Disease Course and Risk of Relapse in Juvenile Localized Scleroderma: A Single‐Center Retrospective Study

Juvenile localized scleroderma (JLS), also known as morphea, is a rare autoimmune disorder characterized by inflammation and fibrosis of the skin and underlying tissues, often resulting in notable functional and cosmetic sequelae. Methotrexate (MTX), often administered alongside short-term systemic corticosteroids, remains the cornerstone of therapy. While systemic immunosuppression has been demonstrated to induce disease remission, relapse following treatment cessation remains a significant concern. Reported relapse rates in the literature vary widely, ranging from 12.5% to 53%, and pediatric patients appear more susceptible to relapse than adults [1-9]. Despite this, limited data exist on pediatric predictors of relapse, particularly in relation to clinical features such as age at onset, ANA status, JLS subtype, and duration of MTX therapy. To address this knowledge gap, we conducted a retrospective cohort study at Alberta Children's Hospital (Calgary, Alberta, Canada), evaluating remission and relapse patterns in children with JLS patients treated with MTX over a 6-year period (2014–2019). Ethics approval was obtained from the University of Calgary Conjoint Research Ethics Board (REB 18-2039). Diagnosis was based on standard clinical criteria, and patients with more than one superficial plaque were treated according to Childhood Arthritis and Rheumatology Research Alliance (CARRA) protocols consensus treatment plans with systemic corticosteroids (either intravenous [IV] methylprednisolone or oral [PO] prednisone) for 3 months, along with maintenance MTX (PO or subcutaneous [SC]) if their JLS is felt to be active clinically and/or based on skin biopsy [10]. Duration of the MTX treatment was based on the clinical judgment of the treating physicians. The average weekly dose of methotrexate administered across the cohort was 15 mg/m2, either PO or SC, depending on the patient's preference. Dosage for methylprednisolone was 30 mg/kg/day (up to a maximum of 1 g/day) IV for 3 consecutive days per month for 3 months. PO prednisone was also dosed according to the CARRA CTPs [10]. Patients who experienced a disease flare after discontinuing systemic therapy were restarted on the consensus protocol, which included 3 months of systemic corticosteroids along with maintenance methotrexate (MTX). For patients flaring while on MTX, treatment was adjusted by either increasing the MTX dose, switching to subcutaneous administration, or adding mycophenolate mofetil (MMF) [11, 12]. During active systemic therapy, adjunctive topical agents—such as calcipotriol/betamethasone and topical tacrolimus—were applied to specific active lesions. These topical treatments were typically discontinued prior to MTX cessation. Following MTX discontinuation, no routine adjunctive or maintenance therapy was administered unless there was clinical evidence of a disease flare. In such cases, systemic and/or topical immunomodulatory therapy was reinstated. A total of 24 patients were included in the cohort, of whom 22 (91.7%) completed a course of MTX therapy. Two patients opted not to continue systemic treatment for personal reasons and were managed with topical agents alone. All MTX-treated patients achieved disease remission. Eleven patients (50.0%) achieved remission within 6 months of treatment initiation, and 21 patients (95.5%) within 1 year. The mean duration of MTX therapy was 28.7 ± 14.5 months (range: 14.0–73.1 months), and the mean time to remission was 6.7 ± 3.8 months (range: 2.1–16.3 months). The median age at baseline was 12.1 years (IQR = 10.6–14.3), with 70.8% (n = 17) of patients being female. Most had the linear subtype of JLS with trunk/limb distribution (n = 14; 58.3%), while six patients (25.0%) had craniofacial distribution, one of whom also had trunk/limb involvement. Another six patients (25.0%) had other JLS distributions, including one with a mixed subtype that also had linear trunk/limb involvement. ANA status was positive in 37.5% of the cohort. Extracutaneous manifestations were present in 45.8% of patients: neurologic (n = 4; 16.6%), ophthalmologic (n = 1; 4.2%), musculoskeletal (n = 6; 25.0%), and Raynaud's phenomenon (n = 2; 8.3%). Seven patients (29.2%) required physiotherapy or occupational therapy. The baseline cutaneous disease activity, as measured by the modified Localized Scleroderma Skin Severity Index (mLoSSI), ranged from 1.25 to 7.5, with a reported median score of 5.5. Of the 22 patients treated with MTX, 20 completed an adequate course and subsequently discontinued therapy during the study, while 2 remained on MTX at their last follow-up after achieving remission. Among the 20 patients who discontinued MTX, 6 (30.0%) experienced disease relapse. An additional three patients relapsed while still receiving a lower dose of MTX, resulting in a total of nine relapses in the cohort. Relapses were managed with MTX plus corticosteroids in 6 patients (66.7%) and MTX monotherapy in three patients (33.3%), and no patients required mycophenolate. The mean MTX duration without subsequent relapse