RARE DISEASE
Localized scleroderma
Localized scleroderma
Localized scleroderma
Synonyms: Localized fibrosing scleroderma
Synonyms: Localized fibrosing scleroderma
Synonyms: Localized fibrosing scleroderma
Drug discovery
3
drugs
With orphan designations
Overview
Localized scleroderma (LS) is an autoimmune disorder characterized by collagen overproduction, causing skin fibrosis and inflammation without systemic organ involvement. It presents as morphea (circumscribed plaques) or linear scleroderma (streaks affecting skin, muscle, or bone). While primarily cutaneous, deep tissue involvement may lead to limb asymmetry, joint contractures, or facial deformities. Diagnosis relies on clinical assessment and biopsy confirmation.
Burden
Disability-adjusted life years (DALY) disproportionately affect ages 15–54, driven by chronic disability [4].
Extracutaneous complications (e.g., musculoskeletal, neurological) occur in 20% of pediatric cases [6][19].
Quality-of-life impacts include disfigurement, pain, and fatigue, despite non-life-threatening progression [14][19].
Categories: rare skin diseases
Research Papers
859 drug discovery papers about Localized scleroderma, with 3 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
859 drug discovery papers about Localized scleroderma, with 3 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-08-05 | Co-Occurrence of En Coup de Sabre, Parry-Romberg Syndrome, and Hemimasticatory Spasm: A Case Report.
En coup de sabre (ECDS) and Parry-Romberg syndrome (PRS) are rare, localised scleroderma subtypes, often considered to be overlapping variants of morphea. Hemimasticatory spasm (HMS), a distinct rare neuromuscular disorder characterised by unilateral paroxysmal contraction of the jaw muscles, has rarely been reported in association with these conditions. A 20-year-old man presented with a linear, cicatricial alopecic patch over the left parietal scalp, along with indurated and bound-down skin over the left cheek. This was followed by progressive depression and asymmetry of the left midface, accompanied by paroxysmal spasms during mastication and swallowing. Examination revealed cicatricial alopecia over the left parietal region and an atrophic plaque over the ipsilateral cheek. The left lower lip and tongue were atrophic, while the ipsilateral masseter muscle was visibly hypertrophied. Histopathological findings of the cheek lesion were consistent with morphea. A clinical diagnosis of co-existing ECDS, PRS, and HMS was made. Botulinum toxin type A was used to treat HMS, with marked reduction in symptoms and improvement in quality of life. This case highlights the rare but meaningful association between ECDS, PRS, and HMS, underscoring the importance of early recognition and multidisciplinary intervention. Botulinum toxin remains a valuable therapeutic option for managing symptomatic HMS in such contexts.
2026-07-28 | Spatially resolved gene programs and cell neighborhoods of scleroderma fibroblasts 2261024
Abstract Introduction Systemic sclerosis (SSc, scleroderma) is a chronic autoimmune disease with high mortality, characterized by progressive fibrosis of the skin and internal organs. Skin involvement is among the earliest manifestations of disease, and changes in skin pathology can mirror systemic progression. While single-cell studies have revealed striking transcriptional diversity among dermal fibroblasts in SSc, the spatial organization and immune signals that govern their function remain unclear. Methods To address this, we performed high-resolution spatial transcriptomic profiling of clinically affected and unaffected skin from SSc donors alongside healthy controls. Results We identify known disease-associated fibroblast subsets, including COMP+ myofibroblasts, which localize within cell neighborhoods enriched in activated endothelial and immune cells. In contrast, LGR5+/PI16+ fibroblasts — abundant in healthy skin and previously shown to contain a T cell-inducible gene program — are significantly reduced in both clinically involved and uninvolved SSc skin and occupy distinct microenvironments from disease-associated cells. Conclusion Our findings provide a spatial framework for understanding fibroblast heterogeneity and identify potential therapeutic strategies aimed at reinforcing protective fibroblast programs to prevent or delay fibrosis in scleroderma. Funding Source R21AI185642 NIAID/NIH, National Scleroderma Foundation Topic Categories Immune Mechanisms of Human Disease (HUM)
2026-07-16 | IL-17 Signaling Inhibitors in Localized Scleroderma: A Single-Center Case Series of Nine Patients.
