Chilblains in immune-mediated inflammatory diseases: a review.

Chilblains were first described over a hundred years ago as cutaneous inflammatory lesions, typically on the digits, occurring on cold exposure. Chilblains can be primary, or secondary to a number of conditions such as infections, including COVID-19, and immune-mediated inflammatory disorders (IMIDs) with SLE being the commonest. Chilblain lupus erythematosus (CHLE) was first described in 1888 as cold-induced erythematous lesions before the terms 'chilblains' or 'perniosis' were coined. Diagnostic criteria exist for both chilblains and CHLE. Histopathologically, CHLE lesions show interface dermatitis with perivascular lymphocytic infiltrate. Immunofluorescence demonstrates linear deposits of immunoglobulins and complement in the dermo-epidermal junction. This narrative review focuses on chilblains secondary to immune-mediated inflammatory disorders, primarily the epidemiology, pathogenesis and treatment of CHLE.

The Overlap between Genetic Susceptibility to COVID-19 and Skin Diseases.

Coronavirus disease 2019 (COVID-19) mainly affects the respiratory system, but the involvement of other organ systems has also been commonly reported. Acute acro-ischemia or chilblain like lesions were among the first recognized dermatological presentations of COVID-19. Though the occurrence of such lesions has been attributed to the similar interferon-1 mediated immune response in both COVID-19 and systemic lupus erythematosus, we propose another possible explanation based on a common genetic background. In a recent genome-wide association study, the 3p21.31 region was found to be associated with COVID-19 severity. This region also contains the TREX1 gene. Missense mutations of the TREX1 gene are responsible for familial chilblain lupus and its genetic polymorphisms have been implicated in the pathogenesis of systemic lupus erythematosus. Based on this observation, herein we have reviewed other COVID-19 risk loci for potential overlap with dermatological conditions.

Perniosis during the COVID-19 pandemic: Negative anti-SARS-CoV-2 immunohistochemistry in six patients and comparison to perniosis before the emergence of SARS-CoV-2.

BACKGROUND: Acral inflammatory lesions that have some resemblance to idiopathic or autoimmune-associated perniosis (chilblains) have been described in multiple countries during the COVID-19 pandemic. METHODS: We examined histopathologic findings in six consecutive such cases from five patients received in mid-May to mid-June of 2020, evaluating immunohistochemical staining for the SARS-CoV-2 nucleocapsid protein. We compared these six cases to eight cases diagnosed as perniosis between January and June of 2019. RESULTS: Five of six lesions with perniosis-like histopathology during the COVID-19 pandemic had distinctive tight cuffing of lymphocytes; intravascular material was present in one case. SARS-CoV-2 immunohistochemical staining using an antibody directed at the nucleocapsid protein was negative in all six cases. Only one of eight specimens with microscopic findings of perniosis received prior to the COVID-19 pandemic had tightly cuffed perivascular lymphocytes, and none had obvious intravascular occlusion. CONCLUSIONS: A tightly cuffed pattern of perivascular lymphocytes is a feature of perniosis during the COVID-19 pandemic. The absence of SARS-CoV-2 nucleocapsid protein in these cases suggests against the virus being directly present in these lesions.

[Familial chilblain lupus: Four cases spanning three generations]. / Lupus-engelures familial : quatre cas sur trois générations.

BACKGROUND: Familial chilblain lupus is a hereditary form of cutaneous lupus erythematosus seen in young children. It shows autosomal dominant inheritance due to mutations in the TREX-1 gene, or, more rarely, SAMHD1 or TMEM173 (STING). It belongs to the type I interferonopathies, i.e. inflammatory diseases associated with excessive interferon production and characterized by a positive "interferon signature". This is a rare entity with fewer than 10 families described to date. We report a new family followed over several years. PATIENTS AND METHODS: The patients were four subjects from the same family and spanning three generations (a brother and sister aged 17 and 15 years, their 39-year-old mother, and their 60-year-old grandfather). The initial cutaneous lesions on the extremities were described as papular, erythematous, purplish, infiltrated, hyperkeratotic, pruritic and/or painful. They occurred in childhood, improved during summer and stabilized over time. Immunological abnormalities such as positive antinuclear antibodies were noted. The interferon signature was positive in all patients. Molecular analysis of TREX-1, SAMHD1 and STING genes in both children showed no evidence of mutation. DISCUSSION: The cutaneous involvement was classic except for absence of the scarring and mutilating progression, photosensitivity and vasculopathy reported in other families. There was no intrafamily variability other than unconstant immunological abnormalities. At the molecular level, no mutations in the known genes were identified. A complementary molecular analysis is in progress. CONCLUSION: We report a new case of familial LEF, thus adding to knowledge about this very rare form of lupus erythematosus.

