thereafter. The primary endpoint was 75% improvement from baseline in Psoriasis Area and Severity Index (PASI 75) at week 16. RESULTS: A total of 730 patients received either ADA + C/B (n = 366) or ADA + vehicle (n = 364). PASI 75 response was initially higher with the combination therapy [14.8% for ADA + C/B vs. 5.8% for ADA + vehicle at week 2 (P < 0.001); and 40.7% vs. 32.4%, respectively, at week 4 (P = 0.021)]. After week 4, the trend was towards a higher response with ADA monotherapy, with no statistical difference in the PASI 75 response at week 16 (64.8% for ADA + C/B vs. 70.9% for ADA monotherapy, P = 0.086). Safety findings were consistent with previous ADA trials. CONCLUSIONS: ADA + C/B resulted in more rapid and higher efficacy within the first 4 weeks; thereafter, the trend was towards a higher response with ADA monotherapy. There was no statistical difference in the PASI 75 response at week 16. Both treatment regimens were well tolerated.

Topical corticosteroids in psoriasis: strategies for improving safety.

Corticosteroids are a mainstay of topical therapy for psoriasis. While efficacious and relatively safe when used carefully, the potential for side effects, notably skin atrophy and adrenal suppression, have been associated with excesses in potency, prolonged or widespread use. The International Psoriasis Council Working Group on Topical Therapy has reviewed the efficacy and safety of topical corticosteroids and recommends strategies for safe, long-term use of these agents.

Efalizumab for severe refractory atopic eczema: retrospective study on 11 cases.

BACKGROUND: Efalizumab is a recombinant humanized murine monoclonal antibody against CD11a, approved for the treatment of plaque psoriasis. However, recent reports suggest that it also may be effective in the treatment of severe atopic dermatitis (AD). OBJECTIVE: To evaluate the clinical effect of efalizumab in AD. METHODS: A systematic retrospective study of the medical files of patients treated with efalizumab for AD in Danish dermatology departments. Positive outcome was defined as improvement of the disease registered in the patient's file over a period exceeding 6 months. RESULTS: Two of eleven patients had a positive outcome. Nine patients stopped treatment due to progression of AD or lack of effect. LIMITATIONS: Retrospective study. CONCLUSIONS: Only a minority of patients with severe AD responded to efalizumab treatment in a standard dose.

The expression and phosphorylation of eukaryotic initiation factor 4E are increased in lesional psoriatic skin.

BACKGROUND: Overexpression of the eukaryotic initiation factor (eIF) 4E results in increased translation of mRNAs encoding proteins involved in cell cycle control, proliferation, apoptosis and angiogenesis. Phosphorylation of eIF4E is conducted by MAP kinase interacting serine/threonine kinase 1 and 2, and phosphorylation of eIF4E has previously been associated with increased release of proinflammatory cytokines from keratinocytes. The actions of eIF4E are counteracted by the eIF4E-binding protein 1 (4E-BP1). OBJECTIVES: To characterize the mRNA and protein expression of eIF4E, as well as the phosphorylation of eIF4E in psoriatic skin. METHODS: Biopsies were collected from patients with psoriasis. mRNA expression and protein levels of eIF4E were evaluated by quantitative reverse transcription-polymerase chain reaction and Western blotting, respectively. eIF4E distribution was determined by immunofluorescence analysis. RESULTS: We found a significant increase in mRNA expression and protein level of eIF4E in lesional as compared with nonlesional psoriatic skin. Immunofluorescence analysis demonstrated that eIF4E was located throughout the epidermis and was primarily cytoplasmic in distribution. The level of phosphorylated eIF4E protein was found to be strongly upregulated, and 4E-BP1 expression was also increased. CONCLUSIONS: We have demonstrated for the first time that the level of total and phosphorylated eIF4E and the expression of 4E-BP1 are increased in lesional psoriatic skin. As eIF4E-regulated proteins have been reported to be upregulated in psoriasis, it appears that the increase in eIF4E is only incompletely counteracted by 4E-BP1. Therefore, eIF4E might contribute to the pathogenesis of psoriasis.