Phase 3 Studies Comparing Brodalumab with Ustekinumab in Psoriasis.

BACKGROUND: Early clinical studies suggested that the anti-interleukin-17 receptor A monoclonal antibody brodalumab has efficacy in the treatment of psoriasis. METHODS: In two phase 3 studies (AMAGINE-2 and AMAGINE-3), patients with moderate-to-severe psoriasis were randomly assigned to receive brodalumab (210 mg or 140 mg every 2 weeks), ustekinumab (45 mg for patients with a body weight ≤100 kg and 90 mg for patients >100 kg), or placebo. At week 12, patients receiving brodalumab were randomly assigned again to receive a brodalumab maintenance dose of 210 mg every 2 weeks or 140 mg every 2 weeks, every 4 weeks, or every 8 weeks; patients receiving ustekinumab continued to receive ustekinumab every 12 weeks, and patients receiving placebo received 210 mg of brodalumab every 2 weeks. The primary aims were to evaluate the superiority of brodalumab over placebo at week 12 with respect to at least a 75% reduction in the psoriasis area-and-severity index score (PASI 75) and a static physician's global assessment (sPGA) score of 0 or 1 (clear or almost clear skin), as well as the superiority of brodalumab over ustekinumab at week 12 with respect to a 100% reduction in PASI score (PASI 100). RESULTS: At week 12, the PASI 75 response rates were higher with brodalumab at the 210-mg and 140-mg doses than with placebo (86% and 67%, respectively, vs. 8% [AMAGINE-2] and 85% and 69%, respectively, vs. 6% [AMAGINE-3]; P<0.001); the rates of sPGA scores of 0 or 1 were also higher with brodalumab (P<0.001). The week 12 PASI 100 response rates were significantly higher with 210 mg of brodalumab than with ustekinumab (44% vs. 22% [AMAGINE-2] and 37% vs. 19% [AMAGINE-3], P<0.001). The PASI 100 response rates with 140 mg of brodalumab were 26% in AMAGINE-2 (P=0.08 for the comparison with ustekinumab) and 27% in AMAGINE-3 (P=0.007). Rates of neutropenia were higher with brodalumab and with ustekinumab than with placebo. Mild or moderate candida infections were more frequent with brodalumab than with ustekinumab or placebo. Through week 52, the rates of serious infectious episodes were 1.0 (AMAGINE-2) and 1.3 (AMAGINE-3) per 100 patient-years of exposure to brodalumab. CONCLUSIONS: Brodalumab treatment resulted in significant clinical improvements in patients with moderate-to-severe psoriasis. (Funded by Amgen; AMAGINE-2 and AMAGINE-3 ClinicalTrials.gov numbers, NCT01708603 and NCT01708629.).

Use of biological drugs in patients with psoriasis and psoriatic arthritis in Italy: Results from the PSONG survey.

This Italian multicenter retrospective study compared the drug survival and efficacy of different anti-TNF agents in psoriasis (PsO) and psoriatic arthritis (PsA) patients. A database of PsO/PsA patients treated with adalimumab, etanercept, and infliximab from May 2013 to May 2014 was analyzed. PASI 75, 90, and 100 was calculated at each time point to evaluate efficacy. Drug survival rate and probability of maintaining PASI response were evaluated. The impact of dependent variables on probability of PASI 75 loss was evaluated by logistic regression. 1,235 patients were included, 577 with PsO and 658 with PsA. Highest survival rates were observed with adalimumab followed by etanercept and infliximab in PsO and PsA patients. The probability of maintaining PASI response was significantly higher for adalimumab followed by infliximab. For PsO patients, the odds of losing PASI 75 was higher in etanercept-treated patients (OR: 8.1; 95% CI: 4.2-15.6, p < .001) or infliximab (OR: 6.6; 95% CI: 2.6-16.3, p < .001) vs. adalimumab. Likewise, for PsA patients the odds of losing PASI 75 was higher in etanercept-treated patients (OR: 2.3; 95% CI: 1.4-3.8, p = .01) or infliximab (OR: 2.2; 95% CI: 1.1-4.1, p = .018) vs. adalimumab. Adalimumab could be the best therapeutic option over other anti-TNF agents for the treatment of PsO and PsA patients.

Tofacitinib versus etanercept or placebo in moderate-to-severe chronic plaque psoriasis: a phase 3 randomised non-inferiority trial.