JAK inhibitor ruxolitinib inhibits the expression of cytokines characteristic of cutaneous lupus erythematosus.

This study was stimulated by the clinical observation of a rapid response of a chilblain lupus patient to treatment with JAK1/2-kinase inhibitor ruxolitinib. We investigated the in vivo expression of phospho-JAK2 in CLE skin samples as well as the immunomodulatory in vitro effect of ruxolitinib in cultured immortalized keratinocytes and in a 3D human epidermis model (epiCS). Our results demonstrate that ruxolitinib significantly decreases the production of CLE-typical cytokines (CXCL10, CXCL9, MxA) and might be a promising drug for future clinical studies in patients with CLE and related autoimmune skin diseases.

Familial Chilblain Lupus - What Can We Learn from Type I Interferonopathies?

PURPOSE OF REVIEW: Familial chilblain lupus belongs to the group of type I interferonopathies and is characterized by typical skin manifestations and acral ischaemia. This review aims to give an overview of clinical signs and the pathophysiological mechanisms. RECENT FINDINGS: There are several mutations that can lead to this autosomal dominant disease. Most frequent is a mutation of the gene for TREX-1. However, as well cases of families with mutations in the SAMHD1 gene and, recently, with one for the gene that codes for the protein stimulator of interferon genes have been described. These genes are involved in the process of the detection of intracellular DNA, and their mutation results in an increased production of type I interferons and their gene products, resulting in auto-inflammation and auto-immunity. JAK inhibitors have been successfully used to treat this disorder. Familial chilblain is a rare disorder with very distinct clinical signs. Its pathophysiological mechanism gives insight into the process of interferon-induced inflammation in auto-immune diseases.

[Type I interferonopathies]. / Interféronopathies de type I.

Type I interferonopathies are a group of Mendelian disorders characterized by a common physiopathology: the up-regulation of type I interferons. To date, interferonopathies include Aicardi-Goutières syndrome, familial chilblain lupus, spondyenchondromatosis, PRoteasome-associated auto-inflammatory syndrome (PRAAS) and Singleton-Merten syndrome. These diseases present phenotypic overlap including cutaneous features like chilblain lupus, that can be inaugural or present within the first months of life. This novel set of inborn errors of immunity is evolving rapidly, with recognition of new diseases and genes. Recent and improved understanding of the physiopathology of overexpression of type I interferons has allowed the development of targeted therapies, currently being evaluated, like Janus-kinases or reverse transcriptase inhibitors.

A rare manifestation of STING-associated vasculopathy with onset in infancy: a case report.

BACKGROUND: STING-associated vasculopathy with onset in infancy (SAVI) is a rare type I interferonopathy caused by heterozygous variants in the STING gene. In SAVI, STING variants confer a gain-of-function which causes overactivation of type I interferon (IFN) signaling leading to autoinflammation and various degrees of immunodeficiency and autoimmunity. CASE PRESENTATION: We report the case of a 5 year old child and his mother, both of whom presented with systemic inflammatory symptoms yet widely varying organ involvement, disease course and therapeutic response. Genetic testing revealed a heterozygous STING variant, R281Q, in the child and his mother that had previously been associated with SAVI. However, in contrast to previously reported SAVI cases due to the R281Q variant, our patients showed an atypical course of disease with alopecia totalis in the child and a complete lack of lung involvement in the mother. CONCLUSIONS: Our findings demonstrate the phenotypic breadth of clinical SAVI manifestations. Given the therapeutic benefit of treatment with JAK inhibitors, early genetic testing for SAVI should be considered in patients with unclear systemic inflammation involving cutaneous, pulmonary, or musculoskeletal symptoms, and signs of immunodeficiency and autoimmunity.

