lcSSc Subset Research Articles

Phenotype of limited cutaneous systemic sclerosis patients with positive anti-topoisomerase I antibodies: data from the EUSTAR cohort.

To characterize patients with positive anti-topoisomerase I (ATA) in lcSSc. SSc patients enrolled in the EUSTAR cohort with a disease duration of ≤3 years at database entry were considered. We assessed the risk of major organ involvement in the following groups: ATA-lcSSc vs ACA-lcSSc and vs ANA without specificity (ANA)-lcSSc, and ATA-lcSSc vs ATA-dcSSc. Cox regression models with time-dependent covariates were performed with the following outcomes: new-onset interstitial lung disease (ILD), ILD progression [forced vital capacity (FVC) decline ≥10% and ≥5% vs values at ILD diagnosis), primary myocardial involvement (PMI), pulmonary hypertension (PH), any organ involvement and all-cause mortality. We included 1252 patients [194 ATA-lcSSc (15.5%)], with 7.7 years (s.d. 3.5) of follow-up. ILD risk was higher in ATA-lcSSc vs ACA- and ANA-lcSSc and similar to ATA-dcSSc, although with less frequent restrictive lung disease. The risk of FVC decline ≥10% (35% of ATA-lcSSc) was lower in ATA-lcSSc than in ATA-dcSSc, whereas FVC decline ≥5% occurs similarly between ATA-lcSSc (58% of patients) and other SSc subsets, including ATA-dcSSc. The risk of PMI was similar in ATA-lcSSc and ANA-lcSSc but lower than in ACA-lcSSc; no difference in PH and mortality risk was observed among lcSSc subsets. The risk of any organ involvement, PMI and PH was lower and the mortality tended to be lower in ATA-lcSSc vs ATA-dcSSc. ATA-lcSSc patients have a high risk of ILD, albeit with a lower risk of progression compared with ATA-dcSSc, supporting careful screening for ILD in this subgroup.

Antinuclear antibody pattern and autoantibody profiling of systemic sclerosis patients in a tertiary referral center in North India.

Antinuclear antibody (ANA) pattern and autoantibody (autoAb) profiling of 150 adult systemic sclerosis (SSc) patients concerning their clinical association and diagnostic significance were analyzed by indirect immunofluorescence (IIF), immunoblot, and fluorescence enzyme immunoassay. One hundred and forty-three (95.3%) patients had positive ANA: DNA topoisomerase I (topo I)-like pattern-84(56%); speckled pattern-44(29.3%);centromere pattern-7(4.6%); and nucleolar pattern-4(2.6%). Three distinct topo I-like immunofluorescence patterns were detected at 1:40 dilution. Topo I-like pattern (32/75-limited cutaneous systemic sclerosis (lcSSc) vs. 52/75-diffuse cutaneous systemic sclerosis (dcSSc); p < 0.001) was found to be associated with dcSSc subset and speckled pattern (lcSSc 28/75 vs. dcSSc 16/75; p < 0.03) with lcSSc subset. One hundred and thirty-eight(92%) patients were positive for SSc-associated autoAbs. The frequency distribution of autoAbs to topo I, centromere A (CENP A) and centromereB (CENP B), RNA polymerase III (RP11, RP155), fibrillarin (U3RNP), nucleolus organizer region (NOR)-90, Th/To, PM-Scl75, PM-Scl100, Ku, platelet-derived growth factor receptor (PDGFR) and Ro-52, were 87(58%), 9(6%), 8(5.3%), 6(4%), 9(6%), 0, 6(4%), 6(4%), 8(5.3%), 5(3.3%), 11(7.3%),0 and 46(30.6%), respectively. Topo I autoAb was strongly associated with dcSSc (35/75 lcSSc vs. 52/75 dcSSc; p < 0.004), Raynaud's (p < 0.003), interstitial lung disease (ILD) (p < 0.001) and pulmonary arterial hypertension (PAH) (p < 0.04). This study helps in defining SSc clinical subset, prognostic markers of disease severity, characterization of the topo I-like ANA pattern, and provides a definite association between the ANA patterns and corresponding autoAb.

