A gene network regulated by the transcription factor VGLL3 as a promoter of sex-biased autoimmune diseases.

Autoimmune diseases affect 7.5% of the US population, and they are among the leading causes of death and disability. A notable feature of many autoimmune diseases is their greater prevalence in females than in males, but the underlying mechanisms of this have remained unclear. Through the use of high-resolution global transcriptome analyses, we demonstrated a female-biased molecular signature associated with susceptibility to autoimmune disease and linked this to extensive sex-dependent co-expression networks. This signature was independent of biological age and sex-hormone regulation and was regulated by the transcription factor VGLL3, which also had a strong female-biased expression. On a genome-wide level, VGLL3-regulated genes had a strong association with multiple autoimmune diseases, including lupus, scleroderma and Sjögren's syndrome, and had a prominent transcriptomic overlap with inflammatory processes in cutaneous lupus. These results identified a VGLL3-regulated network as a previously unknown inflammatory pathway that promotes female-biased autoimmunity. They demonstrate the importance of studying immunological processes in females and males separately and suggest new avenues for therapeutic development.

Systemic Lupus Erythematosus: New Diagnostic and Therapeutic Approaches.

Systemic lupus erythematosus (SLE) is a devastating autoimmune disease that can result in substantial morbidity and mortality. Diagnosis and treatment of SLE are clinical challenges. Patient presentation and response to therapy are heterogeneous because of the complex immune dysregulation that results in SLE disease pathogenesis. An intricate interplay between genetic risk and skewing of adaptive and innate immune system responses leads to overproduction of type I interferons and other cytokines, complement activation, immune-complex deposition, and ultimately inflammation and tissue damage. Here, we review the classification criteria as well as standard and emerging diagnostic tools available to identify patients with SLE. We then focus on medical management, including novel therapeutics, nonpharmacologic interventions, and comorbidity management.

Single-cell profiling of prurigo nodularis demonstrates immune-stromal crosstalk driving profibrotic responses and reversal with nemolizumab.

BACKGROUND: Prurigo nodularis (PN) is a chronic neuroimmune skin disease characterized by bilaterally distributed pruritic hyperkeratotic nodules on extremities and trunk. Neuroimmune dysregulation and chronic scratching are believed to both induce and maintain the characteristic lesions. OBJECTIVES: This study sought to provide a comprehensive view of the molecular pathogenesis of PN at the single-cell level to identify and outline key pathologic processes and the cell types involved. Features that distinguish PN skin from the skin of patients with atopic dermatitis were of particular interest. We further aimed to determine the impact of the IL31RA antagonist, nemolizumab, and its specificity at the single-cell level. METHODS: Single-cell RNA-sequencing of skin from 15 healthy donors and nonlesional and lesional skin from 6 patients each with PN and atopic dermatitis, combined with spatial-sequencing using the 10x Visium platform. Integration with bulk RNA-sequencing data from patients treated with nemolizumab. RESULTS: This study demonstrates that PN is an inflammatory skin disease characterized by both keratinocyte proliferation and activation of profibrotic responses. This study also demonstrates that the COL11A1+ fibroblast subset is a major contributor to fibrosis and is predominantly found in the papillary dermis of PN skin. Activation of fibrotic responses is the main distinguishing feature between PN and atopic dermatitis skin. This study further shows the broad effect of nemolizumab on PN cell types, with a prominent effect driving COL11A1+ fibroblast and keratinocyte responses toward normal. CONCLUSIONS: This study provides a high-resolution characterization of the cell types and cellular processes activated in PN skin, establishing PN as a chronic fibrotic inflammatory skin disease. It further demonstrates the broad effect of nemolizumab on pathological processes in PN skin.

Emerging biologic therapies for systemic lupus erythematosus.

