Cutaneous Autoimmune Diseases Research Articles

Dermatologic Conditions in Down Syndrome: A Multi-Site Retrospective Review of International Classification of Diseases Codes.

As the population and life expectancy of people with Down syndrome increases, identifying common skin conditions throughout the lifespan will help inform clinical care and research. We sought to evaluate dermatologic conditions diagnosed in pediatric and adult patients with Down syndrome. This multicenter retrospective study analyzed demographic and outpatient visit International Classification of Diseases codes of patients with Down syndrome evaluated at outpatient dermatology clinics in the United States or Canada between 2011 and 2021. A total of 1529 patients with Down syndrome were identified from eight academic medical centers: 50.8% were children (0-12 years), 25.2% were adolescents (13-17 years), and 24% were adults (18 years and older). Eczematous dermatitis was the most common diagnosis overall (26%), followed by folliculitis (19.3%) and seborrheic dermatitis (15.6%). Other notable diagnoses included dermatophyte infections (13%), alopecia areata (11.6%), and psoriasis (6.7%). About 4.3% of visits included a code for high-risk medication use. Eczematous dermatitis, alopecia areata, and folliculitis were the most common diagnoses observed in children; folliculitis, hidradenitis suppurativa, and eczematous dermatitis in adolescents; and seborrheic dermatitis, eczematous dermatitis, and folliculitis in adults. Dermatologic conditions in patients with Down syndrome vary by age, but are most often eczematous, adnexal, and cutaneous autoimmune disorders. This multicenter retrospective review identifies skin diseases that should be prioritized for clinical care guideline development and research in the Down syndrome community.

Direct Immunofluorescence in Cutaneous Vesiculobullous Lesions: A Cross-sectional Study in a Tertiary Care Center

Introduction: Cutaneous noninfectious autoimmune vesiculobullous diseases are a wide variety of lesion. They can show clinical and histopathological overlap, posing diagnostic challenges. Clinically, vesiculobullous lesions might not present with typical morphology and distribution in all cases. The specific histomorphological changes are observed only in an early and intact bulla. Immunofluorescence (IF) is a histochemical staining technique which detects antibodies in the tissue and body fluids. IF an adjuvant to histopathology is considered as gold standard in the diagnosis of vesiculobullous diseases. Methodology: A two-year retrospective cross-sectional descriptive study was conducted in the department of pathology, in a tertiary care center from January 2018 to December 2019. Paraffin embedded hematoxylin and eosin slides were retrieved from the archives and analyzed. Biopsies received in Michel’s medium were utilized for immunofluorescence study. Results: A total of 67 cases with Vesiculobullous lesions were analysed. The most common lesion diagnosed was Bullous Pemphigoid (BP) (29 cases -46.7%), followed by Pemphigus Vulgaris (PV) (19 cases- 30.6%). The highest number of cases were noted in the 7th decade, with a slight female preponderance. Sixteen out of 19 cases of pemphigus vulgaris and 28 out of 29 cases of bullous pemphigoid showed positive histomorphological correlation with IF. The PPV for pemphigus vulgaris was 100% and sensitivity was 84.2%, and in bullous pemphigoid, both the PPV and sensitivity was 96.5%. Higher concordance was noted between Histopathology and IF diagnosis in cases of BP in comparison to PV. Conclusion: Vesiculobullous lesions are heterogeneous in nature and can have clinical and histopathological overlap, posing diagnostic challenges. IF is considered gold standard and is necessary for the diagnosis in every case. A combined clinical, histopathological and IF examination is the best approach to accurate diagnosis. Keywords Bullous, Pemphigus, Vesiculobullous, Direct Immunofluorescence

Reversal and prevention of deregulated autophagy in cutaneous autoimmune disorders—a pilot study on vitiligo with nutrigenomics based approach of “Maximum Nutrition and Minimum Medication”

