The syndrome of chronic inflammation of the exocrine glands, principally the salivary and lacrimal glands, was first described by Henrik Sjögren, a Swedish ophthalmologist, who published in 1933 the first complete description of a disorder he named keratoconjunctivitis sicca . He reported that the disorder occurred most often in menopausal women and that arthritis was a prominent feature of the disease, as well as raised erythrocyte sedimentation rate (ESR), anemia, and fever. This disease has been considered to be rare in children and adolescents; however, it has almost certainly been underdiagnosed and is probably more common than previously realized. It is now recognized that this disorder can affect children and adolescents, and that the presentation may be different from that in adults with this condition, which is one factor contributing to the low recognition of the disorder.
Definition and Epidemiology
Sjögren Syndrome (SS) is defined as a chronic autoimmune disease characterized by inflammation of the exocrine glands. The principal inflammatory targets are the salivary and lacrimal exocrine glands, resulting in dryness of the mucosal surfaces of the mouth and eyes. However, there can be more extensive exocrinopathy involving the skin, respiratory tract, and urogenital tracts. Extraglandular or systemic features can also be part of the disorder. Table 30-1 outlines the principal clinical manifestations of SS.
|Dry eyes||Xerophthalmia, keratoconjunctivitis sicca|
|Pulmonary involvement||Interstitial pulmonary disease|
|Small airways disease|
|Renal tubular acidosis|
|Neurological involvement||Peripheral neuropathy|
|Central nervous system disease—rare|
The reported incidence and prevalence of primary SS in the adult population varies depending on population studied. Estimates range from a prevalence rate of 0.098% to 3.6%, and an incidence rate ranging from 3.9 to 5.3 per 100,000 individuals. A recent population-based epidemiology study done in Olmstead County, Minnesota, USA, using a medical records linkage data system and the American-European Consensus Group classification criteria for identification of cases, reported an annual incidence of 5.1 (95% confidence interval [CI] 4.1-6.1) per 100,000 individuals, increasing with age to 10.7 per 100,000 in people over the age of 75. To date, there have been no studies reporting accurate incidence or prevalence of SS in childhood.
Sjögren syndrome is described as primary Sjögren syndrome (pSS) when there is no association with other autoimmune disease, and as secondary Sjögren syndrome (sSS) when there is another autoimmune disease present, most commonly systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA).
Accurately diagnosing pSS is challenging, as many of the cardinal symptoms are common, and there is currently no gold standard diagnostic test. Therefore, since the mid-1960s, a number of classification criteria sets have been proposed. However, none of the proposed classification criteria sets for pSS in adults have gained universal acceptance. The American-European Consensus Group (AECG) criteria, revised in 2002 (shown in Box 30-1 ), have been validated in adults with SS in whom the criteria has a sensitivity of 89.5% and a specificity of 95.2%. In 2012, a new set of classification criteria was published by Shiboski et al. and called the Sjögren International Collaborative Clinical Alliance criteria (SICCA-ACR) ( Box 30-2 ). These criteria were developed in an attempt to simplify the process of making an accurate diagnosis while also defining a uniform group of patients to participate in clinical trials. The new criteria put less emphasis on subjective oral symptoms and do not include any objective salivary gland testing such as sialography or scintigraphy. A positive labial salivary gland biopsy is required. Patients with a positive antinuclear antibody (ANA) and rheumatoid factor (RF) but without positive anti-SSA or anti-SSB can satisfy the autoantibody criteria. A recent comparison of these two criteria sets was done by Rasmussen and colleagues using a study cohort of 646 adult patients seen at two specialty clinics in the United States. There was a concordance rate of 81% between the two criteria sets, which suggests they are not significantly different. However, there was a subset of patients who fulfilled only one set of criteria but not the other; these differences primarily related to differences in the evaluation and scoring of ocular disease. In this comparison study, the most valuable criteria for confirming the diagnosis of SS regardless of classification system used were presence of anti-Ro/La serology and a positive minor salivary gland biopsy. In a small case series of eight children diagnosed with pSS, reported by Saad-Magalhaes and colleagues, all patients underwent minor salivary gland biopsy, and all samples showed lymphocyte infiltration, although only five of eight had definitive focus scores. However, this paper demonstrates the possible value of this procedure in diagnosing pSS in children and adolescents.