BACKGROUND: New therapeutic options are needed for patients with psoriasis. Tofacitinib, an oral Janus kinase inhibitor, is being investigated as a treatment for moderate-to-severe chronic plaque psoriasis. In this study, we aimed to compare two tofacitinib doses with high-dose etanercept or placebo in this patient population. METHODS: In this phase 3, randomised, multicentre, double-dummy, placebo-controlled, 12-week, non-inferiority trial, adult patients with chronic stable plaque psoriasis (for ≥12 months) who were candidates for systemic or phototherapy and had a Psoriasis Area and Severity Index (PASI) score of 12 or higher and a Physician's Global Assessment (PGA) of moderate or severe, and had failed to respond to, had a contraindication to, or were intolerant to at least one conventional systemic therapy, were enrolled from 122 investigational dermatology centres worldwide. Eligible patients were randomly assigned in a 3:3:3:1 ratio to receive tofacitinib 5 mg or 10 mg twice daily at about 12 h intervals, etanercept 50 mg subcutaneously twice weekly at about 3-4 day intervals, or placebo. Randomisation was done by a computer-generated randomisation schedule, and all patients and study personnel were masked to treatment assignment. The co-primary endpoints were the proportion of patients at week 12 with at least a 75% reduction in the PASI score from baseline (PASI75 response) and the proportion of patients achieving a PGA score of "clear" or "almost clear" (PGA response), analysed in the full analysis set (all patients who were randomised and received at least one dose of study drug). This study is registered with ClinicalTrials.gov, number NCT01241591. FINDINGS: Between Nov 29, 2010, and Sept 13, 2012, we enrolled 1106 eligible adult patients with chronic plaque psoriasis and randomly assigned them to the four treatment groups (330 to tofacitinib 5 mg twice daily, 332 to tofacitinib 10 mg twice daily, 336 to etanercept 50 mg twice weekly, and 108 to placebo). Of these patients, 1101 actually received their assigned study medication (329 in the tofactinib 5 mg group, 330 in the tofacitinib 10 mg group, 335 in the etanercept group, and 107 in the placebo group). At week 12, PASI75 responses were recorded in 130 (39·5%) of 329 patients in the tofacitinib 5 mg group, 210 (63·6%) of 330 in the tofacitinib 10 mg group, 197 (58·8%) of 335 in the etanercept group, and six (5·6%) of 107 in the placebo group. A PGA response was achieved by 155 (47·1%) of 329 patients in the tofacitinib 5 mg group, 225 (68·2%) of 330 in the tofacitinib 10 mg group, 222 (66·3%) of 335 in the etanercept group, and 16 (15·0%) of 107 in the placebo group. The rate of adverse events was similar across the four groups, with serious adverse events occurring in seven (2%) of 329 patients in the tofacitinib 5 mg group, five (2%) of 330 in the tofacitinib 10 mg group, seven (2%) of 335 in the etanercept group, and two (2%) of 107 in the placebo group. Three (1%) of 329 patients in the tofacitinib 5 mg group, ten (3%) of 330 in the tofacitinib 10 mg group, 11 (3%) of 335 in the etanercept group, and four (4%) of 107 patients in the placebo group discontinued their assigned treatment because of adverse events. INTERPRETATION: In patients with moderate-to-severe plaque psoriasis, the 10 mg twice daily dose of tofacitinib was non-inferior to etanercept 50 mg twice weekly and was superior to placebo, but the 5 mg twice daily dose did not show non-inferiority to etanercept 50 mg twice weekly. The adverse event rates over 12 weeks were similar for tofacitinib and etanercept. This study indicates that in the future tofacitinib could provide a convenient and well-tolerated therapeutic option for patients with moderate-to-severe plaque psoriasis. FUNDING: Pfizer Inc.

IL12B (p40) Gene Polymorphisms Contribute to Ustekinumab Response Prediction in Psoriasis.

BACKGROUND: Psoriasis is characterized by multiple genetic variations. Some of these variations, such as the presence of HLA-Cw6 or TNFAIP3 single-nucleotide polymorphisms (SNPs), have been correlated to the response to biologic treatments. OBJECTIVE: The aim of our study was to evaluate the effects of IL12B and IL6 SNPs on the response to ustekinumab. METHODS: We retrospectively analyzed the genotypes of 64 patients who had been treated with ustekinumab for up to 1 year. Efficacy data were evaluated using 'intention to treat-last observation carried forward' analysis. RESULTS: We confirmed the positive role of HLA-Cw6 as a predictor of the response to ustekinumab and discovered that presence of the GG genotype on the IL12B rs6887695 SNP and absence of the AA genotype on the IL12B rs3212227 SNP significantly increase the probability of therapeutic success in HLA-Cw6 positive patients. CONCLUSIONS: The availability of pharmacogenetic data will influence therapeutic decisions in the clinical management of psoriatic patients.