Localized scleroderma (LSc) is an autoimmune fibrosing disorder characterized by inflammation and sclerosis of the skin and underlying soft tissues. IL-17 signaling has been implicated in active inflammatory lesions, but treatment options for severe or refractory LSc remain limited. Here, we present nine patients with LSc treated with IL-17A or IL-17 receptor A inhibitors at our institution (ixekizumab, secukinumab, or brodalumab). These biologics were administered to patients refractory to conventional therapies or anticipated to have treatment-resistant disease, following institutional approval for unapproved drug use. Five patients improved, two stabilized, and two progressed. One patient developed pustulotic arthro-osteitis during brodalumab treatment, possibly representing a paradoxical reaction; no other major adverse events were observed. Although these uncontrolled retrospective data do not establish efficacy, they suggest that IL-17 pathway inhibition merits further study in selected patients with refractory LSc.
2026-07-14 | Redistribution of Gaze Patterns in Facial Localized Scleroderma Following Autologous Fat Transfer: An Eye-Tracking Study.
The study aimed to use eye-tracking technology objectively quantifying changes in visual attention patterns in observers viewing faces of patients with facial localized scleroderma (LoS) before and after autologous fat transplantation (AFT). In this retrospective observational study, preoperative and postoperative standardized photographs of 30 patients with facial localized scleroderma (LoS) were presented to 50 observers. Gaze data were recorded using an eye tracker. Fixation proportions were analyzed for all affected regions and for specific facial subunits. A total of 30,266 fixation points were recorded. Postoperatively, the fixation proportion on the affected hemiface significantly decreased by 4.92% (p<0.05), with a concomitant increase in fixations redirected toward the unaffected side. Furthermore, an increase of 2.39% (p<0.05) in fixation proportion was observed in the central T-zone (periorbital and nasal regions). Subunit analysis revealed reductions in fixations on the affected cheek (16.12% to 10.39%, p<0.05) and forehead (17.18% to 13.23%, p<0.05). Stratified analysis showed that severe dermal atrophy and severe dyspigmentation were associated with less postoperative fixation reduction, whereas fixation reduction did not differ significantly by subcutaneous atrophy severity. AFT alters observers' visual attention by reducing fixations on the affected facial areas and redirecting gaze toward the unaffected side and the central T-zone. This shift suggests a partial redistribution of social-perceptual gaze patterns toward a more typical facial viewing pattern. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .
2026-07-08 | CCN3-derived peptide BLR-200 impairs YAP activation and attenuates bleomycin-induced skin fibrosis through blocking the generation of Sfrp2-positive fibroblasts
ABSTRACT An autocrine pro-adhesive/pro-contractile signaling loop, through the mechanosensitive transcriptional cofactor YAP, promotes fibrosis. The CCN family of matricellular proteins modify adhesive signaling. Of these, CCN3 is antifibrotic. We show that BLR-200, a CCN3-derived peptide, has anti-fibrotic properties in the bleomycin-induced model of scleroderma skin fibrosis. In vitro, BLR-200 delayed, but did not abolish, fibroblast adhesion to collagen and nuclear YAP localization. In vivo , BLR-200 prevented/treated bleomycin-induced skin fibrosis, and reduced bleomycin-induced expression of profibrotic genes including α-smooth muscle actin, CCN1 and CCN2. Lineage tracing and scRNA-seq analyses revealed that the myofibroblasts in this model were quantitatively derived from collagen-lineage Pi16+/Col15+ve fibroblasts. BLR-200 prevented myofibroblast differentiation in this model and trajectory of fibroblasts toward a Sfrp2-positive subset, a cell type associated with poor clinical outcome. BLR-200 impairs YAP activation in vitro and appearance of translationally-relevant fibroblast subtypes in vivo and is a novel anti-fibrotic agent for SSc skin fibrosis. HIGHLIGHTS -SSc skin fibrosis, a major unmet need, is driven by an activated mechanotransduction/YAP pathway; how to block this pathway clinically is unclear -members of the CCN family of matricellular proteins are adhesive signaling modifiers; herein, we identify BLR-200, a synthetic peptide derived from CCN3, based on its ability to impair, but not ablate, YAP nuclear localization and fibroblast spreading/attachment to collagen -BLR-200 blocks and treats progression of bleomycin-induced skin fibrosis -In the bleomycin model, lineage tracing analysis revealed that collagen-lineage cells are the primary source of myofibroblasts -BLR-200 blocks myofibroblast differentiation concomitant with reduced progression toward Col8a1+ve and Sfrp2+ ve fibroblasts, populations implicated in SSc pathogenesis -BLR-200 represents a novel, translationally relevant drug candidate for SSc skin fibrosis
2026-08-05 | Co-Occurrence of En Coup de Sabre, Parry-Romberg Syndrome, and Hemimasticatory Spasm: A Case Report.