Chronic Cutaneous Lupus Erythematosus in a White Population: Dermoscopic Characteristics by Clinical Subtype, Lesion Location and Disease Duration.

INTRODUCTION: Chronic cutaneous lupus erythematosus (CCLE) comprises three major clinical variants: discoid lupus erythematosus (DLE), chilblain lupus erythematosus (CHLE), and lupus erythematosus profundus, also referred to as lupus erythematosus panniculitis (LEP). The aim of the current study was to systematically describe the dermoscopic features of CCLE in Polish patients with Fitzpatrick skin phototypes I-III. METHODS: The videodermoscopic images from patients with various clinical variants of CCLE (DLE, CHLE and LEP) were reviewed. Predefined parameters for dermoscopic evaluation in general dermatology were used to describe the findings in lesions located beyond the scalp. In the analysis of trichoscopic findings in lesions located on the scalp, dermoscopic features of follicular openings, hair shafts, the perifollicular surface, the interfollicular surface and vessel morphology were considered. Based on personal experience, several additional dermoscopic and trichoscopic characteristics were included in the analysis. RESULTS: A total of 85 lesions from 26 patients (16 women and 10 men; mean age 40.8 ± 11.2 years) were assessed. DLE on glabrous skin showed polymorphous vessels (89.1%), pink-red background (70.9%), follicular plugs (67.3%) and white scaling (58.2%), while scalp DLE was characterized by polymorphous vessels (83.3%), yellow dots (66.7%), follicular plugs (55.6%) and a reduced number of follicles (55.6%). Labial DLE (n = 2) showed linear branched and linear curved vessels, white structureless areas, red structureless (hemorrhagic) areas and red dots/globules. White scaling (61.1% vs. 34.1%; p = 0.042), gray-brown dots/globules (44.4% vs. 12.2%; p = 0.015) and peripheral pigmentation (100.0% vs. 46.2%; p = 0.036) were significantly more common in long-lasting (> 1 year) DLE lesions. CHLE (n = 5) presented with polymorphous vessels, white scales, pink-red background, red structureless areas and red dots/globules. LEP showed polymorphous vessels, white-yellow scales, follicular plugs, white structureless areas and red hemorrhagic areas. CONCLUSIONS: Dermoscopy might be useful in the preliminary diagnosis of DLE, and its role in the diagnosis of CHLE and LEP needs further elucidation.

A Novel Type I Interferon Primed Dendritic Cell Subpopulation in TREX1 Mutant Chilblain Lupus Patients.

Heterozygous TREX1 mutations are associated with monogenic familial chilblain lupus and represent a risk factor for developing systemic lupus erythematosus. These interferonopathies originate from chronic type I interferon stimulation due to sensing of inadequately accumulating nucleic acids. We here analysed the composition of dendritic cell (DC) subsets, central stimulators of immune responses, in patients with TREX1 deficiency. We performed single-cell RNA-sequencing of peripheral blood DCs and monocytes from two patients with familial chilblain lupus and heterozygous mutations in TREX1 and from controls. Type I interferon pathway genes were strongly upregulated in patients. Cell frequencies of the myeloid and plasmacytoid DC and of monocyte populations in patients and controls were similar, but we describe a novel DC subpopulation highly enriched in patients: a myeloid DC CD1C+ subpopulation characterized by the expression of LMNA, EMP1 and a type I interferon- stimulated gene profile. The presence of this defined subpopulation was confirmed in a second cohort of patients and controls by flow cytometry, also revealing that an increased percentage of patient's cells in the subcluster express costimulatory molecules. We identified a novel type I interferon responsive myeloid DC subpopulation, that might be important for the perpetuation of TREX1-induced chilblain lupus and other type I interferonopathies.

