S2k guideline: Diagnosis and therapy of localized scleroderma.

The updated S2k guideline deals with the diagnosis and therapy of localized scleroderma (LoS). LoS represents a spectrum of sclerotic skin diseases in which, depending on the subtype and localisation, structures such as adipose tissue, muscles, joints, and bones may also be affected. Involvement of internal organs or progression to systemic sclerosis does not occur. LoS can be classified into four main forms: limited, generalized, linear, and mixed forms, with some additional subtypes. For cases of limited skin involvement, the guideline primarily recommends therapy with topical corticosteroids. UV therapy can also be recommended. In subtypes with severe skin or musculoskeletal involvement, systemic therapy with methotrexate is recommended. During the active phase of the disease, systemic glucocorticosteroids can be used additionally. In cases of methotrexate and steroid refractory courses, contraindications, or intolerance, mycophenolate mofetil, mycophenolic acid, or abatacept can be considered as second-line systemic therapies. In the case of linear LoS, autologous adipose-derived stem cell transplantation can also be performed for correcting soft tissue defects.

Global research status of localised scleroderma reported over the period 1993-2022: A 30-year bibliometric analysis.

Localised scleroderma predominantly affects the skin with an unknown aetiology. Despite its clinical importance, no comprehensive bibliometric analysis has been conducted to assess the existing research landscape and future prospects for localised scleroderma. The articles related to localised scleroderma were retrieved from the WoSCC database and analysed by VOSviewer 1.6.10.0 (Leiden University, Netherlands), CiteSpace 6.1.R1 (Dreiser University, USA), and HistCite 2.1 (New York, United States). 2049 research papers pertaining to localised scleroderma spanning the years from 1993 to 2022 were extracted from the WoSCC database. The United States exhibited the highest productivity with 644 papers, accounting for 31.43% of the total output, followed by Germany with 206 papers (10.05%) and Italy with 200 papers (9.76%). Regarding academic institutions and journals, the University of Texas System and Dermatology published the most significant number of papers, and Professor Ihn, H emerged as the most prolific contributor among scholars. The top 10 cited references primarily concentrated on the diagnosis and treatment of localised scleroderma. "Phototherapy" and "methotrexate (MTX)" surfaced as the most recent and noteworthy keywords, representing the research hotspots in the domain of localised scleroderma. This bibliometric analysis furnishes valuable insights into the contemporary research landscape of localised scleroderma.

Ocular and eyelid involvement in collagen vascular diseases. Part II. Dermatomyositis, scleroderma, and sarcoidosis.

Collagen vascular disease is a heterogeneous group of autoimmune diseases that affect multiple organ systems. Sjögren syndrome, dermatomyositis, scleroderma, systemic lupus erythematosus, and sarcoidosis are collagen vascular diseases that often present with characteristic cutaneous manifestations. Although less known, various ocular manifestations that affect both external and internal structures of the eye can also be seen in these conditions. Multidisciplinary management between dermatologists and ophthalmologists is essential in the early diagnosis and management of collagen vascular diseases affecting both the skin and eye. In part II of our series, we discuss the ocular manifestations, diagnosis, and therapeutic options of dermatomyositis, scleroderma, and sarcoidosis.

Recent Advances in Treatment of Systemic Sclerosis and Morphea.

Systemic sclerosis (SSc) and morphea are autoimmune sclerosing diseases that cause significant morbidity, and in the case of SSc, mortality. The pathogenesis of both SSc and morphea share vascular dysfunction, auto-reactive T cells and Th2-associated cytokines, such as interleukin 4, and overproduction of transforming growth factor beta (TGFß). TGFß stimulates fibroblast collagen and extra-cellular matrix production. Although morphea and SSc have similar pathogenic pathways and histological findings, they are distinct diseases. Recent advances in treatment of morphea, skin sclerosis in SSc, and interstitial lung disease in SSc are focused on targeting known pathogenic pathways.

Brown adipose tissue transplantation improves skin fibrosis in localized scleroderma.

Adipose tissue transplantation shows great therapeutic potential in reversing localized scleroderma-associated skin fibrosis. Brown adipose tissue (BAT) can specifically secrete various cytokines against fibrosis, but its therapeutic potential in improving skin fibrosis has not yet been demonstrated. In this study, we have demonstrated the superior therapeutic efficacy of BAT transplantation for sclerotic skin by transplanting two distinct types of adipose tissue. In comparison to the white adipose tissue (WAT) group, mice treated with BAT transplantation exhibited a significant reduction in dermal thickness. BAT transplantation effectively reverses skin sclerosis through mechanisms involving inflammation reduction, promotion of angiogenesis, inhibition of myofibroblast accumulation, and collagen deposition. This therapeutic effect can be attributed to its unique paracrine effects. Furthermore, transcriptome sequencing (RNA-Seq) revealed upregulation of pathways associated with lipogenesis and fatty acid metabolism in BAT while downregulating pathways are related to transforming growth factor ß(TGF-ß), epithelial-mesenchymal transition (EMT), and inflammatory response. These findings suggest that BAT transplantation holds great promise as a novel approach for localized scleroderma treatment.