En coup de sabre (ECDS) and Parry-Romberg syndrome (PRS) are rare, localised scleroderma subtypes, often considered to be overlapping variants of morphea. Hemimasticatory spasm (HMS), a distinct rare neuromuscular disorder characterised by unilateral paroxysmal contraction of the jaw muscles, has rarely been reported in association with these conditions. A 20-year-old man presented with a linear, cicatricial alopecic patch over the left parietal scalp, along with indurated and bound-down skin over the left cheek. This was followed by progressive depression and asymmetry of the left midface, accompanied by paroxysmal spasms during mastication and swallowing. Examination revealed cicatricial alopecia over the left parietal region and an atrophic plaque over the ipsilateral cheek. The left lower lip and tongue were atrophic, while the ipsilateral masseter muscle was visibly hypertrophied. Histopathological findings of the cheek lesion were consistent with morphea. A clinical diagnosis of co-existing ECDS, PRS, and HMS was made. Botulinum toxin type A was used to treat HMS, with marked reduction in symptoms and improvement in quality of life. This case highlights the rare but meaningful association between ECDS, PRS, and HMS, underscoring the importance of early recognition and multidisciplinary intervention. Botulinum toxin remains a valuable therapeutic option for managing symptomatic HMS in such contexts.
2026-07-28 | Spatially resolved gene programs and cell neighborhoods of scleroderma fibroblasts 2261024
Abstract Introduction Systemic sclerosis (SSc, scleroderma) is a chronic autoimmune disease with high mortality, characterized by progressive fibrosis of the skin and internal organs. Skin involvement is among the earliest manifestations of disease, and changes in skin pathology can mirror systemic progression. While single-cell studies have revealed striking transcriptional diversity among dermal fibroblasts in SSc, the spatial organization and immune signals that govern their function remain unclear. Methods To address this, we performed high-resolution spatial transcriptomic profiling of clinically affected and unaffected skin from SSc donors alongside healthy controls. Results We identify known disease-associated fibroblast subsets, including COMP+ myofibroblasts, which localize within cell neighborhoods enriched in activated endothelial and immune cells. In contrast, LGR5+/PI16+ fibroblasts — abundant in healthy skin and previously shown to contain a T cell-inducible gene program — are significantly reduced in both clinically involved and uninvolved SSc skin and occupy distinct microenvironments from disease-associated cells. Conclusion Our findings provide a spatial framework for understanding fibroblast heterogeneity and identify potential therapeutic strategies aimed at reinforcing protective fibroblast programs to prevent or delay fibrosis in scleroderma. Funding Source R21AI185642 NIAID/NIH, National Scleroderma Foundation Topic Categories Immune Mechanisms of Human Disease (HUM)
2026-07-16 | IL-17 Signaling Inhibitors in Localized Scleroderma: A Single-Center Case Series of Nine Patients.
Localized scleroderma (LSc) is an autoimmune fibrosing disorder characterized by inflammation and sclerosis of the skin and underlying soft tissues. IL-17 signaling has been implicated in active inflammatory lesions, but treatment options for severe or refractory LSc remain limited. Here, we present nine patients with LSc treated with IL-17A or IL-17 receptor A inhibitors at our institution (ixekizumab, secukinumab, or brodalumab). These biologics were administered to patients refractory to conventional therapies or anticipated to have treatment-resistant disease, following institutional approval for unapproved drug use. Five patients improved, two stabilized, and two progressed. One patient developed pustulotic arthro-osteitis during brodalumab treatment, possibly representing a paradoxical reaction; no other major adverse events were observed. Although these uncontrolled retrospective data do not establish efficacy, they suggest that IL-17 pathway inhibition merits further study in selected patients with refractory LSc.
2026-07-14 | Redistribution of Gaze Patterns in Facial Localized Scleroderma Following Autologous Fat Transfer: An Eye-Tracking Study.