Epidemiology and clinical characteristics of systemic sclerosis overlap syndrome (SSc-OS), and the factors significantly associated with SSc-OS in Thai patients with systemic sclerosis.

To investigate the epidemiology and characteristics of systemic sclerosis (SSc) overlap syndrome (SSc-OS). This study included patients enrolled in the Siriraj Systemic Sclerosis Cohort registry during November 2013 to September 2019. SSc-OS was defined as SSc patients who also met criteria for rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), dermatomyositis (DM), polymyositis (PM), Sjogren, and/or antiphospholipid antibody syndrome. Baseline and 1-year characteristics were compared between SSc and SSc-OS. 185 patients (age 50.3 ± 11.4 years, 85.4% female, disease duration 2.7 years, 75.1% diffuse cutaneous subset, 75.6% anti-Scl-70 positivity) were included. The incidence and prevalence rate of SSc-OS was 3.2/100 patient-years and 17.8%. Regarding SSc-OS, 12.4%, 2.2%, 1.1%, 1.6%, and 0.5% of patients were classified as SSc-RA, SSc-SLE, SSc-PM, SSc-RA-SLE, and SSc-SLE-PM. SSc-OS had a higher prevalence of limited cutaneous subset (lcSSc), usual interstitial pneumonia, finger contractures, ESR >20 mm/hr., globulin >3.5 g/dL, rheumatoid factor, anti-citrullinated peptide antibody, and antiphospholipid antibodies. LcSSc subset (OR: 11.3, 95%CI: 2.0-62.6) and globulin >3.5 g/dL (OR: 6.2, 95%CI: 1.6-23.6) were associated with SSc-OS. SSc-OS is associated with the lcSSc subset. RA is the most common overlap syndrome. LcSSc patients with globulin >3.5 g/dL are associated with SSc-OS.

The incidence rate of pulmonary arterial hypertension and scleroderma renal crisis in systemic sclerosis patients with digital ulcers on endothelin antagonist receptors (ERAs) and phosphodiesterase-5 inhibitors (PDE5i).

Endothelin antagonist receptors (ERAs) and phosphodiesterase-5 inhibitors (PDE5i) are beneficial in pulmonary arterial hypertension (PAH) and digital ulcers (DU) and prevent from DU recurrences. Our study aimed to determine the difference in the incidence rate of PAH and scleroderma renal crisis (SRC) in patients with SSc and DU (SSc-DU) under ERAs/PDE5i or without treatment. We conducted a retrospective cohort study including SSc-DU patients from the Spanish Scleroderma Registry (RESCLE). The primary outcome was the incidence rate of PAH and SRC in patients under ERAs/PDE5i or not. Some 544 patients out of 1817 (29.9%) in the RESCLE database had DU, 221 (40.6%) under ERAs/PDE5i and 323 (59.4%) not. The incidence rate (95% CI) difference between patients under treatment or not under did not reach statistical significance in PAH [-0.1 (-4.8, 4.69), P = 0.988] or in SRC [0.7 (-2.2, 3.7), P = 0.620]. However, the time from the first DU to the diagnosis of SRC was delayed in treated patients [mean (s.d.) 7.6 (5.8) years vs 2.9 (5.3); P = 0.021]. The dcSSc subset was more prevalent in the treatment group (36 vs 26%; P = 0.018), along with anti-topoisomerase I antibodies (34 vs 18%; P < 0.001) and tendon friction rubs (12 vs 6%; P = 0.038), whereas the lcSSc subset was more prevalent in the no-treatment group (57 vs 66%; P = 0.031) along with ACA (37 vs 46%; P = 0.031). There was no difference in the incidence rate of PAH and SRC between groups. However, treatment with ERAs and/or PDE5i appeared to delay the occurrence of SRC.

Older age onset of systemic sclerosis - accelerated disease progression in all disease subsets.