PURPOSE OF REVIEW: The approval of belimumab and anifrolumab has expanded the scope of treatment for systemic lupus erythematosus (SLE) patients. However, many patients remain refractory to currently available therapies and suffer from drug toxicities. This review will discuss approved and target-specific therapeutics in development that bring hope for better SLE treatments. RECENT FINDINGS: Since the last review on this subject in the journal, the FDA has approved anifrolumab and belimumab for SLE and lupus nephritis (LN), respectively. A fully humanized anti-CD20, obinutuzumab, met the primary end point in a phase II trial in LN. A Tyk2 inhibitor, deucravacitinib, and an antibody targeting plasmacytoid dendritic cells, litifilimab, met the primary end point in phase II trials in SLE and cutaneous lupus erythematosus (CLE). Ustekinumab and baricitinib met the primary end point in phase II but not in phase III trials. SUMMARY: While many drug candidates which met the end points in phase II trials have failed phase III trials, the number of target-specific therapies for SLE has continued to expand.

Social determinants of depression in systemic lupus erythematosus: A systematic scoping review.

Social determinants of health (SDOH) influence inequities in systemic lupus erythematosus (SLE). While these inequities contribute to overall disease experience, there is little consensus guiding our understanding of the psychological implications of SDOH in SLE. Given the paucity of evidence in this area, the aim of this scoping review was to systematically assess the volume and features of available research literature on associations of SDOH with depression in SLE over the past 20 years, from 1 January 2000 to 16 November 2021. We developed a search strategy for PubMed and EMBASE that included keywords for depression and lupus. After screening 2188 articles, we identified 22 original articles that met our inclusion criteria. At least one SDOH was associated with depression in two of the six studies with unadjusted estimates and 13 of the 16 studies with adjusted estimates. Results provide consistent but sparse evidence that SDOH are associated with depression in SLE. Additionally, depression epidemiology in SLE may differ from the general population such that depression risk is more similar across genders and racial/ethnic groups. More work is needed to identify the SDOH that have the greatest impact on depression and mental health among SLE patients, as well as how and when to intervene.

DDX58(RIG-I)-related disease is associated with tissue-specific interferon pathway activation.

BACKGROUND: Singleton-Merten syndrome (SGMRT) is a rare immunogenetic disorder that variably features juvenile open-angle glaucoma (JOAG), psoriasiform skin rash, aortic calcifications and skeletal and dental dysplasia. Few families have been described and the genotypic and phenotypic spectrum is poorly defined, with variants in DDX58 (DExD/H-box helicase 58) being one of two identified causes, classified as SGMRT2. METHODS: Families underwent deep systemic phenotyping and exome sequencing. Functional characterisation with in vitro luciferase assays and in vivo interferon signature using bulk and single cell RNA sequencing was performed. RESULTS: We have identified a novel DDX58 variant c.1529A>T p.(Glu510Val) that segregates with disease in two families with SGMRT2. Patients in these families have widely variable phenotypic features and different ethnic background, with some being severely affected by systemic features and others solely with glaucoma. JOAG was present in all individuals affected with the syndrome. Furthermore, detailed evaluation of skin rash in one patient revealed sparse inflammatory infiltrates in a unique distribution. Functional analysis showed that the DDX58 variant is a dominant gain-of-function activator of interferon pathways in the absence of exogenous RNA ligands. Single cell RNA sequencing of patient lesional skin revealed a cellular activation of interferon-stimulated gene expression in keratinocytes and fibroblasts but not in neighbouring healthy skin. CONCLUSIONS: These results expand the genotypic spectrum of DDX58-associated disease, provide the first detailed description of ocular and dermatological phenotypes, expand our understanding of the molecular pathogenesis of this condition and provide a platform for testing response to therapy.

Cytokine responses in nonlesional psoriatic skin as clinical predictor to anti-TNF agents.

BACKGROUND: A major issue with the current management of psoriasis is our inability to predict treatment response. OBJECTIVE: Our aim was to evaluate the ability to use baseline molecular expression profiling to assess treatment outcome for patients with psoriasis. METHODS: We conducted a longitudinal study of 46 patients with chronic plaque psoriasis treated with anti-TNF agent etanercept, and molecular profiles were assessed in more than 200 RNA-seq samples. RESULTS: We demonstrated correlation between clinical response and molecular changes during the course of the treatment, particularly for genes responding to IL-17A/TNF in keratinocytes. Intriguingly, baseline gene expressions in nonlesional, but not lesional, skin were the best marker of treatment response at week 12. We identified USP18, a known regulator of IFN responses, as positively correlated with Psoriasis Area and Severity Index (PASI) improvement (P = 9.8 × 10-4) and demonstrate its role in regulating IFN/TNF responses in keratinocytes. Consistently, cytokine gene signatures enriched in baseline nonlesional skin expression profiles had strong correlations with PASI improvement. Using this information, we developed a statistical model for predicting PASI75 (ie, 75% of PASI improvement) at week 12, achieving area under the receiver-operating characteristic curve value of 0.75 and up to 80% accurate PASI75 prediction among the top predicted responders. CONCLUSIONS: Our results illustrate feasibility of assessing drug response in psoriasis using nonlesional skin and implicate involvement of IFN regulators in anti-TNF responses.

