Ronald Vender

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.

Secukinumab is superior to ustekinumab in clearing skin of subjects with moderate-to-severe plaque psoriasis up to 1 year: Results from the CLEAR study

Background: Secukinumab demonstrated superior efficacy to ustekinumab at week 4 and week 16 of the CLEAR study, with comparable safety, in subjects with moderate‐to‐severe plaque psoriasis. Objective: To compare the efficacy and safety of secukinumab and ustekinumab use over 52 weeks. Methods: Analysis of 52‐week data from CLEAR, a randomized, double‐blind, phase 3b study. Results: Among 676 randomized subjects, secukinumab demonstrated superiority to ustekinumab at week 52 in the proportion of subjects with ≥90% improvement in Psoriasis Area and Severity Index (PASI 90) (76% vs 61% [P < .0001]); PASI 100 responses were 46% versus 36% (P = .0103) and Investigators Global Assessment responses of clear/almost clear skin were 80% versus 65% (P < .0001). Subjects on secukinumab reported greater reductions in psoriasis‐related pain, itching, and scaling, and greater improvement across all quality‐of‐life measures evaluated (Dermatology Life Quality Index [DLQI], EuroQoL 5‐Dimension Health Questionnaire, Work Productivity and Activity Impairment Questionnaire‐Psoriasis, and Health Assessment Questionnaire‐Disability Index). At week 52, 72% of subjects on secukinumab versus 59% on ustekinumab (P = .0008) reported no impact of skin disease on their lives (DLQI 0/1 response). Safety and tolerability was comparable. Limitations: There was no placebo arm. Conclusion: In this head‐to‐head, double‐blind study, secukinumab demonstrated sustained superior efficacy in comparison with ustekinumab in clearing skin through week 52, greater improvement in quality of life, and a favorable and comparable safety profile.

Use of calcipotriene cream (Dovonex cream) following acute treatment of psoriasis vulgaris with the calcipotriene/betamethasone dipropionate two-compound product (Taclonex): a randomized, parallel-group clinical trial.

AbstractIntroduction: A calcipotriene/betamethasone dipropionate two-compound product (Taclonex® ointment) has been shown to be safe and effective in the treatment of psoriasis over 4 weeks. Since treatment of psoriasis is generally long-term, the objective of this study was to investigate the efficacy and safety of transferring patients to maintenance treatment with calcipotriene cream (Dovonex® cream) following a 4-week treatment period with the two-compound product. Methods: Patients with psoriasis were randomized to one of the following three treatment groups: 4 weeks of the two-compound product followed by 8 weeks of calcipotriene cream (calcipotriene cream group); 4 weeks of the two-compound product followed by 8 weeks of calcipotriene cream on weekdays and the two-compound product on weekends (alternating group); 4 weeks of the two-compound product followed by 8 weeks of vehicle of calcipotriene cream (vehicle group). All medications were applied once daily. Results: A total of 1136 patients were randomized: 383 to the calcipotriene cream group, 377 to the alternating group, and 376 to the vehicle group. The mean percentage change in the Psoriasis Area and Severity Index from baseline to the end of the trial was −44.5% in the calcipotriene cream group, -58.4% in the alternating group, and −33.1% in the vehicle group. The mean difference between the calcipotriene cream and vehicle groups (primary treatment comparison) was −11.7% (95% CI −17.9, −5.5), which was statistically significant (p < 0.001), and the mean difference between the alternating and vehicle groups was -24.7% (95% CI −30.9, −18.5), which was also statistically significant (p < 0.001). For the investigators’ For the investigators(p < 0.001), showing superior efficacy in the nonvehicle groups. The results were similar for the patients’ global assessment of response to treatment. There were 43 patients (11.3%) with adverse drug reactions in the calcipotriene cream group, 28 (7.6%) in the alternating group, and 32 (8.6%) in the vehicle group. There were no statistically significant differences in the incidence of adverse drug reactions in the calcipotriene cream group relative to the vehicle group (odds ratio 1.36; 95% CI 0.84, 2.21; p = 0.21), or in the alternating group relative to the vehicle group (odds ratio 0.87; 95% CI 0.51, 1.48; p = 0.61). Conclusion: Four weeks of treatment with the calcipotriene/betamethasone dipropionate two-compound product followed by 8 weeks of maintenance treatment with calcipotriene cream is effective and safe. As an alternative maintenance regimen, treatment with calcipotriene cream on weekdays and the two-compound product on weekends is also effective and safe.

Prevalence and Epidemiology of Onychomycosis

The prevalence of onychomycosis has been estimated at approximately 6.48% (95% confidence interval 6.09–6.88%) within the Canadian population. Dermatophytes are the most commonly cultured organisms, appearing in approximately 75 to 91% of nails with fungal involvement, with Trichophyton rubrum and Tricophyton mentagrophytes most commonly isolated. However, Candida spp and nondermatophyte molds are also sometimes cultured. The most common presentation is distal and lateral subungual onychomycosis (DLSO), which can involve 75% of patients with pedal onychomycosis. The distribution of DLSO, superficial white onychomycosis, and proximal subungual onychomycosis (PSO) has been reported to be 360:59:1 in patients with mycologic confirmation of onychomycosis; however, some reported that the incidence of PSO is slightly higher in immunocompromised individuals. Age, gender, family history, and the presence of tinea pedis are all elements associated with a nail fungal infection. In addition, many conditions, including diabetes mellitus, immune disorders, and vascular disease, have been associated with the presence of onychomycosis. When choosing the best treatment regimen for individuals with onychomycosis, it is very important to consider all of the factors involved, including the infecting species, the presentation of the disease, the level of disease progression, and its predisposing factors.