Rhodamine intense pulsed light versus conventional intense pulsed light for facial telangiectasias.

Facial telangiectasias represent the major aesthetic alterations of several chronic inflammatory disorders arising on facial skin. We herein report on relevant clinical results of a new subtype of intense pulsed light treatments, the so-called rhodamine intense pulsed light (r-IPL), in comparison with conventional IPL (c-IPL) treatments on forty-five patients affected by facial telangiectasias. The aim of this study is to determinate whether r-IPL represents an effective and safe treatment for the most common superficial vascular alterations and could be advised as a first choice therapy for facial telangiectasias.

Serum Protein Profile Changes in Psoriatic Patients Undergoing Treatment With Infliximab.

UNLABELLED: The therapeutic paradigm in psoriasis includes antitumor necrosis alpha agents that have been proved effective and safe as long-term therapy. Recently, it has been described a correlation between the use of biologic agents and the occurrence of monoclonal gammopathies, which are haematological conditions characterized by clonal plasma cells proliferation producing a monoclonal immunoglobulin that accumulates in the blood. OBJECTIVE: The aim of this study is to detect electrophoretic abnormalities in psoriatic patients undergoing treatment with infliximab. RESEARCH DESIGN AND METHODS: A retrospective study evaluating all charts from the clinic database of all patients treated with infliximab. The evaluation of serum protein profile is routinely performed in the clinical setting during biologic therapies. We reported the occurrence MGUS in infliximab-treated patients. RESULTS: The study analysis included 141 charts. Overall, 23 patients showed a MGUS in their electrophoretic profile, though in 6 cases MGUS was detected at the baseline. Thereby, 17 cases (12.06% of the study population) developed MGUS during infliximab therapy. CONCLUSIONS: Serum protein electrophoresis test represents a useful tool to detect and monitor any potentially harmful condition that could occur during treatment with a biologic agent. Particularly, it could be crucial for the detection of MGUS, which does not affect clinical response, and it does not represent a criteria to withdraw the treatment.

Oral ponesimod in patients with chronic plaque psoriasis: a randomised, double-blind, placebo-controlled phase 2 trial.

BACKGROUND: We assessed the efficacy, safety, and tolerability of ponesimod, an oral, selective, reversible modulator of sphingosine 1-phosphate receptor 1, in patients with moderate to severe chronic plaque psoriasis. METHODS: Between Sept 22, 2010, and Oct 24, 2012, patients with psoriasis area and severity index (PASI) scores higher than 10 were enrolled into this multicentre double-blind, phase 2 study. They received 20 mg or 40 mg ponesimod or placebo once daily for 16 weeks. Those with at least 50% reduction in PASI score at 16 weeks and who were receiving ponesimod were rerandomised to receive maintenance ponesimod therapy or placebo until week 28. The primary endpoint was reduction in PASI score from baseline of at least 75% (PASI75) at week 16. This study is registered with ClinicalTrials.gov, number NCT01208090. FINDINGS: Of 326 patients initially randomised (20 mg ponesimod n=126, 40 mg ponesimod n=133, and placebo n=67) PASI75 was achieved at week 16 in 58 (46·0%), 64 (48·1%), and nine (13·4%), respectively. The treatment effect was significant for the two ponesimod doses (both p<0·0001). Of 219 patients who entered the maintenance period, PASI75 was achieved by week 28 in 35 (71·4%) of 49 who continued on 20 mg ponesimod and 41 (77·4%) of 53 on 40 mg ponesimod, and in 19 (42·2%) of 45 who swapped from 20 mg to placebo and 19 (40·4%) of 47 from 40 mg to placebo. Ponesimod was associated with dyspnoea, raised liver enzyme concentrations, and dizziness. INTERPRETATION: Significant clinical benefit was seen at week 16 that increased with maintenance therapy. FUNDING: Actelion Pharmaceuticals.

