Anti-topoisomerase I Antibody Research Articles

FRI0484 Nailfold Videocapillaroscopy Patterns Associated with Calcinosis and Acro-Osteolysis in Systemic Sclerosis

BackgroundCalcinosis and acro-osteolysis are frequent in systemic sclerosis (SSc) and are easily detected by X-rays (1). Recent findings indicate that these lesions may be related to digital vasculopathy. Accumulating evidence...

Child‐onset systemic sclerosis positive for anticentromere antibodies: Two Japanese cases

Systemic sclerosis (SSc) is an uncommon connective tissue disease of childhood. Moreover, pediatric SSc positive for anticentromere antibodies (ACA) is extremely rare. We describe two cases of ACA-positive SSc in Japanese girls with clinical findings. Case 1 is a 15-year-old female. From disease onset at 7 years, she developed limited cutaneous (no internal involvement) SSc positive for ACA and anti-U1RNP antibodies, but negative for antitopoisomerase I antibodies (ATA). She also showed calcinosis, sclerodactyly, and telangiectasia, but not Raynaud's phenomenon. Case 2 is also a 15-year-old female with onset at the same age. Her diagnosis was limited cutaneous SSc positive for ACA, anti-SSA/Ro antibodies, and anti-thyroid antibodies, but not ATA. She showed sclerodactyly, telangiectasia, and Raynaud phenomenon, as well as complicated Sjögren's syndrome and chronic thyroiditis with euthyroidism. We reported that two Japanese girls with SSc were positive for ACA and other antibodies with the exception of ATA.

Preliminary criteria for the very early diagnosis of systemic sclerosis: results of a Delphi Consensus Study from EULAR Scleroderma Trials and Research Group

ObjectiveTo identify a core set of preliminary items considered as important for the very early diagnosis of systemic sclerosis (SSc).MethodsA list of items provided by European League Against Rheumatism (EULAR)...

Predictors of interstitial lung disease in early systemic sclerosis: a prospective longitudinal study of the GENISOS cohort.

IntroductionThe objective of the present study was to examine the association of baseline demographic and clinical characteristics with sequentially obtained measurements of forced vital capacity (FVC), expressed as a percentage of the predicted value, and to identify predictors of the decline rate in FVC over time in the Genetics versus Environment in Scleroderma Outcome Study (GENISOS).MethodsTo date, 266 patients have been enrolled in GENISOS, a prospective, observational cohort of patients with early systemic sclerosis. In addition to pulmonary function tests (PFTs), clinical and laboratory data were obtained from each patient. We analyzed 926 FVC measurements utilizing generalized linear mixed models. The predictive significance of baseline variables for the decline rate in FVC was investigated by the interaction term between the variable and the follow-up time within the first 3 years after enrollment as well as throughout the entire follow-up time.ResultsThe cohort consisted of 125 white, 54 African American, and 77 Hispanic patients with average disease duration of 2.5 years at enrollment. The mean follow-up time was 3.8 years, ranging up to 11.4 years. A number of baseline variables, including antibody status, African American ethnicity, disease type, baseline PFT values, modified Rodnan Skin Score, fibrosis on chest radiograph, and lung and skin subscores of the Severity Index, were associated with serially measured FVC levels. However, only the presence of anti-topoisomerase I antibodies (ATA) was associated with lower FVC levels (P < 0.001) as well as accelerated decline rate in FVC within the first 3 years of follow-up (P = 0.02). None of the baseline variables predicted the rate of decline in FVC on long-term follow-up. Patients with rapidly progressive ILD, however, were under-represented in the long-term follow-up group because the accelerated rate of decline in FVC was associated with poor survival (P = 0.001).ConclusionsPresence of ATA was the only baseline variable associated with differential FVC levels, predicting the rate of decline in FVC within the first 3 years of follow-up. The association of faster decline in FVC with poor survival further emphasizes the need for identification of predictive biomarkers by collection of genetic information and serial blood samples in cohort studies.

Association of interleukin 23 receptor polymorphisms with anti-topoisomerase-I positivity and pulmonary hypertension in systemic sclerosis.

