Norman Wasel

Secukinumab in Plaque Psoriasis — Results of Two Phase 3 Trials

BACKGROUND Interleukin-17A is considered to be central to the pathogenesis of psoriasis. We evaluated secukinumab, a fully human anti-interleukin-17A monoclonal antibody, in patients with moderate-to-severe plaque psoriasis. METHODS In two phase 3, double-blind, 52-week trials, ERASURE (Efficacy of Response and Safety of Two Fixed Secukinumab Regimens in Psoriasis) and FIXTURE (Full Year Investigative Examination of Secukinumab vs. Etanercept Using Two Dosing Regimens to Determine Efficacy in Psoriasis), we randomly assigned 738 patients (in the ERASURE study) and 1306 patients (in the FIXTURE study) to subcutaneous secukinumab at a dose of 300 mg or 150 mg (administered once weekly for 5 weeks, then every 4 weeks), placebo, or (in the FIXTURE study only) etanercept at a dose of 50 mg (administered twice weekly for 12 weeks, then once weekly). The objective of each study was to show the superiority of secukinumab over placebo at week 12 with respect to the proportion of patients who had a reduction of 75% or more from baseline in the psoriasis area-and-severity index score (PASI 75) and a score of 0 (clear) or 1 (almost clear) on a 5-point modified investigators global assessment (coprimary end points). RESULTS The proportion of patients who met the criterion for PASI 75 at week 12 was higher with each secukinumab dose than with placebo or etanercept: in the ERASURE study, the rates were 81.6% with 300 mg of secukinumab, 71.6% with 150 mg of secukinumab, and 4.5% with placebo; in the FIXTURE study, the rates were 77.1% with 300 mg of secukinumab, 67.0% with 150 mg of secukinumab, 44.0% with etanercept, and 4.9% with placebo (P<0.001 for each secukinumab dose vs. comparators). The proportion of patients with a response of 0 or 1 on the modified investigators global assessment at week 12 was higher with each secukinumab dose than with placebo or etanercept: in the ERASURE study, the rates were 65.3% with 300 mg of secukinumab, 51.2% with 150 mg of secukinumab, and 2.4% with placebo; in the FIXTURE study, the rates were 62.5% with 300 mg of secukinumab, 51.1% with 150 mg of secukinumab, 27.2% with etanercept, and 2.8% with placebo (P<0.001 for each secukinumab dose vs. comparators). The rates of infection were higher with secukinumab than with placebo in both studies and were similar to those with etanercept. CONCLUSIONS Secukinumab was effective for psoriasis in two randomized trials, validating interleukin-17A as a therapeutic target. (Funded by Novartis Pharmaceuticals; ERASURE and FIXTURE ClinicalTrials.gov numbers, NCT01365455 and NCT01358578, respectively.).

A Canadian online survey to evaluate awareness and treatment satisfaction in individuals with moderate to severe plaque psoriasis.

Background  Psoriasis is a chronic inflammatory disease associated with comorbidities and decreased quality of life. This survey is aimed to better understand the impact of disease on Canadian patients, and to examine awareness and use of available treatment options.

A Canadian Self-Administered Online Survey to Evaluate the Impact of Moderate-to-Severe Psoriasis among Patients

Background: Few population studies of individuals living with psoriasis have been performed in Canada. Objective: The objective of this survey was to understand the severity and impact of psoriasis on the lives of Canadian patients. Methods: An online survey was conducted using a consumer panel. Eligible subjects reported a diagnosis of psoriasis and provided a self-reported level of severity. In addition, subjects had to either (a) have psoriasis covering at least 3% of their body surface area; (b) have psoriasis on a sensitive area of the body; or (c) be currently undergoing treatment for their psoriasis with systemic medication and/or phototherapy. Results: A total of 514 panelists met the inclusion criteria and completed the survey. Current moderate, severe, or very severe psoriasis was reported by 65% of respondents. Nearly all subjects (96%) had psoriasis affecting a sensitive area of the body. At the time of the survey, 18% were taking systemic medication and/or phototherapy. Comorbidities, such as obesity and high blood pressure, were highly prevalent, with 75% of respondents reporting at least one other diagnosis. Data from the SF-8 and Dermatology Life Quality Index instruments indicated that psoriasis negatively impacted quality of life. Conclusion: Moderate-to-severe psoriasis places a burden on Canadian patients, some of whom may be receiving suboptimal treatment or treatment not appropriate for the severity of their condition.