Platelet-Rich Plasma Combined Fat Transplantation for the Treatment of Bleomycin-Induced Murine Scleroderma.

BACKGROUND: Low-fat retention induced by inflammation limits the clinical application of fat grafting for treating localized scleroderma (LS) patients. Novel methods to improve the therapeutic outcome are needed. OBJECTIVE: The aim of the study is to investigate the effect of platelet-rich plasma (PRP)-assisted fat transplantation on skin fibrosis and adipose survival in the LS model. METHODS: The LS model was established by the injection of bleomycin into BALB/C nude mice, which were randomly divided into the following 4 groups: healthy control, LS disease group model, fat transplantation group, and PRP+ fat transplantation group. The mice received a subcutaneous injection at back with phosphate-buffered saline, fat, or 20% PRP+ fat. Factors of immunoregulation, angiogenesis and adipogenesis were measured. RESULTS: Platelet-rich plasma-combined fat transplantation significantly attenuated dermis fibrosis by reducing the production of type III collagen. The fat retention in the PRP+ fat transplantation group was 43 ± 4 mg, significantly higher than 22 ± 15 mg in the fat transplantation group (P = 0.0416). The level of tumor necrosis factor α and interleukin 2 showed no significant difference between the groups. The expression of angiogenesis factors, vascular endothelial growth factor, hepatocyte growth factor, platelet-derived growth factor, and CD31, significantly increased in the PRP+ fat transplantation group. The expression of adipogenesis factors, insulin-like growth factor 1 receptor, extracellular signal-regulated kinase, anti-CCAAT-enhancer-binding proteins, and peroxisome proliferator-activated receptor γ, also significantly increased in the PRP+ fat transplantation group. CONCLUSIONS: The results demonstrated that PRP-combined fat transplantation attenuated dermis fibrosis and raised fat survival in the LS model by promoting angiogenesis and adipogenesis through insulin-like growth factor 1 receptor/extracellular signal-regulated kinase signaling pathway.

Adipose-Derived Stem Cells Attenuate Skin Fibrosis and Improve Fat Retention of a Localized Scleroderma Mouse Model.

BACKGROUND: Although autologous fat grafting is a feasible surgical technique to improve facial deformity in patients with localized scleroderma, its success is limited by the low graft retention induced by the local inflammatory environment. This study investigated the potential effect of adipose-derived stem cells (ASCs) on skin fibrosis and fat retention in a localized scleroderma mouse model. METHODS: BALB/C nude mice that were induced by bleomycin to establish a localized scleroderma model were divided randomly into five groups: blank control; fat grafting; and low, moderate, and high doses of ASC-assisted fat grafting. The backs of the mice were subcutaneously injected with phosphate-buffered saline or fat, or fat with low, moderate, and high doses of ASCs (1 × 10 5 /mL, 5 × 10 5 /mL, and 25 × 10 5 /mL, respectively). The skin fibrosis and fat retention were analyzed after 1 month or 3 months, respectively. RESULTS: Compared to the disease model group, the fat-grafting group, and the low- and moderate-dose ASC-enriched groups, the high-dose ASCs significantly attenuated skin fibrosis, inhibited the production of type III collagen and transforming growth factor-ß1, increased fat graft retention, enhanced the expression of angiogenesis-related cytokines and angiogenesis, and increased the expression of adipogenesis-related cytokines. CONCLUSIONS: The results demonstrated that high-dose ASCs attenuated skin fibrosis and improved fat retention in a localized scleroderma model by reducing inflammation and by promoting angiogenesis and adipogenesis. The authors further demonstrated that ASCs enhanced adipogenesis through the AKT/ERK signaling pathway. CLINICAL RELEVANCE STATEMENT: Fat grafting has been used to treat localized scleroderma patients but with low fat retention. In this study, ASC attenuated skin fibrosis and improved fat retention in the localized scleroderma model, providing evidence for cell therapy in future application of localized scleroderma treatment.

Post-treatment course of acute lipodermatosclerosis.