IL23R has been identified as a susceptibility gene for development of multiple autoimmune diseases. We investigated the possible association of IL23R with systemic sclerosis (SSc), an autoimmune disease that leads to the development of cutaneous and visceral fibrosis. We tested 9 single-nucleotide polymorphisms (SNP) in IL23R for association with SSc in a cohort of 1402 SSc cases and 1038 controls. IL23R SNP tested were previously identified as SNP showing associations with inflammatory bowel disease. Case-control comparisons revealed no statistically significant differences between patients and healthy controls with any of the IL23R polymorphisms. Analyses of subsets of SSc patients showed that rs11209026 (Arg381Gln variant) was associated with anti-topoisomerase I antibody (ATA)-positive SSc (p = 0.001)) and rs11465804 SNP was associated with diffuse and ATA-positive SSc (p = 0.0001, p = 0.0026, respectively). These associations remained significant after accounting for multiple comparisons using the false discovery rate method. Wild-type genotype at both rs11209026 and rs11465804 showed significant protection against the presence of pulmonary hypertension (PHT). (p = 3x10(-5), p = 1x10(-5), respectively). Polymorphisms in IL23R are associated with susceptibility to ATA-positive SSc and protective against development of PHT in patients with SSc.

Coincidental association of mycosis fungoides and occupational systemic sclerosis?

We report a 58-year-old man with mycosis fungoides (MF) and occupational systemic sclerosis (SSc) induced by silica exposure. He was engaged in tunnel construction from the age of 18 to 33 years. He developed MF at the age of 30. Diagnosis of silicosis was made at the age of 52 and SSc at the age of 58. Physical examinations revealed sclerotic skin changes on his forearms and fingers and poikiloderma on the left popliteal fossa and inguinal region. Both antinuclear antibody and antitopoisomerase-I antibody were positive. We could find no apparent difference between his clinical features and those of idiopathic SSc except for the presence of silicosis and MF. Systemic therapy with interferon-gamma for MF did not improve the skin sclerosis. We discuss the relationship of silica exposure to both MF and SSc.

An allograft inflammatory factor 1 (AIF1) single nucleotide polymorphism (SNP) is associated with anticentromere antibody positive systemic sclerosis

To identify genetic associations between allograft inflammatory factor 1 (AIF1) and systemic sclerosis (SSc), or its subsets, using a single nucleotide polymorphism (SNP) in a replicate case-control study. The frequencies of alleles and genotypes of an SNP, rs2269475, for the AIF1 gene were examined in two large independent cohorts of SSc patients (n = 1015 total), and compared with two groups of normal controls (n = 893 total). Both cases and controls were stratified by ethnicity (Caucasian, African American and Hispanic) and by autoantibody status [anti-centromere antibodies (ACA) and anti-topoisomerase I antibody (ATA)]. The minor T allele and CT/TT genotype frequencies of the AIF1 SNP were not observed more frequently in SSc patients of the three ethnic groups (individually or combined) when compared with controls. On the other hand, T and CT/TT frequencies were significantly increased in ACA-positive Caucasian SSc patients, and all ACA-positive SSc patients (the three ethnic groups combined), when compared with ACA-negative SSc patients and with normal controls, with odds ratios of approximately 1.5. The data demonstrate a genetic association between AIF1 and the ACA-positive subset of SSc. This polymorphism is a non-synonymous substitution and therefore likely to represent an important functional change in AIF1. Since vascular pathology is a prominent feature in ACA-positive SSc patients, the observed association with a vasculotrophic inflammatory gene is biologically plausible and warrants further research.

HLA associations in three mutually exclusive autoantibody subgroups in UK systemic sclerosis patients.

Systemic sclerosis (SSc) is characterized by the presence of autoantibodies, mostly IgG, which target a limited set of nuclear proteins. These antinuclear antibodies (ANA) associate with disease subgroups and specific organ involvement. Here we show that there is mutual exclusivity of individual ANA in 130 UK SSc patients, confirm clinical associations with antibody profile and extend the analysis to include genetic data. The ANA mutual exclusivity observed leads to the possibility that SSc, in these patients, is in fact three separate diseases. An alternative explanation for exclusivity relates to the fact that optimal production of IgG antibody requires T-cell help, a process restricted by the HLA class II presentation of antigen peptide. If each autoantibody has a different and tight MHC restriction, then there is a possibility that these groups arose from a common pathway and were modified by genetics into the mutually exclusive groups observed, making the separate disease theory less tenable. In order to answer this question, we have determined MHC class II restriction precisely using high-resolution HLA genotyping (SSP) coupled with an amino acid analysis program in our 130 UK SSc patients. DRB1*11 was associated with anti-topoisomerase-I antibody (ATA)-positive patients (P = 0.007) and when combined with ATA (RR = 15.82), dcSSc (RR = 11.45), or both (RR = 21.9), represented the strongest risk factor for pulmonary fibrosis. Patients with antibodies to RNA polymerases I, II and III were associated with DQB1*0201. At the amino acid level, 20 positions in DRB1 and 20 positions in DQB1 showed some significant correlation with an ANA group. Clearly, however, the linkages to MHC class II alleles are not nearly strong enough to explain the mutually exclusive nature of the autoantibody groups and our results support, but do not prove, the separate disease theory.