Association of Rosacea with Depressive and Anxiety Symptoms: A General Population Study.

BACKGROUND: The association between rosacea and psychiatric comorbidity has been reported previously. However, there is a lack of general population studies about this subject area. OBJECTIVES: The aim of this study was to the association between rosacea with depressive and anxiety symptoms at the population level. METHODS: A clinical whole-body examination was performed by dermatologists for 1,932 subjects belonging to the Northern Finland Birth Cohort 1966 Study during the 46-year follow-up survey. The presence of depressive and anxiety symptoms was gathered by using validated Hopkins Symptom Checklist-25 (HSCL-25) included in the self-administered questionnaires. Binary logistic regression analysis was used to identify associations between rosacea and psychological symptoms. RESULTS: Rosacea was found in dermatological evaluation in 15.1% of the study subjects (n = 292). In logistic regression analyses, after adjusting for confounding factors, those with rosacea had 1.6-fold (OR 1.55, 95% CI: 1.02-2.32) risk for psychiatric symptoms according to HSCL-25 when compared with controls. In separate analyses of the HSCL-25 depression subscale, the risk was increased, especially for depressive symptoms (OR 1.56, 95% CI: 1.10-2.18). CONCLUSIONS: Patients with rosacea seem to have increased risk for depressive and anxiety symptoms in general population. Physicians treating patients with rosacea should pay more attention to the psychosocial health of patients.

Association between Pruritus and Psychosocial Well-being: A Population-based Study among 6,809 Subjects.

Pruritus has an extensive impact on functional, social and psychosocial behaviour. The association between pruritus and psychological well-being has mostly been studied among selected patient groups, whereas population-based studies are lacking. The aim of this study was to determine the association between pruritus and insomnia, quality of life, depression and anxiety at the population level in the general population. A cross-sectional population-based study was conducted in 2012 to 2013. Study subjects (n = 6,809) belonging to the Northern Finland Birth Cohort 1966 Study participated in a large follow-up study at the age of 45-47 years. They completed an extensive health questionnaire including questions on pruritus and several previously validated questionnaires regarding symptoms of psychosocial well-being. Pruritus affected 19.9% of the study subjects weekly, being more common in women than in men (p < 0.001). A significant association was found between both localized and generalized pruritus and symptoms of insomnia, depression, anxiety and decreased quality of life. The association was seen even in those with mild psychological symptoms/insomnia, and it affected both sexes. The severity of psychological symptoms increased with increasing frequency of pruritus. In conclusion, pruritus has a multiple effect on psychosocial well-being. Physicians should consider possible psychosocial symptoms in patients with pruritus.

Cardiovascular and Metabolic Profile of Subjects with Acne in a Cohort of Middle-aged Patients: A General Population Study of 1,932 Subjects.

Acne vulgaris is one of the most common inflammatory skin diseases, but there are few studies of adult acne and its association with general health. The aim of this study was to examine the prevalence and clinical characteristics of adult acne at the population level among 1,932 subjects belonging to the Northern Finland Birth Cohort 1966 Study. In addition, cardiovascular and metabolic profiles of acne cases and their controls were analysed. The prevalence of adult acne was 7.9% (n = 150) with no statistical difference between the sexes. The majority of subjects presented with papulopustular acne (77.1%). Comedo acne (10.8% of all subjects) was more common in females than in males (p < 0.005). Males with acne had more abnormality in their metabolic factors than did acne-free controls; plasma glucose and insulin levels at 60 min after the 75 g glucose load were higher in males with acne than in controls (p < 0.01 for both). Corresponding associations were not seen in females. In conclusion, adult acne is common in middle-age, presenting a slightly different clinical picture in females than in males. In addition, male subjects with acne may have a higher risk of metabolic disturbances than do controls, and thus, comprehensive evaluation of patients with adult acne is needed.

Comorbidities and Medication Use in Finnish Patients with Psoriasis: A Population-Based Registry Study.

