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Objective To determine the potential clinical and pathological significance of altered expression of interleukin 6 (IL-6) in systemic sclerosis (SSc). Methods Serum IL-6 and soluble IL-6 receptor levels were measured in patients with SSc (n=68) and healthy controls (n=15). Associations between serum IL-6 level and C reactive protein, platelet count and key clinical outcomes in SSc were explored. Expression of IL-6 in skin biopsies was also examined and western blot and reverse transcription PCRanalysis were performed using cultured dermal fibroblasts. The effect of IL-6 trans-signalling on production of extracellular matrix proteins was assessed and downstream signalling pathways were examined using pharmacological inhibitors. Results Serum IL-6 level was frequently elevated in patients with SSc, particularly in those with diffuse cutaneous SSc (dcSSc) with thrombocytosis and elevated acute phase markers. Prominent expression in the skin was observed in dermal fibroblasts, mononuclear cells and endothelial cells in patients with early dcSSc. In vitro experiments supported a potent profibrotic effect of IL-6 trans-signalling via the JAK2/STAT3 and ERK pathways. High IL-6 expression early in dcSSc appears to be associated with more severe skin involvement at 3 years and worse long-term survival than in those without elevated IL-6 levels. Conclusion Our results confirm the overexpression of IL-6 in dcSSc and support the potential of IL-6 as a surrogate marker for clinical outcome in this disease. The data also provide rationale for clinical studies targeting IL-6 trans-signalling as a potential antifibrotic therapy for SSc.

Objectives:To assess the prevalence and patterns of cardiac abnormalities as detected by cardiac magnetic resonance imaging (MRI) in systemic sclerosis (SSc).Methods:Fifty-two consecutive patients with SSc underwent cardiac MRI to determine morphological, functional, perfusion at rest and delayed enhancement abnormalities.Results:At least one abnormality on cardiac MRI was observed in 39/52 patients (75%). Increased myocardial signal intensity in T2 was observed in 6 patients (12%), thinning of left ventricle (LV) myocardium in 15 patients (29%) and pericardial effusion in 10 patients (19%). LV and right ventricle (RV) ejection fractions were altered in 12 patients (23%) and 11 patients (21%), respectively. LV diastolic dysfunction was found in 15/43 patients (35%). LV kinetic abnormalities were found in 16/52 patients (31%) and myocardial delayed contrast enhancement was detected in 11/52 patients (21%). No perfusion defects at rest were found. Patients with limited SSc had similar MRI abnormalities to patients with diffuse SSc. Seven of 40 patients (17%) without pulmonary arterial hypertension had RV dilatation.Conclusions:This study shows that MRI is a reliable and sensitive technique for diagnosing heart involvement in SSc and for analysing its mechanisms, including its inflammatory, microvascular and fibrotic components. Compared with echocardiography, MRI appears to provide additional information by visualising myocardial fibrosis and inflammation. RV dilatation appeared to be non-specific for pulmonary arterial hypertension but could also reflect myocardial involvement related to SSc. Further studies are needed to determine whether cardiac MRI abnormalities have an impact on the prognosis and treatment strategy.

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.

ObjectiveTo investigate and distinguish detailed nailfold videocapillaroscopy (NVC) findings in patients with limited (lcSSc) and diffuse (dcSSc) cutaneous systemic sclerosis (SSc).MethodsA total of 157 patients was recruited, 100 with lcSSc, 27 with dcSSc and 30 with primary Raynaud phenomenon (pRP). The NVC SSc pattern and the absolute number of capillaries (per linear millimetre) were performed at the first NVC analysis. ‘Early’/‘Active’ NVC status (capillary dilations, microhaemorrhages and giant capillaries) and ‘Late’ NVC status (number of capillaries, altered microvascular architecture and abnormal capillary shapes) were scored.ResultsA statistically significant difference in the absolute number of capillaries between patients with lcSSc, dcSSc and pRP was found (p<0.001). Capillary number loss was present in both SSc subgroups and it was significantly higher in patients with dcSSc compared with lcSSc (4.89±1.53 vs 6.18±1.75, p<0.001). A significantly higher ‘Late’ NVC status score was observed in patients with dcSSc (p<0.001), including lower capillary density (p<0.001), altered shapes (p<0.001) and presence of abnormal shapes (p=0.005). Correlations showed that higher modified Rodnan Skin Score is associated with decreased capillary number and higher ‘Late’ NVC status score (p<0.001). Additionally, a statistically significant association was established between ‘Late’ SSc pattern and dcSSc (p=0.004) and between ‘Early’ SSc pattern and lcSSc (p=0.010). The absolute capillary number was normal and significantly higher in patients with pRP (p<0.001) than in all patients with SSc.ConclusionsThe current investigation underlines the importance of NVC detailed analysis and scoring in discriminating the severity of microvascular damage between lcSSc and dcSSc.

