ABSTRACT
Objectives: Psoriasis is a chronic skin disease requiring a multidimensional approach, given its varying appearance, presence of comorbidities and complex treatment regimens. Psoriasis care is however often performed fragmented and, in case of flares, reactive with little integrated information on and for the patient. Literature suggests a multileveled approach of psoriasis, but the effects of its implementation have not yet been validated. The aim of this study is to analyze the impact of a multileveled psoriasis consultation format, named PsoPlus, which has been implemented since 2012 in the Department of Dermatology at Ghent University Hospital in Belgium.Methods: The patient population was divided into two groups: one following the regular consultation and one following the PsoPlus format. Demographic data, clinical outcome and treatment approach of psoriasis patients were compared.Results: Patients who opted for the specialized PsoPlus consultation were younger and had longer disease duration. Decision parameters such as disease severity and quality of life were reported more often in the PsoPlus group. In the latter, a higher rate of patients were started on systemic therapy compared to the regular consultation group, and reporting on adverse events was done more frequently.Conclusion: The implementation of a specialized consultation with comprehensive guidance facilitates documentation on disease-relevant parameters such as disease severity and quality of life. This format can be seen as a guidance for capturing data in a structured manner, with evidence showing that it significantly impacts treatment decision, treating not only psoriasis but the patient as a whole.
Subject(s)
Psoriasis , Quality of Life , Chronic Disease , Humans , Psoriasis/therapy , Referral and Consultation , Severity of Illness IndexABSTRACT
Background: Inherited CARD9 deficiency constitutes a primary immunodeficiency predisposing uniquely to chronic and invasive fungal infections. Certain mutations are shown to negatively impact CARD9 protein expression and/or NF-κB activation, but the underlying biochemical mechanism remains to be fully understood. Objectives: To investigate a possible founder origin of a known CARD9 R70W mutation in five families of Turkish origin. To explore the biochemical mechanism of immunodeficiency by R70W CARD9. Methods: We performed haplotype analysis using microsatellite markers and SNPs. We designed a model system exploiting a gain-of-function (GOF) CARD9 L213LI mutant that triggers constitutive NF-κB activation, analogous to an oncogenic CARD11 mutant, to study NF-κB signaling and signalosome formation. We performed reporter assays, immunoprecipitation and confocal imaging on HEK cells overexpressing different CARD9 variants. Results: We identified a common haplotype, thus providing evidence for a common Turkish founder. CARD9 R70W failed to activate NF-κB and abrogated NF-κB activation by WT CARD9 and by GOF CARD9. Notably, R70W CARD9 also exerted negative effects on NF-κB activation by CARD10, CARD11, and CARD14. Consistent with the NF-κB results, the R70W mutation prevented GOF CARD9 to pull down the signalosome partner proteins BCL10 and MALT1. This reflected into drastic reduction of BCL10 filamentous assemblies in a cellular context. Indeed, structural analysis revealed that position R70 in CARD9 maps at the putative interface between successive CARD domains in CARD9 filaments. Conclusions: The R70W mutation in CARD9 prevents NF-κB activation by inhibiting productive interactions with downstream BCL10 and MALT1, necessary for assembly of the filamentous CARD9-BCL10-MALT1 signalosome.
Subject(s)
B-Cell CLL-Lymphoma 10 Protein/metabolism , CARD Signaling Adaptor Proteins/genetics , Founder Effect , Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein/metabolism , Mutation , NF-kappa B/metabolism , Signal Transduction , CARD Signaling Adaptor Proteins/chemistry , Cell Line , Disease Susceptibility , Female , Gain of Function Mutation , Humans , Male , Models, Molecular , Pedigree , Protein Binding , Protein Conformation , Structure-Activity Relationship , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolismABSTRACT
The recent interest and elucidation of the JAK/STAT signaling pathway created new targets for the treatment of inflammatory skin diseases (ISDs). JAK inhibitors in oral and topical formulations have shown beneficial results in psoriasis and alopecia areata. Patients suffering from other ISDs might also benefit from JAK inhibition. Given the development of specific JAK inhibitors, the expression patterns of JAKs in different ISDs needs to be clarified. We aimed to analyze the expression of JAK/STAT family members in a set of prevalent ISDs: psoriasis, lichen planus (LP), cutaneous lupus erythematosus (CLE), atopic dermatitis (AD), pyoderma gangrenosum (PG) and alopecia areata (AA) versus healthy controls for (p)JAK1, (p)JAK2, (p)JAK3, (p)TYK2, pSTAT1, pSTAT2 and pSTAT3. The epidermis carried in all ISDs, except for CLE, a strong JAK3 signature. The dermal infiltrate showed a more diverse expression pattern. JAK1, JAK2 and JAK3 were significantly overexpressed in PG and AD suggesting the need for pan-JAK inhibitors. In contrast, psoriasis and LP showed only JAK1 and JAK3 upregulation, while AA and CLE were characterized by a single dermal JAK signal (pJAK3 and pJAK1, respectively). This indicates that the latter diseases may benefit from more targeted JAK inhibitors. Our in vitro keratinocyte psoriasis model displayed reversal of the psoriatic JAK profile following tofacitinib treatment. This direct interaction with keratinocytes may decrease the need for deep skin penetration of topical JAK inhibitors in order to exert its effects on dermal immune cells. In conclusion, these results point to the important contribution of the JAK/STAT pathway in several ISDs. Considering the epidermal JAK3 expression levels, great interest should go to the investigation of topical JAK3 inhibitors as therapeutic option of ISDs.