Abstract Nutritional status of patients, specially prolonged starvations is an important sub-component of the environmental factors, speculated to have indirect impact on the initiation, propagation, resolution, and exacerbation stages of autoimmunity. The study was based on the hypothesis of conscious, selective, and self-destruction, that is, deregulated autophagy of skin and hair in low dietary protein scenario triggered with prolonged starvations. It was aimed to reverse the self-destruction/deregulated autophagy by providing early morning, low carb-high protein nutrition, and correcting underlying micronutrient deficiency and studying its effect on reducing auto-immunity and eventually reducing disease burden and recurrence. Methods: In this retrospective study, patients were divided into two categories based on disease activity and nutrition. Group A: “novice group” of vitiligo patients who presented at an early stage of their disease were managed with basic standard of therapeutics. Group B: “stabilized group” of vitiligo who were given surgical treatment and followed up for 3 years for any recurrences. Personalized diet plan aimed at reversing high carb-low protein diet and avoiding prolonged overnight starvation adhering to early morning breakfast respecting the circadian rhythm and balanced with additional plant based protein was advised. All detectable underlying micronutrient deficiencies were corrected. Results: Thirty patients were enrolled in the study, 20 in group A and 10 in group B. We observed visible signs of improvement in group A, with early vitiligo (90%) with topical therapy and nutritional intervention as early as 3 weeks. Following surgical procedure in group B, 50% patients had near complete pigmentation at the end of 3 months and 30% within next 3 months. At the end of 6 months, all patients had significant improvement in VASI and VIDA score, however two patients in each group had recurrence at end of 1 year who deviated from nutritional protocol and were found to be deficient in protein intake and micronutrients deficiency was detected on blood investigation. The improvement in VASI scores with conventional treatment and nutritional intervention was found to be statistically significant at 6 months and 1-year interval in group A with paired t test (P = 0.013). Similarly, improvement in VASI was statistically very significant at 6 months and 1-year duration in surgically treated vitiligo group B (P = 0.001). These patients were put on immunosuppressive therapies in first group after correction of deficiencies and managed with supportive and conventional therapy in second group in subsequent 3 years follow up. Conclusion: Nutritious diet aimed at correction of underlying protein and micronutrient deficiency with special emphasis on circadian rhythm may arrest the natural progression of disease at an early stages of the disease and prime the body for oral immunosuppressive drugs. This approach may prevent the recurrence in patients already stabilized with standard care of therapeutics and surgery in future.

Cutaneous Disorders Masking Celiac Disease: Case Report and Mini Review with Proposal for a Practical Clinical Approach.

Celiac disease (CD) is an immune-mediated systemic gluten-related disorder characterized by a wide spectrum of intestinal and extra-intestinal manifestations, including damage to cutaneous and connective tissue. We report a rare case of chronic severe dermatitis involving connective tissue and cutaneous vascular vessels as the main clinical presentation of undiagnosed seronegative gluten disorder. A gluten-free diet dramatically improved the intestinal and cutaneous clinical damage in the patient. Pitfalls and the steps of differential diagnosis are described. We also review the literature regarding studies of CD and connective tissue diseases to extend the knowledge of these rare associations. We propose a practical diagnostic approach in suspected CD in autoimmune cutaneous disorders.

107 Tissue-restricted PD-1 agonists as local immune suppressants – a novel approach to treat cutaneous inflammation and autoimmune diseases

107 Tissue-restricted PD-1 agonists as local immune suppressants – a novel approach to treat cutaneous inflammation and autoimmune diseases

Gene signature from cutaneous autoimmune diseases provides potential immunotherapy-relevant biomarkers in melanoma

Immune checkpoint inhibitors (ICIs) are promising agents for treating melanoma. Given that autoimmune skin diseases exhibit hyper immune reaction, investigation of immune cells from autoimmune skin disease is crucial to validate the effectiveness of ICIs in melanoma treatment. We employed multipanel markers to predict the response to immune checkpoint inhibitors by characterizing the gene expression signatures of skin immune cells in systemic lupus erythematosus (SLE), atopic dermatitis (AD), and psoriasis (PS). By analyzing single-cell RNA sequencing data from each dataset, T cell gene signatures from autoimmune skin diseases exhibit a complex immune response in tumors that responded to immunotherapy. Based on that CD86 and CD80 provide essential costimulatory signals for T cell activation, we observed that interaction of CD86 signaling has been enhanced in the T cells of patients with SLE, AD, and PS. Our analysis revealed a common increase in CD86 signals from dendritic cells (DCs) to T cells in patients with SLE, AD, and PS, confirming that dendritic cells produce pro-inflammatory cytokines to activate T cells. Thus, we hypothesize that T cell gene signatures from autoimmune skin diseases exhibit a pro-inflammatory response and have the potential to predict cancer immunotherapy. Our study demonstrated that T cell gene signatures derived from inflammatory skin diseases, particularly SLE and PS, hold promise as potential biomarkers for predicting the response to immune checkpoint blockade therapy in patients with melanoma. Our data provide an understanding of the immune-related characteristics and differential gene expression patterns in autoimmune skin diseases, which may represent promising targets for melanoma immunotherapy.

