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Lung involvement is the most frequent cause of death in patients with systemic sclerosis (SSc). As lung involvement is frequently asymptomatic, the current recommendation is to carry out thoracic computed tomography (CT) in all patients newly diagnosed with SSc. There is currently disagreement on how patients with SSc for whom no lung involvement was found at the time of diagnosis, should be followed up. Based on a consensus of Austrian rheumatologists, pneumologists and radiologists it is recommended that for asymptomatic patients with a negative CT at the time of initial diagnosis, a transthoracic ultrasound examination should be carried out annually and a lung function examination every 6-12 months. In the presence of a positive lung ultrasound finding a supplementary CT for further clarification is recommended. Based on the data situation, annual CT follow-up controls are recommended for patients with a high risk as defined by appropriate risk factors., (© 2022. The Author(s).)

Large data bases and the projects arising from them have led to a much improved understanding of systemic sclerosis over the last decade. Serology has developed further so that more autoantibodies are available for routine testing. Capillary microscopy has become standard and relevant progress has also been made in therapy. Many diagnostic terms found in medical documentation do not adequately reflect this progress. The nomenclature is inconsistent and, therefore, confusing. The international classification of diseases (ICD) nomenclature is, from our point of view, also in need of improvement. This article aims to reestablish a common German language standard for systemic sclerosis, which reflects current knowledge and is suitable for implementation in the clinical routine.

Objective: Polymorphisms in the genes encoding interleukin 4 (IL4), interleukin 13 (IL13), and their corresponding receptors have been associated with multiple immune-mediated diseases. Our aim was to validate these previous observations in patients with systemic sclerosis (SSc) and scrutinize the effect of the polymorphisms on gene expression in various populations of peripheral blood leukocytes., Methods: We genotyped a cohort of 2488 patients with SSc and 2246 healthy controls from The Netherlands, Spain, United Kingdom, Italy, Germany, and France. Taqman assays were used to genotype single-nucleotide polymorphisms (SNP) in the following genes: (1) IL4 (-590C>T/rs2243250); (2) IL4 receptor alpha (IL4RA) (Q576R/rs1801275); (3) IL13 (R130Q/rs20541 and -1112C>T/rs1800925); and (4) IL13RA1 (43163G>A/rs6646259). The effect of these polymorphisms on expression of the corresponding genes was assessed using quantitative RT-PCR on RNA derived from peripheral blood B cells, T cells, plasmacytoid dendritic cells, monocytes, and myeloid dendritic cells. We investigated whether these polymorphisms influenced development of pulmonary complications over 15 years in patients with SSc., Results: None of the investigated polymorphisms was associated with SSc or any SSc clinical subtype. We did not observe any effect on transcript levels in the cell subtypes or on development of pulmonary complications., Conclusion: Our data showed that polymorphisms in IL4, IL13, and their receptors do not play a role in SSc and do not influence the expression of their corresponding transcript in peripheral blood cells.

Objective: To investigate whether polymorphisms in Toll-like receptor (TLR) genes, previously reported to be associated with immune-mediated diseases, are involved in systemic sclerosis (SSc)., Methods: We genotyped 14 polymorphisms in the genes for TLRs 2, 4, 7, 8, and 9 in a discovery cohort comprising 452 SSc patients and 537 controls and a replication cohort consisting of 1,170 SSc patients and 925 controls. In addition, we analyzed 15-year followup data on 964 patients to assess the potential association of TLR variants with the development of disease complications. We analyzed the functional impact of the associated polymorphism on monocyte-derived dendritic cells., Results: In the discovery cohort, we observed that a rare functional polymorphism in TLR2 (Pro631His) was associated with antitopoisomerase (antitopo) positivity (odds ratio 2.24 [95% confidence interval 1.24-4.04], P=0.003). This observation was validated in the replication cohort (odds ratio 2.73 [95% confidence interval 1.85-4.04], P=0.0001). In addition, in the replication cohort the TLR2 variant was associated with the diffuse subtype of the disease (P=0.02) and with the development of pulmonary arterial hypertension (PAH) (Cox proportional hazards ratio 5.61 [95% confidence interval 1.53-20.58], P=0.003 by log rank test). Functional analysis revealed that monocyte-derived dendritic cells carrying the Pro63His variant produced increased levels of inflammatory mediators (tumor necrosis factor α and interleukin-6) upon TLR-2-mediated stimulation (both P<0.0001)., Conclusion: Among patients with SSc, the rare TLR2 Pro631His variant is robustly associated with antitopoisomerase positivity, the diffuse form of the disease, and the development of PAH. In addition, this variant influences TLR-2-mediated cell responses. Further research is needed to elucidate the precise role of TLR-2 in the pathogenesis of SSc., (Copyright © 2012 by the American College of Rheumatology.)

