Periodontal Ehlers-Danlos Syndrome Is Caused by Mutations in C1R and C1S, which Encode Subcomponents C1r and C1s of Complement

Periodontal Ehlers-Danlos syndrome (pEDS) is an autosomal-dominant disorder characterized by early-onset periodontitis leading to premature loss of teeth, joint hypermobility, and mild skin findings. A locus was mapped to an approximately 5.8 Mb region at 12p13.1 but no candidate gene was identified. In an international consortium we recruited 19 independent families comprising 107 individuals with pEDS to identify the locus, characterize the clinical details in those with defined genetic causes, and try to understand the physiological basis of the condition. In 17 of these families, we identified heterozygous missense or in-frame insertion/deletion mutations in C1R (15 families) or C1S (2 families), contiguous genes in the mapped locus that encode subunits C1r and C1s of the first component of the classical complement pathway. These two proteins form a heterotetramer that then combines with six C1q subunits. Pathogenic variants involve the subunit interfaces or inter-domain hinges of C1r and C1s and are associated with intracellular retention and mild endoplasmic reticulum enlargement. Clinical features of affected individuals in these families include rapidly progressing periodontitis with onset in the teens or childhood, a previously unrecognized lack of attached gingiva, pretibial hyperpigmentation, skin and vascular fragility, easy bruising, and variable musculoskeletal symptoms. Our findings open a connection between the inflammatory classical complement pathway and connective tissue homeostasis

How is disease severity associated with quality of life in psoriasis patients? : Evidence from a longitudinal population-based study in Sweden

BACKGROUND: Assessing the impact of disease severity on generic quality of life (QOL) is a critical step in outcomes research and in the development of decision-analytic models structured around health states defined by clinical measures. While data from routine clinical practice found in healthcare registers are increasingly used for research, more attention should be paid to understanding the relationship between clinical measures of disease severity and QOL. The purpose of this work was therefore to investigate this relationship in psoriasis using a population-based dataset. METHODS: Severity was measured by the Psoriasis Area and Severity Index (PASI), which combines severity of erythema, induration, and desquamation into a single value ranging from 0 to 72. The generic EQ-5D-3L utility instrument, under the UK tariff, was used to measure QOL. The association between PASI and EQ-5D-3L was estimated using a population-based dataset of 2674 patients with moderate to severe psoriasis enrolled over ten years in the Swedish psoriasis register (PsoReg). Given the repeated measurement of patients in the register data, a longitudinal fixed-effects model was employed to control for unobserved patient-level heterogeneity. RESULTS: Marginal changes in PASI are associated with a non-linear response in EQ-5D-3L: Moving from PASI 10 to 9 (1 to 0) is associated with an increase of 0.0135 (0.0174) in EQ-5D-3L. Furthermore, unobserved patient-level heterogeneity appears to be an important source of confounding when estimating the relationship between QOL and PASI. CONCLUSIONS: Using register data to estimate the impact of disease severity on QOL while controlling for unobserved patient-level heterogeneity shows that PASI appears to have a larger impact on QOL than previously estimated. Routine collection of generic QOL data in registers should be encouraged to enable similar applications in other disease areas

Evaluating equality in psoriasis healthcare : a cohort study of the impact of age on prescription biologics

BACKGROUND: Inequality in healthcare has been identified in many contexts. To the best of our knowledge, this is the first study investigating age inequity in the form of prescription patterns of biologics in psoriasis care. OBJECTIVE: To determine whether psoriasis patients have equitable opportunities to receive biologic medications as they age. If patients do not receive equitable treatment, a subsequent objective is to determine the magnitude of the disparity. METHODS: A cohort of biologic-naïve psoriasis patients were analysed using Cox proportional hazard models to measure the impact of each additional year of life on the likelihood of initiating biologic treatment, after controlling for sex, body mass index, comorbidities, disease activity, and education level. A supporting analysis used a non-parametric graphical method to study the proportion of patients initiating biologic treatment as age increases, after controlling for the same covariates. RESULTS: The Cox proportional hazards model results in a hazard ratio of a one year increase in age of 0.963 to 0.969 depending on calendar year stratification, which implies that an increase in age of 30 years corresponds to a reduced likelihood of initiating biologic treatment by 61.3-67.6%. The estimated proportion of patients initiating biologic medication is always decreasing as age increases, at a statistically significant level. CONCLUSIONS: Psoriasis patients have fewer opportunities to access biologic medications as they age. This result was shown to be applicable at all stages in a patient's life course and was not only restricted to the elderly, although it implies greater disparities as the age difference between patients increases. These results show that inequity in access to biologic treatments due to age is prevalent in clinical practice today. Further research is needed to investigate the extent to which this result is influenced by patient preferences.

Prevalence and incidence of palmoplantar pustulosis in Sweden : a population-based register study

BACKGROUND: Palmoplantaris pustulosis (PPP) is a chronic relapsing skin condition characterized by sterile pustules on the palm and soles. Population-based estimates of PPP incidence and prevalence are limited. OBJECTIVES: To estimate the prevalence and incidence of PPP in the Swedish general population and to estimate the prevalence of psoriasis vulgaris among the PPP population. METHODS: The Swedish National Patient Register, covering all inpatient and outpatient non-primary care for the Swedish population, was used. We identified cases (2004-2015) with one ICD-10 diagnostic code (base case) for PPP. The point prevalence estimates at the end of this period (31 December 2015) were obtained by linkage to the Swedish Total Population Register. In sensitivity analyses, we used alternative case defintions:1) requiring two visits, 2) requiring two visits of which one within dermatology/internal medicine. RESULTS: The base case prevalence of PPP was estimated to be 147/100 000 (women=227, men=68) and the annual prevalence was estimated to 26/100 000 in 2015. Among the PPP population, 17% were registered with a diagnostic code for psoriasis vulgaris. The incidence of PPP in 2015 was estimated to be 12.7/100 000 (women=18.7, men=6.6). The criteria used had an impact on prevalence and incidence estimates; strict case 1) 72/100 000 and 2) 5.4/100 000. CONCLUSIONS: Results indicate that the population-based prevalence of PPP may be larger than previous estimated. However, the estimates were sensitive to employed PPP case criteria. The findings enhance demands for studies using validated diagnostic algorithms potentially also including data from the primary care setting