Therapeutic options for psoriasis vulgaris have changed during recent decades with the introduction of biologics. Few nationwide studies are available on psoriasis treatment patterns, and those from Finland predate the use of biologics. The aim of this retrospective, population-based registry study was to identify patients with psoriasis vulgaris and their treatment patterns in the secondary care setting in Finland. The study cohort included 41,456 adults with a diagnosis of psoriasis vulgaris in the public secondary healthcare setting from 2012 through 2018. Data on comorbidities, pharmacotherapy, and phototherapy were collected from nationwide healthcare and drug registries. Patients in the cohort had a wide range of comorbidities, with 14.9% having psoriatic arthritis. Treatment was based largely on topical and conventional systemic medications. Conventional medications were used by 28.9% of patients, and methotrexate was the most common option (20.9%). Biologics were used by 7.3% of patients, mostly as second- and third-line treatment. The use of conventional systemic medications, topical treatments, and phototherapy decreased after the initiation of biologics. This study of psoriasis vulgaris in Finland provides a framework for the development of future care practices.

Serum reactivity in dermatitis herpetiformis: an international multicentre study.

BACKGROUND: Dermatitis herpetiformis (DH) is a rare gluten-induced skin disorder characterized predominantly by IgA autoantibodies against endomysium, tissue transglutaminase (TG2/tTG), epidermal transglutaminase (TG3/eTG) and deamidated gliadin. To date, circulating autoantibody reactivity has not been systematically described. OBJECTIVES: Characterization of serum reactivities in DH. METHODS: This multicentre international study analysed sera from 242 patients with DH taken at the time of initial diagnosis. DH-specific IgA and IgG serum autoantibodies were analysed by indirect immunofluorescence (IF) on monkey oesophagus, and by enzyme-linked immunosorbent assay (ELISA) based on recombinant TG2/tTG, TG3/eTG and deamidated gliadin (GAF3X). RESULTS: IgA indirect IF microscopy on monkey oesophagus revealed the highest reactivity (84.3%; specificity 100%) followed by IgA TG2/tTG ELISA (78.5%, specificity 99.0%), IgA TG3/eTG ELISA (72.7%, specificity 95.0%) and IgA GAF3X ELISA (69.0%, specificity 98.5%). CONCLUSIONS: Serum IgA and IgG autoantibodies against endomysium, TG2/tTG, TG3/eTG and deamidated gliadin are highly prevalent in DH. Indirect IF microscopy on monkey oesophagus (IgA) provides the highest diagnostic accuracy that can be further enhanced by 4.5% when combined with IgA TG2/tTG ELISA.

S2k guidelines on the management of paraneoplastic pemphigus/paraneoplastic autoimmune multiorgan syndrome initiated by the European Academy of Dermatology and Venereology (EADV).

BACKGROUND: Paraneoplastic pemphigus (PNP), also called paraneoplastic autoimmune multiorgan syndrome (PAMS), is a rare autoimmune disease with mucocutaneous and multi-organ involvement. PNP/PAMS is typically associated with lymphoproliferative or haematological malignancies, and less frequently with solid malignancies. The mortality rate of PNP/PAMS is elevated owing to the increased risk of severe infections and disease-associated complications, such as bronchiolitis obliterans. OBJECTIVES: These guidelines summarize evidence-based and expert-based recommendations (S2k level) for the clinical characterization, diagnosis and management of PNP/PAMS. They have been initiated by the Task Force Autoimmune Blistering Diseases of the European Academy of Dermatology and Venereology with the contribution of physicians from all relevant disciplines. The degree of consent among all task force members was included. RESULTS: Chronic severe mucositis and polymorphic skin lesions are clue clinical characteristics of PNP/PAMS. A complete assessment of the patient with suspected PNP/PAMS, requiring histopathological study and immunopathological investigations, including direct and indirect immunofluorescence, ELISA and, where available, immunoblotting/immunoprecipitation, is recommended to achieve a diagnosis of PNP/PAMS. Detection of anti-envoplakin antibodies and/or circulating antibodies binding to the rat bladder epithelium at indirect immunofluorescence is the most specific tool for the diagnosis of PNP/PAMS in a patient with compatible clinical and anamnestic features. Treatment of PNP/PAMS is highly challenging. Systemic steroids up to 1.5 mg/kg/day are recommended as first-line option. Rituximab is also recommended in patients with PNP/PAMS secondary to lymphoproliferative conditions but might also be considered in cases of PNP/PAMS associated with solid tumours. A multidisciplinary approach involving pneumologists, ophthalmologists and onco-haematologists is recommended for optimal management of the patients. CONCLUSIONS: These are the first European guidelines for the diagnosis and management of PNP/PAMS. Diagnostic criteria and therapeutic recommendations will require further validation by prospective studies.