Subject(s)
Janus Kinase 3/metabolism , Molecular Targeted Therapy , Skin Diseases/drug therapy , Administration, Topical , Adolescent , Adult , Aged , Aged, 80 and over , Child , Child, Preschool , Female , Gene Expression Regulation, Enzymologic/drug effects , Humans , Infant , Inflammation/complications , Janus Kinase 3/antagonists & inhibitors , Janus Kinase 3/genetics , Male , Middle Aged , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , STAT Transcription Factors/genetics , STAT Transcription Factors/metabolism , Skin/drug effects , Skin/metabolism , Skin/pathology , Skin Diseases/complications , Skin Diseases/enzymology , Young AdultSubject(s)
MicroRNAs/blood , MicroRNAs/genetics , Psoriasis/blood , Area Under Curve , Biomarkers/blood , Case-Control Studies , Feasibility Studies , Female , Humans , Male , Middle Aged , Psoriasis/genetics , ROC Curve , Severity of Illness Index , TranscriptomeABSTRACT
Chronic mucocutaneous or invasive fungal infections are generally the result of primary or secondary immune dysfunction. Patients with autosomal recessive CARD9 mutations are also predisposed to recurrent mucocutaneous and invasive fungal infections with Candida spp., dermatophytes (e.g., Trichophyton spp.) and phaeohyphomycetes (Exophiala spp., Phialophora verrucosa). We study a consanguineous family of Turkish origin in which three members present with distinct clinical phenotypes of chronic mucocutaneous and invasive fungal infections, ranging from chronic mucocutaneous candidiasis (CMC) in one patient, treatment-resistant cutaneous dermatophytosis and deep dermatophytosis in a second patient, to CMC with Candida encephalitis and endocrinopathy in a third patient. Two patients consented to genetic testing and were found to have a previously reported homozygous R70W CARD9 mutation. Circulating IL-17 and IL-22 producing T cells were decreased as was IL-6 and granulocyte/macrophage colony-stimulating factor (GM-CSF) secretion upon stimulation with Candida albicans. Patients with recurrent fungal infections in the absence of known immunodeficiencies should be analyzed for CARD9 gene mutations as the cause of fungal infection predisposition.
Subject(s)
CARD Signaling Adaptor Proteins/genetics , Candidiasis, Chronic Mucocutaneous/genetics , Immunologic Deficiency Syndromes/genetics , Invasive Fungal Infections/genetics , Tinea/genetics , CARD Signaling Adaptor Proteins/deficiency , CARD Signaling Adaptor Proteins/immunology , Candida/growth & development , Candida/pathogenicity , Candidiasis, Chronic Mucocutaneous/immunology , Candidiasis, Chronic Mucocutaneous/pathology , Child , Consanguinity , Female , Gene Expression , Genes, Recessive , Genetic Predisposition to Disease , Granulocyte-Macrophage Colony-Stimulating Factor/genetics , Granulocyte-Macrophage Colony-Stimulating Factor/immunology , Homozygote , Humans , Immunologic Deficiency Syndromes/immunology , Immunologic Deficiency Syndromes/pathology , Interleukin-17/genetics , Interleukin-17/immunology , Interleukin-6/genetics , Interleukin-6/immunology , Interleukins/genetics , Interleukins/immunology , Invasive Fungal Infections/immunology , Invasive Fungal Infections/pathology , Male , Middle Aged , Mutation , Pedigree , T-Lymphocytes , Tinea/immunology , Tinea/pathology , Trichophyton/growth & development , Trichophyton/pathogenicity , Turkey , Interleukin-22ABSTRACT
BACKGROUND: Psoriasis is a complex and heterogeneous disease resulting from interactions between genetic, immunological, and environmental factors. To make the most optimal treatment decision, the dermatologist must therefore have a detailed overview of the patient's history and lifestyle. OBJECTIVES: We sought to offer an overview of the various relevant aspects in clinical dermatological assessment of psoriasis patients, emphasizing the importance of a multidisciplinary and integrated clinical approach. METHODS: We gathered information on psoriasis management and developed a tailored checklist covering all health-related aspects associated with psoriasis. RESULTS: Demographics, personal and family history were elaborately described as well as drug history to discuss how they affect psoriasis management. Relevant patient information such as the vaccination status or cardiovascular profile were included in the checklist as well and treatment recommendations were adapted and updated in accordance with evidence-based literature. This checklist also emphasizes the importance of drug surveillance, proper follow-up and specialist referral, and why the dermatologist needs to address these health-related aspects when assessing psoriasis patients, going beyond optimal skin care. CONCLUSIONS: Our comprehensive overview can be used as a consultation checklist for good clinical practice in psoriasis patient management and aid in treatment decision.
