ORIGINAL ARTICLE

Overlap syndromes in children presenting with the sicca syndrome; a diagnostic challenge

M.W. Heijstek¹, B.J.E.G. Bast²* and N.M. Wulffraat¹

¹ Department of Pediatric Immunology and Rheumatology, Wilhelmina Children's Hospital, P.O. Box

   85090, Utrecht 3508 AB, The Netherlands

² Department of Immunology, University Medical Centre Utrecht, P.O. Box 85090, Utrecht 3508 AB, The

Netherlands

Key words:

Sjögren’s syndrome, Mixed Connective Tissue Disease, pediatrics, classification, autoantibodies.

CONTACT:

N.M. Wulffraat

Wilhelmina Children's Hospital,

P.O. Box 85090,

Utrecht 3508 AB, The Netherlands

Tel.: +31-30-250-4003; Fax: +31-30-250-5350

E-mail address: n.wulffraat@wkz.azu.nl

Abstract

Sjogren’s syndrome (SS) is an autoimmune disease of the exocrine glands, which occurs rarely in childhood. Diagnosing SS in children can be difficult, since diagnostic criteria are based on adults and overlap exists between SS and other autoimmune diseases, such as mixed connective tissue disease (MCTD).  The aim of this retrospective analysis was to analyse if I) diagnostic criteria for SS in  pediatric patients with presenting sicca syndrome are sufficient and II) to analyse how these criteria discriminate between SS and MCTD.

The clinical, laboratory, immunological and imaging features of seven primary SS patients and four MCTD pediatric patients with presenting sicca symptoms were compared. The applicability of diagnostic criteria for SS and MCTD in children was evaluated.

Only one primary SS patient fulfilled all diagnostic criteria for SS. In most patients, insufficient investigations were performed to make a definite diagnosis possible. All MCTD patients fulfilled MCTD criteria. The most common presenting symptom in primary SS was recurrent parotitis and oral symptoms were more prominent than ocular manifestations. Eye symptoms were the predominant sign in MCTD patients. Musculoskeletal and cutaneous extraglandular manifestations were reported in the majority of patients, and these tend to be more severe in MCTD patients. In contrast to the MCTD patients, characteristic autoantibodies (SS-A, SS-B and RNP) were absent in 5 out of 7 of primary SS patients.

In clinical practice the obligatory investigations to make the diagnosis of SS possible are often omitted. Therefore, the currently used diagnostic criteria for SS are not decisive in  the pediatric patient, in contrast to the criteria used for MCTD. The combination of ocular and oral symptoms seemed more sensitive and specific than most other criteria. Although overlap exists between MCTD and SS, these syndromes can be distinguished. Anti-SS-A and anti-SS-B antibodies can be absent in the pediatric SS patients, but may develop after a more prolonged disease course.

Introduction

Sjogren’s syndrome (SS) is a chronic autoimmune disorder affecting the exocrine glands. The lacrimal and salivary glands are particularly affected, leading to xerophthalmia and xerostomia, respectively. Sjogren’s syndrome can occur alone (primary SS) or in association with another autoimmune disease (secondary SS) such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis or mixed connective tissue disease (MCTD). Approximately 60% of SS patients have secondary SS [1].

Primary SS may be accompanied by systemic extraglandular manifestations [2]. These manifestations include severe fatigue, musculoskeletal symptoms (myalgia, myositis, non-erosive arthritis, arthralgia), cutaneous abnormalities (vasculitis, purpura), pulmonary (interstitial lung disease), renal (renal tubular acidosis), gastrointestinal and neurological involvement, lymphadenopathy or hepatosplenomegaly and hematologic abnormalities [3].

SS mainly affects predominantly women and typically has its onset in the fourth to sixth decades of life. Several criteria are being used to classify and diagnose SS in adults. The diagnosis is based on a combination of clinical, serological and histopathological manifestations [2, 4-7]. Although SS rarely occurs in the pediatric patient, there are several reports of primary and secondary SS in childhood [3, 8-14]. Despite similarities, the clinical and immunological presentation in childhood differs in several aspects from the disease in adults. [3,13]. Some consider the classification criteria for adults valuable for the diagnostic process of the pediatric patient as well [9,14], whereas others propose new classification criteria for the pediatric patient [15].

