Yves Poulin

Topical treatment of actinic keratoses with 3·0% diclofenac in 2·5% hyaluronan gel

Summary Background  Actinic keratoses (AKs) are premalignant skin lesions, which, if left untreated, can develop into squamous cell carcinoma. Current treatments for AKs are destructive and are often associated with significant adverse events. The development of an effective and well‐tolerated topical treatment for AK is desirable.

Efficacy and safety of apremilast, an oral phosphodiesterase 4 inhibitor, in patients with moderate‐to‐severe plaque psoriasis over 52 weeks: a phase III, randomized controlled trial (ESTEEM 2)

Apremilast, an oral phosphodiesterase 4 inhibitor, regulates immune responses associated with psoriasis.

Interleukin 17A: Toward a new understanding of psoriasis pathogenesis

Molecular and cellular understanding of psoriasis pathogenesis has evolved considerably over the last 30 years beginning in the early 1980s when psoriasis was thought to be a skin disease driven by keratinocyte hyperproliferation. During the next 20 years, the role of the immune system and T-helper (Th) cells in psoriasis pathogenesis was recognized. The presence of the interleukin (IL)-12 cytokine in psoriatic lesions led to the postulate that psoriasis is mediated by Th1 cells. Recent evidence has revealed a role for Th17 cells, and other immune cells, as proximal regulators of psoriatic skin inflammation. IL-17A, the principal effector cytokine of Th17 cells, stimulates keratinocytes to produce chemokines, cytokines, and other proinflammatory mediators thereby enabling IL-17A to bridge the innate and adaptive immune systems to sustain chronic inflammation. This model underlies the rationale for inhibiting IL-17A signaling as a potential therapeutic approach to disrupt the psoriatic inflammatory loop. Several monoclonal antibodies that inhibit the IL-17 pathway are in clinical development. These agents exhibit promising clinical efficacy and tolerability profiles including immunohistochemical improvement in psoriatic plaques. Results from clinical trials with IL-17 pathway inhibitors are refining our understanding of psoriasis pathogenesis and may provide a new therapeutic approach for patients with moderate to severe psoriasis.

Risk of Serious Infection With Biologic and Systemic Treatment of Psoriasis Results From the Psoriasis Longitudinal Assessment and Registry (PSOLAR)

IMPORTANCE The efficacy of treatment for psoriasis must be balanced against potential adverse events. OBJECTIVE To determine the effect of treatment on the risk of serious infections in patients with psoriasis. DESIGN, SETTING, AND PARTICIPANTS A multicenter, longitudinal, disease-based registry (Psoriasis Longitudinal Assessment and Registry [PSOLAR]) at dermatology centers. Participants were adult patients with psoriasis who were receiving or were eligible to receive conventional systemic or biologic agents. The registry opened on June 20, 2007, and data included herein were collected through August 23, 2013. EXPOSURES Patients were prescribed psoriasis therapies as in standard clinical practice. Patients will be followed for up to 8 years. Data were collected and serious adverse events (including serious infections) were assessed at regular intervals. MAIN OUTCOMES AND MEASURES Cohort characteristics are described based on evaluation at entry into the registry. The cumulative incidence rates of serious infections are reported across treatment cohorts, including ustekinumab, infliximab, adalimumab, etanercept, and nonbiologics (with or without methotrexate). A multivariate analysis using a Cox proportional hazards regression model was used to identify predictors of the time to the first serious infection using the nonmethotrexate/nonbiologics cohort as the reference. RESULTS Data were analyzed from 11,466 patients with psoriasis (22,311 patient-years). Differences in patient characteristics were found between the biologics and nonmethotrexate/nonbiologics cohorts (eg, age, sex, body mass index, and disease characteristics), as well as among the individual biologic groups (eg, a higher prevalence of psoriatic arthritis in the infliximab cohort). The cumulative incidence rate of serious infections was 1.45 per 100 patient-years (n = 323) across treatment cohorts, and the rates were 0.83, 1.47, 1.97, and 2.49 per 100 patient-years in the ustekinumab, etanercept, adalimumab, and infliximab cohorts, respectively, and 1.05 and 1.28 per 100 patient-years in the nonmethotrexate/nonbiologics and methotrexate/nonbiologics cohorts, respectively. The most commonly reported types of serious infections across the registry were pneumonia and cellulitis. Increasing age, diabetes mellitus, smoking, significant infection history, infliximab exposure, and adalimumab exposure were each associated with an increased risk of serious infection. CONCLUSIONS AND RELEVANCE Results from PSOLAR suggest a higher risk of serious infections with adalimumab and infliximab compared with nonmethotrexate and nonbiologic therapies. No increased risk was observed with ustekinumab or etanercept. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00508547.