JAK-STAT inhibitors in Immune mediated diseases: An Overview.

For any biological response, transmission of extracellular signals to the nucleus is required for DNA transcription and gene expression. In that respect, cytokines/chemokines are well-known inflammatory agents which play a critical role in signalling pathways by activating the Janus kinase-signal transducers and activators of transcription (JAK-STAT) signalling proteins (Janus kinase-signal transducers and activators of transcription) which are a group of intracellular kinase molecules. Cytokines are a category of small proteins (∼5-25 kDa) that play a major role in cell signalling and are major drivers of an autoimmune response. Here we will discuss the role of Janus kinase-signal transducers and activators of transcription kinase cascades in the inflammatory-proliferative cascades of autoimmune disease and about the recent progress in the development of oral synthetic Janus kinase inhibitors (JAKi) and their therapeutic efficacies in dermatologic and systemic autoimmune diseases. Therapeutic efficacy of Janus kinase inhibitors is now well established in the treatment of array of autoimmune and inflammatory disease: spondylarthritis with a special focus on psoriatic arthritis (PsA) and its dermatologic manifestations (psoriasis) and ankylosing spondylitis (AS), atopic dermatitis (AD), alopecia areata (AA), rheumatoid arthritis (RA) and inflammatory bowel disease (IBD). In addition to the first-generation Janus kinase inhibitors several new-generation Janus kinase inhibitors are currently being evaluated. It is expected that these Janus kinase inhibitors likely have higher potency and less adverse effects as compared to their predecessors. Here we have discussed: (1) the functional significance of the Janus kinase-signal transducers and activators of transcription kinase cascades in the inflammatory-proliferative processes of autoimmune diseases and its cellular/molecular mechanisms and (2) progress in the development of oral synthetic Janus kinase inhibitors and their therapeutic efficacies in several systemic and cutaneous autoimmune diseases.

JAK inhibitor: Introduction.

The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway is a key regulatory signaling system for cellular proliferation, differentiation, and apoptosis. In addition, JAK signaling pathway plays critical roles in orchestrating immune response through its interactions with the cytokine receptors and the transcriptions factors. Several key cytokines use JAK-STAT signaling proteins to transduce intra-cellular signals which are involved in the pathogenesis of autoimmune and inflammatory diseases such as in psoriatic disease (psoriasis, psoriatic arthritis), atopic dermatitis, alopecia areata, vitiligo, rheumatoid arthritis, ankylosing spondylitis, lupus erythematosus, Sjogren's syndrome, and other autoimmune diseases. In recent years, understandings of the molecular mechanisms of JAK-STAT pathway in the inflammatory proliferative cascades of autoimmune diseases has led to the development of JAK inhibitors and has opened a new dimension for the treatment of systemic and cutaneous inflammatory diseases. In this symposium we have provided a broad perspective on the use of Janus kinase inhibitors in cutaneous autoimmune diseases.

Association of vitiligo with multiple cutaneous and extra-cutaneous autoimmune diseases: a nationwide cross-sectional study.

Previous studies found conflicting results about associations of vitiligo with different autoimmune diseases. To evaluate associations of vitiligo with multiple autoimmune diseases. A cross-sectional study representativeof 612,084,148 US patients from theNationwide Emergency Department Sample(NEDS) 2015-2019was performed. Vitiligo and autoimmune diseases were identified using International Classification of Diseases-10 codes. The most frequent autoimmune disorders in patients with vitiligo were type 1 diabetes, rheumatoid arthritis, systemic lupus erythematosus (SLE), autoimmune thyroiditis, Addison's disease, and systemic sclerosis (SSc). Vitiligo was associated with any autoimmune disorder (adjusted odds ratio [95% confidence interval] 1.45 [1.32-1.58]). Cutaneous disorders with largest effect-sizes were alopecia areata (186.22 [115.31-300.72]) and SSc (32.13 [25.28-40.82]). Non-cutaneous comorbidities with largest effect-sizes were primary sclerosing cholangitis (43.12 [18.98-97.99]), pernicious anemia (41.26 [31.66-53.78]), Addison's disease (33.85 [26.68-42.9]), and autoimmune thyroiditis (31.65 [26.34-38.02]). Vitiligo is associated with multiple cutaneous and non-cutaneous autoimmune diseases, especially in females and older age.

