Patients with autoimmune skin diseases are at increased risk of adverse pregnancy outcomes.

BACKGROUND: Increased rates of adverse pregnancy outcomes have been reported in association with rheumatologic diseases such as systemic lupus erythematosus, rheumatoid arthritis, dermatomyositis. However, little is known about pregnancy outcomes in patients with autoimmune skin diseases. OBJECTIVE: This study aimed to determine the frequency of adverse pregnancy outcomes in patients with autoimmune skin diseases. We hypothesized that similar to rheumatic diseases, the rate of adverse pregnancy outcomes in patients with autoimmune skin diseases would be higher than the general population. STUDY DESIGN: This is a case control study using the TriNetX US Collaborative Network, which is a database of electronic medical records of >95 million patients seen at 57 healthcare organizations in the United States. All pregnant women between the ages of 15 and 44 years who were seen at a healthcare organization between January 1, 2016 and December 31, 2021 were included. Participants with autoimmune skin disease were matched to healthy controls and controls with systemic rheumatologic conditions (systemic lupus erythematosus or rheumatoid arthritis). For both the autoimmune skin disease and healthy control groups, those with systemic rheumatologic condition or hidradenitis suppurativa were excluded. The primary outcomes were adverse pregnancy outcomes defined as spontaneous abortion, gestational hypertension, preeclampsia or eclampsia, gestational diabetes mellitus, intrauterine growth restriction, preterm premature rupture of membranes, preterm birth, and stillbirth. Patients with autoimmune skin diseases and controls were 1:1 propensity score-matched by age, race, ethnicity, comorbidities, obesity, and substance use. For each outcome, odds ratio with a 95% confidence interval was calculated. RESULTS: A total of 2788 patients with autoimmune skin diseases were matched to 2788 healthy controls. Patients with autoimmune skin diseases were at a higher risk of spontaneous abortions than controls (odds ratio, 1.54; 95% confidence interval, 1.36-1.75; P<.001). Compared with patients with systemic lupus erythematosus, patients with autoimmune skin diseases were at lower risk of having infants with intrauterine growth restriction (odds ratio, 0.59; 95% confidence interval, 0.4-0.87; P=.01), preterm birth (odds ratio, 0.68; 95% confidence interval, 0.47-0.98; P=.04), and stillbirth (odds ratio, 0.50; 95% confidence interval, 0.25-0.97; P=.04). The differences in adverse pregnancy outcomes between patients with autoimmune skin diseases and those with rheumatoid arthritis were not statistically significant. CONCLUSION: Patients with autoimmune skin diseases are at a higher risk of spontaneous abortions than patients without autoimmune skin diseases. When analyzed by each autoimmune skin disease, patients with cutaneous lupus erythematosus or vitiligo remained at increased risk of spontaneous abortions compared with patients without autoimmune skin diseases. Patients with autoimmune skin diseases have similar risks of adverse pregnancy outcomes as patients with rheumatoid arthritis, but lower risks than patients with systemic lupus erythematosus.

Clinical Characteristics Associated with Musculoskeletal Extracutaneous Manifestations in Pediatric and Adult Morphea: A Prospective, Cohort Study.

Morphea is an autoimmune condition of the skin associated with functional sequelae resulting from musculoskeletal involvement. Systematic investigation of risk for musculoskeletal involvement is limited, particularly in adults. This knowledge gap impairs patient care because practitioners are unable to risk stratify patients. To address this gap, we determined the frequency, distribution, and type of musculoskeletal (MSK) extracutaneous manifestations affecting joint and bone with overlying morphea lesions using cross-sectional analysis of 1,058 participants enrolled in two prospective cohort registries (Morphea in Children and Adults Cohort [n = 750] and National Registry for Childhood Onset Scleroderma [n = 308]). Additional analysis included the identification of clinical features associated with MSK extracutaneous manifestations. MSK extracutaneous manifestations occurred in 274 of 1,058 participants (26% overall, 32% pediatric, and 21% adults). Children had a limited range of motion of larger joints (i.e., knees/hips/shoulders), whereas the involvement of smaller joints (i.e., toes/temporomandibular joint) was more common in adults. Multivariable logistic regression showed that deep tissue involvement had the strongest association with musculoskeletal features, with a lack of deep tissue involvement having a negative predictive value of 90% for MSK extracutaneous manifestations. Our results underscore the need to evaluate MSK involvement in adult and pediatric patients and the utility of using depth of involvement in addition to anatomic distribution to risk stratify patients.

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.

Measuring asymmetry in facial morphea via 3-dimensional stereophotogrammetry.

