Systemic sclerosis (SSc) is a collagen disease with immune abnormalities, vasculopathy, and fibrosis. Ca blockers and prostaglandins are used to treat peripheral circulatory disturbances. Chronic limb-threatening ischemia (CLTI) is a disease characterized by extremity ulcers, necrosis, and pain due to limb ischemia. Since only a few patients present with coexistence of CLTI and SSc, the treatment outcomes of revascularization in these cases are unknown. In this study, we evaluated the clinical characteristics and treatment outcomes of seven patients with CLTI and SSc, and 35 patients with uncomplicated CLTI who were hospitalized from 2012 to 2022. A higher proportion of patients with uncomplicated CLTI had diabetes and male. There were no significant differences in the age at which ischemic ulceration occurred, other comorbidities, or in treatments, including antimicrobial agents, revascularization and amputation, improvement of pain, and the survival time from ulcer onset between the two subgroups. EVT or amputation was performed in six or two of the seven patients with CLTI and SSc, respectively. Among those who underwent EVT, 33% (2/6) achieved epithelialization and 67% (4/6) experienced pain relief. These results suggest that the revascularization in cases with CLTI and SSc should consider factors such as infection and general condition, since revascularization improve the pain of these patients.

BACKGROUND: Despite advancements in managing autoimmune rheumatic diseases (ARDs) with existing treatments, many patients still encounter challenges such as inadequate responses, difficulty in maintaining remission, and side effects. Chimeric Antigen Receptor (CAR) T-cell therapy, originally developed for cancer, has now emerged as a promising option for cases of refractory ARDs.
METHODS: A search of the literature was conducted to compose a narrative review exploring the current evidence, potential safety, limitations, potential modifications, and future directions of CAR-T cells in ARDs.
RESULTS: CAR-T cell therapy has been administered to patients with refractory ARDs, including systemic lupus erythematosus, antisynthetase syndrome, and systemic sclerosis, demonstrating significant improvement. Notable responses include enhanced clinical symptoms, reduced serum autoantibody titers, and sustained remissions in disease activity. Preclinical and in vitro studies using both animal and human samples also support the efficacy and elaborate on potential mechanisms of CAR-T cells against antineutrophil cytoplasmic antibody-associated vasculitis and rheumatoid arthritis. While cautious monitoring of adverse events, such as cytokine release syndrome, is crucial, the therapy appears to be highly tolerable. Nevertheless, challenges persist, including cost, durability due to potential CAR-T cell exhaustion, and manufacturing complexities, urging the development of innovative solutions to further enhance CAR-T cell therapy accessibility in ARDs.
CONCLUSIONS: CAR-T cell therapy for refractory ARDs has demonstrated high effectiveness. While no significant warning signs are currently reported, achieving a balance between therapeutic efficacy and safety is vital in adapting CAR-T cell therapy for ARDs. Moreover, there is significant potential for technological advancements to enhance the delivery of this treatment to patients, thereby ensuring safer and more effective disease control for patients.

Nowadays, silica products are widely used in daily life, especially in skin applications, which inevitably increases the risk of silica exposure in general population. However, inadequate awareness of silica\'s potential hazards and lack of self-protection are of concern. Systemic sclerosis (SSc) is characterized by progressive tissue fibrosis under environmental and genetic interactions. Silica exposure is considered an important causative factor for SSc, but its pathogenesis remains unclear. Within this study, we showed that lower doses of silica significantly promoted the proliferation, migration, and activation of human skin fibroblasts (HSFs) within 24 h. Silica injected subcutaneously into mice induced and exacerbated skin fibrosis. Notably, silica increased histone deacetylase-4 (HDAC4) expression by inducing its DNA hypomethylation in normal HSFs. The elevated HDAC4 expression was also confirmed in SSc HSFs. Furthermore, HDAC4 was positively correlated with Smad2/3 phosphorylation and COL1, α-SMA, and CTGF expression. The HDAC4 inhibitor LMK235 mitigated silica-induced upregulation of these factors and alleviated skin fibrosis in SSc mice. Taken together, silica induces and exacerbates skin fibrosis in SSc patients by targeting the HDAC4/Smad2/3 pathway. Our findings provide new insights for evaluating the health hazards of silica exposure and identify HDAC4 as a potential interventional target for silica-induced SSc skin fibrosis.

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Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by skin and internal organ fibrosis and obliterative vasculopathy. Few effective treatments are currently available for fibrosis in SSc, therefore, demand persists for novel therapies. Although use of Ginkgo biloba extract (GBE) has been reported to improve blood circulation and alleviate liver and lung fibrosis, its effect on skin fibrosis in SSc remains unclear. In this study, the effects and underlying mechanisms of GBE on skin fibrosis in bleomycin (BLM)-induced mouse model of SSc was investigated. GBE significantly reduced dermal thickness and protein levels of profibrotic factors in the BLM-induced SSc mouse model. Moreover, GBE inhibited the gene expression of profibrotic factors, such as COL1A1, α-SMA, and connective tissue growth factor (CTGF), in fibroblasts by suppressing transforming growth factor (TGF)-β signaling. Furthermore, GBE inhibited the transdifferentiation of adipocytes into myofibroblasts. Thus, our findings suggest that GBE is a promising therapeutic candidate for the treatment of SSc.