ObjectivesSystemic sclerosis is a heterogeneous, multisystem disease. It can occur at any age, but most patients develop the disease between the age of 40 to 50 years. There is controversial evidence on whether/how the age at disease onset affects their clinical phenotype. We here investigate the relationship between age at disease onset and symptoms in a large cohort of SSc patients (lcSSc, dcSSc and SSc-overlap syndromes).MethodsClinical data of the registry of the German Network for Systemic Scleroderma including 3281 patients were evaluated and subdivided into three age groups at disease onset (<40 years, 40–60 years, >60 years).ResultsAmong all SSc patients, 24.5% developed their first non-Raynaud phenomenon symptoms at the age <40 years, and 22.5% were older than 60 years of age. In particular, older patients at onset developed the lcSSc subset significantly more often. Furthermore, they had pulmonary hypertension more often, but digital ulcerations less often. Remarkably, the course of the disease was more rapidly progressing in the older cohort (>60 years), except for gastrointestinal and musculoskeletal involvement. No significant difference was found for the use of corticosteroids. However, significantly, fewer patients older than 60 years received immunosuppressive treatment.ConclusionIn this large registry, ∼25% of patients developed SSc at an age above 60 years with an increased frequency of lcSSc. In this age group, an onset of internal organ involvement was significantly accelerated across all three subsets. These findings suggest that, in the elderly cohort, more frequent follow-up examinations are required for an earlier detection of organ complications.

Spanish scleroderma risk score (RESCLESCORE) to predict 15-year all-cause mortality in scleroderma patients at the time of diagnosis based on the RESCLE cohort: Derivation and internal validation.

A few scores predicting the short-term risk of mortality in Systemic sclerosis (SSc) have been reported to date. Our study aimed to create a predictive 15-year all-cause mortality score at the time of the diagnosis of SSc. The study was based on the Spanish Scleroderma Registry (RESCLE). The cohort was split up in derivation (DC) and validation cohort (VC). A multivariate analysis to detect variables related to all-cause mortality within the first 15years from SSc diagnosis was performed, assigning points to the rounded beta values to create the score (RESCLESCORE). 1935 SSc patients were included. The variables in the final model were as follows: age at diagnosis (+2 points>65years-old), male gender (+1 point), lcSSc subset (-1 point), mode of onset other than Raynaud's (+1 point), cancer (+1 point) and visceral involvement, such as ILD (+1 point), PAH (+1 point), heart (+1 point) and renal involvement (+2 points). Autoantibodies did not achieve statistical significance in the multivariate analysis. The 3 categories of risk to predict 15-year all-cause mortality at the time of diagnosis were as follows: low risk (5% vs. 7%, p=.189), intermediate risk (26.5% vs. 25.5%, p=.911) and high risk (47.8% vs. 59%, p=.316). The AUC was 0.799 (DC) vs. 0.778 (VC) (p=.530). In conclusion, the RESCLESCORE demonstrated an excellent ability to categorize SSc patients at the time of diagnosis in separate 15-year all-cause mortality risk strata at the time of diagnosis.

Treg/Th17 cell balance and phytohaemagglutinin activation of T lymphocytes in peripheral blood of systemic sclerosis patients.

