John Toole

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.

Near-infrared spectroscopy for dermatological applications

The clinical diagnosis of many dermatological conditions suffers from inadequacies and a histopathological analysis of skin biopsies remains the standard for confirmation of a diagnosis. We suggest that near-infrared (IR) spectroscopy may be a suitable non-invasive, objective tool for characterizing skin conditions. This paper will highlight our in vivo near-IR spectroscopic characterization of skin tumors presented for differential diagnosis of skin cancer. In vivo visible and near-IR spectra (400‐ 2500 nm) were collected from actinic keratoses, basal cell carcinomata, benign nevi, dysplastic nevi, actinic lentigines and seborrheic keratoses by placing a fiber optic probe on the skin. Linear discriminant analysis (LDA) was used to determine whether spectra could be classified according to lesion type and resulted in accuracies of 70‐98% in differentiating benign from pre-malignant or malignant lesions. Near-IR spectroscopy is a promising non-invasive technique for the screening of skin lesions. # 2002 Published by Elsevier Science B.V.

Canadian Clinical Practice Guidelines for Rosacea

Rosacea is a chronic facial inflammatory dermatosis characterized by background facial erythema and flushing and may be accompanied by inflammatory papules and pustules, cutaneous fibrosis and hyperplasia known as phyma, and ocular involvement. These features can have adverse impact on quality of life, and ocular involvement can lead to visual dysfunction. The past decade has witnessed increased research into pathogenic pathways involved in rosacea and the introduction of novel treatment innovations. The objective of these guidelines is to offer evidence-based recommendations to assist Canadian health care providers in the diagnosis and management of rosacea. These guidelines were developed by an expert panel of Canadian dermatologists taking into consideration the balance of desirable and undesirable outcomes, the quality of supporting evidence, the values and preferences of patients, and the costs of treatment. The 2015 Cochrane review “Interventions in Rosacea” was used as a source of clinical trial evidence on which to base the recommendations.

Management of acne: Canadian clinical practice guideline

Acne is one of the most burdensome diseases globally.[1][1],[2][2] Its prevalence among those aged 12 to 24 years is estimated to be 85%, although it can persist beyond young adulthood despite treatment.[3][3]–[5][4] Acne can adversely affect quality of life[6][5]–[13][6] and may lead to

A Case Indistinguishable Between Indeterminate Cell Histiocytosis and Cutaneous Rosai-Dorfman Disease.

Histiocytic disorders are characterized by the accumulation of macrophages or dendritic cells, 2 types of antigen-presenting cells derived from CD34+ progenitors, in various tissues. There are over 100 described subtypes of histiocytosis with a wide range and significant overlap of clinical and histopathologic features. Langerhans cells are epithelial dendritic cells characterized by strong S-100 protein and CD1a immunostaining. Langerhans cells are the predominant component of Langerhans cell histiocytosis (LCH). Macrophages usually lack the Langerhans cell markers but express CD68 and Ki-M1p. Histiocytic disorders with a predominant macrophage component are called non-Langerhans cell histiocytosis (NLCH). Indeterminate cell histiocytosis (ICH) is a rare proliferative disorder of histiocytes that usually presents as a cutaneous disease with multiple pink to brown papules and nodules. ICH is characterized by immunophenotypic features of both Langerhans cells and macrophages and illustrates overlap between LCH and NLCH. Cutaneous Rosai-Dorfman disease (CRDD) is a very rare variant of sinus histiocytosis with massive lymphadenopathy (SHML). SHML is a type of NLCH. CRDD is restricted to the skin and can present as single or multiple red-brown papules and nodules. The lesional histiocytes typically stain S-100 protein positive, CD68 positive, and CD1a negative.

Classification of infrared spectra from skin tumors

The clinical differential diagnosis of skin tumors is an often-challenging task, to which the probing of skin with mid- and near-infrared (IR) light may be contributory. The development of objective methods for the analysis of IR spectra remains a major hurdle to developing clinically useful applications. The authors highlight different processing methods for IR spectra from skin biopsies and in-vivo skin tumors. Spectroscopic maps of biopsies of basal cell, squamous cell and melanocytic neoplasms were objectively grouped into distinct clusters that corresponded with tumor, epidermis, dermis, follicle and fat. Normal and abnormal skin components were located within maps using a search engine based upon linear discriminant analysis (LDA). In all instances, areas of tumor were distinct from normal tissue in biopsies. In-vivo, near-IR spectroscopy and LDA allowed discrimination between benign and malignant skin lesions with a high degree of accuracy. We conclude that IR spectroscopy has significant diagnostic promise in the skin cancer arena. The analytical methods described can now be used to create a powerful classification scheme in which to detect skin tumor cells within biopsied and living skin.