Objective: To determine the prevalence of and independent factors associated with joint involvement in a large population of patients with systemic sclerosis (SSc)., Methods: This study was cross-sectional, based on data collected on patients included in the European League Against Rheumatism (EULAR) Scleroderma Trials and Research (EUSTAR) registry. We queried this database to extract data regarding global evaluation of patients with SSc and the presence of any clinical articular involvement: synovitis (tender and swollen joints), tendon friction rubs (rubbing sensation detected as the tendon was moved), and joint contracture (stiffness of the joints that decreased their range of motion). Overall joint involvement was defined by the occurrence of synovitis and/or joint contracture and/or tendon friction rubs., Results: We recruited 7286 patients with SSc; their mean age was 56 +/- 14 years, disease duration 10 +/- 9 years, and 4210 (58%) had a limited cutaneous disease subset. Frequencies of synovitis, tendon friction rubs, and joint contractures were 16%, 11%, and 31%, respectively. Synovitis, tendon friction rubs, and joint contracture were more prevalent in patients with the diffuse cutaneous subset and were associated together and with severe vascular, muscular, renal, and interstitial lung involvement. Moreover, synovitis had the highest strength of association with elevated acute-phase reactants taken as the dependent variable., Conclusion: Our results highlight the striking level of articular involvement in SSc, as evaluated by systematic examination in a large cohort of patients with SSc. Our data also show that synovitis, joint contracture, and tendon friction rubs are associated with a more severe disease and with systemic inflammation.

Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of the skin and internal organs that leads to profound disability and premature death. To identify new SSc susceptibility loci, we conducted the first genome-wide association study in a population of European ancestry including a total of 2,296 individuals with SSc and 5,171 controls. Analysis of 279,621 autosomal SNPs followed by replication testing in an independent case-control set of European ancestry (2,753 individuals with SSc (cases) and 4,569 controls) identified a new susceptibility locus for systemic sclerosis at CD247 (1q22-23, rs2056626, P = 2.09 x 10(-7) in the discovery samples, P = 3.39 x 10(-9) in the combined analysis). Additionally, we confirm and firmly establish the role of the MHC (P = 2.31 x 10(-18)), IRF5 (P = 1.86 x 10(-13)) and STAT4 (P = 3.37 x 10(-9)) gene regions as SSc genetic risk factors.

Objectives: Both increased and decreased apoptosis may be involved in generating autoimmunity. This study addressed the question of whether apoptosis and apoptosis-regulating proteins are altered in systemic sclerosis (SSc). Patients and methods. Peripheral lymphocytes of 39 SSc patients and 47 healthy control persons were studied for apoptosis, Bcl-2 and Bax levels, expression of Fas (CD95) and activation markers (CD25, HLA-DR) as determined by fluorocytometry. Serum Fas and Fas ligand were measured by ELISA., Results: SSc lymphocytes (mainly CD4(+)) expressed increased amounts of Bcl-2, while Bax was not elevated. Apoptosis rates of SSc lymphocytes were increased in unsupplemented medium, but returned to normal in the presence of autologous plasma. SSc patients had increased percentages of activated and CD95(+) lymphocytes and elevated soluble Fas and soluble FasL levels in serum. Activating anti-CD95 antibodies further increased the apoptosis rate., Conclusions: Increased in vitro apoptosis, elevated lymphocytic Bcl-2 content and the increased number of Fas-positive T cells are not specific for peripheral blood from SSc patients, but indicate deregulation of lymphocyte homeostasis in this disease.

We investigated the effects of photopheresis in systemic sclerosis by analysing its influence on lymphocytes with regard to apoptosis and expression of bcl-2 and fas. Peripheral blood lymphocytes isolated immediately before and 24 h after photopheresis were investigated for apoptosis, bcl-2 and fas expression by fluorocytometry, and compared to controls. In addition, leucocytes from systemic sclerosis patients taken directly from the photopheresis system were tested for apoptosis after 24 h in culture. fas expression was similar in controls and patients with systemic sclerosis just before photopheresis, but increased 24 h after photopheresis, mainly due to an increase of CD4+CD95+ cells. bcl-2 was overexpressed in scleroderma peripheral lymphocytes, but not influenced by photopheresis. As compared to healthy controls, the percentage of apoptotic cells 24 h after photopheresis was high in cultured lymphocytes, but not ex vivo. The significant increase in fas on peripheral lymphocytes observed in this study may be a major operative mechanism of photopheresis in addition to (and possibly related to) the induction of apoptosis.

Objective: To determine the value of the circulating intercellular adhesion molecule (cICAM-1) as a marker for the inflammatory and fibrotic processes in systemic sclerosis (SSc)., Methods: We determined serum levels of cICAM-1 and of the soluble interleukin-2 receptor (sIL-2R) by an enzyme-linked immunosorbent assay in 33 patients with SSc. These values were compared to the concentrations of acute phase reactants and to the extent of skin involvement in diffuse and limited scleroderma., Results: cICAM-1 was elevated in patients with diffuse SSc (498 +/- 134 ng/ml) as compared with 82 healthy controls (312 +/- 71 ng/ml) (mean +/- SD, p < 0.0001). The elevation of cICAM-1 did not correlate with the duration of disease, the pattern of organ manifestations or the type of treatment. While the concentrations of acute phase proteins were not elevated in SSc, a significant correlation between increased serum sIL-2R and cICAM-1 was observed., Conclusion: Increased levels of cICAM-1 indicate an activation of immune processes in SSc. The clinical value of the cICAM-1 determination in SSc can only be judged in longitudinal studies.