Uniting biobank resources reveals novel genetic pathways modulating susceptibility for atopic dermatitis.

BACKGROUND: Atopic dermatitis (AD) is a common chronic inflammatory skin disease with high heritability. Previous genome-wide association studies have identified several loci predisposing to AD. These findings explain approximately 30% of the variance in AD susceptibility, suggesting that further work is required to fully understand the genetic underpinnings. OBJECTIVE: We sought to gain additional understanding of the genetic contribution to AD risk by using biobank resources. METHODS: We completed a genome-wide meta-analysis of AD in 796,661 individuals (Ncases = 22,474) from the FinnGen study, the Estonian Biobank, and the UK Biobank. We further performed downstream in silico analyses to characterize the risk variants at the novel loci. RESULTS: We report 30 loci associating with AD (P < 5 × 10-8), 5 of which are novel. In 2 of the novel loci, we identified missense mutations with deleterious predictions in desmocollin 1 and serpin family B member 7, genes encoding proteins crucial to epidermal strength and integrity. CONCLUSIONS: These findings elucidate novel genetic pathways involved in AD pathophysiology. The likely involvement of desmocollin 1 and serpin family B member 7 in AD pathogenesis may offer opportunities for the development of novel treatment strategies for AD in the future.

Association between bleeding periodontal pockets and eczemas: Results of the Northern Finland Birth Cohort 1966.

AIM: To investigate whether the periodontal condition as measured by bleeding periodontal pockets is associated with atopic dermatitis, seborrheic dermatitis, and eczema nummulare. MATERIALS AND METHODS: The study population (n = 1871) was obtained from the 46-year follow-up study of the Northern Finland Birth Cohort 1966 study (NFBC1966). The periodontal condition was measured by the number of sites with bleeding periodontal pockets that were ≥4 mm deep. The whole skin of the participants was clinically examined, and diagnoses of skin diseases were made according to the International Classification of Diseases. Prevalence rate ratios (PRR) and 95% confidence intervals (95% CIs) were estimated using Poisson regression models with robust error variance. RESULTS: In this cohort, comprising 46-year-old participants of NFBC1966, the presence of 1-3 and ≥4 bleeding-deepened periodontal pockets (≥4 mm deep) were associated with seborrheic dermatitis (PRR 1.9, 95% CI: 1.3-2.8 and PRR 2.2, 95% CI: 1.4-3.3, respectively) and with eczema nummulare (PRR 1.7, 95% CI: 0.9-3.1 and PRR 1.7, 95% CI: 0.9-3.3, respectively). For non-smokers, the corresponding estimates were 1.7 for seborrheic dermatitis (95% CI: 1.1-2.6) and 1.8 (95% CI: 1.1-3.1) and 1.4 for eczema nummulare (95% CI: 0.7-2.9) and 1.2 (95% CI: 0.5-2.9), respectively. No association was found between bleeding-deepened periodontal pockets and atopic dermatitis. Further adjustments for C-reactive protein, diabetes, and inflammatory diseases did not essentially change the risk estimates among either the total population or the non-smokers. CONCLUSION: Bleeding periodontal pockets appeared to be associated with the presence of seborrheic dermatitis and eczema nummulare.

Ocular Symptoms and Rosacea: A Population-Based Study.

