Gene Expression Signatures in Inflammatory and Sclerotic Morphea Skin and Sera Distinguish Morphea from Systemic Sclerosis.

Morphea is an inflammatory fibrotic disorder of the skin that has been likened to systemic sclerosis (SSc). We sought to examine the molecular landscape of morphea by examining lesional skin gene expression and blood biomarkers and comparing the gene expression profiles with those from site-matched nonlesional and SSc lesional skin. We found the morphea transcriptome is dominated by IFN-γ-mediated T helper 1 immune dysregulation, with a relative paucity of fibrosis pathways. Specifically, expression profiles of morphea skin clustered with the SSc inflammatory subset and were distinct from the those of SSc fibroproliferative subset. Unaffected morphea skin also differed from unaffected SSc skin because it did not exhibit pathological gene expression signatures. Examination of downstream IFN-γ-mediated chemokines, CXCL9 and CXCL10, revealed increased transcription in the skin but not in circulation. In contrast to transcriptional activity, CXCL9 was elevated in serum and was associated with active, widespread cutaneous involvement. Taken together, these results indicate that morphea is a skin-directed process characterized by T helper 1 immune-mediated dysregulation, which contrasts with fibrotic signatures and systemic transcriptional changes associated with SSc. The similarity between morphea and the inflammatory subset of SSc on transcriptional profiling indicates that therapies under development for this subset of SSc are also promising for treatment of morphea.

CXCL9 Links Skin Inflammation and Fibrosis through CXCR3-Dependent Upregulation of Col1a1 in Fibroblasts.

Morphea is characterized by initial inflammation followed by fibrosis of the skin and soft tissue. Despite its substantial morbidity, the pathogenesis of morphea is poorly studied. Previous work showed that CXCR3 ligands CXCL9 and CXCL10 are highly upregulated in the sera and lesional skin of patients with morphea. We found that an early inflammatory subcutaneous bleomycin mouse model of dermal fibrosis mirrors the clinical, histological, and immune dysregulation observed in human morphea. We used this model to examine the role of the CXCR3 chemokine axis in the pathogenesis of cutaneous fibrosis. Using the REX3 (Reporting the Expression of CXCR3 ligands) mice, we characterized which cells produce CXCR3 ligands over time. We found that fibroblasts contribute the bulk of CXCL9-RFP and CXCL10-BFP by percentage, whereas macrophages produce high amounts on a per-cell basis. To determine whether these chemokines are mechanistically involved in pathogenesis, we treated Cxcl9-, Cxcl10-, or Cxcr3-deficient mice with bleomycin and found that fibrosis is dependent on CXCL9 and CXCR3. Addition of recombinant CXCL9 but not CXCL10 to cultured mouse fibroblasts induced Col1a1 mRNA expression, indicating that the chemokine itself contributes to fibrosis. Taken together, our studies provide evidence that CXCL9 and its receptor CXCR3 are functionally required for inflammatory fibrosis.

Autoantigen microarrays reveal myelin basic protein autoantibodies in morphea.

BACKGROUND: Morphea is an autoimmune, sclerosing skin disorder. Despite the recent emphasis on immune dysregulation in morphea, the role of autoantibodies in morphea pathogenesis or utility as biomarkers are poorly defined. METHODS: Autoantigen microarray was used to profile autoantibodies from the serum of participants from the Morphea in Adults and Children (MAC) cohort. Clinical and demographic features of morphea patients with myelin basic protein (MBP) autoantibodies were compared to those without. MBP immunohistochemistry staining was subsequently performed in morphea skin to assess for perineural inflammation in areas of staining. Immunofluorescence staining on mouse brain tissue was also performed using patient sera and mouse anti-myelin basic protein antibody to confirm the presence of MBP antibodies in patient sera. RESULTS: Myelin basic protein autoantibodies were found in greater frequency in morphea (n = 50, 71.4%) compared to systemic sclerosis (n = 2, 6.7%) and healthy controls (n = 7, 20%). Patients with MBP antibodies reported pain at higher frequencies. Morphea skin biopsies, highlighted by immunohistochemistry, demonstrated increased perineural inflammation in areas of MBP expression. Immunofluorescence staining revealed an increased fluorescence signal in myelinated areas of mouse brain tissue (i.e. axons) when incubated with sera from MBP antibody-positive morphea patients compared to sera from MBP antibody-negative morphea patients. Epitope mapping revealed target epitopes for MBP autoantibodies in morphea are distinct from those reported in MS, and included fragments 11-30, 41-60, 51-70, and 91-110. CONCLUSIONS: A molecular classification of morphea based on distinct autoantibody biosignatures may be used to differentially classify morphea. We have identified anti-MBP as a potential antibody associated with morphea due to its increased expression in morphea compared to healthy controls and systemic sclerosis patients.

