Autoantibodies In Systemic Sclerosis Research Articles

Right Bundle Branch Block: A Predictor of Mortality in Early Systemic Sclerosis

ObjectiveTo evaluate the prognostic significance of baseline electrocardiogram (ECG) abnormalities in a multiethnic cohort of patients with early systemic sclerosis (SSc) and to determine the serological, clinical, and echocardiogram correlates of ECG findings.MethodsSSc patients with disease duration of≤5 years were enrolled in the GENISOS (Genetics versus Environment in Scleroderma Outcome Study) cohort. At the first visit, a standard 12 lead ECG was obtained along with demographic information, clinical data, and autoantibodies. The results of echocardiograms were also recorded. All ECGs were interpreted by a cardiologist unaware of the patients' clinical data.ResultsOf 265 SSc patients with average disease duration at enrollment of 2.5 years, 140 (52.8%) had abnormal ECG findings. These findings were not associated with SSc disease type or autoantibody profile but were associated with more severe heart and lung involvement. A total of 75 patients (28.3%) died over a follow up time of 9.9 years. Complete right bundle branch block (± left anterior hemiblock) on ECG, present in 7 (2.6%) patients, predicted a higher risk of mortality (HR: 5.3; 95% CI: 2.1 to 13.4; p<0.001). The predictive significance of right bundle branch block was independent of age at enrollment, gender, ethnicity and risk factors for coronary artery disease.ConclusionECG abnormalities are common in patients with early SSc and are associated with the severity of lung and heart involvement. Right bundle branch block is an independent predictor of mortality, and should be considered a marker of disease severity in SSc.

Revisiting ANCA-associated vasculitis in systemic sclerosis: clinical, serological and immunogenetic factors

To define the clinical, serological, histological and immunogenetic features of patients with scleroderma and ANCA-associated vasculitis (AAV). We examined a clinical database of 2,200 patients with either limited or diffuse cutaneous systemic sclerosis (SSc). Patients with a confirmed diagnosis of vasculitis who were ANCA positive with either MPO or PR3 reactivity had their clinical features, serology, histology and HLA haplotypes examined in detail. From this SSc cohort, 35 patients (1.6%) had evidence of vasculitis, and the SSc autoantibody profiles in this group were comparable to those previously published from the whole cohort. Of these 35 patients, 8 (0.4% of whole SSc cohort) had either anti-MPO or anti-PR3 antibodies and two further patients were ANCA positive without defined specificities. Of the eight ANCA-positive patients, seven had limited cutaneous SSc and anti-MPO antibodies and only one had anti-PR3 antibodies, associated with diffuse cutaneous SSc. Two ANCA-positive patients had anti-U3RNP antibodies, usually associated with overlap disease. None of the patients had granulomatous disease. The majority had glomerulonephritis, renal arteritis and pulmonary fibrosis. There were several shared HLA haplotypes from the DP and DQ loci in these overlap patients. SSc in overlap with ANCA-associated vasculitis is rare, and clinical features are more mixed than when either of these two conditions occurs separately. From our database, U3RNP antibodies may be more associated with overlap AAV than the other scleroderma-specific antibodies.

Lack of association of platelet-derived growth factor (PDGF) receptor autoantibodies and severity of chronic graft-versus-host disease (GvHD)

The existence of platelet-derived growth factor (PDGF) receptor autoantibodies in systemic sclerosis is conflicting, and such antibodies were also detected in patients with chronic graft-versus-host disease (GvHD) after allogeneic peripheral blood stem cell transplantation (PBSCT). We therefore aimed to screen for PDGF receptor autoantibodies in patients with chronic GvHD. We evaluated the existence of PDGF receptor autoantibodies in 39 patients, while 17 patients presented with a limited and 8 patients with an extensive chronic GvHD, respectively. Furthermore, 14 out of 39 patients had no chronic GvHD. We detected at least low levels of PDGF receptor autoantibodies in nearly all (35 of 39) patients after allogeneic PBSCT. Interestingly, only one of six patients with high levels of PDGF receptor autoantibodies presented with an extensive chronic GvHD, while the remaining six patients had no clinical signs of chronic GvHD. Thus, there was no correlation between the quantitative detection of antibodies directed against the PDGF receptor and the presence or severity of chronic GvHD. Platelet-derived growth factor receptor autoantibodies could easily be detected in patient sera. Nevertheless, we did not observe any correlation between the presence of PDGF receptor autoantibodies and the severity of chronic GvHD in patients who underwent allogeneic PBSCT.