SIRT1 downregulation provokes immune-inflammatory responses in hair follicle outer root sheath cells and may contribute to development of alopecia areata

BackgroundSilent information regulator 1 (SIRT1), a type III histone deacetylase, is involved in various cutaneous and systemic autoimmune diseases including systemic lupus erythematosus, rheumatoid arthritis, and psoriasis. However, little is known about the role of SIRT1 in the development of alopecia areata (AA). ObjectivesThis study investigated whether SIRT1 regulates the hair follicle immune system and is involved in AA pathogenesis. MethodsSIRT1 expression in human scalp tissue was analyzed using immunohistochemical staining, qPCR, and western blotting. The regulatory effect of SIRT1 was evaluated after stimulation with the double-stranded RNA mimic polyinosinic:polycytidylic acid (poly I:C) in hair follicle outer root sheath (ORS) cells and C3H/HeJ mice. ResultsSIRT1 expression was significantly reduced in the AA scalp compared to the normal scalp. SIRT1 inhibition upregulated MHC class I polypeptide-related sequence A and UL16 binding protein 3 in hair follicle ORS cells. SIRT1 inhibition also promoted the production of Th1 cytokines (IFN-γ and TNF-α), IFN-inducible chemokines (CXCL9 and CXCL10), and T cell migration in ORS cells. Conversely, SIRT1 activation suppressed the autoreactive inflammatory responses. The counteractive effect of the immune response by SIRT1 was mediated through the deacetylation of NF-κB and phosphorylation of STAT3. ConclusionSIRT1 downregulation induces immune-inflammatory responses in hair follicle ORS cells and may contribute to AA development.

Interleukin-21 in autoimmune and inflammatory skin diseases.

Studies on the role of interleukins (ILs) in autoimmune and inflammatory diseases allow for the better understanding of pathologic mechanisms of disease and reshaping of treatment modalities. The development of monoclonal antibodies targeting specific ILs or IL signaling pathways (i.e., anti-IL-17/IL-23 in psoriasis or anti-IL-4/IL-13 in atopic dermatitis) is the shining example of therapeutic interventions in research. IL-21, belonging to the group of ɣc-cytokines (IL-2, IL-4, IL-7, IL-9, and IL-15), is gaining attention for its pleiotropic role in several types of immune cells as activator of various inflammatory pathways. In both health and disease, IL-21 sustains T- and B-cell activity. Together with IL-6, IL-21 helps to generate Th17 cells, promotes CXCR5 expression in T cells, and their maturation into follicular T helper cells. In B cells, IL-21 sustains their proliferation and maturation into plasma cells and promotes class switching and antigen-specific antibody production. Due to these characteristics, IL-21 is a main factor in numerous immunologic disorders, such as rheumatoid arthritis and MS. Studies in preclinical skin disease models and on human skin strongly suggest that IL-21 is crucially involved in inflammatory and autoimmune cutaneous disorders. Here, we summarize the current knowledge of IL-21 in well-known skin diseases.

Eosinophilia and elevated IgE serum levels: a red flag: when your diagnosis is not a common atopic eczema or common allergy.

The hallmark of type 2 inflammation is eosinophilia and/or high IgE serum levels, mostly in atopic dermatitis. Nevertheless, many dermatoses may present similar findings. Our aim is to explore the biological and clinical spectrum of cutaneous manifestations involving tissue and/or systemic eosinophilia, and distinct serum levels of IgE, where atopic dermatitis or other primary allergic eczema, not always is the definitive diagnosis. A total of 37 scientific papers were enrolled in this narrative review. A diagnostic approach for patients with elevated serum IgE level and a list of conditions not related to atopic dermatitis that runs through inborn errors of immunity, inflammatory disorders, lung disorders, malignancy, infections/infestations are displayed. Regarding to peripheral eosinophilia, differential diagnosis is also explored and clinical patterns of skin diseases associated with tissue eosinophilia are listed, to facilitate our diagnosis. We should maintain a high level of suspicion about other differential diagnosis involving eosinophilia and IgE dysregulation, especially in patients very young (when innate errors of the immunity may present) and in middle to elderly patients classified as having atopic dermatitis, due to the possibility of cutaneous hematological malignancies, paraneoplasia or autoimmune blistering diseases.