Apremilast, an oral phosphodiesterase 4 (PDE4) inhibitor, in patients with moderate to severe plaque psoriasis: Results of a phase III, randomized, controlled trial (Efficacy and Safety Trial Evaluating the Effects of Apremilast in Psoriasis [ESTEEM] 1).

BACKGROUND: Apremilast works intracellularly to regulate inflammatory mediators. OBJECTIVE: ESTEEM 1 evaluated efficacy/safety of apremilast at 30 mg twice a day for moderate to severe plaque psoriasis. METHODS: This phase III, multicenter, double-blind, placebo-controlled study randomized adults (2:1) to apremilast or placebo. At week 16, the placebo group switched to apremilast through week 32, followed by a randomized treatment withdrawal phase to week 52. Binary end points were analyzed using χ(2) test; continuous end points used analysis of covariance. RESULTS: In all, 844 patients were randomized (n = 282, placebo; n = 562, apremilast). At week 16, significantly more patients taking apremilast achieved 75% or greater reduction from baseline Psoriasis Area and Severity Index score (PASI-75) (33.1%) versus placebo (5.3%, P < .0001; primary end point). Most (61.0%) patients rerandomized to apremilast at week 32 achieved PASI-75 at week 52 versus 11.7% rerandomized to placebo. Of patients rerandomized to apremilast at week 32, mean percentage change from baseline PASI score was -88% to -81% (weeks 32-52). During the placebo-controlled period, 55.7% and 69.3% of patients randomized to placebo and apremilast, respectively, had 1 or more adverse events. Most adverse events were mild/moderate in severity. No new significant adverse events emerged with continued apremilast exposure versus the placebo-controlled period. LIMITATIONS: Data were limited to 52 weeks and may not generalize to nonplaque psoriasis. CONCLUSIONS: Apremilast was effective in moderate to severe plaque psoriasis.

Chronically sun-damaged melanomas express low levels of nuclear glutathione-S-transferase-π: an epidemiological and clinicopathological study in Italy.

The detoxifying enzyme glutathione-s-transferase pi (GST-π) is present in keratinocytes and melanocytes and exerts a protective role against tumour progression. Melanomas close to melanocytic naevus remnants occur less frequently on sun-exposed areas, whereas solar dermal elastosis, hallmark of chronic sun-damage, characterise melanomas on sun-exposed skin. We evaluated the expression of GST-π in 113 melanomas associated to melanocytic naevus remnants or to solar dermal elastosis, classified according to clinical characteristics, history of sun exposure, histological subtypes and AJCC staging. Chronically sun-damaged melanomas, identified by moderate-severe solar dermal elastosis, showed a lower nuclear GST-π expression and a higher thickness than those related to melanocytic naevus remnants (p < 0.03). Multivariate logistic regression analysis demonstrated that male gender and chronic sun-exposure are independent risk factors significantly associated to melanomas localised on the trunk (OR = 3.36, 95% CI: 1.31-8.65; OR = 5.97, 95% CI: 1.71-20.87). If confirmed on a larger series, lower expression of nuclear GST-π in melanoma cells could represent a possible marker of chronically sun-damaged melanoma pathogenesis.

Thymic stromal lymphopoietin links keratinocytes and dendritic cell-derived IL-23 in patients with psoriasis.

BACKGROUND: Thymic stromal lymphopoietin (TSLP) is a major proallergic cytokine that promotes TH2 responses through dendritic cell (DC) activation. Whether it also plays a role in human autoimmune inflammation and associated pathways is not known. OBJECTIVE: In this study we investigated the potential role of several epithelium-derived factors, including TSLP, in inducing IL-23 production by human DCs. We further dissected the role of TSLP in patients with psoriasis, an IL-23-associated skin autoimmune disease. METHODS: The study was performed in human subjects using primary cells and tissue samples from patients with psoriasis and healthy donors. We analyzed the production of IL-23 in vitro by blood and skin DCs. We studied the function for TSLP and its interaction with other components of the inflammatory microenvironment in situ and ex vivo. RESULTS: We found that TSLP synergized with CD40 ligand to promote DC activation and pathogenic IL-23 production by primary blood and skin DCs. In situ TSLP was strongly expressed by keratinocytes of untreated psoriatic lesions but not in normal skin. Moreover, we could demonstrate that IL-4, an important component of the TH2 inflammation seen in patients with atopic dermatitis, inhibited IL-23 production induced by TSLP and CD40 ligand in a signal transducer and activator of transcription 6-independent manner. CONCLUSION: Our results identify TSLP as a novel player within the complex psoriasis cytokine network. Blocking TSLP in patients with psoriasis might contribute to decreasing DC activation and shutting down the production of pathogenic IL-23.

