A subgroup of patients with primary Sjögren's Syndrome (SS) and positive anticentromere antibodies (ACA) were recognized as having features intermediate between SS and systemic sclerosis (SSc). Our goal was to describe this group clinically and serologically and define its tendency to evolve to full blown SSc.
Among 535 patients with primary SS we identified 20 ACA positive (ACA+/SS). We compared them to 61 randomly selected ACA negative SS patients (ACA-/SS), 31 ACA positive SSc patients with sicca manifestations [SSc/(+) sicca] and 20 ACA positive SSc patients without sicca manifestations [SSc/(-) sicca].
Prevalence of ACA among SS patients was 3.7%. Cases and controls did not differ in sex ratio and age at disease onset. ACA+/SS patients had a lower prevalence of dry eyes, hypergammaglobulinaemia, anti-Ro and anti-La antibodies and a higher prevalence of Raynaud's phenomenon and dysphagia compared to ACA-/SS patients. They also had lower prevalence of telangiectasias, puffy fingers, sclerodactyly, Raynaud's phenomenon, digital ulcers and gastroesophageal reflux in comparison to both of the SSc subgroups and a lower prevalence of dyspnoea and lung fibrosis compared to the SSc/(+) sicca subgroup. Two patients originally having ACA+/SS evolved to full blown SSc. Four deaths occurred, all among SSc patients. Kaplan Meier analysis showed a significant difference between cases and controls in time from disease onset to development of gastroesophageal reflux, telangiectasias, digital ulcers, arthritis, puffy fingers, xerostomia, hypergammaglobulinaemia and dysphagia.
ACA+/SS has a clinical phenotype intermediate between ACA-/SS and SSc and shows little tendency to evolve to SSc.
Sjögren's Syndrome (SS) is a chronic autoimmune disease characterized by lymphocytic infiltration of the exocrine glands. It can present both with glandular and extraglandular manifestations [1,2] and may be either primary or associated with other rheumatic diseases. In approximately 60% of cases SS develops secondarily to other autoimmune conditions, most commonly rheumatoid arthritis, systemic lupus erythematosus or systemic sclerosis (SSc), while among those with various other systemic autoimmune diseases SS has a prevalence of 20% [1,3]. A subset of patients with primary disease, who present features intermediate between SS and limited cutaneous SSc has been previously recognized [4-6]. Their common characteristic is the finding of anticentromere antibodies (ACA) detected by immunofluorescence on Hep-2 cells. It remains to be answered whether these ACA positive SS patients represent merely a SS subgroup or if they constitute a transitional phase in the evolution to full blown SSc. Our goal was to clinically and immunologically characterize ACA positive SS patients in comparison to both ACA negative SS patients and ACA positive SSc patients, and to determine their tendency to evolve to definite SSc.
Materials and methods
We retrospectively studied the charts of 535 SS patients seen in our outpatient clinic between 1981 and 2009. Amongst them we identified 20 ACA positive patients (ACA+/SS), who fulfilled the American-European consensus criteria for the classification of SS . Our control groups consisted of 61 subjects randomly selected from the pool of ACA negative SS patients (ACA-/SS) (1 out of every nine patients) and another 51 ACA positive SSc patients, divided in two subgroups depending on the presence (SSc/(+) sicca, n = 31) or absence (SSc/(-) sicca, n = 20) of concomitant sicca manifestations. Twelve SSc patients in the first subgroup fulfilled criteria for secondary SS according to the American European consensus group criteria. Diagnosis of SSc was based on the preliminary classification criteria of the American Rheumatism Association  and the criteria for classification of early SSc, proposed by LeRoy and Medsger in 2001 . Patients satisfying criteria for prescleroderma or very early SSc, as recently put forward by the European League Against Rheumatism Scleroderma Trials and Research Group (EUSTAR) , were not included in the SSc group, since our main goal was to examine progression of ACA+/SS patients to definite SSc. The design of our study was approved by the Laikon Hospital Ethics Committee and written informed consent was obtained from all participants or from the first degree relatives of those deceased.