Epidemiology of moderate-to-severe plaque psoriasis in a Canadian surveyed population.

Background: Limited data are available on the epidemiologic features of psoriasis in Canada. Objective: To investigate the epidemiologic features and burden of moderate-to-severe psoriasis in a Canadian population. Methods: An online survey was conducted using a consumer panel. Eligible respondents indicated a diagnosis of psoriasis and plaque-type psoriasis of at least moderate severity. Eligibility was validated according to self-reported body surface area (BSA) involvement, sensitive areas affected, and/or current treatment. Results: Of the 514 respondents who completed the survey, 62% estimated a BSA involvement of ≥ 3% within the past 5 years. Onset of psoriasis occurred earlier in females than in males. Nail involvement was more commonly reported in individuals with psoriatic arthritis compared to those without. Several symptoms were more likely described as “constantly” or “near constantly” experienced by females than by males. Comorbidities commonly reported were hypertension, dyslipidemia, and overweight or obesity. Conclusions: The findings are consistent with a substantial burden attributed to moderate-to-severe plaque psoriasis in a Canadian population.

2016 Addendum to the Canadian Guidelines for the Management of Plaque Psoriasis 2009

Disclaimer: As in the original guidelines, physicians should use their best clinical judgment when determining whether and how to apply treatment recommendations in the individualized care of patients. This document is not intended to replace the guidance found in the relevant Canadian product monographs or other official information available for the therapeutics discussed. Every reasonable effort has been made to ensure the accuracy of this document. Any errors made here will be corrected in the next edition of the guidelines. Drug names: As in the original guidelines document, generic names have been used throughout this document. Any new trade name or generic name used in the addendum has been has listed in Appendix I at the end of this document. Directions for readers: This addendum should be used in conjunction with the original 2009 Canadian Guidelines for the Management of Plaque Psoriasis as a tool to guide physicians in clinical decision making. All changes to the content of the 2009 guidelines are presented by chapter, which correspond to the chapters in the original document. All new information is cross-referenced by page number and section/subsection to the original guidelines where the addendum applies. A table listing only new recommendations or modifications to existing recommendations follows each chapter. Legend XXXX X = If only additional references are added to existing text in the original guidelines, these are indicated in bold. All original text from the 2009 Guidelines is underlined. All new recommendations or modifications to existing recommendations are indicated in bold.

Minocycline-induced cutaneous pigmentation.

Background: Minocycline-induced cutaneous pigmentation is an adverse effect that may be more common than is generally realized. It is usually reported in patients undergoing chronic minocycline therapy for acne vulgaris. Objective: The case of a 69-year-old woman taking minocycline for rheumatoid arthritis is presented, and its differential diagnosis discussed in order to characterize the clinical features of minocycline-induced cutaneous pigmentation. Conclusion: Patients undergoing minocycline therapy for rheumatoid arthritis may develop bluish-grey pigmentation over the legs and forearms.

Skin disorders in Ashkenazi Jews: a review

Medical conditions unique to or more common in specific ethnic groups may derive their ethnic predilection from many factors, including specific climatic conditions, dietary or cultural habits, and genetic predispositions. The skin diseases and conditions affecting a number of ethnic groups, such as native Americans, Mediterraneans, Blacks, Hispanics, and Asians, have been studied and reviewed. 1–6 In fact, there are reports that many of these ethnic groups have a propensity for certain skin diseases. For example, native Americans are associated with a higher incidence of actinic prurigo, 3 whereas individuals of Mediterranean origin have a greater frequency of Behcet’s disease, pemphigus vulgaris, and Kaposi’s sarcoma. 4–6

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.

Lupus Vulgaris Occurring in a Locus Minoris Resistentiae

Background: The pathogenesis of lupus vulgaris, a form of cutaneous tuberculosis, is not always clear, especially in patients who do not have coexistent extracutaneous tuberculosis and in patients with single lesions. Objectives: To report a case of lupus vulgaris in a locus minoris resistentiae (a site of reduced resistance) and to use a unique set of clinical circumstances and laboratory tests to reconstruct the pathogenesis of the lesion and the response to treatment. Conclusion: Lupus vulgaris can occur in a locus minoris resistentiae; local trauma and possibly other factors, such as increased temperature, topical corticosteroids, and the virulence of the infecting strain, may facilitate the growth of Mycobacterium tuberculosis present at a locus minoris resistentiae as a result of a silent bacillemia.