Systemic Sclerosis (SSc) is an autoimmune disease characterized by fibrosis and vasculopathy. A key feature is the presence of T cells in inflammatory lesions. To establish the differences in peripheral blood T helper (Th) subpopulations in diffuse cutaneous (dc) and limited cutaneous (lc) SSc patients, blood samples from 57 dcSSc and 78 lcSSc patients were obtained. Controls were collected from healthy volunteers ( n  = 16), active systemic lupus erythematosus (aSLE) patients ( n  = 13), and active rheumatoid arthritis (aRA) patients ( n  = 12). Mononuclear cells were analyzed by flow cytometry to determine Th1 (CD4+/IFN-γ+), Th2 (CD4+/IL-4+), Th17 (CD4+/IL-17+), and regulatory T cells (Tregs; CD4+/CD25+/Foxp3+) subsets. Th17 and Th1 subsets were increased in SSc groups versus healthy controls ( P  < 0.001) and aSLE patients ( P  < 0.001 for Th17 and P  < 0.008 for Th1). Th2 cells were higher in dcSSc patients than in the healthy and aSLE groups ( P  = 0.03 and P  = 0.009, respectively). Tregs were increased in the aRA group when compared with SSc patients and healthy controls ( P  ≤ 0.003). Patients with immunosuppressive treatment had lower numbers of Th17 and Th2 cells ( P  = 0.02). Our results shed further light into the preponderant role of Th17 and Th1 in patients with SSc. However, these findings certainly deserve to be studied in depth.

We aimed to clarify the clinical features of Japanese patients with systemic sclerosis (SSc), especially with reference to organ involvement and autoantibodies. A cohort of 405 patients with SSc who attended our institution from 1973 to 2008 was identified retrospectively. Data on clinical features, including autoantibodies, organ involvement, and overlap of other connective tissue diseases, were obtained by following the medical records until 2009. The percentage of male patients during or after 1990 was greater than that before 1990 (3.9 vs. 10.6%, respectively). Limited cutaneous SSc (lSSc) was twice as frequent as diffuse cutaneous SSc (dSSc). About half of the patients had lung involvement (50.4%), while only 3.2% had scleroderma renal crisis. Male gender was associated with lung involvement, and dSSc was associated with most organ involvements except for pulmonary arterial hypertension (PAH). Anti-Scl-70 antibody was associated with lung or heart involvement, while anti-U1-RNP antibody was only associated with PAH. Conversely, patients with anti-centromere antibody had less organ involvement. SSc–Sjögren overlap syndrome was related to lSSc, further overlapping systemic lupus erythematosus (SLE), and less lung or heart involvement. In conclusion, these results not only confirmed previous reports but revealed several other findings, such as the increased proportion of male patients in recent years and the relationships between clinical features.

Objective:Cartilage oligomeric matrix protein (COMP) accumulates in systemic sclerosis (SSc) skin and is upregulated by transforming growth factor (TGF)β. To further characterise the response to TGFβ in SSc, we investigated TGFβ1 and COMP expression and myofibroblast staining in SSc skin.Methods:Skin biopsies from patients with diffuse cutaneous SSc (dSSc), limited cutaneous SSc (lSSc) and healthy controls were evaluated for COMP mRNA expression using real-time PCR. COMP, α-smooth muscle actin (SMA) and TGFβ were assessed in skin sections and in cultured fibroblasts by immunohistochemistry. Clinical disease status was assessed by the modified Rodnan skin score (mRSS).Results:Myofibroblasts expressing SMA and COMP were found coexpressed in many cells in dSSc dermis, but each also stained distinct cells in the dermis. Cultured SSc dermal fibroblasts also showed heterogeneity for COMP and SMA expression, with cells expressing SMA, COMP, both or neither. TGFβ treatment increased COMP and SMA-expressing cells. COMP mRNA expression in lesional skin from patients with dSSc correlated with the mRSS and TGFβ1 staining.Conclusion:These findings suggest that TGFβ upregulation of COMP and/or SMA expression in subpopulations of fibroblasts contributes to different pathways of fibrosis and that multiple TGFβ regulated genes may serve as biomarkers for the degree of SSc skin involvement.