Hitting the Bullseye in Autoimmunity: Targeting Biologics through Tethering: Examining a Therapeutic Potential for Vitiligo and Beyond

Biologic therapies targeting aberrant immune responses in cutaneous and systemic autoimmune diseases have had a significant impact on reducing mortality and morbidity for conditions that could not be treated with conventional drugs. However, their systemic effects increase vulnerability to infections, malignancies, and development of secondary autoimmune complications, underscoring the need for localized, targeted delivery of biologics. The article by Ying-Chao et al. (2022) titled “A keratinocyte-tethered biologic enables location-precise treatment in mouse vitiligo” highlights the potential for using bispecific antibodies (BsAbs) as a novel method of localized drug delivery through tethering, where one of the two antibody specificities is used to target a structural surface protein to anchor the biologic within the tissue.

019 Investigating OX40L and its role in mediating cutaneous and systemic autoimmune disease

Systemic lupus erythematosus (SLE) is a devastating systemic inflammatory disease, with prominent female bias. Recent literature suggests the OX40/OX40L costimulatory pathway may play an important role in development of SLE. GWAS have identified TNFSF4 (OX40L) as an SLE susceptibility locus. OX40L stimulation of T cells through the OX40 receptor has been shown to promote a T follicular helper (Tfh) phenotype, and Ox40l knockout has been demonstrated to ameliorate the SLE phenotype in transgenic and induced lupus mouse models.

214 Pre-existing cutaneous autoimmune disease may improve survival in patients treated with anti-PD-1 or anti-PD-L1 therapy: A population level cohort study

Immune checkpoint inhibitors (ICIs) are associated with immune-related adverse events (irAEs) that resemble autoimmune diseases (ADs). Despite similarities of irAEs and ADs, ICI clinical trials largely exclude patients with history of AD. This study explores the impact of baseline ADs on survival among ICI-treated patients using observational data. Using the TriNetX Diamond Network, 17,497 patients with history of ADs prior to anti-programmed cell death receptor/ligand 1 therapy for malignant neoplasms of digestive organs, bronchus/lung, melanoma, and urinary tract were matched to 17,497 ICI recipients without history of ADs on demographics, cancer type, and ICI target.

Oxeiptosis: a novel pathway of melanocytes death in response to oxidative stress in vitiligo

Vitiligo is a cutaneous depigmenting autoimmune disease caused by the extensive destruction of epidermal melanocytes. Convincing data has defined a critical role for oxidative stress in the pathogenesis of vitiligo. Oxeiptosis is a caspase-independent cell death modality that was reportedly triggered by oxidative stress and operative in pathogen clearance. However, whether oxeiptosis exists in oxidative stress-induced melanocytes demise in vitiligo remains undetermined. In the present study, we initially found that other cell death modalities might exist in addition to the well-recognized apoptosis and necroptosis in H2O2-treated melanocytes. Furthermore, AIFM1 was found to be dephosphorylated at Ser116 in oxidative stress-induced melanocytes death, which was specific to oxeiptosis. Moreover, KEAP1 and PGAM5, upstream of the AIFM1 in oxeiptosis, were found to operate in melanocytic death. Subsequently, the KEAP1-PGAM5-AIFM1 signaling pathway was proved to be involved in oxidative stress-triggered melanocytes demise through the depletion of KEAP1 and PGAM5. Altogether, our study indicated that oxeiptosis might occur in melanocytes death under oxidative stress and contribute to the pathogenesis of vitiligo.

Is Covid vaccine(Covishield) giving rise to de novo cutaneous autoimmune disorders and aggravating the existing ones –a case series of 10 patients with review of literature.