BACKGROUND: Objectively determining tissue loss in craniofacial morphea is challenging. However, 3-dimensional (3D) stereophotogrammetry is a noninvasive modality that may be a useful adjunct. OBJECTIVE: To prospectively evaluate 3D stereophotogrammetry in the assessment of craniofacial linear morphea. METHODS: Participants underwent clinical, quality-of-life, and 3D-stereophotogrammetry assessments. Traditional photographs and 3D-stereophotogrammetry images were rated as mild, moderate, or severe by 2 experts and 2 nonexperts. In addition, interrater and intrarater reliability (on delayed rescoring) were calculated. RESULTS: Of 23 patients with craniofacial morphea, 3D stereophotogrammetry detected pathologic asymmetry in 14 (20.6%) patients. Providers rated patients as more severely affected when using 3D stereophotogrammetry versus when using traditional photographs (19% severe on 3D stereophotogrammetry vs 0% severe on traditional photographs, P = .004). Qualitative ratings of both traditional and 3D images showed high inter- and intrarater reliability between experts and nonexperts alike. Physicians' Global Assessment of Damage scores correlated with mouth asymmetry (P = .0021), cheek asymmetry (P = .04), and 3D-stereophotogrammetry ratings (median, mild: 27.5 vs moderate: 46.5 vs severe: 64, P = .0152). Lower face asymmetry correlated with worse quality-of-life scores (P = .013). LIMITATIONS: Small sample size and cross-sectional design. CONCLUSION: 3D stereophotogrammetry can reliably detect and quantify asymmetry in craniofacial morphea with greater sensitivity than that observed with traditional assessment alone. 3D stereophotogrammetry may be a useful adjunct to clinical examination.

Morphea disease activity during pregnancy: A case series.

Little is known about pregnancy in women with morphea. We aimed to describe the clinical presentation, pregnancy outcomes, and medical management of morphea during pregnancy. We conducted a case series of female patients of reproductive age (18-49 years) who were part of the longitudinal MAC (Morphea in Adults and Children) cohort seen in the outpatient dermatology clinic at the University of Texas Southwestern from July 2007 to February 2022. Women who were pregnant during research visits and had at least 6 months of follow-up in the MAC cohort were included. Data collected included demographics, morphea characteristics, pregnancy outcomes, and medication history. Median clinical disease activity and damage scores using the Localized Scleroderma Cutaneous Assessment Tool were recorded. Ten patients were pregnant during the study period. Five patients had pediatric-onset morphea and five had adult-onset morphea. Eight patients had linear and two had plaque morphea. Six patients had at least one morphea lesion on their abdomen. Median age at first pregnancy was 31 years (interquartile range [IQR], 26.0-35.8 years) and median duration of morphea was 13.5 years (IQR, 4.8-19.0 years). In seven patients, damage scores were stable with no increased morphea activity. Three patients (30%) experienced reactivation of morphea activity during pregnancy with a median Localized Scleroderma Activity Index of 4 (IQR, 2.5-10). Only one patient required immunosuppressive therapy during pregnancy for her morphea diagnosis. Seven of 10 patients had cesarean deliveries and one adverse fetal outcome was reported. In this small series, most patients maintained stability of their morphea and there were no adverse pregnancy outcomes directly related to morphea.

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.

Morphea: progress to date and the road ahead.

Morphea is a rare autoimmune condition causing inflammation and sclerosis of the skin and underlying soft tissue. It is characterized by periods of activity (inflammation admixed with fibrosis), ultimately resulting in permanent damage (pigment change and tissue loss). Damage resulting from unchecked activity can lead to devastating, permanent cosmetic and functional sequelae including hair loss; cutaneous, soft tissue and bony atrophy; joint contractures; and growth restriction of the affected body site in children. This makes the early identification of activity and initiation of appropriate treatment crucial to limiting damage in morphea. To this end, recent investigative work has focused on validation of clinical, biomarker, imaging, and histologic outcomes aimed at accurately quantifying activity and damage. Despite promising results, further work is needed to better validate these measures before they can be used in the clinic and research settings. Although there has been recent approval of less toxic, targeted therapies for many inflammatory skin conditions, none have been systematically investigated in morphea. The mainstays of treatment for active morphea are corticosteroids and methotrexate. These are often limited by substantial toxicity. The paucity of new treatments for morphea is the result of a lack of studies examining its pathogenesis, with many reviews extrapolating from research in systemic sclerosis. Recent studies have demonstrated the role of dysregulated immune and fibrotic pathways in the pathogenesis of morphea, particularly interferon (IFN) gamma related pathways. Active morphea lesions have been found to display an inflammatory morphea signature with CXCR3 receptor ligands, as well as a distinct fibrotic signature reflecting fibroblast activation and collagen production. CXCL9 and 10 have been associated with increased measures of disease activity. While immune dysfunction is thought to play the primary role in morphea pathogenesis, there are other factors that may also contribute, including genetic predisposition, environmental factors, and vascular dysregulation. There remains an essential need for further research to elucidate the pathogenesis of morphea and the mode of action of dysregulated upstream and downstream immune and fibrotic pathways. These studies will allow for the discovery of novel biomarkers and targets for therapeutic development.

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.

Changes in Disease Activity and Damage Over Time in Patients With Morphea.