It is obvious that the diagnosis of both SS and MCTD can be difficult. This is especially true in children, since the diagnostic criteria are based on adult studies and until now no validated criteria for SS and MCTD in childhood exist. Additionally, overlap exists between these syndromes. MCTD is a syndrome with clinical features of rheumatoid arthritis, scleroderma, systemic lupus erythematosus and juvenile dermatomyositis occurring in conjunction with a speckled antinuclear antibody (ANA) pattern and high levels of antibody to ribonucleoprotein (RNP). Several diagnostic and classification criteria for MCTD are being used [16]. The reliability of these classification sets have been compared, with different results [17, 18]. No consensus has been reached according to which criteria should be used. Kasukawa’s criteria appeared to be suitable to diagnose MCTD in children [19].

Primary SS can give rise to systemic extraglandular manifestations and secondary SS can occur in up to 35% of patients with MCTD [17]. Sicca symptoms occurred in 42% of 55 patients with MCTD [20].  In the present study, the clinical findings of primary SS and MCTD pediatric patients with accompanying sicca symptoms are compared in order to determine the similarities and differences between these two groups. The applicability of the European diagnostic criteria for SS and the Kasukawa criteria for MCTD in childhood is addressed.

Patients and methods

           Patients were diagnosed between 1990 and 2004 at the Department of Paediatric Immunology and Rheumatology, Wilhelmina Children's Hospital, Utrecht, The Netherlands. Data of 11 patients were analysed retrospectively. Seven patients that were suspected to have  primary SS and four patients with MCTD who had accompanying symptoms of dry eyes, dry mouth or recurrent parotid swelling were included. Thirteen MCTD patients without these symptoms were excluded from this study. In order to diagnose SS and MCTD we used the European classification criteria and Kasukawa’s criteria, respectively (Table 1).

Table 1. European Criteria for Sjögren’s syndrome and Kasukawa criteria for Mixed Connective Tissue Disease

European Criteria (SS; ref 15)	Kasukawa Criteria (MCTD; ref 19)
1. Ocular symptoms · Dryness > 3 months and / or · Feeling of sand in the eye and / or · Use of tear substitutes 2. Oral symptoms · Dryness > 3 months and / or · Recurrent parotid swelling and / or · Liquids to aid in swallowing food 3. Ocular signs · Pathological Schirmer test (£ 5 mm/5 min) and / or · Pathological Rose Bengal staining (van Bijsterveld score ³ 4) 4. Histopathology · Focus score ³ 1 (more than 50 mononuclear cells per 4 mm^2) 5. Salivary gland involvement · Pathological sialogram and / or · Pathological sialometry and / or · Pathological scintigram 6. Autoantibodies · Anti-SS-A and / or anti-SS-B	1. Common symptoms · Raynaud’s phenomenon · Swollen fingers/hands 2. Auto-antibody · Anti-RNP antibody 3. Disease categories A. SLE-like conditions* B. Progressive systemic sclerosis-like symptoms** C. Polymyositis-like symptoms*** *Polyarthritis, lymphadenopathy, facial erythema, pericarditis, pleuritis, leukopenia(<4000/ml), thrombocytopenia (<100.000/ml) **Sclerodactyly, pulmonary fibrosis, restrictive lung disease (vital capacity < 80% or diffusion capacity <70%), hypomotility, dilatation of the esophagus *** Muscle weakness, increased serum level of creatine kinase, myogenic pattern on EMG
Primary SS: 4 out of 6 items Suspected SS: 3 out of 6 items Secondary SS: item 1 or 2 plus at least two items from among category 3, 4 and 5	MCTD 1. Positive in ³1 common symptom plus 2. Positive anti-RNP plus 3. Positive in ³ 1 item 2 of the categories A, B and C

The clinical, laboratory and detailed immunological manifestations as well as imaging results were documented. Autoantibody tests included ANA, anti-extractable nuclear antigen (ENA; i.e.  antibodies such as anti-RNP, anti-Ro/SS-A and anti-La/SS-B), anti-dsDNA antibodies and rheumatoid factor (RF). Investigations to detail ocular and oral symptoms included the Schirmer’s test, Rose Bengal Staining, tear Break-Up-Time (BUT), parotid ultrasound, sialometry, sialochemistry, sialography and sublabial salivary gland biopsy. Investigations to verify extraglandular manifestations were performed on clinical grounds and included chest X-ray, lung function tests, CO-diffusion capacity, barium swallow, oesophageal manometry, electrocardiographs (ECG), cardiac ultrasound, electromyography (EMG), cerebral or muscle MRI and skin biopsies. The presence of diagnostic criteria and the various disease manifestations were compared between the two patient groups.

Results

Diagnostic Criteria

Seven patients were suspected to have primary Sjogren’s syndrome. The presence of diagnostic criteria for SS in our patients is presented in Table 2.