Corrigendum: A novel type I interferon primed dendritic cell subpopulation in TREX1 mutant chilblain lupus patients.

[This corrects the article DOI: 10.3389/fimmu.2022.897500.].

Efficacy and Safety of Janus Kinase Inhibitors in Type I Interferon-Mediated Monogenic Autoinflammatory Disorders: A Scoping Review.

IMPORTANCE: Type I interferon (IFN)-mediated monogenic autoinflammatory disorders (interferonopathies) are childhood-onset rare multisystemic diseases with limited treatment options. The Janus kinase (JAK) inhibitors are promising potential therapeutic candidates for immune-mediated chronic inflammatory skin diseases. OBJECTIVE: To review the use of JAK inhibitors to improve decision-making when treating interferonopathies with cutaneous manifestations. EVIDENCE REVIEW: The MEDLINE, EMBASE, CINAHL, Scopus, and Web of Science databases were searched for studies that used JAK protein inhibitors to treat IFN-related monogenic diseases with cutaneous manifestations in humans. The search results are reported using the scoping review approach. FINDINGS: Seventeen open-label studies assessing the efficacy of ruxolitinib, baricitinib, or tofacitinib reported variable responses in patients with chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) and related syndromes, stimulator of IFN genes [STING]-associated vasculopathy with onset in infancy (SAVI), familial chilblain lupus (FCh-L), gain-of-function mutations of STAT1 (GOF-STAT1), or Aicardi-Goutiéres syndrome. JAK inhibitors improved clinical and analytical parameters and decreased flare numbers, plasma inflammatory markers, and expression of IFN-stimulated genes. BK viremia and upper respiratory infections were the most frequent and severe adverse events. Significant heterogeneity in efficacy assessment methods and poor reporting of safety events were detected. CONCLUSIONS AND RELEVANCE: Evidence of the use of JAK inhibitors in patients with interpheronopathies is scarce and of low methodological quality. Future clinical trials should use validated scales and report drug safety in a more accurate way.

Type I interferonopathies with novel compound heterozygous TREX1 mutations in two siblings with different symptoms responded to tofacitinib.

BACKGROUND: Type I interferonopathies are a group of rare autoimmune diseases characterised by excessive activation of type I interferon that leads to disturbances in immune function. Three prime repair exonuclease 1 (TREX1) is an important exonuclease and plays an important role in DNA damage repair. TREX1 mutations are associated with many type I interferonopathies. Studies have been published on the effectiveness of tofacitinib in the treatment of type I interferonopathies. The aim of this study is to identify the pathogenic variation in a Chinese family with type I interferonopathies and to observe the therapeutic effects of tofacitinib. METHODS: A Chinese family with two members with type I interferonopathies was investigated. Whole exome sequencing and Sanger sequencing were applied for mutation screening using peripheral blood DNA of the patient and her family members. Sequencing results were analysed using bioinformatics software tools including VarCards and PolyPhen-2. Close clinical follow-up and observation were used to record changes in the disease before and after treatment with tofacitinib. RESULTS: Compound heterozygous variants of TREX1 were observed in the patient's genome. One was a missense variant (NM_016381; c.C227T; p.Ala76Val) from the patient's father, and the other was a frameshift variant (NM_016381; c.458dupA; p.Gln153Glnfs*3) from the patient's mother. One of the proband's elder brothers with similar skin lesions also carried these two variants. This brother of the proband had more serious cutaneous involvement with the comorbidity of cerebral palsy. These TREX1 variants have not been reported in previous studies and are predicted to be highly pathogenic. The proband was given tofacitinib that led to a marked improvement. CONCLUSIONS: We identified two novel complex heterozygous variants in the TREX1 gene, which may underlie the molecular pathogenesis of the type I interferonopathies observed in members of this family. Tofacitinib could be an alternative treatment for this disease.

Type I Interferon Induction in Cutaneous DNA Damage Syndromes.

