Epidemiology, management and the associated burden of mental health illness, atopic and autoimmune conditions, and common infections in alopecia areata: protocol for an observational study series.

INTRODUCTION: Alopecia areata (AA) is a common cause of immune-mediated non-scarring hair loss. Links between AA and common mental health, autoimmune and atopic conditions, and common infections have previously been described but remain incompletely elucidated and contemporary descriptions of the epidemiology of AA in the UK are lacking. METHODS AND ANALYSIS: Retrospective study series using a large population-based cohort (5.2 million) from the Oxford Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC) database, exploring four themes: AA epidemiology, mental health comorbidities, autoimmune/atopic associations and common infections.In the epidemiology theme, we will describe the incidence and point prevalence of AA overall and by age, sex and sociodemographic factors. Healthcare utilisation (primary care visits and secondary care referrals) and treatments for AA will also be assessed. In the mental health theme, we will explore the prevalence and incidence of mental health conditions (anxiety, depressive episodes, recurrent depressive disorder, adjustment disorder, agoraphobia, self-harm and parasuicide) in people with AA compared with matched controls. We will also explore the mental health treatment patterns (medication and psychological interventions), time off work and unemployment rates. Within the autoimmune/atopic associations theme, we will examine the prevalence of atopic (atopic dermatitis, allergic rhinitis, asthma) and autoimmune conditions (Crohn's disease, ulcerative colitis, coeliac disease, type 1 diabetes, Hashimoto's thyroiditis, Graves' disease, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, systemic lupus erythematosus (SLE), polymyalgia rheumatica, Sjögren's syndrome, psoriasis, vitiligo, multiple sclerosis, pernicious anaemia) in people with AA compared with matched controls. We will also estimate the incidence of new-onset atopic and autoimmune conditions after AA diagnosis. Within the common infections theme, we will examine the incidence of common infections (respiratory tract infection, pneumonia, acute bronchitis, influenza, skin infection, urinary tract infection, genital infections, gastrointestinal infection, herpes simplex, herpes zoster, meningitis, COVID-19) in people with AA compared with matched controls. ETHICS AND DISSEMINATION: The Health Research Authority decision tool classed this a study of usual practice, ethics approval was not required. Study approval was granted by the RCGP RSC Study Approval Committee. Results will be disseminated through peer-reviewed publications. OBSERVATIONAL STUDY REGISTRATION NUMBER: NCT04239521.

Perforin, COVID-19 and a possible pathogenic auto-inflammatory feedback loop.

During COVID-19 infection, reduced function of natural killer (NK) cells can lead to both compromised viral clearance and dysregulation of the immune response. Such dysregulation leads to overproduction of cytokines, a raised neutrophil/lymphocyte ratio and monocytosis. This in turn increases IL-6 expression, which promotes scar and thrombus formation. Excess IL-6 also leads to a further reduction in NK function through downregulation of perforin expression, therefore forming a pathogenic auto-inflammatory feedback loop. The perforin/granzyme system of cytotoxicity is the main mechanism through which NK cells and cytotoxic T lymphocytes eliminate virally infected host cells, as well as being central to their role in regulating immune responses to microbial infection. Here, we present epidemiological evidence suggesting an association between perforin expression and resistance to COVID-19. In addition, we outline the manner in which a pathogenic auto-inflammatory feedback loop could operate and the relationship of this loop to genes associated with severe COVID-19. Such an auto-inflammatory loop may be amenable to synergistic multimodal therapy.