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.

Paclitaxel-induced diffuse scleroderma with possible scleroderma-renal crisis: a case report and literature review of taxanes-induced scleroderma.

INTRODUCTION/OBJECTIVES: Scleroderma is a rare complication in taxanes therapy. Although individual cases of taxanes-induced scleroderma have been reported, the clinical manifestation and treatment outcomes were reviewed and summarized rarely. This study reported a patient who developed diffuse scleroderma and possible scleroderma renal crisis after paclitaxel therapy for ureter cancer. METHOD: A PubMed literature review on published cases of taxanes-induced scleroderma up until April 2022 was included for analysis. RESULTS: The search identified 27 patients with adequate information for analysis. Of the 28 patients, including the one presented here, 22 were female. Peripheral edema was the most common symptom in all but one patient, and often accompanied by erythema in 11. Symptoms usually occurred in half of the patients within the 4th course of treatment. Skin lesions gradually progressed to skin fibrosis, and extended proximally. Internal organ involvements were uncommon. Antinuclear antibody tests were positive occasionally, but anti-Scl70 and anti-centromere usually were negative. Taxanes therapy was discontinued, continued and unavailable in 21, 3, and 4 patients, respectively. Corticosteroids for skin lesions with or without immunosuppressive drugs were given to 15 patients. Of 25 patients with available skin outcomes, 19 improved. There was no significant skin improvement between those who did or did not receive skin treatment (62.5% vs. 75.0%, p = 0.37). Skin usually improved after discontinuing taxanes. CONCLUSION: Taxanes-induced scleroderma is different from idiopathic scleroderma. Physicians should be aware of this condition in order to provide early diagnosis and apply appropriate management in order to avoid serious complications from severe skin sclerosis. Key Points • Scleroderma is a rare but unique and serious complication of taxanes therapy • Skin manifestations and distribution are similar to idiopathic scleroderma, but vascular phenomenon, internal organ involvement and scleroderma-associated auto-antibodies are presented rarely. Skin improvement usually occurs shortly after discontinuing taxanes • The role of immunosuppressive therapy in treating taxanes-induced scleroderma is not clear.

Atezolizumab-induced scleroderma: a rare complication.

Few cases of programmed death-ligand 1 inhibitor-induced scleroderma have been reported and their clinical features remain unpublished. Optimal management is, therefore, unknown and an autoantibody association has yet to be identified. We present the case of a female in her 60s who developed skin thickening after starting atezolizumab for metastatic non-small cell lung cancer. Skin biopsy 7 months after symptom onset showed histological changes consistent with scleroderma. Anti-PM/SCL-75 antibody was positive. Atezolizumab was discontinued and treatment was started with mycophenolate mofetil. After 5 months, she experienced mild improvement in skin thickening. Earlier identification of this complication may limit morbidity in this disease process, which otherwise has limited treatment options. In suspected cases, obtaining scleroderma-associated autoantibodies may help with earlier diagnosis.

Morphea following treatment with pembrolizumab for melanoma with metastatic lymph nodes: case report and review of literature.

Pembrolizumab is a humanized IgG4 isotype mAb that the targets and blocks the programmed cell death protein 1 receptor on lymphocytes. Its use in treating metastatic melanoma is associated with increased overall survival compared to other older immunotherapies. Several adverse effects have been noted including both systemic and cutaneous manifestations. As a relatively novel treatment option, many new cutaneous manifestations are still being observed, occurring at various times after initiation of therapy. Previously noted cutaneous adverse effects include sarcoid-like reactions, rash, and changes in preexisting lesions or scars. Here we present a case in which biopsy-proven morphea developed after completion of pembrolizumab therapy.

Nivolumab-induced plaque morphea in a malign melanoma patient.

BACKGROUND: Nivolumab is one of the targeted cancer therapy agent that acts to increase the immune responses by inhibition of antiprogrammed-death-receptor 1, which is one of the check points of the immune response. Nivolumab can be used to treat malign melanoma, lung, renal, head and neck, colorectal, hepatocellular cancers, and special cases of Hodgkin lymphoma. AIMS: We aimed to report a rarer cutaneous side effect of nivolumab because of the increasing uses of this agent in various cancer treatments. METHODS: We present a 48-year-old female, metastatic melanoma patient who developed plaque morphea lesion without any systemic involvement during nivolumab treatment. Plaque lesion responded well to use of topical corticosteroid and calcipotriol. RESULTS: Numerous cutaneous side effects associated with nivolumab have been reported in the literature. The most common cutaneous side effects are maculopapular rash, pruritus, and vitiligo. Morphea and disorders from this spectrum reported due to PD-1 inhibitors in the literature are; morphea, sclerodermoid changes, eosinophilic fasciitis, and lichen sclerosis. CONCLUSION: Patients who are treated by PD-1 inhibitors may be examined carefully in terms of morphea and scleroderma-like conditions although they are not as common as other cutaneous side effects.

Biological effects of a new ultraviolet A1 prototype based on light-emitting diodes on the treatment of localized scleroderma.