Type I interferons (IFNs) as part of the innate immune system have an outstanding importance as antiviral defense cytokines that stimulate innate and adaptive immune responses. Upon sensing of pattern recognition particles (PRPs) such as nucleic acids, IFN secretion is activated and induces the expression of interferon stimulated genes (ISGs). Uncontrolled constitutive activation of the type I IFN system can lead to autoinflammation and autoimmunity, which is observed in autoimmune disorders such as systemic lupus erythematodes and in monogenic interferonopathies. They are caused by mutations in genes which are involved in sensing or metabolism of intracellular nucleic acids and DNA repair. Many authors described mechanisms of type I IFN secretion upon increased DNA damage, including the formation of micronuclei, cytosolic chromatin fragments and destabilization of DNA binding proteins. Hereditary cutaneous DNA damage syndromes, which are caused by mutations in proteins of the DNA repair, share laboratory and clinical features also seen in autoimmune disorders and interferonopathies; hence a potential role of DNA-damage-induced type I IFN secretion seems likely. Here, we aim to summarize possible mechanisms of IFN induction in cutaneous DNA damage syndromes with defects in the DNA double-strand repair and nucleotide excision repair. We review recent publications referring to Ataxia teleangiectasia, Bloom syndrome, Rothmund-Thomson syndrome, Werner syndrome, Huriez syndrome, and Xeroderma pigmentosum. Furthermore, we aim to discuss the role of type I IFN in cancer and these syndromes.

Familial chilblain lupus due to a novel mutation in TREX1 associated with Aicardi-Goutie'res syndrome.

BACKGROUND: Familial chilblain lupus (FCL) is a rare, chronic form of cutaneous lupus erythematosus, which is characterized by painful bluish-red inflammatory cutaneous lesions in acral locations. Mutations in TREX1, SAMHD1 and STING have been described in FCL patients. Less than 10 TREX1 mutation positive FCL families have been described in the literature. CASE PRESENTATION: Genetic study was performed in a large, nonconsanguineous Chinese family with 13 members over 4 generations affected by chilblain lupus. Whole exome sequencing was performed for the index patient. Significant variant detection was subsequently validated by resequencing using Sanger sequencing in the index patient and other family members. A novel pathogenic mutation TREX1 p.Asp18His was iditified in the index patient. The mutation was present in affected individuals and was absent in non-affected individuals in the familiy. CONCLUSIONS: We present a four-generation Chinese family with FCL caused by a novel heterozygous mutation TREX1 p.Asp18His, which had been reported in a patient with Aicardi-Goutie'res syndrome. This is the first reported Chinese family with FCL based on mutation in TREX1.

Designation of Autoinflammatory Skin Manifestations With Specific Genetic Backgrounds.

"Autoinflammatory disease (AiD)" has first been introduced in 1999 when the responsible gene for the familial Hibernean fever or autosomal dominant-type familial Mediterranean fever-like periodic fever syndrome was reportedly identified as tumor necrosis factor receptor superfamily 1. Linked with the rapid research progress in the field of innate immunity, "autoinflammation" has been designated for dysregulated innate immunity in contrast to "autoimmunity" with dysregulated acquired immunity. As hereditary periodic fever syndromes represent the prototype of AiD, monogenic systemic diseases are the main members of AiD. However, skin manifestations provide important clinical information and there are even some AiDs originating from skin diseases. Recently, AiD showing psoriasis and related keratinization diseases have specifically been designated as "autoinflammatory keratinization diseases (AiKD)" and CARD14-associated psoriasis and deficiency of interleukin-36 receptor antagonist previously called as generalized pustular psoriasis are included. Similarly, a number of autoinflammatory skin diseases can be proposed; autoinflamatory urticarial dermatosis (AiUD) such as cryopyrin-associated periodic syndrome; autoinflammatory neutrophilic dermatosis (AiND) such as pyogenic sterile arthritis, pyoderma gangrenosm, and acne syndrome; autoinflammatory granulomatosis (AiG) such as Blau syndrome; autoinflammatory chilblain lupus (AiCL) such as Aicardi-Goutieres syndrome; autoinflammatory lipoatrophy (AiL) such as Nakajo-Nishimura syndrome; autoinflammatory angioedema (AiAE) such as hereditary angioedema; and probable autoinflammatory bullous disease (AiBD) such as granular C3 dermatosis. With these designations, skin manifestations in AiD can easily be recognized and, even more importantly, autoinflammatory pathogenesis of common skin diseases are expected to be more comprehensive.