was 25.7 ± 8.6 months, compared with 32.1 ± 19.5 months in those who relapsed (p = 0.45). Mean time to relapse after discontinuation was 14.5 ± 10.3 months. Seven of the nine relapses (77.8%) occurred at the same anatomical site as the original lesion, and eight out of nine (88.9%) occurred in patients with linear trunk/limb disease. Figure 1 illustrates a patient experiencing a relapse at the same site. Exploratory univariable and multivariable logistic regression analyses did not identify any statistically significant clinical predictors of relapse (Table 1). In the univariable analysis, no significant associations were found between relapse and sex (p = 0.40), age at disease onset (p = 0.75), ANA positivity (p = 0.29), or JLS subtype (trunk/limb, p = 0.11; other, p = 0.32). Similarly, multivariable logistic regression revealed no significant associations with sex (p = 1.00), age (p = 0.85), or ANA positivity (p = 1.00). Inclusion of JLS subtype in the multivariable model was not possible due to the limited sample size. Our findings confirm the effectiveness of MTX in achieving disease remission in pediatric JLS, with nearly all patients achieving remission within 1 year of therapy initiation. Previous studies examining the association between MTX treatment duration and relapse have yielded mixed results. Some have suggested that shorter treatment duration may increase the risk of relapse, advocating for prolonged therapy to sustain remission [6, 9, 12]. Conversely, other studies have not found a significant relationship between treatment duration and relapse risk [5, 13], suggesting that additional factors—such as disease subtype or individual patient characteristics—may play a role. Our findings did not identify a significant difference in MTX duration between those who relapsed and those who did not. This may reflect underlying disease heterogeneity or a threshold effect beyond which continued therapy provides diminishing preventive benefit. While most relapses in our study occurred in the linear subtype (89%), this was not statistically significant. Some studies have linked linear involvement to relapse due to a more systemic inflammatory process [4, 5, 14], but others found no association [2]. ANA positivity, which is thought to indicate higher immune autoreactivity [15], showed no consistent association with relapse risk in our study and prior studies [2, 4]. Importantly, MTX was well tolerated. No patients experienced serious adverse events requiring therapy discontinuation. Two patients required MTX dose reduction due to gastrointestinal intolerance; both remained in remission. This study is limited by its retrospective, single-center design and small sample size, which restricts the ability to detect subtle associations. Nonetheless, the findings emphasize the necessity for long-term follow-up, as the mean time to relapse exceeded 1 year after MTX discontinuation. These results underscore the unpredictable nature of disease relapse and the need for vigilant monitoring even after prolonged disease quiescence. In conclusion, MTX remains highly effective in inducing clinical remission in pediatric JLS. Nevertheless, disease relapse following treatment cessation is relatively common, underscoring the necessity for prolonged vigilance and individualized management. In our cohort, no statistically significant clinical predictors of relapse—including age at disease onset, sex, ANA positivity, JLS subtype or MTX treatment duration—were identified, reflecting the heterogeneous nature of disease pathophysiology. Future studies with larger, multicenter cohorts are warranted to systematically evaluate potential relapse risk factors. These may include clinical variables (disease subtype, lesion distribution, extent of cutaneous involvement, presence of extracutaneous manifestations), laboratory markers indicative of subclinical immune activity (ANA titers, erythrocyte sedimentation rate, C-reactive protein, cytokine profiles), imaging-based assessments of residual inflammation or fibrosis (on ultrasound or MRI), and genetic or environmental determinants. A comprehensive, multimodal approach may facilitate the identification of patients at heightened risk for relapse and inform evidence-based strategies for treatment duration, tapering, and post-remission monitoring. Merna Adly: data collection, synthesis and writing of manuscript. Brendan C. Lethebe: statistical analysis. Vimal H. Prajapati, Rebeka Stevenson, and Nadia J. Luca: revision and editing of manuscript. The authors have nothing to report. This study was conducted in accordance with ethical standards and received approval from University of Calgary Conjoint Research Ethics Board (REB 18-2039). Informed consent was obtained from all participants prior to their inclusion in the study. All authors confirm that they have obtained informed consent from the patient(s) or their legal guardian(s) for the publication of this study, including any relevant images or data. Identifying details have been anonymized to protect patient confidentiality. The authors declare no conflicts of interest. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.