A 14-year-old girl is referred to your office for fatigue and arthralgias. While you’re obtaining her past medical history, she divulges that she has had four episodes of bilateral parotitis, each lasting two weeks. An otolaryngologist evaluated her. She lacked sicca symptoms, had a normal complete blood count (CBC), normal inflammatory markers and a negative ANA on multiplex bead assay. She was diagnosed with juvenile recurrent parotitis.
She has a normal physical examination. She denies sicca symptoms, but reports frequent vaginal pruritus.
You order labs and find a normal CBC, as well as normal inflammatory markers, urinalysis and metabolic panel. She is found to have a positive SS-A/Ro antibody on ELISA and negative dsDNA, Smith, RNP and SS-B/La. She has a positive rheumatoid factor (RF) and is hypergammaglobulinemic. She was seen by an ophthalmologist, and ocular surface staining was negative.
You decide to get a minor salivary gland biopsy. The pathologists tell you that she had a few clusters of mononuclear cells but that most of them contained fewer than 50 cells, and the resulting focus score was less than 1 focus/4 mm2.
A salivary gland ultrasound is obtained and reveals increased echogenicity, multiple parotid cysts and inhomogeneity. She does not meet 2016 ACR/EULAR criteria, but you diagnose her with Sjögren’s syndrome based on recurrent parotitis in a child with chronic sialadenitis on ultrasound and positive antibodies.1
This patient, like many children, does not have a conventional presentation for Sjögren’s syndrome. In fact, children rarely present with the classic constellation of symptoms seen in the adult population.
Diagnosis & Challenges
The adage that the eye cannot see what the mind does not know applies well to children with Sjögren’s syndrome. The first challenge to diagnosis is recognizing the disease can occur in children of any age. Sicca symptoms may be a later finding, and the lack of them should not be reassuring. Recurrent or persistent parotitis is the most common clinical feature in children. Extra-glandular manifestations frequently occur.
The second, intertwined challenge is that even when the diagnosis is considered, children often don’t fulfill 2016 ACR/EULAR criteria. This is likely due to a combination of inadequate diagnostic evaluation, challenges in performing these tests in the pediatric population (e.g., ocular surface staining), and abnormal testing that does not reach the threshold of positivity defined in adult cohorts. Certainly, if you have a patient who does meet criteria, no ambiguity exists.
We presented 144 cases of children with Sjögren’s syndrome at the 2018 ACR/ARHP Annual Meeting, with only 26% of the patients diagnosed with the disease meeting 2016 ACR/EULAR criteria.2
Pediatric-specific normative values for these diagnostic tests and pediatric-specific classification criteria are needed. Until these are developed, a perceptive clinician and persistence are often needed to make the diagnosis or be satisfied that it has been excluded.
Salivary gland ultrasonography can aid in establishing a diagnosis and has been shown to correlate with histologic and serologic changes in adults and children with Sjögren’s syndrome. However, normal salivary gland ultrasonography should not prevent getting a biopsy.
Differences Between Children & Adults
While most adults with Sjögren’s syndrome present with features of dryness, children are less likely to come to medical attention with dryness complaints, and fewer children have dry eyes and/or mouth at diagnosis than adults. Parotitis is more common in children, occurring in approximately 60% (compared with less than 25% in adults).3 Other features reported more commonly in children include fevers, lymphadenopathy and positive antibodies (ANA, anti-SSA and/or anti-SSB, and RF).3-7 Beyond glandular manifestations, systemic or extra-glandular manifestations are more common in children, reported in 84–90% of children compared with 26–71% of adults.
The first challenge to diagnosis [of Sjögren’s syndrome] is recognizing the disease can occur in children of any age.
Parotid gland enlargement is the most common presenting symptom in children with Sjögren’s syndrome. The parotid gland enlargement can be unilateral or bilateral. It can develop as a chronic manifestation or as recurrent acute exacerbation. Even though the parotid gland is the most likely gland involved, submandibular and lacrimal glands can also be involved. At times parotid swelling may be the only presenting symptom in children. In these cases, careful evaluation into other causes of parotid swelling must be considered.
