Introduction

Antibodies to SSA(Ro) and SSB(La) are two kinds of human autoantibodies that have been correlated with autoimmune diseases. In adult patients, they have been found to be associated with a variety of primary rheumatic diseases such as systemic lupus erythematous (SLE), Sjögren’s syndrome (SS), rheumatic arthritis (RA), systemic sclerosis and dermatomyositis, malignancy, fibromyalgia, spondyloarthropathy, polymyalgia rheumatica, polyneuritis, sensitivity hemisyndrome, mothers of children with neonatal lupus, lymphocytic infiltration of the skin, and hepatitis C virus infection [1, 2]. Furthermore, the prevalence of isolated anti-SSA antibodies has been reported to approximately 0.5 % [3].

Anti-SSA and anti-SSB antibodies are found in 60–90 % of adult patients with SS [4]. SS is a chronic autoimmune disease characterized by xerosis of the exocrine glands, and in particular the lacrimal and salivary glands. In some patients, more extensive xerosis may involve the skin, respiratory tract, or urogenital tract. Furthermore, abnormalities of systemic, hematological, and immunological features have been found in SS [5]. To date, no evidence of a relationship between anti-SSA/anti-SSB antibodies and SS in pediatric patients has been found. In addition, to the best of our knowledge, there have not been any studies regarding an association between anti-SSA/anti-SSB antibody and other autoantibodies.

The aim of this study was to describe the manifestations of clinical symptoms and signs, primary rheumatic diseases, and other autoantibodies in pediatric patients with positive anti-SSA and/or anti-SSB antibodies.

Methods

From December 2006 to December 2011, subjects under age 18 with positive anti-SSA and/or anti-SSB antibodies were screened and enrolled at the Division of Pediatric Rheumatology, Department of Pediatrics, National Taiwan University Hospital. Data were collected via medical records, including age, gender, onset of the primary rheumatic disease, clinical symptoms and signs, and the medication used. All of the enrolled subjects (positive anti-SSA and/or anti-SSB) received a Schirmer’s test instead of invasive parotid sialography or salivary scintigraphy. Self-reported questionnaires for eye and oral symptoms were also performed. Laboratory data associated with their primary rheumatic disease were collected, including anti-SSA, anti-SSB, anti-DNA, anti-Sm, anti-RNP, anti-scl70, and anti-Jo-1.

Results

Twenty patients with positive anti-SSA and/or anti-SSB antibodies were enrolled, including three boys and seventeen girls. The median age was 13.9 years (range 10–18 years). The average onset age of primary rheumatic disease was 11.2 years (range 2–18 years). The primary rheumatic diseases included SLE (16/20), vasculitis (1/20), autoimmune lymphoproliferative syndrome (1/20), mucosa-associated lymphoid tissue lymphoma (1/20), and Sjögren’s syndrome (4/20). The medications used were non-steroid anti-inflammatory drugs (6/20), hydroxyquinine (20/20), azathioprine (8/20), methotrexate (2/20), steroids (14/20), and other immunosuppressive drugs (mycophenolate mofetil, 4/20; cyclosporine, 7/20; methotrexate, 2/20). All of the baseline characteristics of these patients are summarized in Table 1.

Table 1 Baseline characteristics and primary disease in our patients
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According to the results of the self-report questionnaire, eight patients had eye symptoms (8/20, 40 %), and ten had oral symptoms (10/20, 50 %). In addition to questionnaire, all of them received Schirmer’s test. Only four patients were documented as dry eye by this test.

The immunological profiles for the primary rheumatic disease are summarized in Table 2. The positive rate of antinuclear antibodies (ANA) was 19/20 (95 %), and positive rate of anti-DNA was 17/20 (85 %). All of the twenty patients had anti-SSA antibodies (20/20, 100 %), and seven had anti-SSB antibodies (7/20, 35 %). Other autoantibodies found in the patients, including anti-Sm (6/20, 30 %) and anti- RNP (10/20, 50 %); however, anti-scl70 and anti-Jo-1 antibodies were not found in any patient.

Table 2 Laboratory data associated with primary rheumatic disease
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The symptoms during follow-up are shown in Table 3. The two most common symptoms were arthritis (12/20, 60 %) and malar rash (8/20, 40 %). Other symptoms including discoid rash, photosensitivity, skin purpura, oral ulcers, and enthesitis were present and associated with their primary rheumatic disease.

