ABSTRACT
Cyclophosphamide (CYC) has been a gold standard of treatment for severe progressive Systemic Sclerosis (SSc), especially in patients with concomitant interstitial lung disease (ILD). This approach was based on results of several interventional studies, including randomized control trials, which mainly addressed SSc-ILD as a primary end point and skin involvement as a second one. The use of CYC is time-limited due to significant adverse events. More recently, other immunosuppressive and biological agents showed efficacy but better safety profile in patients with SSc and SSc-ILD. With regards to other end-points, post-hoc analyses, systematic reviews and metalysis showed that CYC had limited influence on patients' quality of life, event-free survival and mortality. Comprehensive patient's stratification according to a molecular, cellular and phenotypic pattern may help in choosing of personalized medicine with more ambitious treatment effect and should be the future direction. According to the above available data and even if scientific evidence may be missing, experts' opinion has changed the attitude to CYC as an anchor drug in the management of severe SSc. Indeed, CYC has been pushed to the second and even third treatment option after mycophenolate mofetil, tocilizumab or rituximab. This position became obvious during debate on this topic at CORA meeting 2023.
Subject(s)
Lung Diseases, Interstitial , Scleroderma, Diffuse , Scleroderma, Systemic , Humans , Cyclophosphamide/therapeutic use , Immunosuppressive Agents/therapeutic use , Lung Diseases, Interstitial/etiology , Lung Diseases, Interstitial/complications , Quality of Life , Scleroderma, Diffuse/chemically induced , Scleroderma, Diffuse/complications , Scleroderma, Diffuse/drug therapy , Scleroderma, Systemic/complicationsABSTRACT
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.
Subject(s)
Acute Kidney Injury , Scleroderma, Diffuse , Scleroderma, Localized , Scleroderma, Systemic , Humans , Female , Male , Paclitaxel/adverse effects , Scleroderma, Diffuse/chemically induced , Scleroderma, Diffuse/complications , Scleroderma, Diffuse/drug therapy , Taxoids/adverse effects , Scleroderma, Localized/chemically induced , Scleroderma, Localized/drug therapy , Scleroderma, Localized/complications , Scleroderma, Systemic/chemically induced , Scleroderma, Systemic/complications , Scleroderma, Systemic/drug therapy , Acute Kidney Injury/complications , Erythema/complicationsSubject(s)
Appetite Depressants/adverse effects , Overweight/drug therapy , Phentermine/adverse effects , Scleroderma, Diffuse/chemically induced , Adult , Amlodipine/therapeutic use , Appetite Depressants/administration & dosage , Biopsy , Drug Administration Schedule , Drug Therapy, Combination , Female , Hand , Humans , Mycophenolic Acid/therapeutic use , Phentermine/administration & dosage , Scleroderma, Diffuse/diagnosis , Scleroderma, Diffuse/drug therapy , Scleroderma, Diffuse/pathology , Skin/pathology , Time FactorsSubject(s)
Breast Neoplasms/drug therapy , Paclitaxel/adverse effects , Scleroderma, Diffuse/chemically induced , Scleroderma, Diffuse/pathology , Adult , Biopsy, Needle , Breast Neoplasms/pathology , Breast Neoplasms/surgery , Chemotherapy, Adjuvant , Female , Follow-Up Studies , Humans , Immunohistochemistry , Mastectomy/methods , Paclitaxel/therapeutic use , Risk Assessment , Withholding TreatmentABSTRACT
Immune checkpoint inhibitors are approved for select cancer treatment and have shown survival benefit in patients with advanced melanoma. Adverse events, including immune-related adverse events, are common and potentially life-threatening. We describe cases of 2 patients with scleroderma (patient 1 had diffuse scleroderma, and patient 2 had limited scleroderma) that developed while they were receiving pembrolizumab therapy for metastatic melanoma. Prompt recognition and treatment of immune-related adverse events may improve tolerance to immune checkpoint inhibitors and contribute to an understanding of the manifesting autoimmune disease.
Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Agents/therapeutic use , Melanoma/drug therapy , Scleroderma, Diffuse/chemically induced , Scleroderma, Limited/chemically induced , Aged , Humans , Immunotherapy/methods , Male , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Scleroderma, Diffuse/pathology , Scleroderma, Limited/pathologyABSTRACT
The term autoimmune/autoinflammatory syndrome induced by adjuvants (ASIA) or Shoenfeld's syndrome refers to a wide group of immune-mediated diseases triggered by external agents. Several substances, such as vaccine adjuvants, squalene and silicone implants, are implied in the pathogenesis of ASIA syndrome. Treatment and prognosis of this complex condition are not completely known due to lack of good quality evidence. After a brief introductory literature review on ASIA, we report here two cases of patients that developed rapidly progressive systemic sclerosis clinical features after multiple intramuscular local injections of a substance recommended by a non-medical professional called ADE. ADE is an oily vitamin complex for veterinary use, and it was used in these cases for cosmetic muscular definition and enhancement purpose. To our knowledge, this is the first paper to describe the relation between injections of ADE and the development of ASIA with severe systemic sclerosis phenotype. Further investigation is needed to better understand the pathophysiology and to provide the basis for the treatment of this condition.
Subject(s)
Adjuvants, Pharmaceutic/adverse effects , Scleroderma, Diffuse/chemically induced , Adjuvants, Pharmaceutic/administration & dosage , Adult , Humans , Injections, Intramuscular , Male , Rituximab/therapeutic use , Scleroderma, Diffuse/drug therapy , Scleroderma, Diffuse/pathology , Syndrome , Vitamin A/administration & dosage , Vitamin D/administration & dosage , Vitamin E/administration & dosage , Vitamins/administration & dosageSubject(s)
Antineoplastic Agents/adverse effects , Breast Neoplasms/drug therapy , Carcinoma, Ductal, Breast/drug therapy , Docetaxel/adverse effects , Extracellular Matrix/drug effects , Scleroderma, Diffuse/chemically induced , Skin/drug effects , Breast Neoplasms/pathology , Carcinoma, Ductal, Breast/pathology , Cells, Cultured , Chemotherapy, Adjuvant/adverse effects , Extracellular Matrix/metabolism , Extracellular Matrix/pathology , Extracellular Matrix Proteins/metabolism , Female , Fibroblasts/drug effects , Fibroblasts/metabolism , Fibroblasts/pathology , Fibrosis , Humans , Middle Aged , Scleroderma, Diffuse/diagnosis , Scleroderma, Diffuse/drug therapy , Scleroderma, Diffuse/metabolism , Skin/metabolism , Skin/pathologyABSTRACT
OBJECTIVE: Systemic sclerosis (SSc) is a rare intractable disease with unmet medical need and fibrosis-related mortality. Absence of efficient treatments has prompted the development of novel therapeutic strategies, among which mesenchymal stem cells/stromal cells (MSCs) or progenitor stromal cells appear to be one of the most attractive options. The purpose of this study was to use the murine model of hypochlorite-induced SSc to investigate the systemic effects of MSCs on the main features of the diffuse form of the disease: skin and lung fibrosis, autoimmunity, and oxidative status. METHODS: We compared the effects of different doses of MSCs (2.5 × 10(5) , 5 × 10(5) , and 10(6) ) infused at different time points. Skin thickness was assessed during the experiment. At the time of euthanasia, biologic parameters were quantified in blood and tissues (by enzyme-linked immunosorbent assay, quantitative reverse transcription-polymerase chain reaction, assessment of collagen content). Assessments of histology and immunostaining were also performed. RESULTS: A lower expression of markers of fibrosis (Col1, Col3, Tgfb1, and aSma) was observed in both skin and lung following MSC infusion, which was consistent with histologic improvement and was inversely proportional to the injected dose. Importantly, sera from treated mice exhibited lower levels of anti-Scl-70 autoantibodies and enhanced antioxidant capacity, confirming the systemic effect of MSCs. Of interest, MSC administration was efficient in both the preventive and the curative approach. We further provide evidence that MSCs exerted an antifibrotic role by normalizing extracellular matrix remodeling parameters as well as reducing proinflammatory cytokine levels and increasing antioxidant defenses. CONCLUSION: The results of this study demonstrate the beneficial and systemic effects of MSC administration in the HOCl murine model of diffuse SSc, which is a promising finding from a clinical perspective.