BACKGROUND: The symptoms of ocular rosacea are often non-specific and there is no dependable diagnostic test for the disease, which may cause difficulties in diagnostics. The aim of this study was to examine the association between clinical findings of rosacea and self-reported ocular symptoms in a general population of middle-aged subjects. METHODS: A clinical whole-body examination by a dermatologist was performed for 1,932 subjects belonging to the Northern Finland Birth Cohort 1966 Study. The presence of ocular symptoms was self-reported. The difference between rosacea and ocular symptoms was tested. Logistic regression analysis was used to identify associations between rosacea and ocular symptoms. RESULTS: The prevalence of rosacea was 15.1% (n = 292); in the subjects with rosacea, erythematoteleangiectatic rosacea was found in 83.2% (n = 242), papulopustular in 15.4% (n = 45), ocular in 0.03% (n = 1), and phymatic in 0.1% (n = 3). Ocular symptoms in rosacea subjects were common, with dryness (32.3%), tearing (29.4%), foreign-body sensation (21.8%), and photophobia (20.5%) being the most common ones. Foreign-body sensation was reported significantly more often in those with rosacea compared to those without (p < 0.04). In logistic regression analyses, after adjusting, the subjects with rosacea had a 1.5-fold increased risk for decreased visual acuity in the dark (OR 1.48, 95% CI 1.01-2.14) compared to those without rosacea. CONCLUSION: Eye symptoms are common in subjects with rosacea. All patients with rosacea should be asked about ocular symptoms and both skin and eyelids should be examined even if the cutaneous findings are mild.

Risk of Non-cutaneous Cancers in Individuals with Basal Cell Carcinoma: A Population-based Cohort Study.

Evidence of the association between a personal history of basal cell carcinoma and the risk of non-cutaneous malignancies is conflicting. The aim of this study was to retrospectively clarify the risk of non-cutaneous cancers in individuals with basal cell carcinoma using nationwide Finnish registry data for 96,304 patients and 394,503 randomly selected population controls. In this study, individuals with basal cell carcinoma have an increased risk of other cancers (odds ratio (OR) 1.38; 95% confidence interval (95% CI) 1.36-1.40). The risk was most prominent for lip cancer (OR 5.29; 95% CI 4.50-6.21), mycosis fungoides (OR 3.13; 95% CI 2.31-4.23) and soft tissue cancers (OR 2.77; 95% CI 2.43-3.16). In age-adjusted model, men had higher risk of cancers overall compared with women (p < 0.05). In conclusion, the study found increased overall cancer risk among patients with basal cell carcinoma compared with randomly selected population controls.

Hyperhidrosis Comorbidities and Treatments: A Register-based Study among 511 Subjects.

Hyperhidrosis is a dermatological condition that causes psychosocial impairment and has a negative impact on patients' quality of life. The epidemiology of hyperhidrosis is currently poorly understood. The aim of this study was to analyse comorbidities and treatments in 511 subjects with hyperhidrosis selected from the patient records of Oulu University Hospital. The mean age of patients with local hyperhidrosis was 27.9 years and the majority were female (62.7%). The most common anatomical site of symptoms in the youngest age group was the palms, whereas the axillae were a more common site in advanced age. Depression was a common comorbidity in both local (11.6%) and generalized hyperhidrosis (28.6%). Anxiety affected 12.7% of patients with generalized hyperhidrosis. In 36.8% of the patients with local hyperhidrosis there was a delay in diagnosis of more than 10 years. The most commonly used treatments included topical antiperspirants, iontophoresis and botulin toxin injections.

Guselkumab Treatment Outcomes and Persistence in a Nationwide Real-world Cohort of Patients with Plaque Psoriasis.

Guselkumab treatment outcomes and persistence were assessed in a real-world cohort of Finnish patients with difficult-to-treat plaque psoriasis over a median follow-up of 1 year. Data on 181 patients who initiated guselkumab at the 15 study centres were collected retrospectively from the patient charts. Prior exposure to biologic therapies was common, with 56% and 35% having used at least 1 and 2 biologics, respectively. Median guselkumab treatment duration was 11 months with 21 patients (12%) discontinuing treatment during follow-up. Of 85 patients with a follow-up duration of at least 1 year, 73 (86%) were still on guselkumab at 1 year. Significant improvements during follow-up were seen in the absolute Psoriasis Area and Severity Index (PASI) scores with 32 patients (80%) having absolute PASI ≤ 2 after a 9-14-month treatment. Guselkumab treatment was effective and treatment persistence was high in the nationwide Finnish real-life setting.