Associations with Organ Involvement and Autoantibodies in Systemic Sclerosis: Results from the Canadian Scleroderma Research Group (CSRG)

Objective: Serum from SSc patients was analyzed centrally to determine ANA patterns and extractable nuclear antigens (ENAs) between lcSSc and dcSSc and associations with organ involvement. Methods: 1145 SSc patients had ANA and ENA analyzed by indirect immunofluorescence on HEp-2 substrate at a screening serum dilution of 1/160. Most ENA antibodies [Sm. U1-RNP, Ro52, SS-A/Ro60, topoisomeraseI (Topo1), SS-B/La, chromatin, ribosomal P and Jo1] were measured by laser bead immunoassay; and RNA polymerase III (RNAP) by ELISA. Results: ANA was positive in 95% (same in lcSSc, and dcSSc). Centromere pattern was present in 34%, speckled 22%, nucleolar 18%, homogeneous and speckled (H&S) 16%, multiple nuclear dots 6%. Anti-centromere Ab (ACA) occurred in 46% of lcSSc and 11% of dcSSc (P = 0.0001). ENAs that differed between lcSSc and dcSSc subsets were Topo1 (OR 2.4, P = 0.0001) and RNAP (OR 5.6, P 0.0001) more common in dcSSc. Overall, 15% had positive Topo1; usually with a H&S pattern (67%); Topo1 was associated with ILD on CXR (OR 2.3; 95% CI 1.5 - 3.5) and HRCT (OR 3.8; 95% CI 1.8 - 8.2). RNAP occurred in 18.5% (35.4% in dcSSc vs. 8.9% in lcSSc). Scleroderma renal crisis (SRC) was 13 times more likely if RNAP positive; P = 0.0001. ACA was only weakly associated with sPAP > 50 mmHg (OR 1.8; 95%CI 1.1 - 3.0). Conclusion: ANA homogeneous pattern alone is rare in SSc; ACA was significantly more common in lcSSc. Many ENAs are equal in lcSSc and dcSSc except RNAP and Topo1. RNAP has the highest OR of SRC. Topo1 is less strongly associated with ILD. Abstract word count: 249, Body word count 1246, Figures 2, Tables 2. Key Messages: 1) 95% of SSc has a positive ANA and ANA patterns in SSc include centromere, nucleolar, and homogeneous and speckled together; 2) Most ENAs are equal in both dcSSc and lcSSc except anti RNA polymerase III and topoisomerase I; 3) RNA polymerase III has the highest association (odds ratio) with scleroderma renal crisis, topoisomerase I is associated with interstitial lung disease; whereas anticentromere was not associated with elevated pulmonary arterial pressures on echocardiogram.

What autoantibody tests should become widely available to help scleroderma diagnosis and management?

Anti-Th/To autoantibodies have been recognized as serological markers of systemic sclerosis (SSc) for more than 20 years. However, validated immunoassay kits to test this specificity have not been commercially available. SSc autoantibodies are basically mutually exclusive and are associated with a certain subset of the disease and/or with organ involvement. Anti-Th/To are generally considered to be markers of the limited cutaneous type of SSc with the involvement of certain internal organs. The excellent correlation between anti-Rpp25 as detected by their novel chemiluminescent method and anti-Th/To as detected by immunoprecipitation suggest that the new assays may become widely available tests for clinicians in future and could help to clarify the clinical significance of anti-Th/To in SSc as well as other conditions over different races or countries.

Anti-AT(1)R and anti-ET(A)R autoantibodies in systemic sclerosis: clues for possible involvement in disease pathology

BackgroundAutoantibodies that target the angiotensin-II type-1 receptor (AT1R-Abs) and the endothelin-1 receptor type A (ETAR-Abs) were recently identified in systemic sclerosis (SSc). They showed strong association with clinical symptoms such...

