Antinuclear antibody-negative systemic sclerosis
Introduction
Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of skin and internal organs, as well as vasculopathy and immune dysregulation. SSc is a clinically heterogeneous disease that can range from limited skin involvement and minimal internal organ disease to rapidly progressive organ involvement and skin fibrosis resulting in premature death.
Autoantibody formation is one of the hallmarks of SSc. Several studies have shown that the autoantibodies found in patients with SSc carry considerable value in diagnosis and in predicting various clinical outcomes [1], [2], [3], [4]. Although SSc-related autoantibodies are associated with specific genotypes as well as characteristic clinical manifestations, the role of ANA and its subsets in the pathogenesis of SSc is unclear. While the great majority of patients with SSc have circulating antinuclear antibodies (ANA) (90–95%), a small percentage of patients are ANA negative (5–10%) [1], [2]. Although the typical clinical presentations of the different subsets of ANA-positive patients have been extensively examined, the detailed demographic and clinical characteristics of patients without detectable ANA have not been clearly explored.
The purpose of this study was exploratory and to describe the clinical manifestations of this SSc subgroup by determining their clinical and demographic differences compared to ANA-positive patients. Our hypothesis was that ANA-negative patients are a subgroup of SSc with a distinct clinical presentation.
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Study population
Patient information was obtained from the Scleroderma Family Registry and DNA Repository [5] database. Patients were recruited at the University of Texas—Houston and from the following participating sites: the participating Canadian Scleroderma Research Group (CSRG) sites, University of California Los Angeles, University of Michigan, Georgetown University, Boston University, Medical University of South Carolina, Johns Hopkins University, University of Utah, Northwestern University, University
Data analysis
Analysis was carried out using STATA 12 (Statacorp LP, College Station, TX) statistical package. Clinical manifestations were considered the outcome (dependent) variables, and ANA status was the independent variable. Initial comparisons were conducted by chi-square or t-test depending on whether the outcome being analyzed was categorical or continuous, respectively.
Multivariable analysis adjusting for potential confounders, specifically age at enrollment, disease duration, disease type (limited
Demographic characteristics
A total of 3249 patients were included in this study, of whom 208 (6.4%) were ANA negative. Table 1 shows the demographic and basic clinical characteristics of patients with and without ANA. There was no difference for mean age at disease onset, which was 44 years for both groups. When considering the onset of Raynaud’s phenomenon as the starting point for disease onset, there was still no significant difference for mean age at disease onset. There were more males in the ANA-negative group. No
Discussion
This study is the first to specifically focus on the demographic and clinical features of ANA-negative SSc in a large and diverse sample of patients. Our study was of sufficient size for statistical analysis and our survival cohort was also larger than published cohorts to date. We observed that ANA-negative patients represent a distinct subset of patients who have the fibrotic features of SSc but are less likely to have the vasculopathic features of the disease.
We observed that PAH and
Conclusion
In conclusion, the results of this study suggest that SSc patients who are ANA negative constitute a distinct subset of SSc with less vasculopathy (less PAH and digital ulcers and fewer telangiectasias), a greater proportion of males, and possibly, more frequent lower gastrointestinal involvement.
It is important to understand the clinical characteristics and genetics of ANA-negative patients with SSc, because this will allow further understanding the role of ANA in the pathophysiology of SSc.
Acknowledgments
We would like to thank Tony Mattar for his assistance in the database management; Julio Charles for performing the IIF laboratory studies; and all the participating sites, including the Canadian Scleroderma Research Group, University of California Los Angeles, University of Michigan, Georgetown University, Boston University, Medical University of South Carolina, Johns Hopkins University, University of Utah, Northwestern University, University of Alabama Birmingham, and University of Minnesota.
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Grant support: NIH/NIAMS, USA K23 AR061436 (Assassi); N01-AR-0-2251 (Mayes); K24 AR063120-02 (Khanna); RO1-AR055258, P50-AR05414, U01AI09090-01 (Mayes) and the Department of Defense Congressionally Directed Medical Research Programs, USA W81XWH-07-01-0111 (Mayes).