UNASSIGNED: Metoclopramide and domperidone are prokinetic agents commonly used to treat gastrointestinal dysmotility disorders. This study aimed to evaluate the safety and associated side effects of prolonged-use metoclopramide and domperidone as treatment for chronic gastrointestinal dysmotility disorders in patients with systemic sclerosis (SSc).
UNASSIGNED: A quantitative observational survey was conducted by interview questionnaire in rheumatology outpatients at a tertiary teaching hospital in Riyadh, Saudi Arabia. The study included all patients aged 25-80 years diagnosed with SSc. All patients were on metoclopramide or domperidone for the treatment of chronic gastrointestinal dysmotility symptoms over at least 12 weeks.
UNASSIGNED: Eighteen eligible patients were included. Most study participants were diagnosed with SSc complicated by interstitial lung disease (n = 13; 72.2 %). The most frequently reported side effect that occurred while taking prokinetic drugs was shortness of breath (n = 12; 66.7 %). None of the participants reported experiencing depression, galactorrhea, or syncope. CNS side effects were reported in 5.6 %. There were no differences in side effects based on the type and dosage of prokinetic drug used.
UNASSIGNED: Use of metoclopramide and domperidone for the treatment of chronic gastrointestinal dysmotility in SSc patients for 12 weeks or longer was not associated with any troublesome side effects. Further studies with more participants are needed to confirm our findings.

BACKGROUND: Mixed connective tissue disease (MCTD) is defined as a systemic rheumatic disease characterized by the presence of high titer anti-U1 ribonucleoprotein (U1 RNP) antibodies in combination with clinical features commonly seen in systemic lupus erythematosus (SLE), systemic sclerosis (SSc), rheumatoid arthritis (RA) and polymyositis (PM).
METHODS: The annual incidence of MCTD is 1.9 per 100,000 adults. Any organ system can be involved in MCTD however four clinical features that suggest the presence of MCTD rather than another systemic rheumatic disease are Raynaud phenomenon with swollen hands or puffy fingers, absence of severe kidney disease and central nervous system (CNS) disease at first presentation generally, insidious onset of pulmonary hypertension and presence of autoantibodies anti-U1 ribonucleoprotein (U1 RNP), especially antibodies to the 68 kD protein. MCTD, although initially thought to be a disease with a benign course is not considered a valid argument at present. This connective tissue disorder can present with life-threating organ involvement with rapid progression of disease.
CONCLUSIONS: We report two cases of MCTD, one with mild disease and another with life-threatening illness, describing the range of severity at presentation of this disorder.

E. Carwile LeRoy, M.D. was a pioneer in the study of systemic sclerosis (SSc, scleroderma). His early medical training was strongly influenced by notable clinical investigators including Dr Kenneth Brinkhous, Dr Charles Christian and Dr Albert Sjoerdsma. Dr LeRoy is remembered for his seminal observations on the over-production of collagen by scleroderma fibroblasts and for his vascular hypothesis on the pathogenesis of scleroderma. The Division of Rheumatology & Immunology at the Medical University of South Carolina, established by Dr LeRoy, is world renowned for its clinical and translational studies of scleroderma and has produced many of the leaders in the international scleroderma community.

Human parvovirus B19 (B19V) is a single-stranded non-enveloped DNA virus of the family Parvoviridae that has been associated with various autoimmune disorders. Systemic sclerosis (SSc) is an autoimmune connective tissue disorder with high mortality and has been linked to B19V infection. However, the precise mechanism underlying the B19V contribution to the development of SSc remains uncertain. This study investigated the impacts of the functional B19V-VP1 unique region (VP1u) in macrophages and bleomycin (BLE)-induced SSc mice. Cell experimental data showed that significantly decreased viability and migration of both B19V-VP1u-treated U937 and THP-1 macrophages are detected in the presence of celastrol. Significantly increased MMP9 activity and elevated NF-kB, MMP9, IL-6, TNF-α, and IL-1β expressions were detected in both B19V-VP1u-treated U937 and THP-1 macrophages. Conversely, celastrol revealed an inhibitory effect on these molecules. Notably, celastrol intervened in this pathogenic process by suppressing the sPLA2 activity of B19V-VP1u and subsequently reducing the inflammatory response. Notably, the administration of B19V-VP1u exacerbated BLE-induced skin fibrosis in mice, with augmented expressions of TGF-β, IL-6, IL-17A, IL-18, and TNF-α, ultimately leading to α-SMA and collagen I deposits in the dermal regions of BLE-induced SSc mice. Altogether, this study sheds light on parvovirus B19 VP1u linked to scleroderma and aggravated dermal fibrosis.

Systemic sclerosis (SSc) is a complex autoimmune disease characterized by significant fibrosis of the skin and internal organs, with the main involvement of the lungs, kidneys, heart, esophagus, and intestines. SSc is also characterized by macro- and microvascular damage with reduced peripheral blood perfusion. Several studies have reported more than 240 pathways and numerous dysregulation proteins, giving insight into how the field of biomarkers in SSc is still extremely complex and evolving. Antinuclear antibodies (ANA) are present in more than 90% of SSc patients, and anti-centromere and anti-topoisomerase I antibodies are considered classic biomarkers with precise clinical features. Recent studies have reported that trans-forming growth factor β (TGF-β) plays a central role in the fibrotic process. In addition, interferon regulatory factor 5 (IRF5), interleukin receptor-associated kinase-1 (IRAK-1), connective tissue growth factor (CTGF), transducer and activator of transcription signal 4 (STAT4), pyrin-containing domain 1 (NLRP1), as well as genetic factors, including DRB1 alleles, are implicated in SSc damage. Several interleukins (e.g., IL-1, IL-6, IL-10, IL-17, IL-22, and IL-35) and chemokines (e.g., CCL 2, 5, 23, and CXC 9, 10, 16) are elevated in SSc. While adiponectin and maresin 1 are reduced in patients with SSc, biomarkers are important in research but will be increasingly so in the diagnosis and therapeutic approach to SSc. This review aims to present and highlight the various biomarker molecules, pathways, and receptors involved in the pathology of SSc.