OBJECTIVES: We aimed to clarify whether acute lipodermatosclerosis (LDS) progress to chronic LDS without continued compression therapy. METHODS: Between April 2015 and November 2021, 30 patients with acute/subacute LDS, which was diagnosed clinically by presence of isolated, poorly demarcated, tender erythema, and induration limited to the lower leg(s), visited our clinic and were able to be followed up for longer than a year. We reviewed their treatment results and the post-treatment courses. RESULTS: In all cases, the symptoms in the acute phase subsided with compression bandages. After the discontinuation of compression therapy, 18 legs (56%) progressed to chronic LDS, and 14 legs (44%) did not. In the legs without progression, subcutaneous tissue in the affected leg was thicker compared with that in the contralateral leg (median 19.1 mm vs. 13.4 mm, p < 0.05) on the initial visit. In the legs with progression, the difference in subcutaneous tissue thickness between the affected and unaffected legs was not significant (10.0 mm vs. 7.6 mm). CONCLUSIONS: Our findings suggest that in legs which later progress to chronic LDS, subcutaneous tissue contraction due to panniculitis is already present during the acute phase; therefore, long-term compression therapy is unlikely to improve the prognosis.

Improving outcomes in scleroderma: recent progress of cell-based therapies.

Scleroderma is a rare, potentially fatal, clinically heterogeneous, systemic autoimmune connective tissue disorder that is characterized by progressive fibrosis of the skin and visceral organs, vasculopathy and immune dysregulation. The more severe form of the disease, diffuse cutaneous scleroderma (dcSSc), has no cure and limited treatment options. Haematopoietic stem cell transplantation has emerged as a potentially disease-modifying treatment but faces challenges such as toxicity associated with fully myeloablative conditioning and recurrence of autoimmunity. Novel cell therapies-such as mesenchymal stem cells, chimeric antigen receptor-based therapy, tolerogenic dendritic cells and facilitating cells-that may restore self-tolerance with more favourable safety and tolerability profiles are being explored for the treatment of dcSSc and other autoimmune diseases. This narrative review examines these evolving cell therapies.

Specific management of lipodermatosclerosis (sclerotic hypodermitis) in acute and chronic phase.

Lipodermatosclerosis or sclerotic hypodermitis is presented as a complication of venous insufficiency and in particular of post-thrombotic syndrome with a high risk of progression to leg ulcers. However, it has also been described in obese patients without venous insufficiency, and even in the course of various systemic diseases including scleroderma. It most often affects middle-aged women and is usually bilateral, with a typically "inverted champagne bottle" leg appearance. The pathogenic role of venous hypertension explains why compression with bands or stockings is the basis of treatment. In acute phase, which may precede or complicate chronic forms, the pain is so severe that compression is not tolerated. In acute phase, non-steroidal anti-inflammatory drugs, intra-lesional use of triamcinolone, and capsaicin transdermal patches indicated for neuropathic pain have been proposed. In chronic forms, the treatment of superficial venous insufficiency and/or incontinent perforating veins, documented during a Duplex ultrasound scan, is usually proposed, whenever possible. In association with elastic compression, pentoxifylline and colchicine have been used without clear evidence of clinical efficacy. Finally, in the most advanced clinical presentation with the appearance of a sclerotic gaiter associated with ulcerations, surgical treatment with excision-cutaneous grafting associated or not with perforating veins ligation and a fasciotomy may be discussed as a last resort for treatment.

Red legs: how to differentiate between cellulitis, venous eczema and lipodermatosclerosis.

Community nurses often encounter people with red legs. There are a number of reasons why an individual may develop red legs. The most common causes of red legs are cellulitis, venous eczema and lipodermatosclerosis. All have different causes and require different treatments. This article aims to enable readers to differentiate between these conditions which can appear similar, and to offer effective evidence-based care.

From Morphea to Dermatofibrosarcoma Protuberans.