Covid-19 which is an ongoing pandemic, has already caused millions of deaths and disabilities till date. Covid scenario and mass vaccination has completely changed the understanding of dermatological disorders. The clinicians are noticing a sudden increase in new onset autoimmune disorders and aggravation of existing ones. The study is based on 3 hypotheses i.e. antibody dependent enhancement of virus, molecular mimicry and antigen antibody complex formation, explaining the pathogenesis involved in vaccine induced cutaneous autoimmune disorders. METHODS In this prospective observational study, we observed 2 groups of patients following Covishield vaccine-Group 1: appearance of new lesions pertaining to autoimmune disorders Group 2: exacerbation of cutaneous lesions of already existing autoimmune disorder The diagnosis was made based on appearance of clinical signs within 6 weeks of vaccination dose and the clinical diagnosis was established by at least two Dermatologists. RESULTS Ten patients were enrolled in this study over a period of 6 months. Six patients (Group 1) presented with new onset of lesions whereas 4 patients (group 2) presented with exacerbation of existing autoimmune disease. Patients were given medical treatment as per disease severity along with proper nutritional support and antioxidants. CONCLUSION This article highlights the importance of creating awareness and staying vigilant for the appearance of any new autoimmune disease and exacerbation of existing disorder and for future course of action for choice of vaccination and booster doses. A chronological association in last 6 weeks of vaccination dosage must be evaluated in detail and causative association should be considered in autoimmune disorders.

S2k guideline: Diagnosis and management of cutaneous lupus erythematosus - Part1: Classification, diagnosis, prevention, activity scores.

S2k guideline: Diagnosis and management of cutaneous lupus erythematosus - Part1: Classification, diagnosis, prevention, activity scores.

Anti-inflammatory effect of different PRGF formulations on cutaneous surface

Cutaneous autoimmune and inflammatory diseases are a major burden of global disease and many lack effective treatments that can derive in different dermatoses like atopic dermatitis. Despite the increase prevalence and the high health-care costs worldwide, the heterogeniety and multifactoriality of these diseases mean that effective treatment options are scarce. Plasma rich in growth factors (PRGF) technology could be an alternative approach that may help in the management of this cutaneous condition. The aim of this study was to assess the effect of two different PRGF formulations (just activated and autologous topical serum (ATS)) for the management of skin inflammation. Additionally, ATS was assessed over two patients suffering from radiotherapy induced dermatitis. Human organotypic skin explant cultures (hOSECs) were used as human skin models. To induce atopic dermatitis-like conditions, skin explants were treated with both interleukin-4 (IL-4) and interleukin-13 (IL-13). PRGF and ATS were intradermally and topically applied, respectively. Metabolic activity, reactive oxigen species (ROS), necrosis and inflammatory cytokine production were determined. Both PRGF formulations increased tissue viability and significantly reduced the excessive free radical accumulation and the cutaneous cytokine production such as TNF-α and IL-1β. Case reports showed a positive response after ATS treatment in terms of skin quality improvement, local erythema decrease and burning and itching amelioration. The oedema, swelling and desquamation caused by radiation induced dermatitis was also reduced and the patients referred ceased pruritus and pain. This preliminary study suggests that PRGF might aid in the management of inflammatory skin conditions.

Pruritus in autoimmune connective tissue diseases.

Pruritus is one of the most common and bothersome symptoms of skin disorders, and its clinical characteristics and related pathomechanisms have been well described in certain dermatologic conditions, such as atopic dermatitis and urticaria. Although pruritus is believed to be as common in cutaneous autoimmune connective tissue diseases (ACTDs) as in other inflammatory skin disorders, its true characteristics have not been elucidated either qualitatively or quantitatively. Pruritus is present in ACTDs with various prevalence rates, characteristics, and mechanisms depending on the disease types. Pruritus most frequently and severely affects the patients with dermatomyositis, in which itch is strongly correlated with disease activity and severity, thus increased itch could also indicate a disease flare. Patients with other ACTDs, including lupus erythematosus (LE), Sjögren syndrome (SS), morphea, and systemic sclerosis (SSc), also suffer from their fair share of pruritus. Unfortunately, the currently available treatments for ACTDs seem to have only limited and unsatisfactory effects to control pruritus. The extensive impact of pruritus on the patients’ quality of life (QOL) and functioning warrants more targeted and individualized approaches against pruritus in ACTDs. This review will address the prevalence, suggested pathogenesis based on currently available evidences, and potential treatment options of pruritus in various ACTDs of the skin.