AIMTo investigate T-cell activation, the percentage of peripheral T regulatory cells (Tregs), Th17 cells and the circulating cytokine profile in systemic sclerosis (SSc).METHODSWe enrolled a total of 24 SSc patients and 16 healthy controls in the study and divided the patients as having diffuse cutaneous SSc (dcSSc, n = 13) or limited cutaneous SSc (lcSSc, n = 11). We performed a further subdivision of the patients regarding the stage of the disease - early, intermediate or late. Peripheral venous blood samples were collected from all subjects. We performed flow cytometric analysis of the activation capacity of T-lymphocytes upon stimulation with PHA-M and of the percentage of peripheral Tregs and Th17 cells in both patients and healthy controls. We used ELISA to quantitate serum levels of human interleukin (IL)-6, IL-10, tissue growth factor-β1 (TGF-β1), and IL-17A.RESULTSWe identified a decreased percentage of CD3+CD69+ cells in PHA-stimulated samples from SSc patients in comparison with healthy controls (13.35% ± 2.90% vs 37.03% ± 2.33%, P < 0.001). However, we did not establish a correlation between the down-regulated CD3+CD69+ cells and the clinical subset, nor regarding the stage of the disease. The activated CD4+CD25+ peripheral lymphocytes were represented in decreased percentage in patients when compared to controls (6.30% ± 0.68% vs 9.36% ± 1.08%, P = 0.016). Regarding the forms of the disease, dcSSc patients demonstrated lower frequency of CD4+CD25+ T cells against healthy subjects (5.95% ± 0.89% vs 9.36% ± 1.08%, P = 0.025). With regard to Th17 cells, our patients demonstrated increased percentage in comparison with controls (18.13% ± 1.55% vs 13.73% ± 1.21%, P = 0.031). We detected up-regulated Th17 cells within the lcSSc subset against controls (20.46% ± 2.41% vs 13.73% ± 1.21%, P = 0.025), nevertheless no difference was found between dcSSc and lcSSc patients. Flow cytometric analysis revealed an increased percentage of CD4+CD25-Foxp3+ in dcSSc patients compared to controls (10.94% ± 1.65% vs 6.88% ± 0.91, P = 0.032). Regarding the peripheral cytokine profile, we detected raised levels of IL-6 [2.10 (1.05-4.60) pg/mL vs 0.00 pg/mL, P < 0.001], TGF-β1 (19.94 ± 3.35 ng/mL vs 10.03 ± 2.25 ng/mL, P = 0.02), IL-10 (2.83 ± 0.44 pg/mL vs 0.68 ± 0.51 pg/mL, P = 0.008), and IL-17A [6.30 (2.50-15.60) pg/mL vs 0 (0.00-0.05) pg/mL, P < 0.001] in patients when compared to healthy controls. Furthermore, we found increased circulating IL-10, TGF-β, IL-6 and IL-17A in the lcSSc subset vs control subjects, as it follows: IL-10 (3.32 ± 0.59 pg/mL vs 0.68 ± 0.51 pg/mL, P = 0.003), TGF-β1 (22.82 ± 4.99 ng/mL vs 10.03 ± 2.25 ng/mL, P = 0.031), IL-6 [2.08 (1.51-4.69) pg/mL vs 0.00 pg/mL, P < 0.001], and IL-17A [14.50 (8.55-41.65) pg/mL vs 0.00 (0.00-0.05) pg/mL, P < 0.001]. Furthermore, circulating IL-17A was higher in lcSSc as opposed to dcSSc subset (31.99 ± 13.29 pg/mL vs 7.14 ± 3.01 pg/mL, P = 0.008). Within the dcSSc subset, raised levels of IL-17A and IL-6 were detected vs healthy controls: IL-17A [2.60 (0.45-9.80) pg/mL vs 0.00 (0.00-0.05) pg/mL, P < 0.001], IL-6 [2.80 (1.03-7.23) pg/mL vs 0.00 pg/mL, P < 0.001]. Regarding the stages of the disease, TGF-β1 serum levels were increased in early stage against late stage, independently from the SSc phenotype (30.03 ± 4.59 ng/mL vs 13.08 ± 4.50 ng/mL, P = 0.017).CONCLUSIONIt is likely that the altered percentage of Th17 and CD4+CD25-FoxP3+ cells along with the peripheral cytokine profile in patients with SSc may play a key role in the pathogenesis of the disease.