Transcriptomic characterization of prurigo nodularis and the therapeutic response to nemolizumab.

BACKGROUND: Prurigo nodularis (PN) is a debilitating, difficult-to-treat, intensely pruritic, chronic inflammatory skin disease characterized by hyperkeratotic skin nodules. The pathogenesis of PN is not well understood but is believed to involve cross talk between sensory nerve fibers, immune cells, and the epidermis. It is centered around the neuroimmune cytokine IL-31, driving an intractable itch-scratch cycle. OBJECTIVE: We sought to provide a comprehensive view of the transcriptomic changes in PN skin and characterize the mechanism of action of the anti-IL-31 receptor inhibitor nemolizumab. METHOD: RNA sequencing of biopsy samples obtained from a cohort of patients treated with the anti-IL-31 receptor inhibitor nemolizumab and taken at baseline and week 12. Generation and integration of patient data with RNA-Seq data generated from reconstructed human epidermis stimulated with IL-31 and other proinflammatory cytokines. RESULTS: Our results demonstrate that nemolizumab effectively decreases IL-31 responses in PN skin, leading to effective suppression of downstream inflammatory responses including TH2/IL-13 and TH17/IL-17 responses. This is accompanied by decreased keratinocyte proliferation and normalization of epidermal differentiation and function. Furthermore, our results demonstrate how transcriptomic changes associated with nemolizumab treatment correlate with improvement in lesions, pruritus, stabilization of extracellular matrix remodeling, and processes associated with cutaneous nerve function. CONCLUSION: These data demonstrate a broad response to IL-31 receptor inhibition with nemolizumab and confirm the critical upstream role of IL-31 in PN pathogenesis.

Recent advances in cutaneous lupus.

Cutaneous lupus erythematosus (CLE) is an inflammatory and autoimmune skin condition that affects patients with systemic lupus erythematosus (SLE) and exists as an isolated entity without associated SLE. Flares of CLE, often triggered by exposure to ultraviolet (UV) light result in lost productivity and poor quality of life for patients and can be associated with trigger of systemic inflammation. In the past 10 years, the knowledge of CLE etiopathogenesis has grown, leading to promising targets for better therapies. Development of lesions likely begins in a pro-inflammatory epidermis, conditioned by excess type I interferon (IFN) production to undergo increased cell death and inflammatory cytokine production after UV light exposure. The reasons for this inflammatory predisposition are not well-understood, but may be an early event, as ANA + patients without criteria for autoimmune disease exhibit similar (although less robust) findings. Non-lesional skin of SLE patients also exhibits increased innate immune cell infiltration, conditioned by excess IFNs to release pro-inflammatory cytokines, and potentially increase activation of the adaptive immune system. Plasmacytoid dendritic cells are also found in non-lesional skin and may contribute to type I IFN production, although this finding is now being questioned by new data. Once the inflammatory cycle begins, lesional infiltration by numerous other cell populations ensues, including IFN-educated T cells. The heterogeneity amongst lesional CLE subtypes isn't fully understood, but B cells appear to discriminate discoid lupus erythematosus from other subtypes. Continued discovery will provide novel targets for additional therapeutic pursuits. This review will comprehensively discuss the contributions of tissue-specific and immune cell populations to the initiation and propagation of disease.

The Role of Cutaneous Type I IFNs in Autoimmune and Autoinflammatory Diseases.