Ultraviolet A1 (UVA1 ) phototherapy (spectral range 340-400 nm) is a well-established treatment option for various skin diseases such as localized scleroderma. Recent improvements of conventional UVA1 light sources (metal-halide or fluorescent lamps) have brought attention to a new light-emitting diode (LED) technology with remarkable advantages in handling and clinical routine. This study provides a preclinical histological and molecular evaluation of an LED-based UVA1 prototype with a narrower spectral range (360-400 nm) for treating localized scleroderma. Scleroderma mouse models and fibroblasts in vitro were exposed to LED-based UVA1 phototherapy or to irradiation with a commercially available metal-halide lamp emitting low-dose (20, 40 J/cm2 ), medium-dose (60 J/cm2 ) and high-dose (80, 100 J/cm2 ) UVA1 light. Both UVA1 light sources affected inflammatory genes (IL-1α and IL-6) and growth factors (TGFß-1 and TGFß-2). Increased collagen type 1 was reduced after UVA1 phototherapy. Matrix metalloproteinase-1 was more enhanced after a medium dose of LED-based UVA1 phototherapy than after conventional treatment. In vivo, dermal thickness and the amount of collagen were reduced after both treatment methods. Remarkably, myofibroblasts were more effectively reduced by a medium dose of LED-based UVA1 phototherapy. The study indicates that LED-based UVA1 phototherapy yields similar or even better results than conventional treatment. In terms of biosafety and patient comfort, LED-based UVA1 phototherapy offers clear advantages over conventional treatment because of the use of a narrower and less harmful UVA1 spectrum, less heat generation and shorter treatment times at the same irradiation intensity. Clinical studies are required to confirm these results in patients with localized scleroderma.

A case of gemcitabine-related acute lipodermatosclerosis.

INTRODUCTION: Gemcitabine is a chemotherapeutic agent used to treat several solid organ malignancies. The most common cutaneous toxicities are a mild erythematous rash and pruritus, which are often attributed to infectious etiologies. However, certain clinical characteristics may favor a drug-related reaction. Clinicians should recognize these phenomena to avoid potentially unnecessary antibiotic treatment or withdrawal of chemotherapeutic agents. OBJECTIVE: We aim to report a case of gemcitabine-related acute lipodermatosclerosis-like eruption, add to the evolving classification of this condition, and highlight developing literature on gemcitabine that may explain this toxicity. CASE: Dermatology was consulted for presumed cellulitis in a 62-year-old female with pancreatic carcinoma. The patient presented to the emergency department five days after her first dose of gemcitabine with erythema in both lower extremities. A diagnosis of gemcitabine-related acute lipodermatosclerosis was made and the patient was started on topical triamcinolone. CONCLUSION: It is important to recognize gemcitabine-related acute lipodermatosclerosis in order to avoid unnecessary antibiotic use and disruptions in chemotherapy.

Withaferin A attenuates bleomycin-induced scleroderma by targeting FoxO3a and NF-κß signaling: Connecting fibrosis and inflammation.

Scleroderma is an inflammatory autoimmune disease which begins with inflammation due to tissue injury and advances to progressive accumulation of extracellular matrix resulting in scarring and hardening of the skin. Inflammation is a salutary response to tissue injury caused by varied factors. While inflammation is required for systematic wound healing, dysregulated chronic inflammation often leads to tissue scarring. Prominent role of inflammation in pathology and physiology makes it a double edge sword. The objective of this study was to investigate the role of Withaferin A (WFA), a steroidal lactone from Withania somnifera in a 28-day murine model of bleomycin-induced experimental scleroderma. Withaferin A was administered at two doses 2 and 4 mg/kg intraperitoneally for 28 days. At the time of study termination, we observed significant reduction in dorsal skin thickness. Our results indicate that WFA was able to sufficiently suppress pro-inflammatory phase of fibrosis, TGF-ß/Smad signaling and also significantly repressed fibroblast conversion to myofibroblasts. Additionally, our study also demonstrated that WFA modulates FoxO3a-Akt-dependent NF-κß/IKK-mediated inflammatory cascade, which is a prime signaling pathway in fibrogenesis. The findings of this study are persuasive of WFA as an antifibrotic agent with promising therapeutic effects in scleroderma. © 2018 BioFactors, 44(6):507-517, 2018.

Octreotide ameliorates dermal fibrosis in bleomycin-induced scleroderma

Background/aim: Insulin-like growth factor (IGF)-I is a differentiation and growth factor. Antifibrotic action of octreotide has been reported in pulmonary fibrosis. The present study aimed to research the prophylactic and therapeutic potential of octreotide on a bleomycin (BLM)-induced experimental scleroderma model. Materials and methods: Sixty Balb/c female mice were divided into 6 groups. Daily subcutaneous BLM (100 µg) was injected for 3 weeks in groups II and III and for 6 weeks in groups V and VI. Octreotide (100 µg/kg per day) was injected subcutaneously for the first 3 weeks in group III (prophylactic) and the second 3 weeks in group VI (therapeutic). Mice in groups I, II, and III were sacrificed at the end of the third week, while mice in groups IV, V, and VI were sacrificed at the end of the sixth week. Results: Repeated BLM applications increased dermal inflammatory cell counts and dermal thickness, and led to dermal fibrosis at both the third and sixth weeks. Moreover, mRNA expressions of TGF-ß1 and IGF binding protein (IGFBP)-3 and -5 were higher in the BLM- injected sham groups. On the other hand, IGFBP-3 and -5 mRNA expressions were significantly decreased in both the prophylactic and therapeutic octreotide groups. Similarly, octreotide decreased dermal inflammatory infiltrations and dermal thickness. Conclusion: Octreotide has antifibrotic actions on experimentally induced dermal fibrosis. It can be suggested that IGF-I plays pathogenic roles, and octreotide is a candidate for research in the treatment of scleroderma.