Anti-CCP (cyclic citrullinated peptide) is considered the most useful laboratory tool in the diagnosis of rheumatoid arthritis (RA). Some authors have also found this autoantibody in patients with scleroderma (SSc). The study aimed to investigate the prevalence of anti-CCP antibodies in SSc patients from Southern Brazil and their association with clinical and serological profile of the disease. We studied 76 patients with SSc and 100 healthy volunteers for presence of anti-CCP. SSc patients charts were reviewed for clinical and laboratory data. In the SSc group, the diffuse form was present in 20.5%; 62.8% had the limited form; 14.1% had overlap with systemic lupus or polymyositis and 2.5% had SSc sine scleroderma. Anti-CCP was found in nine of 78 (11.5%) SSc patients and in one of 100 healthy volunteers ( p  = 0.0054). No relationship was found with arthritis, skin Rodnan m score, esophageal dysmotility, myocarditis, pulmonary hypertension and lung fibrosis. Positive association was observed with arthralgias ( p  = 0.02). Also, no relationship was noted with the presence of anti-centromere antibodies, anti-Scl-70, anti-RNP or rheumatoid factor. Anti-CCP are more common in SSc patients than in controls. Arthralgias but not arthritis or rheumatoid factor are more frequent in anti-CCP positive patients.

The aims of the present study were to determine the correlation between durometer scores with modified Rodnan skin scores (MRSS), scleroderma symptoms, and physical functions. A total of 31 patients with systemic sclerosis (SSc, 16 diffuse and 15 limited type) were enrolled in this study. Skin involvement was measured using a durometer and MRSS. Health assessment questionnaire (HAQ) disability indices, Keitel function test (KTF) scores, grip strengths, and scleroderma-visual analog scale (scleroderma-VAS) scores were measured. The correlations between durometer scores with MRSS, HAQ disability indices, and scleroderma-VAS scores were assessed. Durometer scores correlated well with MRSS at fingers, hands, forearms, upper arms, thighs, and feet, but poorly correlated with MRSS at the chest, abdomen, and lower legs. Total durometer scores correlated well with MRSS ( r  = 0.537, P  = 0.002) and KTF scores ( r  = 0.608, P  < 0.001), but poorly correlated with HAQ disability indices ( r  = 0.202, P  = 0.276), and individual scleroderma-VAS scores. Durometer-measured skin hardnesses were found to correlate well with the MRSS scores of fingers, hands, forearms, upper arms, thighs, and feet. The authors suggest that these skin sites should be included when durometer measurements are made in systemic sclerosis.

Background Hemifacial atrophy (Parry-Romberg syndrome) is a relatively rare disease. The etiology of the disease is not clear. Some authors postulate its relation with limited scleroderma linearis. Linear scleroderma \"en coup de sabre\" is characterized by clinical presence of most commonly one-sided linear syndrome. In a number of patients, neurological affection is the medium of the disease. The treatment of both scleroderma varieties is similar to the treatment of limited systemic sclerosis. Case presentation We present two cases of a disease: a case of a 49-year-old woman with a typical image of hemifacial atrophy, without any changes of the nervous system and a case of a 33-year-old patient with an \"en coup de sabre\" scleroderma and with CNS tumor. Conclusion We described typical cases of a rare diseases, hemifacial atrophy and \"en coup de sabre\" scleroderma. In the patient diagnosed with Parry-Romberg syndrome, with Borrelia burgdoferi infection and with minor neurological symptoms, despite a four-year case history, there was a lack of proper diagnosis and treatment. In the second patient only skin changes without any neurological symptoms could be observed and only a precise neurological diagnosis revealed the presence of CNS tumor.