Cancer in Italian Patients with Systemic Sclerosis

The association between cancer and systemic sclerosis (SSc) is known, although the underlying mechanisms remain unclear and epidemiological data is conflicting. Since no data exist on cancer in Italian SSc, we examined the frequency and characteristics of cancer in an Italian cohort of SSc patients to examine whether clinical and/or laboratory SSc-specific features represent a risk for developing malignancies in these patients. A retrospective chart review was carried out of 112 Italian SSc patients of whom 109 were women 3 and were men, aged 63±13 years; 81 patients had limited SSc, 25 had diffuse SSc and 6 had sine scleroderma SSc. Fifteen cancers were found in 14 patients. The majority (60%) occurred after SSc onset (average 16 years), 40% occurred before the onset of SSc (average 14 years). The most frequent was breast cancer (prevalence: 4.5%, relative prevalence:33.3%), followed by uterine cancer and lymphomas (prevalence: 2.7%, relative prevalence: 20% each). Lung cancer was not observed. Cancers were unrelated with SSc type, autoantibodies, organ involvement and treatments. In conclusion, clinical features do not seem to be linked with the risk of developing cancer in SSc patients. Interestingly, and in contrast with published data, no lung cancer was present in our patients, although lung involvement was observed in the majority of them. This finding, consistent with a lower prevalence of lung cancer in the Italian female general population, and the absence of associations between SSc-specific features and cancer, suggests that genetic and environmental factors might play a pivotal role in cancer risk in these patients.

Type I interferon system activation and association with disease manifestations in systemic sclerosis

ObjectivesTo study the presence of interferogenic autoantibodies in systemic sclerosis (SSc) and their correlation with clinical manifestations, serum levels of interferon α (IFNα) and chemokines of importance in the disease...

Autoantibodies as predictive tools in systemic sclerosis

The pathogenetic role of autoantibodies in systemic sclerosis (SSc) remains unclear, but these autoantibodies have been established as strong predictors of disease outcome and the pattern of organ complications in patients with this condition. The three most frequently observed types of SSc-specific autoantibody-anti-centromere antibodies, anti-topoisomerase antibodies and anti-RNA polymerase III antibodies-are found in over 50% of patients; the presence of each is generally exclusive of the others. Although a lot less frequently observed, antibodies directed against U3RNP and Th/To are also specific for scleroderma, whereas anti-Pm/Scl, anti-Ku and anti-U1RNP antibodies are seen mainly in patients with overlap syndromes. Up to 11% of patients with SSc can test negative for antinuclear antibodies. Strong links exist between autoantibody specificities and disease presentation and outcome, which make autoantibodies essential assessment tools in patients with SSc.

Autoantibody profiles in systemic sclerosis: Predictive value for clinical evaluation and prognosis

Systemic sclerosis (SSc) is thought to be an autoimmune disease, as autoantibodies against a variety of extractable nuclear antigens can be detected in patient sera. Subgrouping patients based on the type of autoantibodies present can be useful in diagnosis and management. Anti-centromere antibodies (ACA) and anti-topoisomerase I antibodies (anti-topo I) are the classic autoantibodies associated with SSc. ACA are associated with limited cutaneous involvement and isolated pulmonary hypertension, whereas anti-topo I are associated with diffuse skin involvement and pulmonary fibrosis. ACA are predictors for a favorable prognosis, while anti-topo I are correlated with a poor prognosis and SSc-related mortality. Additionally, anti-RNA polymerase antibodies (anti-RNAP) are associated with diffuse cutaneous disease and renal involvement. Anti-nucleolar antibodies define multiple subgroups of patients with SSc. Of these, anti-Th/To antibodies (anti-Th/To) and anti-PM-Scl antibodies (anti-PM-Scl) are associated with limited cutaneous SSc (lSSc), whereas anti-U3RNP antibodies (anti-U3RNP) are associated with diffuse cutaneous SSc (dSSc). In addition, anti-Th/To and anti-U3RNP can be predictors for a less favorable prognosis with a higher frequency of organ involvement, such as pulmonary fibrosis, pulmonary hypertension and renal crisis. Other autoantibodies are less frequently reported: anti-Ku antibodies, anti-U1RNP antibodies, anti-human upstream-binding factor, and anti-U11/U12 antibodies. These antibodies are generally less specific to SSc, but also define clinically distinct patient subsets. Thus, characterization of autoantibodies in SSc together with knowledge of disease characteristics intrinsic to distinct patient populations is helpful for assessing the clinical presentation and prognosis of this disease, and for monitoring patients with SSc.