|Ocular symptoms (positive answer to at least one of the following):|
|Oral symptoms (positive answer to at least one of the following):|
|Ocular signs (objective finding, positive result on at least one of the following):|
|Histopathology: Focal lymphocytic sialadenitis from a minor salivary gland biopsy, evaluated by an expert histopathologist, with a focus score of ≥1 (defined as a number of lymphocytic focuses adjacent to normal mucous acini and containing >50 lymphocytes per 4 mm 2 of glandular tissue)|
|Salivary gland involvement : Objective evidence of salivary gland involvement defined as a positive result for at least one of the following diagnostic tests:|
|Autoantibodies: Presence in the serum of antibodies to Ro (SSA) or La (SSB) antigens, or both|
|For diagnosis of primary SS:|
|Presence of four of six items, provided either histopathology or serology are positive|
|Presence of three of four objective items (ocular signs, histopathology, salivary gland involvement, or autoantibodies)|
|For diagnosis of secondary SS:|
|In patients with a potentially associated disease, presence of either ocular or oral symptoms, plus any two of ocular signs, histopathology, or salivary gland involvement.|
The classification of SS, which applies to individuals with signs and symptoms that may be suggestive of SS, will be met in patients who have at least two of the following three objective features:
Positive serum anti-SSA/Ro and/or anti-SSB/La or positive rheumatoid factor and ANA titer ≥1 : 320
Labial salivary gland biopsy exhibiting focal lymphocytic sialadenitis with a focus score ≥1 focus/4 mm 2
Keratoconjunctivitis sicca with ocular staining score ≥3 (assuming that the individual is not currently using daily eye drops for glaucoma and has not had corneal surgery or cosmetic eyelid surgery in the previous 5 years)
Prior diagnosis of any of the following conditions would exclude participation in SS studies or therapeutic trials because of overlapping clinical features or interference with criteria tests:
History of head and neck radiation treatment
Hepatitis C infection
Acquired immunodeficiency syndrome
Bowman and Fox reviewed the current state of classification criteria for SS and suggest that moving toward a single valid accepted consensus criteria set would be most important for international standardization, particularly in relation to research.
Bartunkova and colleagues have proposed a set of criteria for the diagnosis of pSS in children, but these have not been validated ( Box 30-3 ). The proposed pediatric criteria include parotid enlargement or recurrent parotitis, and additional laboratory tests not included in the adult classification criteria sets (elevated amylase, evidence of renal tubular acidosis [RTA], leukopenia, elevated ESR, ANAs, RF, and hypergammaglobulinemia). These clinical and laboratory findings seem to occur with increased frequency in pediatric SS. Houghton and colleagues compared the usefulness of the AECG adult criteria and the proposed pediatric criteria in a group of six patients in British Columbia, and 128 cases found on literature review. The adult criteria were fulfilled by 14% of the local cases and 39% of reported pediatric cases, whereas the proposed pediatric criteria were fulfilled by 71% of the local cases and 76% of the reported pediatric cases. Although the new proposed pediatric criteria improved the diagnostic accuracy considerably, the conclusion of this study was that neither set of criteria was sensitive when compared with the gold standard of pediatric rheumatologist clinical diagnosis.
One of the principal clinical findings of SS is dryness of the oral mucosa (xerostomia), which is described in 90% of adults with SS. Poor oral salivary flow can result in difficulty in swallowing dry food, a change in taste, halitosis, and an increase in dental caries. Report of these symptoms may be difficult to elicit from children or young adults. Upon examination of the mouth, one may see dry, “sticky” mucosa, dental caries, or atrophy of the filiform papillae on the dorsum of the tongue.
