GENETIC STUDY OF PSORIASIS HIGHLIGHTS ITS CLOSE LINK WITH SOCIO-ECONOMIC STATUS AND AFFECTIVE SYMPTOMS.

Psoriasis is an inflammatory skin disease with an estimated heritability of around 70 %. Previous genome-wide association studies (GWASs) have detected several risk loci for psoriasis. To further improve the understanding of the genetic risk factors impacting the disease, we conducted a discovery GWAS in FinnGen and a subsequent replication and meta-analysis with data from the Estonian Biobank and the UK biobank; the study sample included 925 649 individuals (22 659 cases and 902 990 controls), the largest sample for psoriasis yet. In addition, we conducted downstream analyses to find out more about psoriasis' cross-trait genetic correlations and causal relationships. We report 6 risk loci to our knowledge previously unreported, most of which harbor genes related to nuclear factor kappa-light-chain-enhancer of activated B-cells-signaling pathway and overall immunity. Genetic correlations highlight the relationship between psoriasis and smoking, higher body weight, and lower education level. Additionally, we report causal relationships between psoriasis and mood symptoms, as well as two-directioned causal relationship between psoriasis and lower education level. Our results provide further knowledge on psoriasis risk factors, which may be useful in the development of future treatment strategies.

Identifying atopic dermatitis risk loci in 1,094,060 individuals with sub analysis of disease severity and onset.

Atopic dermatitis (AD) is a common inflammatory skin disease highly attributable to genetic factors. Here, we report results from a genome-wide meta-analysis of AD in 37,541 cases and 1,056,519 controls with data from the FinnGen project, the Estonian Biobank, the UK Biobank, the EAGLE Consortium, and the BioBank Japan. We detected 77 independent AD-associated loci of which 10 were to our knowledge previously unreported. The associated loci showed enrichment in various immune regulatory processes. We further performed subgroup analyses of mild and severe AD, and of early and late-onset AD, with data from the FinnGen project. 55 of the 79 tested variants in the associated loci showed larger effect estimates for severe than mild AD as determined through administered treatment. The age of onset, as determined by the first hospital visit with AD diagnosis, was lower in patients with particular AD-risk alleles. Our findings add to the knowledge of the genetic background of AD and may underlay the development of new therapeutic strategies.

Proteomic changes related to actin cytoskeleton function in the skin of vildagliptin-treated mice.

BACKGROUND: Vildagliptin, a dipeptidyl peptidase-4 inhibitor (DPP-4i) is a widely used type 2 diabetes medication that is associated with an up-to 10-fold increased risk for the development of bullous pemphigoid (BP), an autoimmune skin disease. The mechanism by which vildagliptin promotes the development of BP remains unknown. OBJECTIVE: To elucidate effects of vildagliptin treatment on the mouse cutaneous proteome. METHODS: We analyzed the cutaneous proteome of nondiabetic mice treated for 12 weeks with vildagliptin using label-free shotgun mass spectrometry (MS), two-dimensional difference gel electrophoresis (2D-DIGE), immunohistochemistry, immunoblotting, and quantitative real-time polymerase chain reaction. RESULTS: Although vildagliptin treatment did not cause any clinical signs or histological changes in the skin, separate MS and 2D-DIGE analyses revealed altered cutaneous expression of several proteins, many of which were related to actin cytoskeleton remodeling. Altogether 18 proteins were increased and 40 were decreased in the vildagliptin-treated mouse skin. Both methods revealed increased levels of beta-actin and C->U-editing enzyme APOBEC2 in vildagliptin-treated mice. However, elevated levels of a specific moesin variant in vildagliptin-treated animals were only detected with 2D-DIGE. Immunohistochemical staining showed altered cutaneous expression of DPP-4, moesin, and galectin-1. The changed proteins detected by MS and 2D-DIGE were linked to actin cytoskeleton remodeling, transport, cell movement and organelle assembly. CONCLUSION: Vildagliptin treatment alters the cutaneous proteome of nondiabetic mice even without clinical signs in the skin. Cytoskeletal changes in the presence of other triggering factors may provoke a break of immune tolerance and further promote the development of BP.

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.

Accurate diagnosis of bullous pemphigoid requires multiple health care visits.

Introduction: Accurate use of diagnostic codes is crucial for epidemiological and genetic research based on electronic health record (EHR) data. Methods: This retrospective study validated the International Classification of Diseases (ICD)-10 diagnostic code L12.0 for bullous pemphigoid (BP) using EHR data from two Finnish university hospitals. We found 1225 subjects with at least one EHR entry of L12.0 between 2009 and 2019. BP diagnosis was based on clinical findings characteristic of BP and positive findings on direct immunofluorescence (DIF), BP180-NC16A enzyme-linked immunosorbent assay (ELISA) or indirect immunofluorescence (IIF) assay. Results: True BP was found in 901 patients; the positive predictive value (PPV) for L12.0 was 73.6% (95% CI 71.0-76.0). L12.0 was more accurately registered in dermatology units than any specialized health care units (p<0.001). Including patients with multiple L12.0 registrations (≥3), increased the accuracy of the L12.0 code in both dermatology units and other settings. Discussion: One diagnostic code of L12.0 is not enough to recognize BP in a large epidemiological data set; including only L12.0 registered in dermatology units and excluding cases with <3 L12.0 record entries markedly increases the PPV of BP diagnosis.