BANK1 functional variants are associated with susceptibility to diffuse systemic sclerosis in Caucasians

ObjectiveTo investigate the possible association of the BANK1 gene with genetic susceptibility to systemic sclerosis (SSc) and its subphenotypes.MethodsA large multicentre case–control association study including 2380 patients with SSc and...

Anti-hnRNP and other autoantibodies in systemic sclerosis with joint involvement

To investigate joint involvement in SSc and its relationship with autoantibody to the hnRNP and to anti-cyclic citrullinated peptide (anti-CCP). Sera from 55 SSc patients were investigated. Joint involvement was determined by clinical, radiological and ultrasonographical evaluation. Anti-hnRNP proteins A1 and A2 (anti-hnRNP-A1/A2) antibodies were determined by immunoblotting. Anti-CCP, ACA, anti-topo I (ATA), Sm, U1-RNP, ribosomal RNP, Ro/SSA, La/SSB autoantibody and RF were determined. Six patients were positive for anti-hnRNP-A2 autoantibody and two were anti-A1 positive. Eight patients had joint erosions: seven of the eight patients positive for anti-hnRNP-A2 or A1 presented articular involvement (P < 0.04) and five of the eight erosive patients were positive for either of the two autoantibodies (P < 0.02). Of the four patients positive for anti-CCP, none had anti-hnRNP but three had erosive aspects. ATAs were found in 10 patients, six of which were also positive for anti-hnRNP (P < 0.05). RF was positive in 16 patients and in seven among those with articular involvement (P < 0.04). RF was significantly associated with anti-hnRNP in patients with erosive arthritis (P < 0.02), but not with the presence of anti-hnRNP alone. Epitope mapping of the three strongest anti-hnRNP-A2-positive sera recognized the same major epitope as patients with RA. SSc patients have higher incidence of erosions and anti-hnRNP-A2/A1 positivity. RF test and anti-hnRNP had a statistically significant diagnostic value for articular involvement. These parameters might suggest that autoantibody to both hnRNP antigens might become a non-specific but useful marker for joint involvement in SSc patients and identify SSc patients prone to develop joint damage.

Anti–U3 RNP autoantibodies in systemic sclerosis

To describe the classification, demographic and clinical features, and survival in anti-U3 RNP autoantibody-positive patients with systemic sclerosis (SSc). Medical records of 108 anti-U3 RNP-positive and 2,471 anti-U3 RNP-negative SSc patients first evaluated during 1985-2003 were reviewed. Anti-U3 RNP antibody was detected by protein and RNA immunoprecipitation. Disease classification, demographic and clinical features, organ system involvement, and survival were compared between the 2 patient groups, by Student's t-test, chi-square analysis, and Mantel-Haenszel test. The anti-U3 RNP-positive group had a higher proportion of African American patients (27% versus 5%; P < 0.001) and male patients (29% versus 19%; P = 0.021), and was younger at the time of first physician diagnosis (mean age 42.8 years versus 47.4 years; P = 0.001). The 2 groups had similar proportions of patients with diffuse cutaneous involvement (47% and 45% in those with and those without anti-U3 RNP, respectively). However, among patients with diffuse cutaneous involvement, the mean maximum modified Rodnan skin score was significantly lower in the anti-U3 RNP group (22.3 versus 27.9; P < 0.001). Skeletal muscle involvement was more frequent in anti-U3 RNP-positive patients (25% versus 14%; P = 0.002), as was "intrinsic" pulmonary arterial hypertension (PAH) (31% versus 13%; P < 0.001). The frequency of gastrointestinal involvement, cardiac involvement, pulmonary fibrosis, and "renal crisis" did not differ significantly between the 2 groups. Survival was worse in the anti-U3 RNP-positive group (hazard ratio 1.38 [95% confidence interval 1.05-1.82]). PAH was the most common known cause of death in patients with anti-U3 RNP (30%, versus 10% in the anti-U3 RNP-negative group; P < 0.001). The present findings demonstrate that the frequencies of African American race and male sex are greater among SSc patients with anti-U3 RNP antibody than those without, and the former group is younger at SSc diagnosis. Anti-U3 RNP-positive patients have more frequent skeletal muscle involvement and PAH, the latter being the most common cause of death.