For every study participant we collected demographic, clinical and immunological data, both at first visit and cumulatively over the entire follow up period. Disease onset was defined by the appearance of Raynaud's Phenomenon, sicca manifestations, salivary gland enlargement, arthritis, purpura, puffy fingers, sclerodactyly, digital ulcers, calcinosis, dysphagia, gastroesophageal reflux, pulmonary arterial hypertension or lung fibrosis. Table 1 presents the first disease symptom by disease category. Abnormal findings in minor salivary gland biopsy, Schirmer test and Rose Bengal stain were defined as elsewhere described [7,11]. Tear film break up time of less than 10 seconds and subjective complaints of dry eyes, xerostomia, dyspnoea and dysphagia were additionally documented. Salivary gland enlargement, lymphadenopathy, arthritis, purpura, telangiectasias, puffy fingers, digital ulcers, Raynaud's phenomenon, calcinosis and sclerodactyly were recorded as assessed by the attending physician. Diagnosis of gastroesophageal reflux was based on clinical symptoms of heartburn and regurgitation, further confirmed by gastroscopy . If a right heart catheterization had not been performed, the diagnosis of pulmonary arterial hypertension was made by heart Doppler echocardiography, using a pulmonary artery systolic pressure (PASP) = 40 mmHg as a cutoff, since values above this were shown in a SSc cohort to predict more accurately the finding of pulmonary arterial hypertension in cardiac catheterization . Lung fibrosis was documented by chest x-ray and when needed by high resolution computed tomography, allowing identification of ground glass opacities. Serositis (pleuricy or pericarditis) was diagnosed radiologically or echocardiographically. Recognition of a restrictive pattern on pulmonary function tests required a reduction of total lung capacity below 75% of the predicted value, or the combination of a forced vital capacity (FVC) below 75% of the predicted value and a normal or above normal forced expiratory volume in first second (FEV1)/FVC ratio. Peripheral neuropathy was diagnosed by neurophysiologic testing. Carpal tunnel syndrome was documented based on the recommendations of the National Institute of Occupational Safety and Health . Renal involvement was defined by the development of acute onset hypertension and elevated serum creatinine or impaired creatinine clearance (<60 ml/minute), elevated urinary pH (>6), proteinuria (>300 mg/day) or the presence of active urine sediment. Regarding laboratory tests, white blood cell count <4 K/μL, C3 <75 mg/dl, C4 <10 mg/dl, rheumatoid factor >20 I U/ml and γ-globulin >1.7 g/dl were considered abnormal. For the diagnosis of primary biliary cirrhosis and autoimmune hepatitis the criteria described elsewhere were used [15,16]. The diagnosis of celiac and atrophic gastritis required serological or histological evidence [17,18]. Hashimoto was diagnosed on the grounds of clinical or subclinical hypothyroidism and positive anti-thyroid peroxidase and/or anti-thyroglobulin antibodies . Diagnosis of lymphoma required histological confirmation.
Table 1. First symptom by disease category.
We compared patients' characteristics between the ACA+/SS and each of the control groups, using Pearson's χ2 test, Fisher's exact test and one way analysis of variance (ANOVA) with Bonferroni post hoc analysis, as indicated. Two-sided probability (P) values < 0.05 were considered statistically significant. Median time from disease onset to death or to development of particular clinical symptoms and laboratory findings was derived from Kaplan Meier curves and tested for statistical significance by the log-rank statistic. The Statistical Package for the Social Sciences (version 17, SPSS Inc., Chicago, Illinois, USA) was used for the analysis.
Demographics, follow-up and disease duration of cases and controls
Of the 535 SS patients in our cohort, 20 were ACA positive, corresponding to a prevalence of 3.7%. All patients in this group were female, with an age at disease onset of 52.35 ± 3.35 years [mean ± standard error (SE)]), disease duration of 12.13 ± 1.65 years (mean ± SE) and a follow up of 5.38 ± 1.15 years (mean ± SE). As seen in Table 2, these variables did not differ significantly between cases and controls. Moreover, cases and controls did not differ with regard to sex ratio or smoking habits (Table 3).
Table 2. Age at disease onset, disease duration and duration of follow up of cases and controls
Table 3. Patients' demographics, autoimmune profile and co-morbidities by disease category
Immunological profile and histological findings of cases and controls
Anti-Ro/SS-A and anti-La/SS-B autoantibodies were detected in 30% and 15% of ACA+/SS patients, compared to 70.5% (P = 0.003) and 41% (P = 0.056) of ACA-/SS patients, respectively. The SSc/(+) sicca group did not differ significantly from the ACA+/SS group in the prevalence of anti-Ro/SS-A and anti-La/SS-B autoantibodies, while SSc/(-) sicca patients displayed neither anti-Ro/SS-A nor anti-La/SS-B reactivity in their sera. Other autoantibodies such as anti-U1RNP, anti-Sm and anti-Scl70 occurred rarely and their prevalence did not differ significantly between groups (Table 3).
Minor salivary gland biopsy had been performed in 19 ACA+/SS patients, 57 ACA-/SS patients and 16 SSc/(+) sicca patients, resulting in an equal frequency (94.7%) of abnormal findings in the two SS groups, and a somewhat lower frequency in the SSc/(+) sicca subgroup (75%), although this difference was not significant. Similarly, cases and controls undergoing ocular examination with Rose Bengal stain, Schirmer test and tear film break up time had a comparable prevalence of abnormal results (Table 4).