Parotid enlargement is described in two thirds of adults with pSS, but it may be a more frequent feature in children diagnosed with SS. Review of the reported cases of pediatric SS demonstrates that parotitis is the most common presenting feature, present overall in 50% to 70% of children. In many cases, the sole presenting complaint may be recurrent parotitis. Parotitis may be unilateral but frequently becomes bilateral and can be painful or painless. It is most often episodic, but it may be chronic in some patients. Children with recurrent episodes of parotid swelling are generally seen by a pediatrician or pediatric otolaryngologist for diagnosis. The differential diagnosis of recurrent parotid swelling in childhood ( Box 30-4 ) includes infection, juvenile recurrent parotitis, lymphoma, hemangiomas, and other rare inflammatory conditions. Primary SS should be strongly considered in the differential diagnosis of a child with recurrent parotid swelling, and a complete diagnostic evaluation should be performed. The reason that SS has been considered a “rare” disease in pediatrics is almost certainly the lack of recognition of SS as a potential cause of recurrent parotid swelling in children.
Patients with SS may experience a decrease in tear production due to inflammation of the lacrimal glands, which leads to damage to the corneal and bulbar epithelium (keratoconjunctivitis sicca). The symptoms of ocular involvement in SS include burning sensations in the eye, a feeling of having a foreign body in the eye, a “sandy” or scratchy feeling under the lids, itchiness, erythema of the eyes, or photosensitivity. Description of these symptoms may be difficult to elicit from children. On examination, one may find pericorneal irritation, dilation of conjunctival vessels, or enlargement of the lacrimal glands.
Other Glandular Involvement
Less commonly, dryness can affect the upper respiratory tract or oropharynx, resulting in hoarseness, bronchitis, or pneumonitis. The skin may be dry, and there may be loss of exocrine function in other glands, resulting in pancreatic dysfunction and hypochlorhydria.
Extraglandular manifestations of childhood SS may be less common than those in adults. However, general systemic complaints, such as fatigue, low-grade fever, myalgias, and arthralgias are frequent, particularly at the time of parotitis attacks.
Extraglandular manifestations can be considered in two different pathophysiological groups: (1) Peripheral organ involvement due to lymphocytic invasion in the epithelia of organs other than the exocrine glands, e.g., interstitial nephritis or obstructive bronchiolitis; and (2) extraepithelial involvement secondary to immune complex deposition and subsequent inflammation.
The types of extraglandular manifestations that may be seen in SS are shown in Table 30-1 , with further details on more common findings described below.
Raynaud phenomenon is reported to be relatively common among individuals with SS, and it may precede sicca complaints by years. Purpura or pernio have been reported in SS, and they may be signs suggesting a poor prognosis.
Adults with SS commonly complain of arthralgia, and inflammatory arthritis is reported in approximately 20% of patients. The presence of arthritis has rarely been commented on in case series of children with SS, and it is difficult to determine how often it occurs.
Pulmonary manifestations in patients with pSS are common and may be present in as many as 75% of patients. Dryness of the epithelium of the trachea can result in a dry cough. Small airway obstructive disease and airway hyperactivity may result from lymphocytic infiltration around bronchi and bronchioles.
Interstitial lung disease (ILD) occurs in approximately 8% of adults with pSS and has the appearance of lymphocytic interstitial pneumonitis in many cases. Among a population-based retrospective cohort of patients with SS by Nannini et al. from Rochester, Minnesota, there was a cumulative incidence of ILD of 10% at 1 year after diagnosis, increasing to 20% by 5 years after diagnosis. In this study, patients with SS and ILD had a worse survival rate compared to those without ILD (95% CI 0.99-4.74).