The study aimed to use eye-tracking technology objectively quantifying changes in visual attention patterns in observers viewing faces of patients with facial localized scleroderma (LoS) before and after autologous fat transplantation (AFT). In this retrospective observational study, preoperative and postoperative standardized photographs of 30 patients with facial localized scleroderma (LoS) were presented to 50 observers. Gaze data were recorded using an eye tracker. Fixation proportions were analyzed for all affected regions and for specific facial subunits. A total of 30,266 fixation points were recorded. Postoperatively, the fixation proportion on the affected hemiface significantly decreased by 4.92% (p<0.05), with a concomitant increase in fixations redirected toward the unaffected side. Furthermore, an increase of 2.39% (p<0.05) in fixation proportion was observed in the central T-zone (periorbital and nasal regions). Subunit analysis revealed reductions in fixations on the affected cheek (16.12% to 10.39%, p<0.05) and forehead (17.18% to 13.23%, p<0.05). Stratified analysis showed that severe dermal atrophy and severe dyspigmentation were associated with less postoperative fixation reduction, whereas fixation reduction did not differ significantly by subcutaneous atrophy severity. AFT alters observers' visual attention by reducing fixations on the affected facial areas and redirecting gaze toward the unaffected side and the central T-zone. This shift suggests a partial redistribution of social-perceptual gaze patterns toward a more typical facial viewing pattern. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .
2026-07-08 | CCN3-derived peptide BLR-200 impairs YAP activation and attenuates bleomycin-induced skin fibrosis through blocking the generation of Sfrp2-positive fibroblasts
ABSTRACT An autocrine pro-adhesive/pro-contractile signaling loop, through the mechanosensitive transcriptional cofactor YAP, promotes fibrosis. The CCN family of matricellular proteins modify adhesive signaling. Of these, CCN3 is antifibrotic. We show that BLR-200, a CCN3-derived peptide, has anti-fibrotic properties in the bleomycin-induced model of scleroderma skin fibrosis. In vitro, BLR-200 delayed, but did not abolish, fibroblast adhesion to collagen and nuclear YAP localization. In vivo , BLR-200 prevented/treated bleomycin-induced skin fibrosis, and reduced bleomycin-induced expression of profibrotic genes including α-smooth muscle actin, CCN1 and CCN2. Lineage tracing and scRNA-seq analyses revealed that the myofibroblasts in this model were quantitatively derived from collagen-lineage Pi16+/Col15+ve fibroblasts. BLR-200 prevented myofibroblast differentiation in this model and trajectory of fibroblasts toward a Sfrp2-positive subset, a cell type associated with poor clinical outcome. BLR-200 impairs YAP activation in vitro and appearance of translationally-relevant fibroblast subtypes in vivo and is a novel anti-fibrotic agent for SSc skin fibrosis. HIGHLIGHTS -SSc skin fibrosis, a major unmet need, is driven by an activated mechanotransduction/YAP pathway; how to block this pathway clinically is unclear -members of the CCN family of matricellular proteins are adhesive signaling modifiers; herein, we identify BLR-200, a synthetic peptide derived from CCN3, based on its ability to impair, but not ablate, YAP nuclear localization and fibroblast spreading/attachment to collagen -BLR-200 blocks and treats progression of bleomycin-induced skin fibrosis -In the bleomycin model, lineage tracing analysis revealed that collagen-lineage cells are the primary source of myofibroblasts -BLR-200 blocks myofibroblast differentiation concomitant with reduced progression toward Col8a1+ve and Sfrp2+ ve fibroblasts, populations implicated in SSc pathogenesis -BLR-200 represents a novel, translationally relevant drug candidate for SSc skin fibrosis
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Drug Discovery Landscape
3 orphan drug designations for Localized scleroderma.
3 orphan drug designations for Localized scleroderma.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
HDF-LV-RTS-MMP1 (human dermal fibroblasts genetically modified with LV-RTS-MMP1) and Veledimex | cell therapies | FDA | 2016-04-19 | — | Castle Creek Biosciences, LLC |
Peptide 144 TGF beta-1-inhibitor | peptides | FDA | 2006-04-26 | — | Digna Biotech, S.L. |
Peptide 144 TGF- ß1 inhibitor (TSLDASIIWAMMQN) | peptides | EMA | 2005-10-28 | — | Digna Biotech S.L. |
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