IFNs are well known as mediators of the antimicrobial response but also serve as important immunomodulatory cytokines in autoimmune and autoinflammatory diseases. An increasingly critical role for IFNs in evolution of skin inflammation in these patients has been recognized. IFNs are produced not only by infiltrating immune but also resident skin cells, with increased baseline IFN production priming for inflammatory cell activation, immune response amplification, and development of skin lesions. The IFN response differs by cell type and host factors and may be modified by other inflammatory pathway activation specific to individual diseases, leading to differing clinical phenotypes. Understanding the contribution of IFNs to skin and systemic disease pathogenesis is key to development of new therapeutics and improved patient outcomes. In this review, we summarize the immunomodulatory role of IFNs in skin, with a focus on type I, and provide insight into IFN dysregulation in autoimmune and autoinflammatory diseases.

Immunopathogenesis of skin injury in systemic lupus erythematosus.

PURPOSE OF REVIEW: Skin injury is the most common clinical manifestation of SLE and is disfiguring, difficult to treat, and incompletely understood. We provide an overview of recently published articles covering the immunopathogenesis of skin injury in SLE. RECENT FINDINGS: Skin of SLE has an inherent susceptibility to apoptosis, the cause of which may be multifactorial. Chronic IFN overexpression leads to barrier disruption, infiltration of inflammatory cells, cytokine production, and release of autoantigens and autoantibody production that result in skin injury. Ultraviolet light is the most important CLE trigger and amplifies this process leading to skin inflammation and potentially systemic disease flares. SUMMARY: The pathogenesis of skin injury in CLE is complex but recent studies highlight the importance of mechanisms driving dysregulated epidermal cell death likely influenced by genetic risk factors, environmental triggers (UV light), and cytotoxic cells and cellular signaling.

Hypersensitive IFN Responses in Lupus Keratinocytes Reveal Key Mechanistic Determinants in Cutaneous Lupus.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease in which 70% of patients experience disfiguring skin inflammation (grouped under the rubric of cutaneous lupus erythematosus [CLE]). There are limited treatment options for SLE and no Food and Drug Administration-approved therapies for CLE. Studies have revealed that IFNs are important mediators for SLE and CLE, but the mechanisms by which IFNs lead to disease are still poorly understood. We aimed to investigate how IFN responses in SLE keratinocytes contribute to development of CLE. A cohort of 72 RNA sequencing samples from 14 individuals (seven SLE and seven healthy controls) were analyzed to study the transcriptomic effects of type I and type II IFNs on SLE versus control keratinocytes. In-depth analysis of the IFN responses was conducted. Bioinformatics and functional assays were conducted to provide implications for the change of IFN response. A significant hypersensitive response to IFNs was identified in lupus keratinocytes, including genes (IFIH1, STAT1, and IRF7) encompassed in SLE susceptibility loci. Binding sites for the transcription factor PITX1 were enriched in genes that exhibit IFN-sensitive responses. PITX1 expression was increased in CLE lesions based on immunohistochemistry, and by using small interfering RNA knockdown, we illustrated that PITX1 was required for upregulation of IFN-regulated genes in vitro. SLE patients exhibit increased IFN signatures in their skin secondary to increased production and a robust, skewed IFN response that is regulated by PITX1. Targeting these exaggerated pathways may prove to be beneficial to prevent and treat hyperinflammatory responses in SLE skin.

Progression of acute-to-chronic atopic dermatitis is associated with quantitative rather than qualitative changes in cytokine responses.

BACKGROUND: Although multiple studies have assessed molecular changes in chronic atopic dermatitis (AD) lesions, little is known about the transition from acute to chronic disease stages, and the factors and mechanisms that shape chronic inflammatory activity. OBJECTIVES: We sought to assess the global transcriptome changes that characterize the progression from acute to chronic stages of AD. METHODS: We analyzed transcriptome changes in paired nonlesional skin, acute and chronic AD lesions from 11 patients and 38 healthy controls by RNA-sequencing, and conducted in vivo and histological assays to evaluate findings. RESULTS: Our data demonstrate that approximately 74% of the genes dysregulated in acute lesions remain or are further dysregulated in chronic lesions, whereas only 34% of the genes dysregulated in chronic lesions are altered already in the acute stage. Nonlesional AD skin exhibited enrichment of TNF, TH1, TH2, and TH17 response genes. Acute lesions showed marked dendritic-cell signatures and a prominent enrichment of TH1, TH2, and TH17 responses, along with increased IL-36 and thymic stromal lymphopoietin expression, which were further heightened in chronic lesions. In addition, genes involved in skin barrier repair, keratinocyte proliferation, wound healing, and negative regulation of T-cell activation showed a significant dysregulation in the chronic versus acute comparison. Furthermore, our data show progressive changes in vasculature and maturation of dendritic-cell subsets with chronicity, with FOXK1 acting as immune regulator. CONCLUSIONS: Our results show that the changes accompanying the transition from nonlesional to acute to chronic inflammation in AD are quantitative rather than qualitative, with chronic AD having heightened TH2, TH1, TH17, and IL36 responses and skin barrier repair mechanisms. These findings provide novel insights and highlight underappreciated pathways in AD pathogenesis that may be amenable to therapeutic targeting.