Long-term efficacy and safety of adalimumab in patients with moderate to severe psoriasis treated continuously over 3 years: Results from an open-label extension study for patients from REVEAL

BACKGROUND REVEAL was a 52-week phase III trial of adalimumab therapy for moderate to severe chronic plaque psoriasis. Patients from REVEAL could enter an open-label extension trial to receive adalimumab for approximately 3 years of total therapy. OBJECTIVE We sought to determine long-term efficacy and safety of continuous adalimumab therapy for patients from REVEAL. METHODS Efficacy and safety over greater than 3 years of treatment were analyzed for 4 groups of patients from REVEAL. Patients who received adalimumab continuously from baseline were grouped by their responses in REVEAL: (1) greater than or equal to 75% improvement in Psoriasis Area and Severity Index (PASI) score (PASI 75) at weeks 16 and 33 (sustained responders); (2) less than PASI 75 at week 16; and (3) greater than or equal to PASI 75 at week 16 with 50% to less than 75% improvement in PASI score at week 33. Results were also analyzed for patients who began adalimumab after 16 weeks of placebo therapy. RESULTS For patients with sustained PASI 75 responses during REVEAL, efficacy was generally well maintained over 3 years, with 75%/90%/100% improvement in PASI score response rates (last observation carried forward) of 83%/59%/33% after 100 weeks and 76%/50%/31% after 160 weeks of continuous therapy. Some patients with less than PASI 75 responses in REVEAL also achieved long-term PASI 75 responses. Efficacy in the placebo/adalimumab group was consistent with the ensemble of results from the other 3 groups. Adverse event rates were consistent with those during REVEAL. LIMITATIONS The REVEAL study design prevented analyzing all patients from the adalimumab arm as one long-term cohort. CONCLUSION Adalimumab efficacy was well maintained over more than 3 years of continuous therapy for patients with sustained initial PASI 75 responses. Maintenance was best at the PASI 100 level.

Topical tofacitinib for atopic dermatitis: a phase IIa randomized trial

Despite unmet need, 15 years have passed since a topical therapy with a new mechanism of action for atopic dermatitis (AD) has been approved. Janus kinase (JAK) inhibitor treatment effect via topical application in patients with AD is unknown.

Evidence that a neutrophil–keratinocyte crosstalk is an early target of IL-17A inhibition in psoriasis

The response of psoriasis to antibodies targeting the interleukin (IL)‐23/IL‐17A pathway suggests a prominent role of T‐helper type‐17 (Th17) cells in this disease. We examined the clinical and immunological response patterns of 100 subjects with moderate‐to‐severe psoriasis receiving 3 different intravenous dosing regimens of the anti‐IL‐17A antibody secukinumab (1 × 3 mg/kg or 1 × 10 mg/kg on Day 1, or 3 × 10 mg/kg on Days 1, 15 and 29) or placebo in a phase 2 trial. Baseline biopsies revealed typical features of active psoriasis, including epidermal accumulation of neutrophils and formation of microabscesses in >60% of cases. Neutrophils were the numerically largest fraction of infiltrating cells containing IL‐17 and may store the cytokine preformed, as IL‐17A mRNA was not detectable in neutrophils isolated from active plaques. Significant clinical responses to secukinumab were observed 2 weeks after a single infusion, associated with extensive clearance of cutaneous neutrophils parallel to the normalization of keratinocyte abnormalities and reduction of IL‐17‐inducible neutrophil chemoattractants (e.g. CXCL1, CXCL8); effects on numbers of T cells and CD11c‐positive dendritic cells were more delayed. Histological and immunological improvements were generally dose dependent and not observed in the placebo group. In the lowest‐dose group, a recurrence of neutrophils was seen in some subjects at Week 12; these subjects relapsed faster than those without microabscesses. Our findings are indicative of a neutrophil–keratinocyte axis in psoriasis that may involve neutrophil‐derived IL‐17 and is an early target of IL‐17A‐directed therapies such as secukinumab.