Table 2.  Application of the European Criteria for SS on our patient patients

	Patient
	S1	S2	S3	S4	S5	S6	S7	M1	M2	M3	M4
1. Ocular symptoms	+	-	+	+	-	+	+	+	+	+	+
· Dryness · Grittiness · Tear substitutes	+	-	+	+	-	+	+	+	+	+	+
	-	-	+	+	-	-	-	+	-	-	-
	+	-	+	+	-	+	+	-	-	+	-
2. Oral symptoms	+	+	+	+	+	+	-	+	+	-	+
· Dryness · Recurrent parotid swelling · Liquids with dry food	+	-	+	-	+	-	-	-	+	-	-
	+	+	-	+	+	+	-	+	-	-	+
	-	-	+	+	-	+	-	-	+	-	-
3. Ocular signs	+	n.d.	?	?	?	n.d.	?	n.d.	?	?	n.d.
· Schirmer test · Bengal red staining	+	n.d.	-	-	-	n.d.	-	n.d.	-	-	n.d.
	n.d.	n.d.	n.d.	n.d.	n.d.	n.d.	n.d.	n.d.	n.d.	n.d.	n.d.
4. Histopathology	-	n.d.	+	n.d.	n.d.	n.d.	n.d.	n.d.	n.d.	n.d.	n.d.
5. Salivary gland involvement*	n.d.	n.d.	n.d.	n.d.	n.d.	n.d.	?	n.d.	n.d.	n.d.	n.d.
6. Auto-antibodies (SS-A or B)	-	-	+	-	-	+	-	-	+	-	-
Positive items	3	1	4	2	1	3	1	2	3	1	2
S1-S7: patients with Sjögren’s syndrome; M1-M4: patients with MCTD *Defined by a positive salivary scintigraphy, parotid sialography and / or sialometry. Patient S7 had normal findings on sialometry. (+) Symptoms present; (-) symptoms absent; (?) no definite score possible; n.d. not done

Only one patient fulfilled all diagnostic criteria. In the majority of patients, no (definite) score could be applied to the items 3, 4 and 5 (ocular signs, histopathology and salivary gland involvement, respectively) because the obligatory investigations were not performed. Instead of Rose Bengal staining, slit lamp eye examination after fluorescence staining and tear Break-Up-Time (BUT) were assessed. A sublabial salivary gland biopsy was performed in only 2 patients and showed focal sialadenitis in one of these patients. In addition, sialometry was performed in another patient.  Salivary gland involvement was not assessed in the other patients.

Four patients were classified as MCTD and had accompanying sicca symptoms. None of the MCTD patients fulfilled all criteria for secondary SS. Again insufficient investigations were performed, to make a definite diagnosis possible.

Patients S3, S4 and S7 had a negative Schirmer’s test according to the diagnostic criteria (£ 5 mm/5 min). However, these patients did have a low tear production with 6-8 mm in 5 minutes (data not shown). Patient M3 had a negative Schirmer test but severe keratitis punctata was seen with slit lamp eye examination. All these patients used tear substitutes.

The presence of diagnostic criteria for MCTD in our patients is presented in Table 3.

Table 3. Application of Kasukawa’s criteria (1987) on our patients

	Patient
	S1	S2	S3	S4	S5	S6	S7	M1	M2	M3	M4
Common symptoms	-	-	+	+	-	-	-	+	+	+	+
Auto-antibody (anti-RNP)	-	-	-	-	-	-	-	+	+	+	+
Disease categories A. SLE-like conditions B. Progressive systemic sclerosis-like symptoms C. Polymyositis-like symptoms	- - -	- - -	+ - -	- - -	- - -	+ - -	- - -	+ - +	+ + -	+ - -	- + +
Fulfilment of criteria	-	-	-	-	-	-	-	+	+	+	+

All MCTD patients fulfilled Kasukawa’s criteria. In contrast, no patient with primary SS fulfilled the criteria. All primary SS patients were anti-RNP negative, three had symptoms that can occur in MCTD.

Glandular Features

The clinical data of all patients are presented in Table 4.  In this study, the mean age of disease onset in children with primary Sjogren’s syndrome was 9.0 years (range: 3-15 years). All but one was female. The most common presenting symptom was recurrent parotid swelling. Overall, oral symptoms were more frequently mentioned than ocular symptoms. Four patients with ocular symptoms mentioned redness of the eyes. Two patients complained of caries and two patients had oral aphthous lesions. Candidiasis and signs of other mucosal involvement (e.g. vulvovaginitis) were absent (data not shown).

