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.

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.

Not Just Skin Deep: Systemic Disease Involvement in Patients With Cutaneous Lupus.

Cutaneous lupus erythematosus, specifically discoid lupus erythematosus, disproportionately affects those with skin of color and may result in greater dyspigmentation and scarring in darker skin types. In this article, we review investigations relevant to cutaneous lupus patients with skin of color at University of Texas Southwestern Medical Center, associations and risk of progression to systemic lupus, and recommendations for monitoring for systemic disease spread. Between 5% and 25% of patients with cutaneous lupus can develop systemic lupus. If they progress to systemic disease, patients often develop mild systemic disease with primarily mucocutaneous and musculoskeletal manifestations. Patients with cutaneous lupus should be followed up closely to monitor for systemic disease involvement. The University of Texas Southwestern Cutaneous Lupus Erythematosus Registry, of which almost two thirds of participants are those with skin of color, is a part of an ongoing effort to better understand the pathophysiologic mechanisms of CLE and to identify prognostic indicators of risk of progression to systemic lupus.

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.

Quantitative assessment of synovitis in Legg-Calvé-Perthes disease using gadolinium-enhanced MRI.

A quantitative method to assess hip synovitis in Legg-Calvé-Perthes disease (LCPD) is not currently available. To develop this method, the areas of synovial enhancement on gadolinium-enhanced MRI (Gd-MRI) were measured by two independent observers. The volume of synovial enhancement was significantly increased in the initial and the fragmentation stages of LCPD (Waldenström stages I and II), with a persistence of synovitis into the reossification stage (stage III). The Gd-MRI method had high interobserver and intraobserver agreements and may serve as a useful method to monitor the effect of various treatments on hip synovitis in LCPD.