Antinuclear antibody-negative systemic sclerosis

https://doi.org/10.1016/j.semarthrit.2014.11.006Get rights and content

Abstract

Objective

To examine the demographic and clinical characteristics of systemic sclerosis (SSc) patients without antinuclear antibodies (ANA) compared to ANA-positive patients.

Methods

SSc patients enrolled in the Scleroderma Family Registry and DNA Repository were included. Relevant demographic and clinical data were entered by participating sites or obtained by chart review. ANA and SSc-related antibodies were determined in all investigated patients using commercially available kits at our laboratories.

Results

This study included 3249 patients, of whom 208 (6.4%) were ANA negative. The proportion of male patients was higher in the ANA-negative group (OR = 1.65; p = 0.008). ANA-negative patients experienced less vasculopathic manifestations of SSc. The percent predicted diffusing capacity of carbon monoxide (DLCO) was higher in ANA-negative patients (p = 0.03). Pulmonary arterial hypertension (PAH) per right heart catheterization was less common in the ANA-negative group (OR = 0.28; p = 0.03). Furthermore, patients with negative ANA had a lower prevalence of telangiectasias and digital ulcers/pits (OR = 0.59, p = 0.03 and OR = 0.38, p = 0.01, respectively). Although diffuse cutaneous involvement was more common, the modified Rodnan Skin Score (mRSS) was lower in the ANA-negative group (2.4 points lower, p = 0.05). Furthermore, they experienced more malabsorption (p = 0.05). There was no difference in the frequency of pulmonary fibrosis or scleroderma renal crisis. All-cause mortality was not different between the 2 groups (p = 0.28).

Conclusions

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, digital ulcers, and fewer telangiectasias), a greater proportion of males, and possibly, more frequent lower gastrointestinal involvement.

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.

Section snippets

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.

References (27)

  • V.D. Steen

    Autoantibodies in systemic sclerosis

    Semin Arthritis Rheum

    (2005)
  • D. Zuchner et al.

    Prevalence, kinetics, and therapeutic modulation of autoantibodies against Sp100 and promyelocytic leukemia protein in a large cohort of patients with primary biliary cirrhosis

    Hepatology

    (1997)
  • K.T. Ho et al.

    The clinical relevance of autoantibodies in scleroderma

    Arthritis Res Ther

    (2003)
  • Y. Hamaguchi

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

    J Dermatol

    (2010)
  • F.C. Arnett

    Is scleroderma an autoantibody mediated disease?

    Curr Opin Rheumatol

    (2006)
  • M.D. Mayes

    The establishment and utility of a population-based registry to understand the epidemiology of systemic sclerosis

    Curr Rheumatol Rep

    (2000)
  • M. Hudson et al.

    Prevalence and clinical profiles of ’autoantibody-negative’ systemic sclerosis subjects

    Clin Exp Rheumatol

    (2013)
  • Preliminary criteria for the classification of systemic sclerosis (scleroderma). Subcommittee for scleroderma criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee

    Arthritis Rheum

    (1980)
  • E.C. LeRoy et al.

    Scleroderma (systemic sclerosis): classification, subsets and pathogenesis

    J Rheumatol

    (1988)
  • V.D. Steen et al.

    Assessment of kidney involvement

    Clin Exp Rheumatol

    (2003)
  • N. Galie et al.

    Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT)

    Eur Heart J

    (2009)
  • V.M. Hsu et al.

    Assessment of pulmonary arterial hypertension in patients with systemic sclerosis: comparison of noninvasive tests with results of right-heart catheterization

    J Rheumatol

    (2008)
  • Y. Hamaguchi et al.

    The clinical relevance of serum antinuclear antibodies in Japanese patients with systemic sclerosis

    Br J Dermatol

    (2008)
  • Cited by (0)

    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).

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