Table 3 Other related symptom and signs
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There were three special cases of note in our study. The first one, case number 12, had had vasculitis since 3 years of age, and several attacks of parotitis were noted once or twice per year. She was our only one case with primary rheumatic disease as vasculitis. The second case of note was a male patient, case number 4, who had had autoimmune lymphoproliferative disease (ALPS) since 2 years of age. The initial presentations were general lymphadenopathy, hepatomegaly, skin rash, serositis, and thrombocytopenia. Despite evidence of genetic defect as Type III or Type IV ALPS, he was diagnosed with ALPS by clinical symptoms and signs. Episodes of pleuritis and appendicitis had also occurred, which may have been the consequence of using immunosuppressants, including steroids, azathioprine, and mycophenolate mofetil.

The third patient, case number 18, was the only case associated with malignancy. Mucosa-associated lymphoid tissue lymphoma originating from the thymus was diagnosed when she was 11 years old. After surgical excision and chemotherapy, she had been disease free for 3 years. However, occasional vasculitis over bilateral legs was noted. Although she had several high-risk factors for Sjögren’s syndrome, including positive anti-SSA, anti-SSB antibodies, and mucosa-associated lymphoid tissue lymphoma, no clinical symptoms or signs compatible with Sjögren’s syndrome were found.

Discussion

This is the first study to describe the clinical characteristics of pediatric patients with anti-SSA and/or anti-SSB antibodies. The target antigens of anti-SSA and anti-SSB antibodies are 60 KD Ro (Ro 60, one subgroup of anti-SSA antibody) and 48 KD La (La 48, one subgroup of anti-SSB antibody) nucleocytoplasmic ribonucleoprotein [6, 7]. In addition, the 52 KD Ro (Ro 52, one subgroup of anti-SSA antibody) protein is another target in mothers whose children have congenital heart block (CHB) [8]. Because more than 75 % of the sera from mothers whose children have CHB contain the antibody to 52 KD Ro [9], anti-Ro 52 is used clinically for predicting the risk of CHB. Anti-SSA antibody is also associated with other connective tissue disease, such as SLE, that mainly affected patients’ risk of SS [10]. In our study, we did not screen the subtypes of anti-SSA and anti-SSB antibody because our patients did not have problems such as congenital heart block. In addition, the method to differentiate subtypes of anti-SSA and anti-SSB is not available in our laboratory.

In adult group, anti-SSA and anti-SSB antibodies are highly correlated with SS. Such autoantibodies were abundant in one study in the Netherlands, which revealed that anti-SSA and/or anti-SSB antibodies were 80 % in adults with SS [11]. In other study, anti-SSA and anti-SSB are found in 60–90 % of adult patients with SS [4]. In our study, pediatric patients with anti-SSA and/or anti-SSB have low risk of having SS (4/20). On the other hand, long-term follow-up is necessary to observe if these patients will or not be attacked by SS in the future.

Our study is remarkable in that anti-ENA, anti-SSA, anti-SSB, anti-Sm, anti- RNP, anti-scl70, and anti-Jo1 antibodies were all investigated in our patients. In these antibodies, anti-scl70 and anti-Jo1 antibodies are highly correlated with systemic sclerosis [12] and dermatomyositis [13, 14]. These two antibodies were not found in our study that might be due to relatively low case number in the study. In addition, anti-Sm antibodies are specific to SLE [15], and that was also compatible with our data in Table 2. Six patients who had anti-Sm antibody were diagnosed as SLE, except case number 4 was also diagnosed with ALPS.

The most common symptoms and signs in our study were arthritis and malar rash, which are common signs in connective tissue diseases, and especially in SLE. The diagnostic criteria of SLE were revised in 1997 [16], and most of the clinical signs and symptoms found in our study are included in these criteria. Interestingly, case number 20 had a main diagnosis of SS with other presentations of abdominal pain, neurological disorder (headache), precocious puberty (under hormone therapy), and a history of Kawasaki disease.

There are several limitations to this study. First, the case number was small. Second, patients with anti-SSA and/or anti-SSB antibodies without rheumatoid disorders were not enrolled in this study as a control group, so we cannot know the true prevalence of anti-SSA and/or anti-SSB antibodies in whole population. Finally, long-term follow-up is needed to see if these patients have more symptoms or other diseases in the future.

In conclusion, we observed that a low proportion of childhood SS (4/20) exists in our patients with positive SSA and/or anti-SSB antibodies. Arthritis and malar rash were the two most common symptoms and signs. It is suggested that we should focus more on the clinical symptoms of SS in patients with anti-SSA and/or anti-SSB antibodies, rather than undertaking invasive diagnostic interventions to rule out Sjögren’s syndrome.