BP180/Collagen XVII: A Molecular View.

BP180 is a type II collagenous transmembrane protein and is best known as the major autoantigen in the blistering skin disease bullous pemphigoid (BP). The BP180 trimer is a central component in type I hemidesmosomes (HD), which cause the adhesion between epidermal keratinocytes and the basal lamina, but BP180 is also expressed in several non-HD locations, where its functions are poorly characterized. The immunological roles of intact and proteolytically processed BP180, relevant in BP, have been subject to intensive research, but novel functions in cell proliferation, differentiation, and aging have also recently been described. To better understand the multiple physiological functions of BP180, the focus should return to the protein itself. Here, we comprehensively review the properties of the BP180 molecule, present new data on the biochemical features of its intracellular domain, and discuss their significance with regard to BP180 folding and protein-protein interactions.

The intracellular domain of BP180/collagen XVII is intrinsically disordered and partially folds in an anionic membrane lipid-mimicking environment.

The trimeric transmembrane collagen BP180, also known as collagen XVII, is an essential component of hemidesmosomes at the dermal-epidermal junction and connects the cytoplasmic keratin network to the extracellular basement membrane. Dysfunction of BP180 caused by mutations in patients with junctional epidermolysis bullosa or autoantibodies in those with bullous pemphigoid leads to severe skin blistering. The extracellular collagenous domain of BP180 participates in the protein's triple-helical folding, but the structure and functional importance of the intracellular domain (ICD) of BP180 are largely unknown. In the present study, we purified and characterized human BP180 ICD. When expressed in Escherichia coli as glutathione-S-transferase or 6 × histidine tagged fusion protein, the BP180 ICD was found to exist as a monomer. Analysis of the secondary structure content by circular dichroism spectroscopy revealed that the domain is intrinsically disordered. This finding aligned with that of a bioinformatic analysis, which predicted a disordered structure. Interestingly, both anionic detergent micelles and lipid vesicles induced partial folding of the BP180 ICD, suggesting that in its natural environment, the domain's folding and unfolding may be regulated by interaction with the cell membrane or accompanying proteins. We hypothesize that the intrinsically disordered structure of the ICD of BP180 contributes to the mechanism that allows the remodeling of hemidesmosome assembly.

Monoallelic Mutations in the Translation Initiation Codon of KLHL24 Cause Skin Fragility.

The genetic basis of epidermolysis bullosa, a group of genetic disorders characterized by the mechanically induced formation of skin blisters, is largely known, but a number of cases still remain genetically unsolved. Here, we used whole-exome and targeted sequencing to identify monoallelic mutations, c.1A>G and c.2T>C, in the translation initiation codon of the gene encoding kelch-like protein 24 (KLHL24) in 14 individuals with a distinct skin-fragility phenotype and skin cleavage within basal keratinocytes. Remarkably, mutation c.1A>G occurred de novo and was recurrent in families originating from different countries. The striking similarities of the clinical features of the affected individuals point to a unique and very specific pathomechanism. We showed that mutations in the translation initiation codon of KLHL24 lead to the usage of a downstream translation initiation site with the same reading frame and formation of a truncated polypeptide. The pathobiology was examined in keratinocytes and fibroblasts of the affected individuals and via expression of mutant KLHL24, and we found mutant KLHL24 to be associated with abnormalities of intermediate filaments in keratinocytes and fibroblasts. In particular, KLHL24 mutations were associated with irregular and fragmented keratin 14. Recombinant overexpression of normal KLHL24 promoted keratin 14 degradation, whereas mutant KLHL24 showed less activity than the normal molecule. These findings identify KLHL24 mutations as a cause of skin fragility and identify a role for KLHL24 in maintaining the balance between intermediate filament stability and degradation required for skin integrity.

Biallelic Mutations in PDE10A Lead to Loss of Striatal PDE10A and a Hyperkinetic Movement Disorder with Onset in Infancy.