Assessment of the long-term safety and effectiveness of etanercept for the treatment of psoriasis in an adult population

BACKGROUND Etanercept is well tolerated and effective in moderate to severe plaque psoriasis. However, effectiveness and safety data beyond 2.5 years have not been reported. OBJECTIVE We sought to assess the effectiveness and safety profile of up to 4 years of etanercept therapy in psoriasis. METHODS We analyzed prospective data from previous trials and open-label extensions, including 506 patients who initiated etanercept therapy in either of two phase III trials. Patients received etanercept, 25 mg twice weekly, 50 mg weekly, or 50 mg twice weekly, depending on which trial therapy was started. Dosage adjustments were allowed in open-label extensions, but no patients exceeded 50 mg twice weekly. Outcomes included change from baseline for the static Physician Global Assessment and Dermatology Life Quality Index scores. Exposure-adjusted adverse event (AE) rates were calculated. RESULTS In all, 75.9% (95% confidence interval 67.9-84.0) and 27.8% (95% confidence interval 19.3-36.2) maintained Dermatology Life Quality Index response (≥ 5-point improvement from baseline) and static Physician Global Assessment response (clear or almost clear) at 48 months, respectively. AE and serious AE rates were 243.5 and 7.8 events per 100 patient-years, respectively. No serious AE rates exceeded 1.0 event per 100 patient-years. Overall infection and serious infection rates were 96.9 and 0.9 events per 100 patient-years, respectively. No cases of tuberculosis or lymphoma were reported. LIMITATIONS Effectiveness data were limited to static Physician Global Assessment and Dermatology Life Quality Index scores. Analysis of AE rates was limited to available comparator databases. CONCLUSION Etanercept demonstrated sustained effectiveness and a favorable safety profile with no cumulative toxicity for up to 4 years, representing, to our knowledge, the longest published study on etanercept use in psoriasis to date.

Development and validation of a comprehensive acne severity scale.

Background: Although more than 25 acne grading systems exist, only 2 are inclusive of truncal acne. There is neither a gold standard nor a consistently used standardized system. Purpose: Our purpose was to develop and validate an acne grading system incorporating severity at the face, chest, and back. Methods: We developed a comprehensive acne severity scale (CASS) by modifying a preexisting facial acne scale, the Investigator Global Assessment, to include truncal acne. The validity and responsiveness of CASS grades were correlated with Leeds scores at baseline and after 6 months of standard acne treatment. Results: Spearman correlations were significant between Leeds and CASS grades for the face (0.823), chest (0.854), and back (0.872), respectively (p < .001). After 6 months of therapy, changes in these scores were also significantly correlated (p < .001) at all three sites. Conclusion: Concurrent validity of CASS is demonstrated by a very strong correlation with Leeds grading. CASS is simpler to use than the Leeds system and more appropriate for translation of research trial results to clinical practice.

Impact of ustekinumab on health-related quality of life and sexual difficulties associated with psoriasis: results from two phase III clinical trials

Background  Ustekinumab, a human anti‐interleukin‐12/23 monoclonal antibody, has been shown to effectively treat moderate‐to‐severe psoriasis which significantly affects health‐related quality of life (HRQoL), including patients’ sexual lives.