Anti-PDGFR-α antibodies measured by non-bioactivity assays are not specific for systemic sclerosis

Objective:To evaluate the presence of anti-PDGFR-α antibodies by immunological methods in patients with systemic sclerosis (SSc).Methods:Fifty-eight women diagnosed with SSc and 36 healthy women controls were included. IgG anti-PDGFR-α were...

Update on autoantibodies in systemic sclerosis

This is a review of autoantibodies described in systemic sclerosis with an emphasis on recently published studies. In the past, most, if not all of the discussion on this topic focused on antinuclear antibodies, but it is now appreciated that autoantibodies to cytoplasmic, cell surface, intercellular and plasma components are also important in the context of systemic sclerosis. A number of recent studies have highlighted the disease associations of autoantibodies and the potential pathogenic role of the more traditional autoantibodies, such as antitopoisomerase I and anticentromere antibodies. The recent identification of autoantibodies directed to the platelet-derived growth factor receptor is of particular interest because of its possible association with the pathogenesis of systemic sclerosis. Autoantibodies in systemic sclerosis are associated with demographic, diagnostic, pathological, and prognostic features of the disease. Emerging research on the pathogenic roles of newer autoantibodies provides valuable insights into disease pathogenesis and potential therapeutic targets.

Autoantibodies in Systemic Sclerosis

To describe the clinical, laboratory, and prognostic features associated with the scleroderma-specific autoantibodies. Using the Pittsburgh Scleroderma Databank, all consecutive patients seen between 1980 and 1995 who had autoantibody studies performed were studied. Anticentromere antibodies (ACA), antitopoisomerase (TOPO), anti-U1-RNP (U1-RNP), anti-RNA Polymerase III (Pol 3), anti-U3-RNP (U3-RNP), anti-Th/To (Th/To), and anti-Pm/Scl (Pm/Scl) were determined according to previously described methods. The frequency of clinical features, organ system outcomes, and survival within the patients with a specific antibody were cumulative over the course of the disease. The frequency of a specific feature was compared across groups to identify significant manifestations and outcomes in patients with a specific antibody. Some demographic, clinical, and organ system findings were associated with the specific antibody, and other features with the scleroderma subtype (limited cutaneous or diffuse cutaneous scleroderma). U3-RNP, U1-RNP, and TOPO were seen more commonly in African-American patients, and ACA was seen in older, female Caucasians. Muscle inflammation was seen in patients with U1-RNP and U3-RNP. Digital tip ulcers and digital tuft resorption were seen more frequently in those with ACA and TOPO. A vasculopathy causing pulmonary hypertension typically occurs with ACA and pulmonary fibrosis with TOPO; however, both types of lung disease were seen in patients with nucleolar antibodies, Th/To and U3-RNP. Importantly, severe interstitial fibrosis was rarely seen in cases with Pol 3. Renal crisis was strongly associated with Pol 3. Survival within limited scleroderma was decreased in the Th/To patients compared with ACA patients. Within the diffuse scleroderma group, patients with Pol 3 had the best survival. Scleroderma autoantibodies are associated with very specific demographic, clinical, organ system, and survival features. The determination of scleroderma autoantibodies may be helpful in assessing the prognosis, monitoring, and treatment of scleroderma patients.

Autoantibodies in systemic sclerosis and fibrosing syndromes: clinical indications and relevance