Deficits in the basal ganglia pathways modulating cortical motor activity underlie both Parkinson disease (PD) and Huntington disease (HD). Phosphodiesterase 10A (PDE10A) is enriched in the striatum, and animal data suggest that it is a key regulator of this circuitry. Here, we report on germline PDE10A mutations in eight individuals from two families affected by a hyperkinetic movement disorder due to homozygous mutations c.320A>G (p.Tyr107Cys) and c.346G>C (p.Ala116Pro). Both mutations lead to a reduction in PDE10A levels in recombinant cellular systems, and critically, positron-emission-tomography (PET) studies with a specific PDE10A ligand confirmed that the p.Tyr107Cys variant also reduced striatal PDE10A levels in one of the affected individuals. A knock-in mouse model carrying the homologous p.Tyr97Cys variant had decreased striatal PDE10A and also displayed motor abnormalities. Striatal preparations from this animal had an impaired capacity to degrade cyclic adenosine monophosphate (cAMP) and a blunted pharmacological response to PDE10A inhibitors. These observations highlight the critical role of PDE10A in motor control across species.

Adult Patients with Atopic Eczema have a High Burden of Psychiatric Disease: A Finnish Nationwide Registry Study.

Atopic dermatitis is associated with several comorbidities. Epidemiological studies on psychiatric comorbidities in adult atopic dermatitis patients are sparse. We analyzed psychiatric comorbidities in a Finnish nationwide adult atopic dermatitis cohort. The study included 57,690 adult patients with atopic dermatitis as cases and 40,363 individuals diagnosed with melanocytic naevi as controls. Data was obtained from the statutory Finnish Care Register for Health Care. The prevalence of preselected comorbidities between the atopic dermatitis and control groups was compared. Every psychiatric disorder studied was more common in patients with atopic dermatitis than in controls. At least one psychiatric diagnosis was found in 17.2% of the atopic dermatitis patients and 13.1% of controls. Psychiatric morbidity is significant in patients with atopic dermatitis and therefore assessing patients' mental health status should be considered as part of standard care.

Pemphigus Foliaceus and Pemphigus Erythematosus are the Most Common Subtypes of Pemphigus in Northern Finland.

Pemphigus is an autoimmune skin disease characterized by blistering and erosions of the skin and mucous membranes. Pemphigus is rare in Northern and Western Europe but its incidence is higher around the Mediterranean Sea. The most common type worldwide is pemphigus vulgaris. The aim of this study was to investigate the incidence of pemphigus subtypes in Northern Finland between 1985 and 2017. A total of 46 patients diagnosed with pemphigus at the Department of Dermatology of Oulu University Hospital were found the female/male ratio was 1.7. In contrast to many other countries it was found that in Northern Finland the superficial pemphigus subtypes were the most common: erythematosus or foliaceus (65%) followed by pemphigus vulgaris (26%). Over the past 4 decades the annual incidence of pemphigus in Finland has increased from 0.76 to 2.8 cases per million persons.

Gliptin-associated Bullous Pemphigoid and the Expression of Dipeptidyl Peptidase-4/CD26 in Bullous Pemphigoid.

Dipeptidyl peptidase-4 inhibitors (DPP-4i or gliptins) increase the risk of developing bullous pemphigoid (BP). To clarify, whether gliptin-associated BP has special features, we analyzed the clinical, histopathological and immunological features of 27 BP patients, 10 of which previously used gliptin medication. Compared to those who had not previously received gliptins, subjects who had, showed higher BP180-NC16A ELISA (enzyme-linked immunosorbent assay) values, fewer neurological co-morbidities and shorter time to remission, but differences were not statistically significant. The HLA-DQB1*03:01 allele was more commonly present among the BP patients than the control population, but was not more common in those with gliptin history. To determine the effect of gliptins on the expression of the DPP-4/CD-26 protein we performed immunohistochemistry, which showed that the skin expression of DPP-4/CD-26 was increased in BP patients, but not affected by prior gliptin treatment. We conclude that DPP-4i medication is common among BP patients and prior gliptin treatment may be associated with some specific features.