Table 4. Patients' clinical characteristics by disease category, cumulatively for the entire follow up period
Clinical and laboratory features of cases and controls
Differences in the prevalence of clinical and laboratory characteristics of cases and controls were detected already at first visit and, as a general rule, they persisted or became even more pronounced, when the entire follow up period was considered. More specifically for the entire follow up period, telangiectasias, puffy fingers, sclerodactyly, Raynaud's phenomenon, digital ulcers and gastroesophageal reflux were significantly less frequent among ACA+/SS patients as compared to both SSc subgroups. The ACA+/SS group also had a lower prevalence of dyspnoea (P = 0.049) and lung fibrosis (P = 0.029) in comparison to the SSc/(+) sicca group. Compared to ACA-/SS, ACA+/SS patients were less prone to develop dry eyes (P = 0.045), but more inclined to develop Raynaud's phenomenon (P = 0.0001) or dysphagia (P = 0.004). Dyspnoea and digital ulcers were also more prominent in the ACA+/SS group, but not at a statistically significant level (Table 4).
Among those having undergone a pulmonary function test, a restrictive pattern was seen in 22.2% of ACA+/SS patients as compared to 30.8% of SSc/(+) sicca patients (P = 1.000), 42.9% of SSc/(-) sicca patients (P = 0.400) and none of the ACA-/SS patients (P = 0.211). Only a small proportion of patients in each group had done a chest high resolution computed tomography, on the basis of a previous chest x-ray marginally indicative of an interstitial pattern. Although small numbers do not allow for safe conclusions, no statistically significant difference was seen in the frequency of ground glass pattern between ACA+/SS patients and controls.
When comparing cases to controls with reference to laboratory findings, no statistically significant differences were observed, with the exception of hypergammaglobulinaemia, which tended to be more frequent in the ACA-/SS compared to the ACA+/SS group (P = 0.068). None of the patients in any of the groups had proteinuria (Table 4).
Prevalence of co-morbidities in cases and controls
Thyroiditis Hashimoto affected 5% of ACA+/SS patients, compared to 24.6% of ACA-/SS patients (P = 0.102) and 12.9% of SSc/(+) sicca patients (P = 0.636). For primary biliary cirrhosis (PBC) the respective proportions were 15%, as compared to 4.9% (P = 0.157) and 9.7% (P = 0.668), while the prevalence for atrophic gastritis was 10%, compared to 3.3% (P = 0.254) and 6.5% (P = 0.640) respectively. None of the SSc/(-) sicca patients had any of the above conditions. Differences between cases and controls were non-significant. Autoimmune hepatitis did not occur in any of the groups and only one patient in the ACA-/SS group had celiac (Table 3).
Evolution of ACA+/SS patients
During our follow up period two patients in the ACA-/SS group and another two in the SSc/(+) sicca subgroup developed lymphoma, while four patients died, all of which had SSc. Differences in mortality and lymphoma development between cases and controls were not significant (Table 3).
The overwhelming majority of ACA positive SSc/(+) sicca patients fulfilled criteria for SSc, already at their first visit. Of the 31 patients in this group, only two started out as ACA+/SS to which a diagnosis of SSc was added, in both cases after one year of follow up. One of these two patients later developed pulmonary arterial hypertension and died. Another three patients with Raynaud's phenomenon, puffy fingers, ACA and sicca manifestations at first visit eventually developed SSc, after 3, 9 and 24 months respectively, but never fulfilled criteria for SS.
Time to development of particular symptoms
Distribution of time from disease onset to development of certain clinical features was examined for the four groups of patients. In comparison to the ACA+/SS group, telangiectasias, digital ulcers and gastroesophageal reflux tended to occur sooner in the SSc subgroups, finally affecting these groups almost entirely. Puffy fingers developed sooner and xerostomia developed later in the SSc/(+) sicca compared to the ACA+SS group. Regarding development of arthritis, it occurred later in the SSc/(-) sicca subgroup compared to the ACA+/SS group. Likewise, when comparing ACA+/SS to ACA-/SS patients, dysphagia appeared earlier in the first group while hypergammaglobulinaemia in the second group. Statistics for survival curves depicting time to death or to development of sclerodactyly and calcinosis could not be calculated since all cases in the ACA+/SS and ACA-/SS groups were censored (Figure 1).
Figure 1. Kaplan Meier analysis. Kaplan Meier curves for time to development of Gastroesophageal reflux (GER), dysphagia, arthritis, telangiectasias, digital ulcers, puffy fingers, xerostomia, and hypergammaglobulinaemia. The X axis depicts time in years from the presentation of the first symptom.