Limited cutaneous systemic sclerosis: the unfairly neglected subset

Systemic sclerosis (SSc) is an autoimmune disease and a disabling condition that reduces life expectancy. Disease heterogeneity is a hallmark of SSc and classification has been hard to establish. Moreover, within the SSc spectrum, subsetting according to the extent of skin involvement has been universally accepted and is used both for research purposes but also for patient care. Therefore, limited cutaneous (lcSSc) and diffuse cutaneous (dcSSc), with different severity and survival, have been recognized for several years as distinct subsets. Any SSc research project using human material takes into account the cutaneous subsets but it is striking to see that the dcSSc subset has been the subject of the very large majority of the research projects so far. This editorial indicates the comparative epidemiology of the two cutaneous subsets and summarizes the main results coming from the recent registries about the respective outcomes of the patients. The data demonstrate the predominance of the lcSSc subset and challenge some ideas that could suggest that the lcSSc subset might be a benign condition. Some clues are also provided regarding the future possibility to enroll more patients having the lc subset in clinical trials and potential shared outcome measures.

AB0837 Circulating micrornas in systemic sclerosis patients reflect microrna profile of cultured scleroderma fibroblasts and correlate with distinct disease features

BackgroundMicroRNAs (miRs) play a role in many pathophysiologic processes, and have been proposed as tissue-based biomarkers, which are released and stably detectable in body fluids.ObjectivesTo analyse serum expression of miRs...

Registry of the Spanish Network for Systemic Sclerosis: Clinical Pattern According to Cutaneous Subsets and Immunological Status

To investigate the incidence of clinical and immunological characteristics of a large cohort of Spanish patients with scleroderma (SSc) and identifying factors associated with particular organ manifestations assessed by a nationwide cross-sectional analysis. We classified SSc patients in 4 subsets using a modification of LeRoy and Medsger classification that included: "prescleroderma" (pre-SSc), limited cutaneous SSc (lcSSc), diffuse cutaneous SSc (dcSSc), and SSc sine scleroderma (ssSSc). Fourteen Spanish centers participated in patient recruitment. On January 2008, the database included 916 consecutive Spanish SSc patients, 801 women (87.4%) and 115 men (12.6%), all of whom fulfilled the classification criteria proposed by LeRoy and Medsger. Epidemiological, clinical, and laboratory data were collected according to a standard protocol. Mean age at diagnosis was 51.2 ± 15.1 years and mean age at disease onset was 44.9.0 ± 15.8 years. lcSSc was the most frequent subset (61.8%) followed by dcSSc (26.5%), ssSSc (7.5%), and preSSc (4%) subsets. Gender ratios were as follows: dcSSc subset, 200 women and 43 men (4.7:1); lcSSc subset, 503 women and 63 men (ratio 7.9:1), and ssSSc subset, 62 women and 7 men (ratio 8.9:1). Digital ulcers, interstitial lung disease (ILD), musculoeskeletal and esophageal involvement, and scleroderma renal crisis were more frequent in dcSSc than lcSSc and ssSSc subsets. The incidence of pulmonary arterial hypertension assessed by echocardiography was similar in all subsets but mean estimated systolic pulmonary arterial pressure was higher in ssSSc than in lcSSc subset (47.3 ± 23.9 mm Hg vs 39.6 ± 19.2 mm Hg; P < 0.03). Cardiac involvement was identified more frequently in ssSSc than in dcSSc and lcSSc subsets (49.3% vs 32.5% and 31.1%, respectively; P = 0.015 and P = 0.004 for both comparisons). Acro-osteolysis (8.2% vs 2.4%, P = 0.049), calcinosis (19.8% vs 7.2%, P < 0.05), and sicca syndrome (37.5% vs 14.5%, P < 0.0001) were more frequent in lcSSc than in ssSSc subsets. The frequency of clinical manifestations related to the presence of anticentromere antibodies or antitopoisomerase I antibodies was very similar to that identified in patients categorized to lcSSc and dcSSc, respectively. However, in multivariate studies, the ranking of the variables according to their overall explanatory effect on the model showed that the contributory effect of the antibody status was not greater than that of the clinical categorization into lcSSc and dcSSc for the majority of disease manifestations, but, in important manifestations, as ILD, absence of anticentromere antibodies was an independent predictor factor. The classification of SSc into dcSSc, lcSSc, and ssSSc subsets is the one that most closely reflects the natural history of the disease, as they presented clear clinical differences. The immunological profile helps to define important visceral alteration as ILD. Finally, to improve early diagnosis of SSc, patients with preSSc should be considered both to trace the true evolution of the disease and to define which patients could benefit from therapeutic measures able to prevent the appearance of visceral involvements.