Recent genetic advances in innate immunity of psoriatic arthritis.

Psoriatic arthritis (PsA) is a heterogeneous disease that affects multiple organ systems including the peripheral and axial joints, entheses and nails. PsA is associated with significant comorbidities including cardiovascular, metabolic, and psychiatric diseases. The pathogenesis of PsA is complex and involves genetic, immunologic and environmental factors. Recent evidence suggests the heritability for PsA to be stronger and distinct from that of PsC. Prominent genes identified via GWAS for PsA include HLA-B/C, HLAB, IL12B, IL23R, TNP1, TRAF3IP3, and REL. We review the genetics of psoriatic arthritis and discuss the role of the innate immune system as important in the pathogenesis of PsA by focusing on key signaling pathways and cellular makeup. Understanding the candidate genes identified in PsA highlights pathways of critical importance to the pathogenesis of psoriatic disease including the key role of the innate immune response, mediated through IL-23/IL-17 axis, RANK and NFκB signaling pathways.

Treatment of cutaneous lupus erythematosus: current approaches and future strategies.

PURPOSE OF REVIEW: Cutaneous lupus erythematosus (CLE) is a highly heterogeneous autoimmune disease. No specific Federal Drug Administration-approved therapies for CLE-alone are available, and resistance to conventional treatments is common. This review will summarize current treatment approaches and pending treatment strategies. RECENT FINDINGS: Research into the pathogenesis of CLE is accelerating. A skewed type I interferon production and response contribute to CLE lesions. The pathophysiology of lesions may be similar among the lesional subtypes, and patients with a more TLR9-driven disease mechanism may have more benefit from hydroxychloroquine. Case reports continue to support the use of dapsone for CLE, especially bullous lupus erythematosus. Rituximab and Belimumab have efficacy in patients with systemic lupus erythematosus and severe active CLE. The significant role for type I interferons in CLE and encouraging clinical data suggest anifrolumab as a very promising agent for CLE. Dapirolizumab, BIIB059, Ustekinumab and Janus kinase inhibitors also have supportive early data as promising new strategies for CLE treatment. SUMMARY: Continued research to understand the mechanisms driving CLE will facilitate the development and approval of new targets. The pipeline for new treatments is rich.

Long-term efficacy and safety of canakinumab in patients with colchicine-resistant familial Mediterranean fever: results from the randomised phase III CLUSTER trial.

OBJECTIVES: To evaluate the long-term efficacy and safety of canakinumab to treat patients with colchicine-resistant familial Mediterranean fever (crFMF) during Epoch 4 (weeks 41 to 113) of the CLUSTER study. METHODS: Patients received open-label canakinumab 150 or 300 mg, every 4 or 8 weeks during a 72-week period. We evaluated disease activity every 8 weeks using the physician global assessment (PGA) of disease activity, counting the number of flares, and measuring concentrations of C reactive protein (CRP) and serum amyloid A (SAA). Safety was studied by determination and classification of observed adverse events (AEs). We analysed safety and efficacy separately in two subgroups of patients receiving a cumulative dose of less than 2700 mg, or equal or more than 2700 mg. RESULTS: Of the 61 patients that started the CLUSTER study, 60 entered Epoch 4 and 57 completed it. During the 72-week period, 35/60 (58.3%) patients experienced no flares, and 23/60 (38.3%) had one flare, as compared with a median of 17.5 flares per year reported at baseline. PGA scores indicated no disease activity for the majority of patients throughout the study. Median CRP concentrations were always lower than 10 mg/L, while median SAA concentrations remained over the limit of normal (10 mg/L) but under the 30 mg/L threshold. No new or unexpected AEs were reported. CONCLUSION: crFMF patients treated with canakinumab during 72 weeks experienced a minimal incidence of flares and good control of clinical disease activity, with no new safety concerns reported.