Table 4. Clinical characteristics of our patients 

The mean age of disease onset in MCTD patients with associated sicca symptoms was 12.5 years (range: 11-15 years). All but one was female. Common presenting symptoms were arthritis and Raynaud’s phenomenon. Two patients had eye symptoms at disease presentation, while the other two patients developed eye symptoms one and four years after the diagnosis of MCTD, respectively. Ocular symptoms were more common than oral symptoms and consisted mainly of dry eyes. No patient complained of caries, candidiasis, oral ulcers or aphthous lesions (data not shown). All patients had systemic features as fatigue or recurrent fever. Associated diseases were absent. The family history was negative for connective tissue diseases.

Extraglandular Manifestations

The majority of patients with primary SS suffered from systemic features as recurrent fever and fatigue. Associated diseases were present in two patients. One patient had hypothyroidism, for which she needed hormone replacement therapy. Anti-thyroglobulin antibodies were absent. The second patient had celiac disease, diagnosed 7 years before the diagnosis of primary SS was made. Three primary SS patients had a positive family history for Sjogren’s syndrome. Two other patients had family members with rheumatoid arthritis.

Extraglandular manifestations are presented in table 5. One patient had leucocytoclastic vasculitis, which is a known cutaneous manifestation of primary SS [21]. Compared to the primary SS patients, cutaneous symptoms and Raynaud’s phenomenon were far more common in MCTD patients. Musculoskeletal symptoms were more severe; non-erosive arthritis was present in three MCTD patients, and two patients had proven myositis (raised CK and myopathic EMG).

Table 5. Extranglandular manifestations

The majority of primary SS patients complained of recurrent abdominal pain and one also had dysphagia. Esophageal manometry in this patient was normal (data not shown). No pulmonary, cardiac, neurological, renal, hepatic or gastrointestinal manifestations were reported in our primary SS patients.

A mild restrictive pulmonary disease was found in two MCTD patients with abnormal lung function tests and a reduced CO diffusion capacity of approximately 80% (data not shown). Patient M1 experienced an unexplained and transient elevation of liver enzymes AST 59 U/L (normal range 15-45U/L) and ALT 51 U/L (normal range 10-50 U/L) indicating mild hepatic involvement. Two MCTD patients complained of chest pain; the ECG and cardiac echo that followed were normal. Gastrointestinal, cardiac, neurological or renal manifestations were absent.

Laboratory manifestations

Laboratory findings are presented in table 6. Apart from mild anaemia in one MCTD patient, no anaemia, thrombocytopenia or leucopenia was found. Erythrocyte sedimentation rate (ESR) was elevated (>15mm/h) in 3 primary SS and one MCTD patient. Serum amylase was tested in 4 SS patients, and it was increased to 173 U/L (normal range 30-120 U/L) in only one patient. Hypergammaglobulinemia was found in two SS patients and in all MCTD patients that were tested. C - reactive protein and levels of C3 and C4 complement were normal in all patients. In the patients that were tested, circulating immune complexes, cryoglobulins and paraproteins were absent and direct Coombs was negative (data not shown).

Table 6 Laboratory test results

Antinuclear autoantibodies (ANA) in a speckled and nucleolar pattern, anti-SS-A, anti-SS-B and rheumatoid factor (RF) were reported in two primary SS patients. Immunoblotting revealed anti-SS-A and B in one patient; the other patient had anti-RNP (33KD), anti-SS-A and anti-SS-B antibodies. The immunoblot of patient S1 revealed anti-scl-70 and anti-RNP (33KD), while other tests remained negative. All MCTD patients were ANA and anti-RNP positive. Three patients were RF positive. Anti-SS-A was found in one patient, anti-SS-B measurements remained negative. Immunofluorescence microscopy revealed a speckled ANA pattern. Immunoblotting showed at least two types of anti-RNP in all patients and anti–SmB (proteins that are part of the Smith antigenic complex) was found in the majority of patients. Other autoantibodies (anti-dsDNA, anti-Jo, ANCA, anticardiolipin, lupus anticoagulant) were absent in all patients (data not shown). Specific autoantibodies were tested when indicated and all remained negative, including the absence of anti-thyroglobulin in the patient with hypothyroidism. Four patients with high RF-levels were tested for anti-CCP, and all were negative.

Discussion

Diagnostic criteria

Only one patient with a diagnosis of primary SS fulfilled all criteria. No patient with MCTD and sicca symptoms fulfilled the criteria for secondary SS. In most patients. insufficient investigations were performed to make a diagnosis according to the European criteria possible. In our hospital we do not use rose Bengal staining when performing the rose Bengal test to diagnose keratoconjunctivitis sicca, but lyssamine green which is less irritating when applied to the eye.  Additionally, we use break up time and slit lamp examination after fluorescein staining [22,23].  We propose to replace fluorescein staining and BUT examination for rose bengal staining as a diagnostic criterion.