Cost-of-illness of patients with systemic sclerosis in a tertiary care centre

The aim of our study was to assess the costs of SSc and to analyse cost drivers. A cross-sectional survey of consecutive patients with SSc was performed in a rheumatology centre in Hungary. Clinical characteristics, the European Scleroderma Study Group activity index, disease severity scale (DSS), scleroderma HAQ (S-HAQ) and health care utilization were recorded. Cost calculation was performed and correlation with clinical variables was analysed. Results were compared with RA and PsA. Eighty patients were involved: 72 (90%) women, mean age (s.d.) 57.4 (9.6) years and disease duration of 6.2 (6.6) years and 25% of the cases had dcSSc. Mean total cost was 9619 (s.d. 6444) euros/patient/year with rate of indirect cost being 56%. Disability-related productivity loss (55.2%) and hospitalization (28.3%) were the highest among the cost items. Patients with dcSSc had significantly higher direct costs (P = 0.005) compared with the lcSSc subset. Disease activity showed significant correlation with total costs, DSS and S-HAQ with direct costs. SSc-related costs were higher than in matched RA and PsA cases. The cost-of-illness of SSc is high with a dominance of productivity loss related costs. Moreover, the disease activity is an important cost driver.

Can CCL2 serum levels be used in risk stratification or to monitor treatment response in systemic sclerosis?

Objective: The chemokine CCL2 has been consistently found to be up-regulated in systemic sclerosis. To explore the potential value of serum CCL2 measurement in disease assessment, we have compared CCL2...

Allograft inflammatory factor‐1 and tumor necrosis factor single nucleotide polymorphisms in systemic sclerosis

Tumor necrosis factor (TNF) alleles have been associated with systemic sclerosis (SSc); however, these alleles may be in linkage with other genes. Allograft inflammatory factor-1 (AIF-1) is a newly identified gene on the short arm of chromosome 6 in the class III region of the human leukocyte antigen. It appears to be involved in inflammation and was originally identified in rat cardiac allografts undergoing rejection. AIF-1 has several sequence variations (single nucleotide polymorphisms, SNPs), three of which result in nonsynonymous changes in amino acid coding. We analyzed the linkage of five TNFA and five AIF-1 SNPs by polymerase chain reaction in 239 Caucasian individuals. The TNFA-1031T/T genotype was found to be associated with SSc (P < 0.0001) and both the DcSSc (diffuse subset of SSc) and the LcSSc (limited subset of SSc) subsets (P= 0.0004 and P= 0.0009, respectively) and the TNFA-237G/G genotype was found to be associated with all SSc (P= 0.0003) and with the DcSSc and LcSSc subsets (P= 0.01 and P= 0.005, respectively). Furthermore, the TNFA-857C/T genotype was associated with LcSSc (P= 0.0003) and TNFA-307A/A genotype associated with DcSSc (P= 0.028). In AIF-1, RS2269475 exon 4A allele, which generates a nonsynonymous change (tryptophan to arginine), was significantly associated in patients with SSc (P= 0.0009) and was associated with those patients who had DcSSc (P= 0.002). A strong linkage disequilibrium was observed between the AIF-1 alleles, A allele of RS2269475 and the A allele of RS4711274 (P < 0.0001), and linkage was observed between AIF-1 and TNFA alleles. Here, we report a novel and significant association of a nonsynonymous change within the AIF-1 with SSc and identified the linkage with TNFA alleles within 50 kb of this gene. Our study lends support that TNFA may be an important inflammatory modulator in SSc and may play a significant role with AIF-1 in disease pathogenesis.