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	- - -	- - -	+ - -	- - -	- - -	+ -