Emerging treatments for scleroderma/systemic sclerosis.

Systemic sclerosis (SSc) is a connective tissue disease characterized by progressive fibrosis of the skin and internal organs and has significant clinical sequelae. Management of SSc cutaneous disease remains challenging and often is driven by extracutaneous manifestations. Methotrexate is the typical first-line therapy for patients with early progressive cutaneous disease. However, in patients with diffuse progressive skin disease and inflammatory arthritis, methotrexate or rituximab monotherapy should be considered. First-line therapy for patients with concomitant myositis includes methotrexate or intravenous immunoglobulin (IVIG). For patients with both cutaneous findings and interstitial lung disease, studies have suggested the efficacy of mycophenolate mofetil or rituximab. Second-line therapies, including UVA-1 phototherapy, IVIG, or rituximab, can be considered in patients with disease refractory to first-line treatments. Clinical trials investigating the utility of emerging therapies such as abatacept and tocilizumab in the treatment of SSc are under way, and preliminary results are promising. Nonetheless, all patients with SSc benefit from a gentle skin-care regimen to alleviate pruritis, which is a commonly reported symptom. Additional cutaneous manifestations of SSc include telangiectasias, calcinosis cutis, microstomia, and Raynaud's phenomenon. Telangiectasia may be managed with camouflage techniques, pulse dye laser, and intense pulse light. Calcinosis cutis therapy is guided by the size of the calcium deposits, although treatment options are limited. Mouth augmentation and oral stretching exercises are recommended for patients with reduced oral aperture. Raynaud's phenomenon is treated with a combination of lifestyle modification and calcium channel blockers, such as amlodipine. Overall, SSc is a clinically heterogenous disease that affects multiple organ systems. Providers should assess extracutaneous involvement and use evidence-based recommendations to select the most appropriate therapy for patients with SSc.

Role of biomarkers in the diagnosis and prognosis of patients with cutaneous lupus erythematosus.

Cutaneous lupus erythematosus (CLE) is a connective tissue disease with varying presentations, and clinical sequelae including itching, dyspigmentation, and scarring. CLE can occur as its own entity or in conjunction with systemic disease, known as systemic lupus erythematosus (SLE). Because CLE is clinically diverse, identification of a biomarker may help not only facilitate early diagnosis and management but also identify individuals at risk for poor prognosis and development of SLE. While potential biomarkers in SLE have been extensively studied, few biomarkers for CLE have been identified and incorporated into clinical practice. Anti-SS-A antibody is a commonly used biomarker for diagnosis of subacute CLE patients. Type I interferon-related proteins such as MxA and guanylate binding protein-1 (GBP-1) and chemokines such as CXCR3, CXCL9, and CXCL10 have been identified as biomarkers that may support diagnosis and track disease activity. First-line oral treatment for CLE currently consists of anti-malarials such as hydroxychloroquine (HCQ), chloroquine (CQ), and quinacrine (QC). Studies have found that an increased myeloid dendritic cell population with higher TNF-α expression may be predictive of poor treatment response to HCQ in CLE patients. Autoantibodies against nuclear antigens (e.g., anti-double-stranded DNA and anti-Smith antibodies) and elevated erythrocyte sedimentation rate have been more commonly found in CLE patients progressing to SLE than those who have not. This review aims to summarize previous and emerging biomarkers for CLE patients.

An Evaluation of the Performance of Current Morphea Subtype Classifications.

Importance: Numerous classification systems for morphea subtypes exist, but none have been systematically evaluated for their ability to categorize patients with morphea into demographically and clinically coherent groups. Although some subtypes, such as linear morphea, are present across all the classification schemes, others list unique subtypes. This creates confusion among investigators and practitioners and impairs accurate categorization of patients for study and clinical evaluation. Objective: To evaluate how frequently the commonly used morphea classification systems categorize patients with morphea into clinically relevant subtypes using cross-sectional analysis of 2 large patient cohorts. Design, Setting, and Participants: This cross-sectional study comprised 944 adults and children from 2 prospective cohorts-the Morphea in Adults and Children at the University of Texas Southwestern Medical Center (Dallas, Texas), which enrolled participants from July 20, 2007, to September 21, 2018, and the National Registry for Childhood-Onset Scleroderma at the University of Pittsburgh (Pittsburgh, Pennsylvania), which enrolled participants from October 23, 2002, to November 13, 2018. Main Outcomes and Measures: Patient demographic characteristics, morphea subtype, quality-of-life measures, disease activity, and damage as measured by Localized Scleroderma Cutaneous Assessment Tool scores during initial visits. Results: A total of 944 participants (444 patients with adult-onset morphea and 500 patients with pediatric-onset morphea; 741 female participants [78%]; median age at onset, 16 years [interquartile range, 8-44 years]) were included in this study. Most participants were White (723 [77%]) and had the linear (474 [50%]) or generalized subtype of morphea (244 [26%]). With the use of the previously published Padua criteria, most patients were classified to have linear morphea (474 [50%]), followed by generalized morphea (244 [26%]), plaque morphea (141 [15%]), mixed morphea (38 [4%]), and pansclerotic morphea (3 [0.3%]). Overall, the Padua criteria successfully classified 900 patients (95%) in comparison with the Peterson criteria (533 [56%]) and the European Dermatology Forum classification (487 [52%]). Conclusions and Relevance: In this cross-sectional study of morphea subtype classification systems, the Padua criteria performed best in classifying patients into subgroups with cohesive demographic and clinical features, supporting its widespread use. However, they have ambiguities that might lead to misclassification, particularly in terms of generalized and pansclerotic morphea and descriptors such as morphea profunda. Consensus-based approaches are needed to address these ambiguities and develop a unified classification scheme.