Sicca symptoms are rarely the presenting problems for children with Sjögren’s syndrome. However, many children have signs and symptoms of oral and ocular dryness.3 It seems like children with Sjögren’s syndrome may have difficulty recognizing and verbalizing their complaints related to sicca symptoms. For that reason, detailed questions should be asked to see if they have sicca symptoms, such as, “Do you feel like you have sand in your eyes?” or “Do you feel the need to drink a lot of water?” or “Do you need to take sips of liquid to help you swallow solid foods?”
Female children with Sjögren’s syndrome also have symptoms of vaginal irritation, such as pruritis and vulvovaginitis. It is estimated that 5% of girls with Sjögren’s syndrome suffer from vaginal irritation.2 Additionally, this symptom is likely under-reported in children and adolescents.
Children with Sjögren’s syndrome can have a wide range of differing extra-glandular manifestations. Lymphadenopathy, fatigue, fever and weight loss are characteristic findings in children with Sjögren’s syndrome and tend to occur more often during flares of active disease.8
Neurologic manifestations occur and can affect the central and peripheral nervous system. These manifestations may include peripheral neuropathy, autonomic neuropathy and meningoencephalitis. An association of Sjögren’s syndrome and neuromyelitis optica has been seen in childhood presentations.9
Around one-fifth of children with Sjögren’s syndrome have renal involvement, such as renal tubular acidosis, nephrocalcinosis or renal insufficiency.10
Children can also develop multiple cutaneous manifestations, such as purpura, annular erythema and cutaneous lupus.
Hematologic manifestations, such as autoimmune cytopenias and polyclonal hypergammaglobulinemia, can be seen in children with Sjögren’s syndrome.
Pulmonary manifestations are rare, but have been reported. They include interstitial and restrictive lung disease, and pulmonary hypertension.11
Gastrointestinal manifestation may occur in children with Sjögren’s syndrome and may present as hepatitis or gastritis.
Treatment goals for Sjögren’s syndrome in childhood is to prevent progression of the disease, decrease pain and enable typical growth and development. Currently, there is no literature about the efficacy of medication to slow disease progression in childhood Sjögren’s syndrome.
The most common medication used is hydroxychloroquine, which is possibly beneficial in children and has minimal side effects. In adults, a decrease in extraglandular symptoms seems to occur in patients treated with hydroxychloroquine.7 No large studies have been completed with children.
During acute exacerbations of parotitis, short courses of oral or intravenous steroids can aid in symptomatic management. Sialagogues have also been used to help increase salivary flow during acute flares of parotitis. Methotrexate and hydroxychloroquine have been used in an attempt to prevent recurrent flares of parotitis.
Multiple immunomodulatory agents, including abatacept, rituximab, mycophenolate mofetil, azathioprine, belimumab and tumor necrosis factor inhibitors, have been used to treat specific extraglandular symptoms in children with Sjögren’s syndrome.
Another vital aspect of children’s care is their oral and ocular health. Children should be referred to oral and ocular healthcare providers. Their dental exams should include frequent cleanings and fluoride treatments (every three to six months). Sicca symptoms may be alleviated with stimulants (e.g., sugar-free gum or sugar-free sour candies) to increase saliva secretion or with saliva replacements. Nonselective muscarinic agonists, such as pilocarpine, have also been tried in severe cases of pediatric sicca.
Yearly ocular exams should be performed, monitoring conjunctival and corneal changes from chronic dryness and/or ocular inflammation. Artificial tears are commonly used for symptomatic relief in children suffering symptoms of dry eyes. For children who have evidence of ocular damage from keratoconjunctivitis sicca, topical anti-inflammatory agents may be beneficial.
Due to the complexity of treating these children, a multidisciplinary team is often needed.
Long-term studies of individuals diagnosed with Sjögren’s syndrome during childhood have not been performed. Based on our collective clinical experience, we expect childhood Sjögren’s syndrome will progress over time to exhibit classic sicca symptoms common in adults. Some children develop exocrine gland dysfunction and sicca symptoms during childhood. However, for those who do not, the timing of progression may be years or decades.
While extra-glandular manifestations may be more common in childhood Sjögren’s syndrome, quality of life in adults is more associated with dryness, pain and fatigue.12
Adults with Sjögren’s syndrome are at increased risk for developing lymphoma. Although lymphoma development has been reported in some children with Sjögren’s syndrome, whether the risk is similar to or greater than that in adults is not yet known.13,14
In summary, Sjögren’s syndrome may develop during childhood, but presentation often differs from that in adults and diagnosis may be less straightforward due to the lack of well-established diagnostic biomarkers or diagnostic criteria. International collaborative studies are in progress to better define and understand the natural history of Sjögren’s syndrome in children, although this will take considerable time.