Discoid Lupus Erythematosus: A Cross-Sectional Study From the Sindh Institute of Skin Diseases, Karachi, Pakistan.

Introduction Discoid lupus erythematosus (DLE) is the most common form of cutaneous lupus erythematosus. It is a chronic, scar-forming, photosensitive autoimmune dermatosis presenting with erythematous and scaly lesions. Predisposed areas include sun-exposed areas like the nose, forehead, and cheeks, as well as the upper body and extremities. The histological findings are typical, with interface dermatitis. Immunoglobulin M (IgM) and immunoglobulin G (IgG) are the most common deposits in the dermoepidermal junction of the involved skin. The most common treatments used are sunscreens, topical corticosteroids, and antimalarials. Immunosuppressive agents, thalidomide, dapsone, and retinoids can be used in refractory cases. The aim of this study was to study the clinicopathologic patterns of DLE in patients presenting to the Institute of Skin Diseases in Sindh, Karachi. Methods A total of 53 consecutive patients with DLE meeting the inclusion criteria were evaluated between February 18, 2018 to March 2, 2019 at the Institute of Skin Diseases. Patients with clinical suspicion of DLE were evaluated and studied prospectively after written informed consent was obtained. Information was then collected from their medical histories, physical examination records, and laboratory investigation reports. Results A total of 53 consecutive patients with clinical and/or histological diagnosis of DLE was included in this study, out of which 75.5% (40) were females with a male to female ratio of 1:3.1. The mean age of the patients at the time of presentation was 36.02 ± 10.04 years, ranging from 14 to 65 years. More than half of the patients (35, 66.0%) were under 40 years of age and 20.8% (11) had a positive family history of DLE. DLE was localized in 36 patients (67.9%) and exposure to the ultraviolet radiation (UVR) was found to be the most frequent induced factor in 46 patients (86.8%), followed by stress which was observed in 14 patients (26.4%). The distribution of commonly affected sites were the face (81.1%), the limbs (71.7%), and the scalp (48.4%) of the patients. Serology antinuclear antibody (ANA) was positive in 56.6% and serology anti-double-stranded deoxyribonucleic acid antibodies (anti-dsDNA) were positive in 45.3% of patients. Smoking, as an induced factor, was more commonly observed among male patients as compared to the female patients with a proportion of 53.8% vs. 2.5%, p < 0.001, while stress was more common among female patients with a proportion of 35% vs. 0%, p = 0.013, respectively. Histopathology with direct immunofluorescence was done in 33 cases which included cases with negative serology or where the diagnosis was in doubt clinically. The main histopathological features observed were periadnexal and perivascular dermal infiltrates, basal cells vacuolization, epidermal atrophy, hyperkeratosis, and follicular plugging. The commonest morphological form observed was the classic discoid plaque form. Conclusion Clinical patterns of DLE in our population comprises of female dominance. Exposure to UVR was the leading inducing factor. The face and limbs were the most commonly involved sites, and the majority of the patients had localized DLE with positive ANA in more than half of those patients. The importance of limiting ultraviolet radiation exposure and toxins (drugs and smoking) should be emphasized in our population.

Chilblain Lupus with Nail Involvement: A Case Report and a Brief Overview.

Chilblain lupus erythematosus is a rare, chronic variant of cutaneous lupus erythematosus that occurs during cold or damp periods on the hands, fingers, or feet. It is often associated with other forms of cutaneous lupus and about 20% of patients develop systemic lupus erythematosus. Various medications have been put forward, including steroids, mycophenolate mofetil, calcium channel blockers, and hydroxychloroquine, but the symptoms do not remit completely.