Dear Editor, Morphea profunda (MP) is a chronic autoimmune disease, a subtype of localized scleroderma that presents clinically as local discomfort due to the impairment of skin motility (1). Dermatofibrosarcoma protuberans (DFSP) is a rare soft tissue neoplasm that not only infiltrates the dermis and subcutaneous tissue, but can also affect the muscles and bones with finger-like extensions, usually present on the trunk and the proximal extremities (2). DFSP is known for its indolent clinical course, locally aggressive behavior, and high local recurrence rates, but relatively low risk of metastatic spread (2). DFSP frequently arises in middle-aged adults, affecting both sexes equally with an incidence of 4 per 1,000,000 people (3). We report the case of a 39-year-old female patient who first presented to our clinic at the age of 20 years due to a brownish atrophic coin-sized lesion appearing on the left side of the abdomen. Medical reports indicated that biopsies had been performed previously on 3 occasions, and histopathologic findings confirmed the diagnosis of MP. The aforementioned lesion on the abdomen had been growing slowly over the years, and the patient finally visited our clinic 15 years later after noticing two palpable nodules developing within the affected skin (Figure 1, A, B). Clinical examination revealed an indurated ill-defined plaque measuring 10 cm with partially atrophic surface and 2 centrally located palpable nodules measuring between 3 and 5 mm. A deep biopsy of the lesion was performed, and histopathology and immunohistochemical analysis of CD34 expression confirmed the diagnosis of dermatofibrosarcoma protuberans (Figure 1, C, D). Computed tomography scans of the thorax, abdomen, and pelvic region were subsequently performed, revealing no further disease progression. Complete excision of the tumor was performed and followed by wide scar re-excision due to narrow surgical margins of only 1 mm. No further disease progression or recurrences have been noted during the follow-up, and the patient has been disease-free for one year postoperatively. Although the etiology of DFSP is unknown, trauma has been hypothesized as a predisposing factor. It usually presents on the trunk and the proximal extremities (4). Patients usually report disease progression over a long period of time, ranging from several months to years. The tumor is associated with variable color changes, even proximal skin discoloration, and often presents with a slowly growing indurated dermal plaque or firm nodule attached to the skin (4). Clinically, it can be difficult to distinguish DFSP from a wide number of diagnoses, including morphea, idiopathic atrophoderma, atrophic scar, anetoderma, lipoatrophy, cellular dermatofibroma, fibrosarcoma, malignant fibrous histiocytoma, atypical fibroxanthoma, desmoplastic melanoma, Kaposi sarcoma, and solitary fibrous tumors (5). Immunohistochemistry staining for CD34 cells can be helpful in differentiation, since spindle cells stain positively in DFSP (6). Due to alteration of dermal collagen, histopathological differential diagnoses of DFSP includes lichen sclerosus, atrophic scars and keloids, as well as morphea (7), atrophic dermatofibroma, and undifferentiated pleomorphic sarcoma (6). The mainstay of DFSP treatment is tumor excision performed either by wide local excision or Mohs surgery and having surgical margins between 1 and 5 cm. Several studies have confirmed that patients treated with the Mohs technique have significantly lower recurrence rates (8). Due to the high number of unsatisfactory primary excisions, wide free surgical margins are important for disease control (3). Radiotherapy might be considered as a therapeutic option for inoperable tumors or relapses, as well as an adjuvant therapy after primary excision or re-excision with positive margins (8). Furthermore, recent findings indicate positive therapeutic efficacy after administration of imatinib mesilat - a tyrosine kinase inhibitor due to over expression of PDGFß (9). Clinical follow-up of patients with DFSP after tumor excision should be performed every six months for the first five years, followed by yearly intervals thereafter for up to 10 years (3). Previous case reports have claimed that the diagnosis of DSFP is commonly delayed as a result of slow tumor growth and nonspecific initial clinical findings (10). To the best of our knowledge, our case is the first description in the literature of DFSP developed within a MP plaque. We speculate that trauma from repeated punch biopsies taken from the sclerotic morpheaform plaque may represent the trigger for the development of the DFSP. Another notable clinical challenge was the surgical excision itself, since the majority of cases presented in literature mentioned unsatisfactory resection margins and a high risk of local disease recurrence. Although complete excision of the neoplasm was performed, re-excision was performed in order to provide wider resection margins. Surgical resection remains the main treatment for dermatofibrosarcoma protuberans, with the main challenge being the achievement of clean excision margins. Proper management of the disease and continuous follow-up are important in order to prevent local recurrence of dermatofibrosarcoma protuberans or its potential metastases.

Adipose-Derived Stem Cell-Enriched Lipotransfer Reverses Skin Sclerosis by Suppressing Dermal Inflammation.