Subject(s)
Autoantibodies/immunology , Lung/pathology , Mesenchymal Stem Cell Transplantation , Pulmonary Fibrosis/therapy , Scleroderma, Diffuse/therapy , Skin/pathology , Actins/genetics , Animals , Collagen Type I/genetics , Collagen Type III/genetics , DNA Topoisomerases, Type I/immunology , Disease Models, Animal , Enzyme-Linked Immunosorbent Assay , Fibrosis , Hypochlorous Acid/toxicity , Lung/immunology , Lung/metabolism , Mice , Oxidants/toxicity , Oxidative Stress/immunology , Pulmonary Fibrosis/chemically induced , Pulmonary Fibrosis/immunology , Pulmonary Fibrosis/pathology , Reverse Transcriptase Polymerase Chain Reaction , Scleroderma, Diffuse/chemically induced , Scleroderma, Diffuse/immunology , Scleroderma, Diffuse/pathology , Skin/immunology , Skin/metabolism , Transcriptome , Transforming Growth Factor beta1/geneticsABSTRACT
BACKGROUND: Occupational exposure is reported as playing a substantial causative role in systemic sclerosis (SSc). OBJECTIVE: We sought to compare the characteristics of SSc in patients with and without occupational exposure to crystalline silica/solvents. METHODS: In all, 142 patients with SSc were enrolled in this prospective study. An expert committee performed blind evaluation of occupational exposure to crystalline silica/solvents. RESULTS: Patients exposed to crystalline silica more often exhibited: diffuse cutaneous SSc (P = .02), digital ulcers (P = .05), interstitial lung disease (P = .0004), myocardial dysfunction (P = .006), and cancer (P = .06). Patients exposed to solvents more frequently developed: diffuse cutaneous SSc (P = .001), digital ulcers (P = .01), interstitial lung disease (P = .02), myocardial dysfunction (P = .04), and cancer (P = .003); in addition, these patients were more frequently anti-Scl 70 positive and anticentromere negative. Under multivariate analysis, significant factors for SSc associated with exposure to silica/solvents were: male gender (odds ratio 19.31, 95% confidence interval 15.34-69.86), cancer (odds ratio 5.97, 95% confidence interval 1.55-23.01), and digital ulcers (odds ratio 2.42, 95% confidence interval 1.05-5.56). LIMITATIONS: The cohort originated from a single geographic region. CONCLUSION: Occupational exposure to crystalline silica/solvents is correlated with more severe forms of SSc characterized by: diffuse cutaneous involvement, interstitial lung disease, general microangiopathy (digital ulcers and myocardial dysfunction), and association with cancer. Occupational exposure should be systematically checked in all patients with SSc, as exposed patients seem to develop more severe forms of SSc.
Subject(s)
Dermatitis, Occupational/etiology , Occupational Exposure/adverse effects , Scleroderma, Systemic/chemically induced , Silicon Dioxide/adverse effects , Solvents/adverse effects , Adult , Aged , Female , Humans , Male , Middle Aged , Prospective Studies , Scleroderma, Diffuse/chemically induced , Scleroderma, Systemic/diagnosisABSTRACT
OBJECTIVES: Epigenetic modifications such as DNA methylation and histone acetylation have been implicated in the pathogenesis of systemic sclerosis. However, histone methylation has not been investigated so far. We therefore aimed to evaluate the role of the trimethylation of histone H3 on lysine 27 (H3K27me3) on fibroblast activation and fibrosis. METHODS: H3K27me3 was inhibited by 3-deazaneplanocin A (DZNep) in cultured fibroblasts and in two murine models of dermal fibrosis. Fibrosis was analysed by assessment of the dermal thickening, determination of the hydroxyproline content and by quantification of the numbers of myofibroblasts. The expression of fos-related antigen 2 (fra-2) was assessed by real-time PCR, western blot and immunohistochemistry and modulated by siRNA. RESULTS: Inhibition of H3K27me3 stimulated the release of collagen in cultured fibroblasts in a time and dose-dependent manner. Treatment with DZNep exacerbated fibrosis induced by bleomycin or by overexpression of a constitutively active transforming growth factor ß receptor type I. Moreover, treatment with DZNep alone was sufficient to induce fibrosis. Inhibition of H3K27me3 induced the expression of the profibrotic transcription factor fra-2 in vitro and in vivo. Knockdown of fra-2 completely prevented the profibrotic effects of DZNep. CONCLUSIONS: These data demonstrate a novel role of H3 Lys27 histone methylation in fibrosis. In contrast to other epigenetic modifications such as DNA methylation and histone acetylation, H3 Lys27 histone methylation acts as a negative regulator of fibroblast activation in vitro and in vivo by repressing the expression of fra-2.