Scleroderma-like cutaneous lesions during treatment with paclitaxel and gemcitabine in a patient with pancreatic adenocarcinoma. Review of literature.

BACKGROUND: Chemotherapy-induced skin sclerosis is generally not associated with other manifestations of systemic sclerosis. It is featured by skin sclerosis without visceral involvement (i.e., Raynaud's phenomenon, esophageal dysmotility, and pulmonary fibrosis), temporal association with chemotherapy administration, and the absence of detectable autoantibodies. The clinical course of scleroderma-like changes induced by paclitaxel or gemcitabine are refractory to treatment and commonly progressive, even after discontinuation of the triggering drugs. OBJECTIVE: Report a case of scleroderma-like cutaneous lesions during combination treatment with nab-paclitaxel and gemcitabine in a patient with pancreatic adenocarcinoma and determine other published cases of scleroderma-like skin changes following treatment with nab-paclitaxel, paclitaxel, or gemcitabine through the period from 2002 to 2018. METHODS: Literature search from the year 2002 onwards using combinations of "Scleroderma" AND "paclitaxel," AND/OR "gemcitabine." RESULTS: Additional to our case report we reviewed 14 other cases in the literature. Most of these cases share three prominent features: skin sclerosis without systemic involvement, temporal association with chemotherapy administration, and absence of detectable scleroderma-specific autoantibodies. CONCLUSION: To our knowledge, this is the first case report of scleroderma-like cutaneous lesions during combination treatment with nab-paclitaxel and gemcitabine in a patient with pancreatic adenocarcinoma. However, given the current literature, these scleroderma-like lesions are most likely induced by nab-paclitaxel or paclitaxel, rather than by gemcitabine.

Scleroderma-like skin changes induced by checkpoint inhibitor therapy.

Checkpoint inhibitors have emerged as beneficial therapies in many different types of malignancy. The most common toxicities of checkpoint inhibitors are immune-related adverse events (irAEs). As clinical experience with these agents increases, more irAEs have been described. We report a case of scleroderma-like skin changes induced by checkpoint inhibitor therapy. A 61-year-old man was treated with nivolumab for oligometastatic renal cell carcinoma. He initially tolerated the therapy well, but after 16 treatments he began experiencing skin thickening and edema of the abdominal wall, which progressed down the trunk and legs. A punch biopsy revealed epidermal attenuation overlying thickened dermal collagen with entrapment and displacement of the eccrine coils and loss of periadnexal adipose tissue. Focally increased plasma cells were present near the junction of the dermis and subcutaneous adipose tissue. Loss of CD34 staining was seen throughout the dermis. These findings were consistent with a diagnosis of scleroderma. After discontinuation of nivolumab and initiation of steroid therapy, the patient's symptoms significantly improved. This case is among the first reports of scleroderma-like changes induced by a checkpoint inhibitor.

The safety and efficacy of light emitting diodes-based ultraviolet A1 phototherapy in bleomycin-induced scleroderma in mice.

PURPOSE: To define the efficacy and safety of narrowband ultraviolet A1 (UVA1) for the treatment of dermal fibrosis in bleomycin-induced mouse model of scleroderma. MATERIALS AND METHODS: 42 DBA/2 strain mice were included in the study: healthy mice and mice with established scleroderma, treated with high or medium dose of UVA1. Non-treated groups served as control. The equipment emitting 365±5nm UVA1 radiation was used in the study. The average cumulative doses were 1200J/cm2 for high and 600J/cm2 for medium dose course. Histological analysis was performed for the evaluation of the dermal thickness and mast cells density. The expressions of p53 and Ki-67 proteins were assessed by immunohistochemical analyses. RESULTS: Skin thickness of mice with scleroderma, treated with high and medium dose of UVA1, were lower (272.9±113.2µm and 394±125.9µm, respectively) in comparison to the dermal thickness of non-treated animals (599±55.7µm). The dermal mast cells count in mice with scleroderma was reduced after high and medium dose treatment to 11±1.7 and 13±2.2, respectively, as compared to that in non-treated mice (23±3.0). No significant upregulation of p53 nor Ki-67 proteins was observed in the skin of healthy mice and mice with scleroderma after high- and medium-dose of UVA1. CONCLUSIONS: The results of this study indicate that 365nm UVA1 with the cumulative doses of 1200J/cm2 and 600J/cm2 is safe and effective for the dermal fibrosis treatment.