Of note, diagnosis in childhood may present a window of opportunity in which to intervene to prevent progression to the typical profound dryness experienced by many adults and will, hopefully, greatly alter the disease course, including a decrease in the risk of lymphoma.
Sara M. Stern, MD, is an assistant professor of pediatrics at the University of Utah School of Medicine, Salt Lake City.
Matthew L. Basiaga, DO, MSCE, is a senior associate consultant at the Mayo Clinic, Rochester, Minn.
Scott M. Lieberman, MD, PhD, is an associate professor of pediatrics at Carver College of Medicine, University of Iowa, Iowa City.
- Shiboski CH, Shiboski SC, Seror R, et al. 2016 American College of Rheumatology/European League Against Rheumatism classification criteria for primary Sjögren’s syndrome: A consensus and data-driven methodology involving three international patient cohorts. Ann Rheum Dis. 2017 Jan;76(1):9–16.
- Basiaga M, Stern SM, Mehta J, et al. A better understanding of childhood Sjögren syndrome: Evaluation of the 2016 ACR/EULAR classification criteria for the use of diagnosing Sjögren syndrome in children [abstract]. Arthritis Rheumatol. 2018;70(suppl 10).
- Yokogawa N, Lieberman SM, Sherry DD, et al. Features of childhood Sjögren’s syndrome in comparison to adult Sjögren’s syndrome: Considerations in establishing child-specific diagnostic criteria. Clin Exp Rheumatol. 2016 Mar–Apr;34(2):343–351.
- Hammenfors DS, Valim V, Bica BERG, et al. Juvenile Sjögren’s syndrome: Clinical characteristics with focus on salivary gland ultrasonography. Arthritis Care Res (Hoboken). 2019 Jan 30. doi: 10.1002/acr.23839. [Epub ahead of print]
- Retamozo S, Acar-Denizli N, Rasmussen A, et al. Systemic manifestations of primary Sjögren’s syndrome out of the ESSDAI classification: Prevalence and clinical relevance in a large international, multi-ethnic cohort of patients. Clin Exp Rheumatol. 2019 May–Jun;
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- Ramos-Casals M, Solans R, Rosas J, et al. Primary Sjögren syndrome in Spain: Clinical and immunologic expression in 1010 patients. Medicine (Baltimore). 2008 Jul;87(4):210–219.
- Demarchi J, Papsidero S, Medina MA, et al. Primary Sjögren’s syndrome: Extraglandular manifestations and hydroxychloroquine therapy. Clin Rheumatol. 2017 Nov;36(11):2455–2460.
- Tomiita M, Saito K, Kohno Y. The clinical features of Sjögren’s syndrome in Japanese children. Acta Paediatr Jpn. 1997 Apr;
- Kornitzer JM, Kimura Y, Janow GL. Primary Sjögren syndrome in a child with neuromyelitis optica spectrum disorder. J Rheumatol. 2016 Jun;43(6):1260–1261.
- Bogdanović R, Basta-Jovanović G, Putnik J, et al. Renal involvement in primary Sjogren syndrome of childhood: Case report and literature review. Mod Rheumatol. 2013 Jan;23(1):182–189.
- Zhang X, Zeng X. Severe pulmonary hypertension in pediatric Sjögren syndrome: A case report. J Clin Rheumatol. 2007 Oct;
- Cornec D, Devauchelle-Pensec V, Mariette X, et al. Severe health-related quality of life impairment in active primary Sjogren’s syndrome and patient-reported outcomes: Data from a large therapeutic trial. Arthritis Care Res (Hoboken). 2017 Apr;69(4):528–535.
- Tesher MS, Esteban Y, Henderson TO, et al. Mucosal-associated lymphoid tissue (MALT) lymphoma in association with pediatric primary Sjogren Syndrome: 2 cases and review. J Pediatr Hematol Oncol. 2019 Jul;=41(5):413–416.
- Collado P, Kelada A, Cámara M, et al. Extranodal marginal zone B cell lymphoma: An unexpected complication in children with Sjögren’s syndrome. Reumatol Clin. 2018 Jul–Aug;14(4):227–229.