Subject(s)
Fibroblasts/enzymology , Histones/metabolism , Jumonji Domain-Containing Histone Demethylases/metabolism , Scleroderma, Diffuse/metabolism , Scleroderma, Diffuse/pathology , Adult , Animals , Antibiotics, Antineoplastic/pharmacology , Bleomycin/pharmacology , Cells, Cultured , Collagen/metabolism , DNA Methylation/drug effects , DNA Methylation/physiology , Dermis/pathology , Disease Models, Animal , Enzyme Inhibitors/pharmacology , Epigenesis, Genetic/drug effects , Epigenesis, Genetic/physiology , Fibroblasts/pathology , Fibrosis/chemically induced , Fibrosis/metabolism , Fibrosis/pathology , Fos-Related Antigen-2/metabolism , Humans , Jumonji Domain-Containing Histone Demethylases/antagonists & inhibitors , Male , Mice , Mice, Inbred DBA , Middle Aged , Scleroderma, Diffuse/chemically induced , Young AdultSubject(s)
Antineoplastic Agents/adverse effects , Hand-Foot Syndrome/etiology , Indoles/adverse effects , Pyrroles/adverse effects , Aged , Arthritis, Rheumatoid/chemically induced , Carcinoma, Renal Cell/drug therapy , Female , Hand-Foot Syndrome/pathology , Humans , Kidney Neoplasms/drug therapy , Scleroderma, Diffuse/chemically induced , SunitinibSubject(s)
Antimetabolites, Antineoplastic/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Carcinoma, Transitional Cell/drug therapy , Deoxycytidine/analogs & derivatives , Deoxycytidine/adverse effects , Lung Neoplasms/drug therapy , Scleroderma, Diffuse/chemically induced , Humans , MaleABSTRACT
We report the first case of scleroderma-like skin sclerosis induced by docetaxel chemotherapy for prostate cancer in Japan. A 67-year-old man underwent radical prostatectomy for cT3aN0M0 prostate cancer in 2003. Thereafter PSA recurrence developed and antiandrogen deprivation therapy was used. However, we diagnosed this case as hormone refractory prostate cancer and began docetaxel chemotherapy in October 2008. There were no nonhematological adverse events through two courses of treatment. He presented to dermatology due to pain and swelling of both upper arms on the second day of the third course. However, when treated with a cooling method, swelling of the upper arms became worse and CPK rose to 1,921 IU/I on the eighth day. We administered a steroid ointment and an antibiotic due to suspicion of thrombophlebitis. Nevertheless, CPK rose to 2,791 IU/I and a skin biopsy was done. In consequence, scleroderma-like skin sclerosis induced by docetaxel chemotherapy was diagnosed. Swelling appeared in both lower limbs and the pain got worse on the 17th day. Therefore docetaxel chemotherapy was discontinued and prednisolone was increased to 30 mg/day, in addition to beginning codeine use for the pain. Thereafter, the painful sclerosis was ameliorated.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Prostatic Neoplasms/drug therapy , Scleroderma, Diffuse/chemically induced , Taxoids/adverse effects , Aged , Docetaxel , Drug Resistance, Neoplasm , Humans , Male , Prednisolone/administration & dosage , Prostatic Neoplasms/etiology , Scleroderma, Diffuse/pathology , Taxoids/administration & dosageABSTRACT
BACKGROUND: Diffuse systemic sclerosis (DSS) is an autoimmune disease that is most often endogenous but which can also be induced by exogenous substances of occupational origin. PATIENTS AND METHODS: We report a case of DSS involving prolonged intermittent occupational exposure to solvents (trichloroethylene [TCE] and perchloroethylene [PCE]). The disease was rapidly fatal with cardiac arrest secondary to myocardial fibrosis. DISCUSSION: In the event of exposure to TCE/PCE, we suggest more systematic prevention and diagnosis of DSS.
Subject(s)
Occupational Diseases/chemically induced , Occupational Exposure/adverse effects , Scleroderma, Diffuse/chemically induced , Tetrachloroethylene/adverse effects , Trichloroethylene/adverse effects , Humans , Male , Middle AgedSubject(s)
Adipose Tissue/pathology , Anabolic Agents/adverse effects , Calcinosis/chemically induced , Foot Ulcer/chemically induced , Scleroderma, Diffuse/chemically induced , Adult , Calcinosis/complications , Calcinosis/diagnosis , Diagnosis, Differential , Fibrosis/chemically induced , Fibrosis/complications , Fibrosis/diagnosis , Foot Ulcer/complications , Foot Ulcer/diagnosis , Humans , Male , Scleroderma, Diffuse/complications , Scleroderma, Diffuse/diagnosisABSTRACT
The name scleroderma is given to a spectrum of diseases which differ clinically and bear different prognostic risks. The origins of the various forms of the disease are unclear. A toxic influence has been suggested, particularly for the progressive systemic scleroderma. However, the imputability of the suspected chemicals often remains unsettled.