Systemic sclerosis, or scleroderma, is associated with a variety of autoantibodies, each of them having their own clinical associations. The fibrosing disorders, other than systemic sclerosis, represent a diverse group of diseases with systemic or localized effect and with limited understanding of their pathogenesis. The purpose of this review is to analyze the literature on the clinical usefulness of examining serum autoantibodies in patients with known or suspected scleroderma and fibrosing disorders. Studies on autoantibodies within the past year highlight their clinical utility in systemic sclerosis. Anticentromere antibodies are most often seen with limited cutaneous involvement and lower frequency of pulmonary fibrosis and lower mortality (despite an increased risk for pulmonary hypertension) compared with anti-Scl-70 and antinucleolar antibodies. Anti-Scl-70 antibodies are associated with diffuse cutaneous involvement, increased frequency of pulmonary fibrosis, and higher mortality. The anti-polymyositis-scleroderma autoantibody is associated with the polymyositis-scleroderma overlap syndrome. Anti-Th/To antibodies are associated with milder skin and systemic involvement but with more severe pulmonary fibrosis and overall worse prognosis. Anti-RNA-polymerase family antibodies and antifibrillarin antibodies are predictive of diffuse cutaneous and systemic involvement and greater mortality. Less specific autoantibodies for systemic sclerosis and limited data on some other autoantibodies limit their clinical utility in patients with systemic sclerosis. For the most part, the association between autoantibodies and fibrosing disorders other than systemic sclerosis remains inconclusive. Autoantibodies in systemic sclerosis provide important and prognostic information and are useful in defining clinical subsets of the disease. When used appropriately, they can be a useful instrument in the management of scleroderma.

Blunted coronary flow reserve in systemic sclerosis.

We investigated whether the non-invasive determination of coronary flow reserve (CFR), as evaluated by transthoracic Doppler echocardiography, might be a potential method to detect early dysfunction of cardiovascular system in patients affected by systemic sclerosis (SSc) without clinical signs or symptoms of cardiac impairment. The possible correlations between the CFR values and the duration of the disease, specific autoantibodies and cutaneous involvement subsets were investigated. Forty-four consecutive patients affected by SSc were analysed. The CFR was detected in the distal left anterior descending coronary artery by contrast-enhanced transthoracic second harmonic Doppler in all SSc patients and in 16 healthy controls. CFR was assessed at rest and during hyperaemia induced by administration of adenosine at 0.14 mg/kg/min over 5 min. The CFR was calculated as the ratio between hyperaemic (peak adenosine infusion) and resting peak diastolic velocity (PdvCFR) and resting velocity time integral (VtiCFR). Past medical history was carefully investigated. Both PdvCFR and VtiCFR were significantly reduced in SSc patients when compared with controls (P<0.0001). In particular, both PdvCFR and VtiCFR were significantly lower in patients with dSSc when compared with patients affected by lSSc (P<0.02 and P<0.04 respectively). No statistically significant correlation was found between CFR values and history of smoking, serum levels of cholesterol or triglycerides, blood pressure, age of patients, duration of SSc and serum autoantibody positivity for ANA, ACA and Scl70. CFR is often reduced in SSc patients. CFR was lower in patients with dSSc than in those affected by lSSc. A reduced CFR value should be considered an indirect sign of heart involvement in scleroderma, but its clinical and prognostic implications need to be clarified.

High prevalence of thyroid autoantibodies in systemic sclerosis and rheumatoid arthritis but not in the antiphospholipid syndrome

High prevalence of thyroid autoantibodies in systemic sclerosis and rheumatoid arthritis but not in the antiphospholipid syndrome

Anti-topoisomerase II alpha autoantibodies in systemic sclerosis-association with pulmonary hypertension and HLA-B35.

We have previously detected autoantibodies against topoisomerase II alpha (anti-topo II alpha) in sera from patients with idiopathic pulmonary fibrosis. To determine whether anti-topo II alpha is also present in systemic sclerosis (SSc) patients with pulmonary involvement, we screened sera from 92 patients and 34 healthy controls. Presence of anti-topo II alpha was investigated with respect to clinical and serological features, including the frequencies of HLA class I and II alleles. Anti-topo II alpha was detected in 20/92 (21.7%) patients. No association was found with either anti-topoisomerase I (Scl-70 or anti-topo I) or anti-centromere antibodies. However, anti-topo II alpha was associated with the presence of pulmonary hypertension (PHT) (as opposed to pulmonary fibrosis), and with a decrease of carbon monoxide diffusing capacity. Anti-topo II alpha was strongly associated with the presence of the class I antigen HLA-B35. No significant association was found with HLA class II antigens. HLA-B35 also turned out to be associated with the presence of PHT. These results indicate that in SSc patients, the presence of anti-topo II alpha is associated with PHT, and that the simultaneous presence of HLA-B35 seems to add to the risk of developing PHT.