Efficacy of switching between tumor necrosis factor-alfa inhibitors in psoriasis: results from the Italian Psocare registry.

BACKGROUND: Some studies have shown that switching patients from one tumor necrosis factor (TNF)-alfa inhibitor to another may be beneficial when they have an inadequate response or an adverse event. OBJECTIVE: We sought to assess the variables predicting the efficacy of the second TNF-alfa inhibitor in patients discontinuing the first TNF-alfa inhibitor. METHODS: Data from all 5423 consecutive patients starting TNF-alfa inhibitor therapy for psoriasis between September 2005 and September 2010 who were included in the Italian Psocare registry were analyzed. RESULTS: In 105 patients who switched to a second TNF-alfa inhibitor who had complete follow-up data, 75% improvement in the Psoriasis Area Severity Index score (PASI 75) was reached by 29% after 16 weeks and by 45.6% after 24 weeks. Patients who switched because of secondary loss of efficacy (loss of initial PASI 75 response) or adverse events/intolerance were more likely to reach PASI 75 than those who switched as a result of primary inefficacy (PASI 75 never achieved) (hazard ratio 2.7, 95% confidence interval 1.3-5.5 vs hazard ratio 2.0, 95% confidence interval 1.0-3.9 and 1, respectively). LIMITATIONS: There was a small number of patients with complete follow-up data. CONCLUSION: PASI 75 response in patients who switched from one anti-TNF-alfa agent to another was significantly reduced in patients who showed primary inefficacy of the first anti-TNF-alfa.

What happened after the clinical trials: long-term safety and efficacy of ustekinumab in daily clinical practice.

BACKGROUND: Ustekinumab has been investigated in patients with psoriasis by randomized clinical trials. There are few data on ustekinumab use under 'real life' conditions outside long-term registries. OBJECTIVE: The aim of our study was to evaluate the efficacy and safety of ustekinumab as a long-term therapy in real life. METHODS: We retrospectively analyzed the data of 71 patients who had been treated with ustekinumab up to 2 years. Efficacy data were analyzed both by 'as treated' and 'intention to treat-last observation carried forward'. RESULTS: A significant improvement in the Psoriasis Area and Severity Index score was observed at 4 weeks and further improvements were observed throughout the treatment. Adverse events were generally mild. CONCLUSIONS: In routine administration ustekinumab seems to be more efficient than reported by randomized clinical trials. Our results are encouraging and can answer the patients' biggest concern on whether ustekinumab is an effective and safe drug for long-term use.

Randomized, within-patient, clinical trial comparing fluorine-synthetic fiber socks with standard cotton socks in improving plantar pustulosis.

BACKGROUND/AIMS: Rubbing the skin may influence the persistence of pustulosis over time. The aim of this study was to assess the impact of a new fabric made with fluorine-synthetic fiber in improving plantar pustulosis. METHODS: A total of 17 patients were randomized to receive on one side a sock made of fluorine-synthetic fiber and on the other a sock made of cotton fabric for 4 weeks. The main outcome was the percentage reduction of lesional area at week 4. RESULTS: The median lesion reduction at week 4 was 42.6% in the fluorine-synthetic fiber arm and 2.7% in the cotton arm (p = 0.148). Among secondary outcomes, the overall reduction over time in the treated areas was significantly in favor of the fluorine-synthetic fiber arm (p = 0.045) as well as the perception of the disease by the patient (p = 0.025). CONCLUSION: Despite the fact that the primary outcome was not reached, there was a tangible reduction in the extension of the treated areas and in the perception of the disease by the patient.

Dermoscopy as an adjuvant tool for detecting skin leiomyomas in patient with uterine fibroids and cerebral cavernomas.