An Open Letter to Health Canada

Regulators are mandated to provide structured guidance on drug development. They approve drugs based upon their scientific and medical merits. They negotiate a disclosure of a drug’s profile—the label. And they provide ongoing monitoring of manufacturing, use, and safety once the drug is marketed. Posting of guidance documents notwithstanding, the foregoing are conducted behind closed doors and subject to coveted decision processes. The warnings and directions provided in the drug label are for the most part warranted. On occasion, the warnings and requirements are restrictive and unwarranted. The recent US Food and Drug Administration (FDA) approval and release of the brodalumab label bears witness. Brodalumab (Siliq), an IL-17R antagonist, was evaluated for the treatment of Crohn disease, psoriasis, and psoriatic arthritis (NCT02024646, NCT02029495). Six completed suicides occurred across all development programs, 4 within the psoriasis studies. One of the suicides reported in the psoriasis program was adjudicated as an accidental overdose of illicit drugs. With more than 4000 patients and nearly 10 000 patient years of exposure, the approximate suicide event rate of 30 per 100 000 patient years is marginally greater than the range of rates reported in the adult US population: 12 to 24 per 100,000. Depression is a known comorbidity of psoriasis. We know that depression is the major risk factor for suicide ideation, suicide attempts, and completion. Interestingly, depression scores improve in psoriasis populations receiving effective therapy, as do patients treated with brodalumab. The US Siliq label contains a boxed warning that advises physicians to be aware of the potential for depression and take action should a patient be at risk of suicide. Warnings of this sort deserve attention for all populations at risk. The label clearly states that no causal association with suicide ideation or completed suicide and brodalumab was found. Absence of implied and mechanistic causality, the cornerstones of Hill’s hypothesis, argues for statistical fluctuation within the sample population. Still, the monograph imposes an onerous burden on prescribers. The boxed warning and registration requirements appear orthogonal to a balanced and scientifically derived statement of facts. Motivation for inclusion of the boxed warning is obscure and unjustified. The Canadian health care system is undermanned and our patients underserviced. Imposing burdensome risk mitigation programs will do little more than impair access and limit therapeutic options available to our patients. As concerned clinicians, we respectfully request Health Canada provide scientifically and clinically sound guidance for brodalumab and not mime the United States.

Acitretin Use in Dermatology

Background: Acitretin has been used for the treatment of severe psoriasis for over 20 years. Objective: The current project was conceived to optimise patient care by recognising the role acitretin can play in the treatment of patients with psoriasis and those with other disorders of keratinisation. Methods: A literature review was conducted to explore the role of acitretin and to assess its value for dermatologic disorders other than severe psoriasis. A panel of Canadian dermatologists developed a clinical pathway using a case-based approach, focusing on specific patient features. Results: The clinical pathway covers plaque psoriasis with hyperkeratotic plantar disease, palmoplantar pustulosis, hyperkeratotic hand dermatitis, lichen planus, lamellar ichthyosis, and hidradenitis suppurativa. Conclusion: The recommendations in our clinical pathway reflect the current use of acitretin in Canada for severe psoriasis and other disorders of keratinisation.

SAT0560 Serious Infection Events in the Psoriasis Longitudinal Assessment and Registry Study: Current Status of Observations

Objectives To report the effect of psoriasis treatments on the risk of serious infections in pts in PSOLAR. Methods PSOLAR is a multicenter, intercontinental, longitudinal, disease-based registry for adult pts with psoriasis, who are eligible to receive systemic therapy based on standards of clinical practice. Cumulative incidence rates of serious infections were reported across treatment cohorts of pts exposed to ustekinumab, infliximab, adalimumab, etanercept, other biologics (e.g., discontinued or experimental drugs), and non-biologic therapy (i.e. including and excluding MTX). Pts exposed to cyclosporine and those who were only exposed to a biologic before the start of registry were excluded. Multivariate analyses using Cox hazard regression methodology were used to identify predictors of time to first serious infection and therapies were compared to MTX alone. The overall registry population, as well as subpopulations of new users of biologics was evaluated. Results Data were analyzed from 11466 pts with psoriasis exposed to a biologic agent or a non-biologic therapy reflecting 22311 pt-years. Demographic and baseline characteristics were generally comparable across cohorts, although the proportions of pts with prior significant infections, cardiovascular disease, and psoriatic arthritis were higher in the infliximab cohort. The cumulative incidence rate of serious infections was 1.45/100PY (n=323) across treatment cohorts, and rates were numerically higher in the infliximab, adalimumab, and other biologics cohorts (2.49, 1.97, and 3.01/100 PY, respectively) compared with the etanercept, ustekinumab, MTX, and non-biologics cohorts (excluding MTX) (1.47, 0.83, 1.28, and 1.05/100PY, respectively). Generally, the most commonly reported serious infections were pneumonia and cellulitis across cohorts. Increasing age, serious infection history, presence of diabetes, infliximab or adalimumab exposure, and current smoking were associated with increased risk for serious infection. In the subpopulation of new users of biologics, only adalimumab was found to be associated with risk of serious infection, while in the narrower subpopulation of bio-naive biologic new users, none of the biologics were found to be associated with serious infection. Conclusions Results from PSOLAR suggest a higher risk of serious infections with adalimumab and infliximab in comparison with methotrexate; increased risk was not observed with ustekinumab or etanercept. Disclosure of Interest R. Kalb Grant/research support from: Janssen Scientific Affairs, LLC, D. Fiorentino Grant/research support from: Janssen Scientific Affairs, LLC, M. Lebwohl Grant/research support from: Janssen Scientific Affairs, LLC, C. Leonardi Grant/research support from: Janssen Scientific Affairs, LLC, J. Toole Grant/research support from: Janssen Scientific Affairs, LLC, Y. Poulin Grant/research support from: Janssen Scientific Affairs, LLC, A. Cohen Grant/research support from: Janssen Scientific Affairs, LLC, K. Goyal Employee of: Janssen Scientific Affairs, LLC, S. Calabro Employee of: Janssen Scientific Affairs, LLC, W. Langholff Employee of: Janssen Scientific Affairs, LLC, S. Fakharzadeh Employee of: Janssen Scientific Affairs, LLC