The influence of interferon on healthy and diseased skin.

Type I interferons (IFNs) are an immunomodulatory class of cytokines that serve to protect against viral and bacterial infection. In addition, mounting evidence suggests IFNs, particularly type I but also IFNγ, are important to the pathogenesis of autoimmune and inflammatory skin diseases, such as cutaneous lupus erythematosus (CLE). Understanding the role of IFNs is relevant to anti-viral responses in the skin, skin biology, and therapeutics for these IFN-related conditions. Type I IFNs (α and ß) are produced by recruited inflammatory cells and by the epidermis itself (IFNκ) and have important roles in autoimmune and inflammatory skin disease. Here, we review the current literature utilizing a PubMed database search using terms [interferon/IFN/type I IFN AND lupus/ cutaneous lupus/CLE/dermatomyositis/Sjogrens/psoriasis/lichen planus/morphea/alopecia areata/vitiligo] with a focus on the role of IFNs in basic keratinocyte biology and their implications in the cutaneous autoimmune and inflammatory diseases: cutaneous lupus erythematosus, dermatomyositis, Sjogren's syndrome, psoriasis, lichen planus, alopecia areata and vitiligo. We provide information about genes and proteins induced by IFNs and how downstream mechanisms relate to clinical disease.

TLR7-Mediated Lupus Nephritis Is Independent of Type I IFN Signaling.

Systemic lupus erythematosus is an autoimmune disease characterized by increased type I IFNs, autoantibodies, and inflammatory-mediated multiorgan damage. TLR7 activation is an important contributor to systemic lupus erythematosus pathogenesis, but the mechanisms by which type I IFNs participate in TLR7-driven pathologic conditions remain uncertain. In this study, we examined the requirement for type I IFNs in TLR7-stimulated lupus nephritis. Lupus-prone NZM2328, INZM (which lack a functional type I IFN receptor), and NZM2328 IL-1ß-/- mice were treated at 10 wk of age on the right ear with R848 (TLR7 agonist) or control (DMSO). Autoantibody production and proteinuria were assessed throughout treatment. Multiorgan inflammation was assessed at the time of decline in health. Renal infiltrates and mRNA expression were also examined after 14 d of treatment. Both NZM2328 and INZM mice exhibited a decline in survival after 3-4 wk of R848 but not vehicle treatment. Development of splenomegaly and liver inflammation were dependent on type I IFN. Interestingly, autoantibody production, early renal infiltration of dendritic cells, upregulation of IL-1ß, and lupus nephritis occurred independent of type I IFN signaling. Development of TLR7-driven lupus nephritis was not abolished by the deletion of IL-1ß. Thus, although IFN-α is sufficient to induce nephritis acceleration, our data emphasize a critical role for IFN-independent signaling in TLR7-mediated lupus nephritis. Further, despite upregulation of IL-1ß after TLR7 stimulation, deletion of IL-1ß is not sufficient to reduce lupus nephritis development in this model.

Sex bias in autoimmunity.

PURPOSE OF REVIEW: To give an overview of recently published articles addressing the mechanisms underlying sex bias in autoimmune disease. RECENT FINDINGS: Recent studies investigating the origins of sex bias in autoimmune disease have revealed an extensive and interconnected network of genetic, hormonal, microbial, and environmental influences. Investigation of sex hormones has moved beyond profiling the effects of hormones on activity and prevalence of immune cell types to defining the specific immunity-related genes driving these changes. Deeper examination of the genetic content of the X and Y chromosomes and genetic escapees of X chromosome inactivation has revealed some key drivers of female-biased autoimmunity. Animal studies are offering further insights into the connections among microbiota, particularly that of the gut, and the immune system. SUMMARY: Sex bias in autoimmune disease is the manifestation of a complex interplay of the sex chromosomes, sex hormones, the microbiota, and additional environmental and sociological factors.