BACKGROUND: Hereditary syndromes frequently need the cooperation of different specialties to increase diagnostic competence. Multiple cutaneous and uterine leiomyomatosis syndrome is a rare autosomal dominant disorder caused by the mutations of the fumarate hydratase gene, demonstrated in 80 to 100 percent of affected individuals. This can be linked to an increased risk of renal cancer in both sexes. The skin involvement is described to highlight the diagnostic role of the cutaneous counterpart in identifying this rare syndrome. CASE PRESENTATION: A 37-year-old woman suffering from several uterine fibroids presented multiple, painful, papulo-nodules on her left subscapular side, both forearms and legs. The patient underwent surgery on six lesions: five were leiomyomas, whilst one was a dermatofibroma. Genetic sequencing did not evidence known fumarate hydratase gene mutations. Dermoscopy showed a brown delicate pigmented network and included leiomyomas among the non-melanocytic benign skin tumours featuring a dermatofibroma-like pattern. Abdominal computerized-tomography scan did not reveal renal cancer, but brain magnetic resonance imaging showed one asymptomatic cerebral cavernoma. The patient benefited from the surgical removal of the five larger cutaneous lesions and from gabapentin, which relieved her pain. CONCLUSIONS: This observation highlights the usefulness of dermoscopy in the diagnosis of cutaneous leiomyomas disclosing multiple cutaneous and uterine leiomyomatosis syndrome. Dermoscopy should be performed for non-melanocytic multiple lesions mimicking leiomyomas in a large number of patients, to establish a strict classification and identify false negative cases or evaluate them as dermatofibromas. In this case, the dermatologist recognized the risk of renal cancer and cerebral cavernomas.

Developmental factor IRF6 exhibits tumor suppressor activity in squamous cell carcinomas.

The transcription factor interferon regulatory factor 6 (IRF6) regulates craniofacial development and epidermal proliferation. We recently showed that IRF6 is a component of a regulatory feedback loop that controls the proliferative potential of epidermal cells. IRF6 is transcriptionally activated by p63 and induces its proteasome-mediated down-regulation, thereby limiting keratinocyte proliferative potential. We hypothesized that IRF6 may also be involved in skin carcinogenesis. Hence, we analyzed IRF6 expression in a large series of squamous cell carcinomas (SCCs) and found a strong down-regulation of IRF6 that correlated with tumor invasive and differentiation status. IRF6 down-regulation in SCC cell lines and primary tumors correlates with methylation on a CpG dinucleotide island located in its promoter region. To identify the molecular mechanisms regulating IRF6 potential tumor suppressive activity, we performed a genome-wide analysis by combining ChIP sequencing for IRF6 binding sites and gene expression profiling in primary human keratinocytes after siRNA-mediated IRF6 depletion. We observed dysregulation of cell cycle-related genes and genes involved in differentiation, cell adhesion, and cell-cell contact. Many of these genes were direct IRF6 targets. We also performed in vitro invasion assays showing that IRF6 down-regulation promotes invasive behavior and that reintroduction of IRF6 into SCC cells strongly inhibits cell growth. These results indicate a function for IRF6 in suppression of tumorigenesis in stratified epithelia.

Clinical markers predictive of primary inefficacy: a "real life" retrospective study in psoriatic patients treated with etanercept.

Overexpression of tumor necrosis factor alpha (TNF-α) has been demonstrated to play a pivotal role in the pathogenesis of both plaque-type psoriasis and psoriatic arthritis. TNF-α blockers, including etanercept, a human protein that acts as a TNF-α soluble receptor, are effective in the treatment of psoriasis. This retrospective study investigated the impact of psoriasis patients' demographic and clinical characteristics on primary inefficacy to etanercept. Our findings suggest that the presence of psoriatic arthritis is a risk factor for primary inefficacy to etanercept in the treatment of psoriasis. However, etanercept efficacy appears to be independent of patient age, gender, or previous biologic treatments.

Treatment adherence to different etanercept regimens, continuous vs. intermittent, in patients affected by plaque-type psoriasis.

Treatment adherence to anti-tumor necrosis factor alpha (anti-TNF-α) agents is marker of treatment success, but overall efficacy of anti-TNF-α therapy decreases over time leading to a progressive loss of adherence. The present observational study was conducted in order to estimate the long-term adherence to etanercept in patients affected by plaque-type psoriasis, evaluating differences among intermittent and continuous treatment regimen. Our findings reflect routine clinical practice in three academic referral centers and show high treatment adherence with etanercept in psoriatic patients. Treatment survival was consistently high in the short/medium term. The univariate analysis showed longer treatment duration in patients undergoing intermittent treatment regimen (mean 1,706 days) compared with continuous regimen (mean 1,249 days). Results showed that a flexible pulsed treatment with etanercept can be optimal in terms of clinical success and adherence.

