Are Anti-Ro52 Antibodies Associated with Pulmonary Involvement in Scleroderma?

Introduction: The presence of anti-Ro52 antibodies has been reported in a wide variety of autoimmune diseases, particularly in myositis, scleroderma and autoimmune liver diseases. Clinical significance of anti-Ro52 antibodies remains controversial. Studies are lacking in clarifying the association of anti-Ro52 with pulmonary involvement in scleroderma. Objectives: To determine if anti-Ro52 antibodies are associated with pulmonary involvement (interstitial, indirect pulmonary hypertension, or both) in scleroderma. Methods: Single center, retrospective study based on immunoblotting panel analysis and patients clinical records. Pulmonary manifestations were sub-grouped in: 1) interstitial (alveolitis and/or fibrosis), 2) pulmonary artery systolic pressure (PASP) ≥40 mmHg plus interstitial pulmonary disease, and 3) isolated PASP≥40 mmHg (purely vascular). Results: Our scleroderma cohort included 200 patients, of which 137 had immunoblotting panels with anti-Ro52 reactivity analysis. The search was conducted between January 2010 and July 2011. The frequency of pulmonary manifestations in patients with positive anti-Ro52 antibodies was 67.7% (n=31), and 60% (n=24) in the negative anti-Ro52 group, showing no significant differences between groups (p=0.621). Still no significant differences were found when pulmonary manifestations were evaluated according to the subgroups (p=0.525). Sensitivity, specificity, positive and negative predictive values of anti-Ro52 reactivity for determining pulmonary involvement in scleroderma were low. Conclusion: No association was found between positive anti-Ro52 antibodies and pulmonary involvement in scleroderma. *Corresponding author: Joao Pedro Ferreira, Unidade de Imunologia Clínica, Hospital de Santo António, Centro Hospitalar do Porto, Porto, Portugal, E-mail: jp7ferreira@hotmail.com Received January 04, 2012; Accepted March 13, 2012; Published March 15, 2012 Citation: Ferreira JP, Almeida I, Marinho A, Cerveira C, Vasconcelos C (2012) Are Anti-Ro52 Antibodies Associated with Pulmonary Involvement in Scleroderma?. J Pulmonar Respirat Med 2:116. doi:10.4172/2161-105X.100011 Copyright: © 2012 Ferreira JP, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Introduction
Antibodies to SSA antigen (Ro52/Ro60), were historically described as a marker for Sjögren syndrome and systemic lupus erythematosus [1]. However, recent publications [2,3] have demonstrated that Ro52 and Ro60 (SSA) antigens consisted of two different proteins representing two distinct autoantibodies systems and have different clinical associations. In clinical practice is desirable to detect these autoantibodies separately [4].
The Ro52 gene has been mapped to the end of the short arm of human chromosome 11 [5] and Ro52 antigen has recently been identified as a 52 kDa protein, belonging to the tripartite motif (TRIM) protein family [6]. So, anti-Ro52 antibodies can also be named as anti-TRIM21 antibodies.
The presence of anti-Ro52 antibodies has been reported in a wide variety of autoimmune diseases, particularly in myositis, scleroderma and autoimmune liver diseases [9,10], and have been associated with nonautoimmune diseases such as viral infections or neoplastic diseases [11].
Some studies found association between anti-Ro52 reactivity and scleroderma [12]. Others described association between anti-Ro52 reactivity and interstitial lung disease [7]. No association between anti-Ro52 antibodies, scleroderma and interstitial lung disease altogether was found in the reviewed literature.
The scarce information about this issue has led to the development of this study.

Objectives
To determine if anti-Ro52 antibodies are associated with pulmonary manifestations in scleroderma.

Studied population
In this single center, retrospective study, the patients were selected on the basis of immunoblotting panels (EUROLINE®) results and patients clinical records.

Inclusion criteria
Patients followed in our center with scleroderma diagnosis criteria
Interstitial pulmonary involvement was determined by radiologist interpretation of high-resolution CT scan (HRCT) and/or bronchoalveolar lavage results.
Doppler study is the most accurate non-invasive measure of PASP with a sensitivity of 90% and a specificity of 75% compared with right heart catheterization [15]. An important point of discussion is the definition of the cut-off value to distinguish normal from abnormal PASP. Some authors consider normal an estimated PASP lower than 30 mmHg [14]. In our center we consider a PASP ≥40 mmHg highly suggestive of pulmonary arterial hypertension (PAH) and a potential indication for right heart catheterisation. For this study purposes we assume that patients with PASP ≥40 mmHg are likely to have elevated pulmonary artery pressure.

Data analysis
Data were registered in Excel® and IBM SPSS software version 19® was used for statistical analysis. For proportion analysis chi-square or Fisher tests were used. A significance (p) < 0,05 was defined. Complementary information in data analysis is mentioned along the text and tables.

Results
Our scleroderma cohort included 200 patients, of which 137 had immunoblotting panels with anti-Ro52 reactivity analysis. The search was conducted between January 2010 and July 2011.
The gender distribution and mean age (SD) of the positive anti-Ro52 group were similar to the initial group (96.8% women; 54.6 (13.7) years, respectively).
Altogether the frequency of pulmonary manifestations in the positive anti-Ro52 antibodies was 67.7% (n=31), and 60% (n=24) in the negative anti-Ro52 group. No significant differences between groups were found (p=0.621).

Discussion
Isolated anti-Ro52 antibodies were detected in various autoimmune diseases. Some authors describe an association between anti-Ro52 antibodies and interstitial lung disease [7].
Some studies report an association of anti-Ro52 antibodies with aggressive anti-tRNA synthetases syndrome [16,17]. However, there have been relatively few studies addressing the frequency of anti-Ro52 antibodies in scleroderma and no comprehensive reports assessing associations of anti-Ro-52 with the specific autoantibodies that are characteristic of scleroderma [12]. In addition, after extensive MEDLINE/PubMed review, we did not find studies reporting an association of anti-Ro52 with pulmonary involvement in scleroderma.
In a large study [12] the authors analysed sera from a substantial cohort of scleroderma patients representing the entire spectrum of disease. Anti-Ro52 was found to be present at a frequency of at least 15% in all antibody groups tested. This frequency appeared to be greater than previously described [18,19]. The data presented in this study demonstrate that anti-Ro52 is prevalent throughout the scleroderma supporting the hypothesis that anti-Ro52 is a general serum marker with limited linkage to a myositis phenotype or other clinical manifestations of scleroderma.
In our study the prevalence of anti-Ro52 antibodies was even greater than previously described [12,18,19] reaching 43.7% of the tested sera. The data presented in our study demonstrate that anti-Ro52 antibodies lack sensitivity, specificity and predictive values for pulmonary involvement diagnosis in scleroderma. In addition, no independent association was found between anti-Ro52 reactivity and pulmonary disease even when pulmonary manifestations where subgrouped in  Table 2: Sensitivity (Ss), specificity (Sp), positive (PPV) and negative (NPV) predictive values of anti-Ro52 reactivity in determining pulmonary involvement in scleroderma IPI, interstitial pulmonary involvement; PARo52A, positive anti-Ro52 antibodies.