Patients with lung disease may present with cough and/or dyspnea, although some are asymptomatic early in their course. Chest x-ray films may be abnormal, showing interstitial changes in 27% (pSS) to 75% (sSS) of asymptomatic patients. A high-resolution computed tomography scan can detect abnormalities not seen on plain radiographs. Abnormalities detected in 65% of asymptomatic patients include interlobular and intralobular thickening and ground glass appearance in lower lung fields. Pulmonary function tests may demonstrate decreased peak flows or diffusing capacity. Less commonly, pulmonary arterial hypertension has been reported. If hilar and/or mediastinal adenopathy or lung nodules are found, an evaluation to rule out lymphoma should be conducted.
Houghton and colleagues reported fraternal twin girls with pSS, one of whom presented with mild dyspnea and was found to have large pulmonary nodules. Biopsy of these nodules substantiated the diagnosis of pSS, with lymphocytic interstitial pneumonitis. Five years after the diagnosis of pSS, clinical worsening prompted reinvestigation, and repeat biopsy demonstrated a mucosa-associated lymphoid tissue (MALT) lymphoma.
Renal involvement in patients with SS is not common, but patients may develop interstitial nephritis or glomerulonephritis. Interstitial nephritis, due to activated lymphocytes infiltrating tubular epithelium, can result in distal renal tubular acidosis (RTA), with hyposthenuria. Glomerulonephritis in SS results from immune complex deposition. Goules et al. reported that 4.9% (35 of 715 adult patients with pSS) of patients had clinically evident renal disease, with 49% of these having glomerulonephritis and 37% interstitial nephritis. Patients with interstitial nephritis had a generally benign long-term outcome; however, the presence of glomerulonephritis was associated with higher mortality or progression to lymphoma.
One report reviewed 12 cases of RTA in children with SS. In this small series, RTA was more frequently seen in pSS in childhood than in adults. Clinically significant hypokalemia was seen in the majority, and some patients had proximal or mixed RTA. Other more rare manifestations in patients with SS include proximal tubular acidosis, membranous or membranoproliferative glomerulonephritis, tubulointerstitial nephritis, and interstitial cystitis.
The spectrum of neurological manifestations associated with SS is broad and includes meningitis, myelopathy, cranial neuropathy, sensorimotor polyneuropathy, and mononeuritis multiplex. A syndrome of purely sensory neuropathy is said to be relatively unique to SS among the rheumatic diseases and has been reported in childhood. A peripheral neuropathy may precede the appearance of sicca symptoms in many patients. There have been reports of optic neuropathy in pediatric-onset SS. Other central nervous system (CNS) manifestations include hemiparesis, movement disorders, brainstem, motor neuron, and cerebellar syndromes. The CNS manifestations reported in SS overlap with those seen in patients with CNS lupus, making the differentiation between these disorders difficult.
Connection between Neonatal Lupus and Sjögren Syndrome
Neonatal lupus syndrome, including congenital heart block, can occur in offspring of women who have anti-Ro and/or anti-La antibodies during their pregnancy (see Chapter 25 ). These autoantibodies are those most commonly found in women with SS. Among mothers of infants with neonatal lupus, SS is as common as lupus. Counseling older adolescents with SS and anti-Ro/La antibodies about the risk of neonatal lupus in future pregnancies is advisable; more intensive pregnancy screening should take place for teenagers with SS who become pregnant.
The primary pathological finding in SS is of lymphocytic infiltration of affected tissues. Salivary gland biopsies show focal aggregates of lymphocytes, plasma cells, and macrophages; there may be larger foci with the appearance of germinal centers. This appearance is characteristic of chronic lymphocytic sialadenitis. A minor salivary gland biopsy is said to be specific for the diagnosis of SS if it is obtained through normal-appearing mucosa, has 5 to 10 glands present but separated by surrounding connective tissue with focal lymphocytic infiltration, and with all or most of the glands abnormal. Focus scores are determined by counting the number of lymphocytes in a 4-mm 2 area, and classified on a scale from grade 0 (no histological abnormalities) to grade 4 (more than one lymphoid nodule present); a score of grade 3 or 4 is indicative of SS.