Importance: Prospective studies of the disease course in patients with morphea are lacking, particularly those comparing adults and children. Objective: To investigate the disease course in patients with morphea treated with standard-of-care therapy using validated clinical outcome measures. Design, Setting, and Participants: Prospective cohort study of 130 adults and children from the Morphea in Adults and Children cohort with at least 2 years of clinical follow-up and Localized Scleroderma Cutaneous Assessment Tool scores recorded at each study visit. Study patients were seen at a tertiary referral center (UT Southwestern Medical Center, Dallas, Texas) from November 1, 2008, through April 1, 2016. The dates of analysis were May 2016 through July 2019. Exposures: All patients received standard-of-care therapy. Main Outcomes and Measures: Patterns in disease activity and recurrence were examined. The time to recurrence of morphea disease activity from the first visit with inactive disease was assessed using survival analysis with the log-rank test to compare differences between morphea subtypes. Results: In total, 130 adults and children (663 study visits) were included in this study. The mean (SD) age of patients was 34.4 (23.8) years, and 101 of 130 (78%) were female. The mean (SD) follow-up was 4.3 (1.7) years. Fifty patients had at least 5 years of follow-up. Most patients were white individuals (96 of 130 [74%]) and had linear subtype (72 of 130 [55%]) or generalized subtype (40 of 130 [31%]). Overall, 13 of 30 (43%) with generalized subtype had recurrence of disease activity compared with 14 of 66 (21%) with linear subtype (hazard ratio, 3.28; 95% CI, 1.38-7.79). The median (interquartile range) time to first recurrence of disease activity after initial resolution of disease activity was 1.1 (0.8-1.9) years for generalized subtype and 2.3 (1.0-3.3) years for linear subtype. Of the 50 patients followed up for at least 5 years, 18 (36%) had recurrence of disease activity. Conclusions and Relevance: Disease activity appeared to improve in most patients with morphea over 6 to 12 months using previously published treatment plans, underscoring their effectiveness. Sclerosis improved more slowly (over 2-5 years), often after discontinuation of treatment, but atrophy increased slightly as sclerosis subsided. Standard-of-care therapy appears to improve disease activity, which allows sclerosis to improve, and provides relative stability of other features of disease damage. A substantial number of patients, particularly those with generalized subtype, have a relapsing-remitting course over many years. Patients with morphea should be monitored for recurrent disease activity over extended periods.

Morphea: Current concepts.

Morphea is an inflammatory, sclerosing skin disorder that can involve the underlying soft tissues. Although the cause of morphea remains poorly investigated, genetic predisposition, immune dysregulation, and environmental factors have been implicated. Morphea is associated with cosmetic and functional sequelae, and internal organ involvement is rare. Early diagnosis and treatment are imperative to minimize damage such as limitation of range of motion. This review summarizes advances in diagnosis and treatment of morphea, allowing clinicians to better serve patients with this condition.

Transcriptional and Cytokine Profiles Identify CXCL9 as a Biomarker of Disease Activity in Morphea.

IFN-related pathways have not been studied in morphea, and biomarkers are needed. We sought to characterize morphea serum cytokine imbalance and IFN-related gene expression in blood and skin to address this gap by performing a case-control study of 87 participants with morphea and 26 healthy control subjects. We used multiplexed immunoassays to determine serum cytokine concentrations, performed transcriptional profiling of whole blood and lesional morphea skin, and used double-staining immunohistochemistry to determine the cutaneous cellular source of CXCL9. We found that CXCL9 was present at increased concentrations in morphea serum (P < 0.0001), as were other T helper type 1 cytokines. CXCL9 serum concentration correlated with the modified Localized Scleroderma Skin Severity Index (r = 0.44, P = 0.0001), a validated measure of disease activity. CXCL9 gene expression was also increased in inflammatory lesional morphea skin (fold change = 30.6, P = 0.006), and preliminary transcriptional profiling showed little evidence for IFN signature in whole blood. Double-staining immunohistochemistry showed CXCL9 co-localized with CD68+ dermal macrophages. In summary, inflammatory morphea is characterized by T helper type 1 cytokine imbalance in serum, particularly CXCL9, which is associated with disease activity. CXCL9 expression in lesional macrophages implicates the skin as the source of circulating cytokines. CXCL9 is a promising biomarker of disease activity in morphea.

Phototherapy for sclerosing skin conditions.

Phototherapy is an effective treatment strategy for a variety of sclerosing skin conditions. There are a number of phototherapeutic modalities used for the treatment of sclerosing skin conditions, including ultraviolet (UV)A1, broadband UVA, psoralen plus UVA, and narrowband UVB phototherapy. As controlled trials with validated outcome measures are lacking for these therapies, existing evidence is largely level II for morphea and is even more minimal for scleroderma and other sclerosing disorders (scleroderma, lichen sclerosus, and chronic graft-versus-host disease, among others). Studies do suggest that phototherapy may be effective for many of these disorders, including those that have been unresponsive to other therapies. Phototherapy remains an attractive therapeutic option for patients due to its efficacy and favorable risk-versus-benefit profile. Phototherapy also offers a therapeutic alternative to systemic immunosuppressives for patients who cannot tolerate these medications.