A treatment for severe nodular acne: a randomized investigator-blinded, controlled, noninferiority trial comparing fixed-dose adapalene/benzoyl peroxide plus doxycycline vs. oral isotretinoin

Oral isotretinoin (ISO) is the gold standard for severe nodular acne. However, as some patients are unwilling or unable to take, or are intolerant to, ISO, other options are needed.

Nail Psoriasis and Biologics

Background: Since the advent of biologic therapies for psoriasis, reports of efficacy in nail psoriasis have appeared in the literature and at international conferences with increasing frequency. Objective: This article aims to review the existing literature on the use of biologics in the treatment of nail psoriasis. Methods: An extensive literature review was conducted using OVID Medline. Studies examining the efficacy of biologics in the treatment of nail psoriasis were documented. Results: A literature review revealed few clinical trials specifically concentrating on nail psoriasis; however, nails have been assessed in larger clinical trials for cutaneous psoriasis. A large, multicenter, phase III, double-blind, placebo-controlled study of infliximab administered as a brief induction regimen at weeks 0, 2, and 6 followed by a single infusion every 8 weeks revealed statistically significant mean percent improvement in the Nail Psoriasis Severity Index (NAPSI) score over placebo at both week 10 (26.8% vs −7.7%, respectively; p < .001) and week 24 (57.2% vs −4.1%, respectively; p < .001). For other biologics, evidence has thus far been largely anecdotal, appearing as either case studies or extracted secondarily from open-label prospective trials in plaque psoriasis or psoriatic arthritis. Conclusion: Infliximab appears to be the most effective treatment for nail psoriasis to date.

Are all seborrheic keratoses benign? Review of the typical lesion and its variants.

Background: Seborrheic keratosis (SK) is one of the more common benign epidermal neoplasms seen in adult and middle-aged patients. Objective: As little is written in the literature about the variants of SK, this article aims to categorize and discuss the different subtypes and their important associations. Methods: An in-depth literature search using OVID Medline and PubMed was conducted to classify the various subtypes of SK. Clinical variants were photographed and used to help document the subtypes. The pathology is described for each. Results: Six subtypes of SK were identified: dermatosis papulosa nigra, stucco keratosis, inverted follicular keratosis, large cell acanthoma, lichenoid keratosis, and flat seborrheic keratosis. Although the etiology and pathogenesis of SKs are still largely debatable, several underlying mechanisms and contributing factors have been identified. All subtypes represent benign lesions, and treatment is usually done for cosmetic reasons. Several of the subtypes may act as cutaneous markers for internal malignancy and should be monitored closely for any atypical changes. Conclusion: Although all subtypes of SK are benign, their association with other malignant lesions and ability to serve as cutaneous markers of internal malignancy emphasize the importance of correctly identifying all variants.

Occurrence of plantar pustular psoriasis during treatment with infliximab.

Background: Pustular psoriasis is an uncommon form of psoriasis that often affects areas of the hands and feet. It typically manifests as small pustules that develop within erythematous areas of the palms and soles. Infliximab, a tumor necrosis factor inhibitor, can be used to treat pustular psoriasis. Infliximab can also be effective in the treatment of various other disorders, including plaque-type psoriasis, psoriatic arthritis, Crohn disease, rheumatoid arthritis, and ankylosing spondylitis. Objective: We present a case of a young woman developing pustular psoriasis for the first time despite being on infliximab treatment for Crohn disease. Results: Infliximab has been successful in the treatment of pustular psoriasis. In rare cases, plaque psoriasis appears for the first time during infliximab treatment for other disorders, such as Crohn disease. Conclusion: Plantar pustular psoriasis occurring for the first time during infliximab treatment is an uncommon occurrence.

Review of Systemic Treatment Options for Adult Atopic Dermatitis

Background: Atopic dermatitis (AD) is a chronic, pruritic inflammatory skin disease resulting from defects in skin barrier and aberrant immune responses. AD significantly affects the quality of life. Not all patients respond to topical therapies, and often systemic therapy is required to control the disease. Objective: To review the treatment options for adult AD patients including those options for patients who do not respond adequately or have contraindications to oral systemic therapy. Methods: A working group of clinicians with experience managing AD was convened to review the current literature on treatment options for adult AD patients. This review is based on the best available evidence from a published systematic review and an additional literature search. Results: Current treatments for AD are reviewed, including options for adult AD patients who do not respond or have contraindications to current systemic therapies. A new approach with targeted therapies is reviewed based on best available evidence. Conclusion: Many AD patients respond satisfactorily to topical or systemic treatments, but for those patients who do not respond or have contraindications, new biologic agents appear to be promising therapies.

Non-melanoma Skin Cancer in Canada Chapter 3: Management of Actinic Keratoses:

Background Actinic keratosis (AK) and cheilitis (AC) are lesions that develop on photodamaged skin and may progress to form invasive squamous cell carcinomas (SCCs). Objective To provide guidance to Canadian health care practitioners regarding management of AKs and ACs. Methods Literature searches and development of graded recommendations were carried out as discussed in the accompanying introduction (chapter 1 of the NMSC guidelines). Results Treatment of AKs allows for secondary prevention of skin cancer in sun-damaged skin. Because it is impossible to predict whether a given AK will regress, persist, or progress, AKs should ideally be treated. This chapter discusses options for the management of AKs and ACs. Conclusions Treatment options include surgical removal, topical treatment, and photodynamic therapy. Combined modalities may be used in case of inadequate response. AKs are particularly common following the longterm immunosuppression in organ transplant patients, who should be monitored frequently to identify emerging lesions that require surgery.