            Performing sublabial salivary gland biopsy yields a small and well documented risk of mostly transient, and infrequently permanent sensory nerve injury. A major advantage of the labial biopsy is its specificity for SS [23-25]. However, minor salivary gland biopsy has been shown to be of low sensitivity (33%) in the pediatric patient [26] .

Other tests included in criteria used so far to evaluate xerostomia (sialography, scintigraphy and sialometry) were performed in one of our patients only . Especially the invasiveness of sialography is a major limitation [25,27]. Computed tomography (CT) and magnetic resonance imaging (MRI) of the parotid gland can detect the parenchymal changes in SS [28]. Parotid sonography has been shown to be in accordance with parotid sialographic and scintigraphic findings [29]. Therefore, it might be considered to use this as a diagnostic criterion in children.

It has been observed that abnormalities in the oral and ocular test are less frequent and less extensive in the patients with secondary SS [23]. This is consistent with our population of MCTD patients with sicca complaints. Schirmer’s test was normal in the patients that were tested and filamentary keratitis was seen in one patient only. Imaging tests were not performed to establish oral involvement. It was hypothesised that the presence of either oral or ocular involvement can be considered as indicative of secondary SS, whereas both signs are required to establish a diagnosis of primary SS [23].All patients with MCTD fulfilled Kasukawa’s criteria used to diagnose MCTD. Primary SS patients did not fulfil MCTD criteria, not even those with numerous extraglandular manifestations. This indicates that, although overlap exists, these two syndromes can be adequately distinguished. The frequency of secondary SS in MCTD patients can be high and it should not be forgotten in clinical follow-up, especially in anti-SS-A or anti-SS-B positive patients. Early diagnosis will make symptomatic treatment possible and may prevent ocular complications (corneal ulceration) and oral hazards (e.g. dental caries and frequent oral Candida infections resulting from a diminished quality of the saliva.)

Clinical features

The most common presenting symptom of primary SS was recurrent non-infectious parotitis and oral symptoms were more common than ocular symptoms. This is in accordance with previous studies regarding SS in childhood [3,8,12,14,15]. Because recurrent parotitis is so often present in SS in childhood, it might be added as an individual criterion in the diagnosis. Compared to previous studies, dry eyes and use of tear substitutes were mentioned relatively often by our patients. In secondary SS, eye symptoms were the predominant sign and recurrent parotitis was less common.

Noteworthy is that the family history was positive for Sjogren’s disease in 3 primary SS patients and for RA in two families. Genetic factors may lead to an increased susceptibility to develop autoimmune diseases. All these diseases are associated with HLA-DR3 [30-32].  Thyroid dysfunction has been reported in 45-50% of patients with primary SS in one series [33,34] and can be found children as well [35]. Celiac disease has been found in 15% of primary SS patients [32].

Serologic and laboratory findings

In previous studies, hypergammaglobulinemia has been reported in 50-100% of primary SS patients [1,8,15]. ANA was found in 70-80% of patients, 50-85% had anti-Ro/SS-A and 30-70% were La/SS-B positive [3,8,12,27]. However, some series in children report lower incidences [9,14]. In this study hypergammaglobulinemia, ANA, anti-SS-A and anti-SS-B were found in only two primary SS patients. Consistent with previous studies [14,36], the detection rate of ANA was higher in secondary SS patients and anti-SS-B was more frequent in primary SS patients. While anti-SS-A and anti-SS-B-antibodies are the hallmark of SS in adults, in children these antibodies may be less frequently found. It might be that these findings will develop eventually in the primary SS patients after a more prolonged disease course.

The high incidence of RF in SS patients is well known and it can be present in 60-75% of SS patients [3,8,12,27]. Noteworthy is the fact that in four patients with high RF-levels, anti-CCP-antibodies were absent. This further illustrates the disease specificity of anti-CCP for RA [37-39].

Summary

Diagnostic criteria used to diagnose SS in adults are not suitable for the pediatric patient. Since disease presentation differs from adults, invasive imaging tests are often omitted in clinical practice and autoantibodies can be absent. In contrast, Kasukawa’s criteria used for MCTD are appropriate for children. Although overlap exists between MCTD and SS, these syndromes can be adequately distinguished.  Careful follow-up is needed to evaluate disease course in these children, to prevent systemic complications in the individual patient, and to make diagnosis and treatment of the associated autoimmune diseases possible.

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