שנת סיום: 2018
כותרת עבודת הדוקטורט:
Pemphigus in Israel: Epidemiology, Mortality, Hematological Biomarkers, and association with autoimmune and neuropsychiatric comorbidities
מנחים: פרופ' שירה זילבר-שגיא, פרופ' ראובן ברגמן, פרופ' ארנון כהן
ABSTRACT
Background: Pemphigus is a rare but life-threating autoimmune bullous disease of the skin and mucous membranes. It typically presents with mucosal ulcerations and superficial blisters and erosions affecting the trunk, face, scalp and proximal limbs. There are two major subtypes of pemphigus: pemphigus vulgaris (PV) and pemphigus foliaceus (PF). The etiopathogenesis of pemphigus is characterized by acantholysis and intraepidermal blister formation, resulting from IgG autoantibodies directed against desmoglein (Dsg) 3 (PV) and/or Dsg 1 (PF), two transmembrane desmosomal glycoproteins. Pemphigus is a disease showing an uneven geographic and ethnic distribution. The prognosis for patients with pemphigus has greatly improved since the introduction of corticosteroid therapy; nevertheless, pemphigus remains a potentially life-threatening disease, with a relatively high mortality rate after diagnosis, ranging in the literature from 5-30% during various lengths of follow-up. Several associations of pemphigus with other autoimmune diseases have been reported, including myasthenia gravis, Sjögren’s syndrome, rheumatoid arthritis, vitiligo, and autoimmune thyroid disease. However, large-scale studies with sufficient statistical power are lacking.
Immunological hypotheses have become increasingly prominent in psychiatric research, suggesting that autoimmunity may be involved in the etiopathogenesis of some patients with symptoms of schizophrenia and bipolar disorder (BD). The association between pemphigus and these diseases was not estimated in the past.
Evidence had recently accumulated suggesting an association between bullous pemphigoid (BP); another autoimmune blistering disease, and neurological conditions. Since both BP and pemphigus share similar pathogenesis involving autoantibody-mediated epithelial damage, it is of interest to investigate whether a similar association with neurological diseases exists among pemphigus patients.
Objectives: To characterize the epidemiology of pemphigus in northwest Israel across the years 2000-2015, shedding light on ethnic variations; to evaluate the overall and cause-specific mortality among pemphigus patients relative to age-. sex-, and ethnicity-matched general population; to recognize risk factors for mortality in pemphigus; to assess the association between pemphigus and autoimmune and neuropsychiatric comorbidities; to investigate two hematological biomarkers (mean platelet volume [MPV] and red blood cell distribution width [RDW]) in patients with pemphigus.
Methods: A retrospective cohort study was designed to estimated trends in the incidence and mortality rates. Pemphigus incidence was retrospectively estimated from January 2000-December 2015. Mortality of pemphigus patients was compared to age- and gender-matched control subjects in the general population by calculating standardized mortality ratios (SMR)s. A Rambam-based case-control study was designed to assess RDW and MPV in pemphigus. MPV, platelet count and other inflammatory parameters were measured for all study participants.
Case-control studies utilizing the database of Clalit Health Services (CHS) were designed to investigate the associations between pemphigus and autoimmune and neuropsychiatric comorbidities. Univariate analysis was performed using Chi-square and Student t-test and a multivariate analysis was performed using a logistic regression model.
Importance and innovativeness: Our study utilizes the largest cohort of patients with pemphigus reported in the literature (n=1985). The large sample size is of great importance given that data collection in pemphigus is difficult due to the disease rarity and limited number of patients available for study. Our study will contribute several novel epidemiological features that were not previously elucidated such as: comparison of the epidemiology of pemphigus between 2 ethnic populations in the same region; comparison between the prognosis of PV and PF, characterizing mortality in PF relative to the general population; the association with neuropsychiatric comorbidities, the levels of RDW and MPV in pemphigus.