Detection of adalimumab and anti-adalimumab levels by ELISA: clinical considerations.

Psoriasis (Ps) is a common and stigmatizing chronic inflammatory skin disease that may cause other chronic inflammatory conditions with overlapping pathology, such as rheumatoid arthritis (RA). Tumor necrosis factor (TNF) is a proinflammatory cytokine that plays a pivotal role in chronic inflammatory and autoimmune diseases such as uveitis, multiple sclerosis, systemic lupus, arthritis, Ps, and Crohn's disease. The TNF superfamily and receptors represent active targets for drug development. Anti-TNF biological therapies, such as infliximab, adalimumab (ADL), and etanercept, are effective in treating RA, spondyloarthritis, Ps, and inflammatory bowel diseases, but long-term treatment can induce anti-drug antibody (ADA) formation associated with lower drug levels and clinical nonresponse. An investigation of the relationship between serum ADL/anti-adalimumab antibody (AAA) concentration, and clinical response in moderate to severe Ps, confirmed an association between ADL and AAA levels and response. Although the detection of ADAs can be used to determine the cause of nonresponse and aid therapy decisions, the contrary observation of long-term responders with low drug levels and detectable ADA suggests that another mechanism is also involved.

Frequency of melanocytic nevi in psoriatic patients is related to treatment and not to disease severity.

BACKGROUND: Few data exist on the relationship between psoriasis and melanocytic lesions. OBJECTIVES: We sought to investigate number of melanocytic nevi in psoriatic patients compared with control subjects and its relationship with disease severity and treatment. METHODS: We performed a prospective study in 189 psoriatic patients and 189 control subjects. Sociodemographic and clinical data were recorded for all participants. RESULTS: As compared with control subjects, patients had fewer nevi overall [χ(2)(5) = 52.24, P < .001], fewer nevi less than 5 mm [χ(2)(4) = 60.28, P < .001], and fewer congenital nevi [χ(2)(1) = 10.41, P = .002]; no differences in atypical nevi and family history of cancer, including melanoma, were observed. Among psoriatic patients, number of biologics used was a risk factor for a higher nevus count [odds ratio 1.35 (95% CI 1.04-1.76), P = .02] whereas disease severity did not correlate with number of nevi. LIMITATIONS: Low number of psoriatic patients naïve to systemic therapies was a limitation. CONCLUSIONS: Psoriatic patients have fewer nevi than control subjects. Frequency of nevi in psoriatic patients is related to treatment, not to disease severity.

IL-21 promotes skin recruitment of CD4(+) cells and drives IFN-γ-dependent epidermal hyperplasia.

Psoriasis is a chronic inflammatory disorder of the skin characterized by epidermal hyperplasia and infiltration of leukocytes into the dermis and epidermis. T cell-derived cytokines, such as IFN-γ and IL-17A, play a major role in the psoriasis-associated epidermal hyperplasia, even though factors/mechanisms that regulate the production of these cytokines are not fully understood. We have recently shown that IL-21 is synthesized in excess in psoriatic skin lesions and causes epidermal hyperplasia when injected intradermally in mice. Moreover, in the human psoriasis SCID mouse model, neutralization of IL-21 reduces both skin thickening and expression of inflammatory molecules, thus supporting the pathogenic role of IL-21 in psoriasis. However, the basic mechanism by which IL-21 promotes skin pathology remains unknown. In this study, we show that CD4(+) cells accumulate early in the dermis of IL-21-treated mice and mediate the development of epidermal hyperplasia. Indeed, IL-21 fails to induce skin damage in RAG1-deficient mice and CD4(+) cell-depleted wild-type mice. The majority of CD4(+) cells infiltrating the dermis of IL-21-treated mice express IFN-γ and, to a lesser extent, IL-17A. Studies in cytokine knockout mice show that IFN-γ, but not IL-17A, is necessary for IL-21-induced epidermal hyperplasia. Finally, we demonstrate that IFN-γ-producing CD4(+) cells infiltrating the human psoriatic plaque express IL-21R, and abrogation of IL-21 signals reduces IFN-γ expression in cultures of psoriatic CD4(+) cells. Data indicate that IL-21 induces an IFN-γ-dependent pathogenic response in vivo, thus contributing to elucidate a mechanism by which IL-21 sustains skin-damaging inflammation.