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.

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.

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.

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.

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.

Dipeptidyl Peptidase 4 Inhibitor‒Associated Bullous Pemphigoid Is Characterized by an Altered Expression of Cytokines in the Skin.

Dipeptidyl peptidase 4 inhibitors (DPP4is), commonly used drugs for treatment of type 2 diabetes, increase the risk for bullous pemphigoid (BP). Currently, the mechanism leading to the loss of immunological tolerance of the cutaneous adhesion molecule BP180 as well as similarities and differences in disease progression between DPP4i-associated BP (DPP4i-BP) and DPP4i-independent regular BP are largely unknown. We analyzed the expression of 32 cytokines and two proteases by Luminex and ELISA assays in samples taken from lesional and nonlesional skin of patients with regular BP or DPP4i-BP and healthy controls. Cytokines mediating B-cell survival and targeting such as BAFF, CCL4, CXCL12, and IL-6 were expressed at a higher level in the lesional regular BP skin than the levels in the lesional DPP4i-BP skin. The DPP4i-BP samples had increased levels of eosinophilic cytokines CCL1, CCL17, CCL26, and IL-5, which correlated with the serum level of anti-BP180 NC16A IgG autoantibodies. The mRNA expression of BAFF, IL6, CCL1, CCL17, CCL26, and IL5 measured by qPCR correlated with the protein levels. Taken together, the cutaneous cytokine profiles were found to provide distinctive molecular fingerprints between regular BP and DPP4i-BP.

Absence of NC14A Domain of COLXVII/BP180 in Mice Results in IL-17‒Associated Skin Inflammation.

The deletion of exon 18 from Col17a1 in transgenic ΔNC14A mice results in the absence of the NC14A domain. NC14A corresponds to the human NC16A domain, the immunodominant epitope in bullous pemphigoid. Before the age of 1 year, 84% of ΔNC14A mice have developed severe itch and skin erosion. Further characterization of mice with mutated CoLXVII (Bp180) revealed acanthosis; subepidermal blistering; and inflammatory cell infiltrates, especially neutrophils, eosinophils, and mast cells in the lesional skin. Direct immunofluorescence analysis detected linear complement C3, IgG, and/or IgA deposition in the dermo‒epidermal junction of symptomatic ΔNC14A mice. Elevated gene expression of IL-17‒associated cytokines was detected in the lesional skin. An increased proportion of dendritic cells, myeloid-derived suppressor cells, and NK cells and a decrease of T cells were found in both the spleen and lymph nodes of symptomatic ΔNC14A mice. The proportions of B cells and regulatory T cells were increased in lymph nodes. An 8-week treatment with an anti‒IL-17A decreased the expression of Il6, Il23a, and Cxcl1 in the nonlesional skin. Our results suggest that the absence of the NC14A domain of CoLXVII in mice causes an autoimmune response against the cutaneous basement membrane and manifests as an IL-17‒associated inflammation in the skin.

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.

Use of gliptins reduces levels of SDF-1/CXCL12 in bullous pemphigoid and type 2 diabetes, but does not increase autoantibodies against BP180 in diabetic patients.

The use of dipeptidyl peptidase 4 (DPP4) inhibitors, (also known as gliptins), is associated with an increased risk of bullous pemphigoid (BP), an autoimmune blistering skin disease. To explore the mechanism behind gliptin-associated BP we investigated circulating autoantibodies against the major BP autoantigen BP180 in serum samples from patients with type 2 diabetes (T2D) with preceding gliptin medication (n = 136) or without (n = 136). Sitagliptin was the most frequently prescribed gliptin (125/136 patients). Using an ELISA assay, we showed that IgG autoantibodies against the immunodominant NC16A domain of BP180 were found in 5.9% of gliptin treated and in 6.6% of non-gliptin treated T2D patients. We found that 28% of gliptin treated patients had IgG autoantibodies recognizing the native full-length BP180 in ELISA, but among non-gliptin treated the seropositivity was even higher, at 32%. Further ELISA analysis of additional serum samples (n = 57) found no major changes in the seropositivity against BP180 during a follow-up period of about nine years. In immunoblotting, full-length BP180 was recognized by 71% of gliptin treated and 89% of non-gliptin treated T2D patients, but only by 46% of the age-and sex-matched controls. The chemokine stromal derived factor-1(SDF-1/CXCL12) is one of the major substrates of DPP4. Immunostainings showed that the expression of SDF-1 was markedly increased in the skin of BP patients, but not affected by prior gliptin treatment. We found that the use of gliptins decreased the serum level of SDF-1α in both BP and T2D patients. Our results indicate that the autoantibodies against the linear full-length BP180 are common in patients with T2D, but seropositivity is unaffected by the use of sitagliptin.