BACKGROUND: Scleroderma is a chronic autoimmune disease with an incidence of 2.7 per 100,000 people. Traditional lipotransfer has been used to treat atrophic sclerotic skin. Enzymatically processed cell-assisted lipotransfer and mechanically processed stromal vascular fraction gel are fat products with abundant adipose-derived stem cells. This study assessed whether adipose-derived stem cell-enriched lipotransfer elicits superior therapeutic effects on scleroderma. METHODS: Scleroderma was induced in nude mice by injections of bleomycin for 4 weeks. Human-derived Coleman fat, cell-assisted lipotransfer, or stromal vascular fraction gel (0.1 ml) was injected into sclerotic lesions. Histologic examinations, terminal deoxynucleotidyl transferase dUTP nick end labeling, and expression analyses of inflammatory factors in skin lesions and transferred fat were performed at 4 weeks after implantation. RESULTS: Dermal thickness was lower in the groups injected with Coleman fat (339.0 ± 19.66 µm), cell-assisted lipotransfer (271.0 ± 16.15 µm), and stromal vascular fraction gel (197.8 ± 12.99 µm) than in the group injected with phosphate-buffered saline (493.3 ± 28.13 µm) ( p < 0.05). The numbers of terminal deoxynucleotidyl transferase dUTP nick end labeling + and Mac2 + cells in fat tissue were significantly higher in the group injected with Coleman fat than in those injected with stromal vascular fraction gel and cell-assisted lipotransfer. Expression of monocyte chemotactic protein-1 and interleukin-6 was significantly lower in the adipose-derived stem cell-enriched groups than in the Coleman fat group. Histologic analysis showed there were far fewer macrophages and myofibroblasts in skin lesions in the adipose-derived stem cell-enriched groups than in the Coleman fat group. CONCLUSIONS: Transplantation of stromal vascular fraction gel and cell-assisted lipotransfer, which contain abundant adipose-derived stem cells, reduces the levels of apoptotic cells and inflammation, significantly reverses skin sclerosis, and elicits superior anti-inflammatory and antifibrotic effects on scleroderma. CLINICAL RELEVANCE STATEMENT: This study provided an alternative adipose-based therapy, adipose-derived stem cell-enriched fat, for sclerotic lesions and showed its validity for interfering with the inflammation and fibrosis.

Immunologic underpinnings and treatment of morphea.

INTRODUCTION: Morphea is a chronic autoimmune fibrosing condition of the skin and underlying tissue with the potential for significant disease-associated morbidity. While the exact etiology of morphea is not fully elucidated, many studies have explored the immunologic drivers of this disease. AREAS COVERED: Using PubMed, we performed a systematic review on morphea, with a focus on both the immune-mediated pathophysiology and treatment of this disease. Based on these findings, we review the literature surrounding what is understood about the role of the immune system in disease onset and course. Additionally, we discuss current treatments used in this disease as well as the potential role for more targeted therapies in the future. EXPERT OPINION: Much work remains to fully elucidate each step in the immunologic march causing morphea. However, there is evidence to suggest that the early inflammatory stages of morphea may be driven predominantly by immunologic events in the Th1/Th17 pathway, while the Th2 pathway may be responsible for the fibrosis and damage observed later in the disease. Standard of care treatments currently continue to focus on therapeutics with broad immune modulating properties. Further work exploring the immunologic underpinnings of morphea will facilitate more targeted treatment approaches over time.

Utility of phototherapy in patients with systemic sclerosis: Systematic review.

Phototherapy is a recommended treatment regimen for different scleroderma spectrum disorders, but so far it has been included neither by European nor by worldwide experts committee in recommendations for the treatment of systemic sclerosis (SSc). The aim of the study was to revisit the utility of dermatological phototherapy in patients with SSc. PubMed using medical subject headings was searched to identify studies evaluating response to dermatological phototherapy in SSc patients. Both UVA1 (340-400 nm) and PUVA (psoralen plus UVA) treatments were found to reduce skin thickening and increase skin elasticity, therefore allowing for the improvement of joint tension mobility, especially in hands. At least several papers showed efficacy of phototherapy in patients who remained non-responsive to previous immunosuppressive therapies. The most probable mechanisms of action of phototherapy in SSc include inhibition of T-cells and prevention from dermal fibrosis. Although most data on the efficacy of phototherapy come from small experimental studies and case reports, phototherapy based on UVA of wavelength manifests relatively mild spectrum of side effects and this should be considered as a treatment option for SSc with dominant cutaneous involvement.

Linear Scleroderma Causing Arrest of Root Development in a Pediatric Patient.

Localized scleroderma (LoS) or morphea is a rare group of inflammatory disorders resulting in excessive collagen deposition and subsequent sclerosis of the skin and subdermal tissues. Linear scleroderma (LiS) or linear morphea is the most common subtype of LoS in children and primarily affects the face and extremities. This case report details the three-year follow-up of a five-year-old girl with LiS of the left upper lip and adjacent oral mucosal tissue. She also presented with a concurrent developmental root defect of the permanent maxillary left central incisor. Intralesional corticosteroids were considered as a first-line treatment; however, parents declined it. Decision was made to biopsy when the lesion showed signs of progression. At subsequent reviews, the affected mucosal surface appeared to have stabilized but progressive notching of the upper lip was noted. In the long term, after cessation of disease activity, the patient will require aesthetic intervention to surgically correct her upper lip.