Morphea patients with mucocutaneous involvement: A cross-sectional study from the Morphea in Adults and Children (MAC) cohort.

BACKGROUND: Demographic and clinical findings of patients with mucocutaneous morphea have not been well characterized, to our knowledge. OBJECTIVE: To determine the demographic and clinical characteristics of morphea patients with mucocutaneous lesions who were enrolled in the Morphea in Adults and Children cohort. METHODS: Cross-sectional study of 735 patients in the Morphea in Adults and Children cohort from 2007 to 2018. RESULTS: A total of 4.6% of linear morphea patients had oral involvement versus 2.4% among the entire cohort, whereas 10.3% of generalized morphea patients had genital involvement versus 3.7% among the entire cohort. Patients with genital lesions were older at disease onset than those with oral morphea (57 versus 11.5 years; P < .001) and had more frequent extragenital lichen sclerosus et atrophicus (59.2% versus 5.6%; P = .004). LIMITATIONS: Selection bias and limited number of affected subjects. CONCLUSION: Oral morphea lesions predominate in younger patients with facial linear morphea, whereas genital lesions predominate in postmenopausal women with overlying extragenital lichen sclerosus et atrophicus.

Chronic lymphocytic leukemia skin infiltrates presenting as eyebrow alopecia and erythematous pruritic papules refractory to treatment with topical steroids.

We describe a patient who presented with erythematous papules and hair loss solely limited to the eyebrows. Clinicians should be aware of this presentation of leukemia cutis and consider this diagnosis in a patient with a history of CLL.

Robust measurement of clinical improvement in patients with cutaneous lupus erythematosus.

Objective: The severity and disease course of cutaneous lupus erythematosus (CLE) are highly variable. Consequently, outcome measures for CLE clinical improvement are heterogeneous, complicating treatment decisions and therapeutic development. This study characterises CLE outcome measures and identifies the influence of clinical improvement thresholds on strengths of associations with patient demographic and clinical factors. Methods: In this pilot cohort study, multivariable models identified factors associated with CLE activity and skin damage improvement, defined as relative decreases in Cutaneous Lupus Activity and Severity Index (CLASI) activity (CLASI-A) and damage (CLASI-D) scores, over ranges of response thresholds. Results: 66 patients with 119 visit-pairs were included in the CLASI-A analysis. 74 patients with 177 visit-pairs were included in the CLASI-D analysis. Factors associated with CLE activity and damage improvement depended on the response threshold. Some associations were stronger at more stringent thresholds, including subacute CLE predominance with increased likelihood of CLASI-A improvement (R2=0.73; 50% reduction: OR 1.724 (95% CI 0.537 to 5.536); 75%: 5.67 (95% CI 1.56 to 20.5)) and African-American race with decreased likelihood of CLASI-D improvement (R2=0.80; 20%: 0.40 (95% CI 0.17 to 0.93); 40%: 0.25 (95% CI 0.08 to 0.82)). Other associations were stable across multiple thresholds, including older age of CLE development with increased likelihood of CLASI-A improvement (R2=0.25; 50%: 1.05 (95% CI 1.01 to 1.09]; 75%: 1.05 (95% CI 1.00 to 1.10)) and higher initial disease activity with decreased likelihood of CLASI-D improvement (R2=0.55; 20%: 0.91 (95% CI 0.84 to 0.98); 40%: 0.88 (95% CI 0.79 to 0.97)). Conclusions: Examining a range of CLASI threshold outcomes can comprehensively characterise changes in disease course in patients with CLE. Insufficiently stringent thresholds may fail to distinguish meaningful clinical change from natural fluctuation in disease activity.