Pachyonychia Congenita: A Research Agenda Leading to New Therapeutic Approaches.

Pachyonychia congenita (PC) is a dominantly inherited genetic disorder of cornification. PC stands out among other genodermatoses because despite its rarity, it has been the focus of a very large number of pioneering translational research efforts over the past 2 decades, mostly driven by a patient support organization, the Pachyonychia Congenita Project. These efforts have laid the ground for innovative strategies that may broadly impact approaches to the management of other inherited cutaneous and noncutaneous diseases. This article outlines current avenues of research in PC, expected outcomes, and potential hurdles.

Pachyonychia Congenita: Clinical Features and Future Treatments.

Pachyonychia congenita (PC) is a rare, autosomal dominant inherited disorder of keratinization that is characterized by a triad of focal palmoplantar keratoderma, plantar pain, and hypertrophic nail dystrophy. It can be debilitating, causing significantly impaired mobility. PC is diagnosed clinically alongside identification of a heterozygous pathogenic mutation in one of five keratin genes: KRT6A, KRT6B, KRT6C, KRT16, or KRT17. Each keratin gene mutation is associated with a distinct clinical phenotype, with variable age of onset and additional features, which has allowed classification by genotype. Additional features include pilosebaceous cysts, follicular hyperkeratosis, natal teeth, oral leukokeratosis, hidradenitis suppurativa, itching, and neurovascular structures. Although classed as rare, the prevalence of PC is likely to be underestimated. There is no cure or specific treatment for PC at present. Current treatments are limited to conservative measures to reduce plantar friction and trauma, mechanical debridement, topical treatments, and treatments for associated features or complications, most commonly infection. However, through active research in collaboration with PC Project, a patient-advocacy group, and the International PC Research Registry, a global registry of PC patients, there are now many new potential therapeutic options on the horizon. This review summarizes the clinical features associated with PC and highlights the current and future treatment of its manifestations.

How to critically appraise a systematic review: an aide for the reader and reviewer.

The number of published systematic reviews has soared rapidly in recent years. Sadly, the quality of most systematic reviews in dermatology is substandard. With the continued increase in exposure to systematic reviews, and their potential to influence clinical practice, we sought to describe a sequence of useful tips for the busy clinician reader to determine study quality and clinical utility. Important factors to consider when assessing systematic reviews include: determining the motivation to performing the study, establishing if the study protocol was prepublished, assessing quality of reporting using the PRISMA checklist, assessing study quality using the AMSTAR 2 critical appraisal checklist, assessing for evidence of spin, and summarizing the main strengths and limitations of the study to determine if it could change clinical practice. Having a set of heuristics to consider when reading systematic reviews serves to save time, enabling assessment of quality in a structured way, and come to a prompt conclusion of the merits of a review article in order to inform the care of dermatology patients.

Global Guidelines in Dermatology Mapping Project (GUIDEMAP): a systematic review of alopecia areata clinical practice guidelines.

INTRODUCTION: Alopecia areata (AA) is a nonscarring alopecia with an estimated global prevalence of 2% and limited data on the efficacy of current treatment. Clinical practice guidelines (CPGs) provide recommendations based on best available evidence. It is unclear how many AA CPGs are available globally. AIM: To systematically search for and identify CPGs on AA and to critically appraise their quality using validated tools. METHODS: We performed a literature search to identify CPGs published between October 2014 and April 2021, using the following databases: MEDLINE, Embase, National Institute for Health and Care Excellence (NICE), Guidelines International Network, Emergency Care Research Institute guidelines trust, Australian CPGs, Turning Research Into Practice database and DynaMed. The systematic review was conducted and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses framework. Three critical appraisal tools were used: Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument, Lenzer's red flags and United States Institute of Medicine's (IOM) criteria of trustworthiness. RESULTS: In total, six AA CPGs from seven manuscripts (one CPG was in two parts published in separate papers) were included. The majority (four of six) of the CPGs focused on treatment. Four CPGs (total of five papers) were in English and two CPGs were only available in the original language (one Russian and one Japanese). All AA CPGs demonstrated low quality in several domains in the AGREE II appraisal, including stakeholder involvement and applicability, with the latter being deemed the worst domain for all CPGs, with an average of 29%. The mean (SD) number of Lenzer's red flags for the included CPGs was 3.4 (1.5) out of a total of 8 possible red flags, while the IOM criteria showed 1.6 (0.8) 'fully met' criteria and 3.1 (1.2) 'not met' out of a total of 9 criteria. CONCLUSION: We found a limited number of AA CPGs, all of which had significant methodological deficiencies. We encourage guideline development groups to use validated checklists/tools to develop reliable and trustworthy CPGs.

Cardiovascular Safety of Biologics Targeting Interleukin (IL)-12 and/or IL-23: What Does the Evidence Say?

There is substantial evidence regarding the association between psoriasis and the elevated risk of cardiovascular (CV) disease. Many patients with psoriasis may also be concerned that their treatments may be associated with a further increase in the risk of CV disease. In this article, we summarize the data regarding the biological role of interleukin (IL)-12/23 in atherogenesis. We performed a literature search for currently known CV safety data from trials and observational studies of treatments targeting IL-12/23 in psoriasis, i.e. the p40 inhibitors ustekinumab and briakinumab, and the p19 inhibitors guselkumab, risankizumab, and tildrakizumab. On balance, extensive evidence supports the CV safety of ustekinumab, with over 14 years of follow-up data in multiple cohort studies and randomized controlled trials (RCTs). One self-controlled study concluded ustekinumab may precipitate short-term raised CV risk, but the study had limitations hindering interpretation. The safety evidence from RCTs on the p19 inhibitors are reassuring thus far, but these studies may not detect rare CV events in real-world patients. We concluded that the overall evidence does not show that ustekinumab is associated with an increase in the risk of CV disease in patients with psoriasis, but further data are awaited to assess the CV safety of p19 inhibitors for the treatment of psoriasis.

Normocomplementaemic urticarial vasculitis: effective treatment with omalizumab.

We report two patients with normocomplementaemic urticarial vasculitis with impressive response to omalizumab. This contrasts recent reports on hypocomplementaemic urticarial vasculitis syndrome, highlighting the need for clinical trials of omalizumab in normocomplementaemic urticarial vasculitis.