Subject(s)
Scleroderma, Systemic/chemically induced , Silicon Dioxide/adverse effects , Autoantibodies/blood , Biomarkers/blood , Diagnosis, Differential , Humans , Hydrocarbons, Aromatic/adverse effects , Prognosis , Scleroderma, Diffuse/chemically induced , Scleroderma, Localized/chemically induced , Scleroderma, Systemic/blood , Scleroderma, Systemic/pathologyABSTRACT
OBJECTIVE: Adenosine regulates inflammation and tissue repair, and adenosine A2A receptors promote wound healing by stimulating collagen matrix production. We therefore examined whether adenosine A2A receptors contribute to the pathogenesis of dermal fibrosis. METHODS: Collagen production by primary human dermal fibroblasts was analyzed by real-time polymerase chain reaction, 14C-proline incorporation, and Sircol assay. Intracellular signaling for dermal collagen production was investigated using inhibitors of MEK-1 and by demonstration of ERK phosphorylation. In vivo effects were studied in a bleomycin-induced dermal fibrosis model using adenosine A2A receptor-deficient wild-type littermate mice, C57BL/6 mice, and mice treated with adenosine A2A receptor antagonist. Morphometric features and levels of hydroxyproline were determined as measures of dermal fibrosis. RESULTS: Adenosine A2A receptor occupancy promoted collagen production by primary human dermal fibroblasts, which was blocked by adenosine A2A, but not A1 or A2B, receptor antagonism. Adenosine A2A receptor ligation stimulated ERK phosphorylation, and A2A receptor-mediated collagen production by dermal fibroblasts was blocked by MEK-1 inhibitors. Adenosine A2A receptor-deficient and A2A receptor antagonist-treated mice were protected from developing bleomycin-induced dermal fibrosis. CONCLUSION: These results demonstrate that adenosine A2A receptors play an active role in the pathogenesis of dermal fibrosis and suggest a novel therapeutic target in the treatment and prevention of dermal fibrosis in diseases such as scleroderma.
Subject(s)
Dermis/metabolism , Fibroblasts/metabolism , Fibrosis/metabolism , Receptor, Adenosine A2A/metabolism , Scleroderma, Diffuse/metabolism , Animals , Cells, Cultured , Collagen/genetics , Collagen/metabolism , Dermis/drug effects , Dermis/pathology , Disease Models, Animal , Enzyme Inhibitors/pharmacology , Fibroblasts/drug effects , Fibroblasts/pathology , Fibrosis/pathology , Fibrosis/prevention & control , Gene Expression , Humans , Hydroxyproline/metabolism , MAP Kinase Kinase 1/antagonists & inhibitors , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , RNA, Messenger/metabolism , Receptor, Adenosine A2A/deficiency , Receptor, Adenosine A2A/genetics , Scleroderma, Diffuse/chemically induced , Scleroderma, Diffuse/pathology , Scleroderma, Diffuse/prevention & control , Triazines/therapeutic use , Triazoles/therapeutic useABSTRACT
INTRODUCTION: Familial occurrence of progressive systemic sclerosis is unusual. The occurrence of conjugal scleroderma is exceptional. EXEGESIS: We report here a case of systemic sclerosis in a wife and husband who both developed the onset of illness within a 10-year period. Solvent exposure was noted. CONCLUSION: The etiology of systemic sclerosis remains unknown. Environmental factors may play role in its pathogenesis.
Subject(s)
Scleroderma, Diffuse/physiopathology , Aged, 80 and over , Echocardiography , Female , Humans , Hypertension, Pulmonary/complications , Male , Scleroderma, Diffuse/chemically induced , Scleroderma, Diffuse/diagnosis , Solvents/toxicityABSTRACT
A scleroderma-like disease has recently been described in association with taxanes. We present the first case of diffuse scleroderma occurring in a woman treated with doxorubicin and cyclophosphamide for breast cancer. The clinical pattern of skin involvement and histological alterations were identical to those found in the classical form of scleroderma. Skin involvement progressed to affect 80% of total body area, and subsequently remained unchanged despite progression of the underlying cancer, making a paraneoplastic aetiology of the scleroderma unlikely. Specific chemotherapeutic agents might be directly responsible for the clinical manifestations and the parameters of progression. Analysis of all similar case reports defines the particular features and clinical course of this phenomenon.