Sjögren’s syndrome (SS) is an autoimmune disorder in which the body attacks the exocrine glands—primarily those that produce moisture to the eyes and mouth—although the disease can extend to adversely affect other parts of the body, including the skin, joints, lungs, kidneys, blood vessels, digestive organs, and nerves. In a recent interview with Value-Based Care in Rheumatology (VBCR), Umbreen Hasan, MD, MBA, FACR, FACP, Consulting Rheumatologist, Minneapolis, MN, and member of the VBCR Editorial Advisory Board, discussed the diagnosis and treatment of the disease.
VBCR: Can you provide a brief overview of SS?
Umbreen Hasan: SS is a chronic inflammatory disease targeting the lacrimal and salivary glands resulting in dryness of the eyes (xerophthalmia) and mouth (xerostomia). The extra glandular mechanisms can represent autoimmune-induced inflammation centered on ductal epithelial structures, or arise from immune complex deposition, as seen in vasculitis. Some manifestations of SS are related to lymphoproliferation, such as lymphoma.
The disease can be categorized as primary SS, which is not associated with other diseases, or as secondary SS, which is associated with rheumatoid arthritis, lupus, or other chronic inflammatory diseases.
Although the cause of SS is unknown, evidence suggests that a genetic component exists. For example, results from a clinical trial in Taiwan showed that first-degree relatives of patients with primary SS had a risk ratio of 12.37 for developing the disease compared with the general population.1 Women are far more likely to develop SS than men because of an X chromosome dose effect.2
VBCR: What are the signs and symptoms of SS?
Dr Hasan: Patients with SS generally present with dry mouth (90%), dry eyes (85%), and bilateral parotid gland involvement (11%).3 Patients may also experience symptoms such as fatigue, xerosis, cutaneous vasculitis, arthropathy (affecting the hands, wrists, and knees), autoimmune hepatitis, neuropathy, and cytopenias.4
VBCR: How is SS diagnosed?
Dr Hasan: According to the latest American College of Rheumatology–European League Against Rheumatism classification criteria, published in January 2017, the inclusion criteria include ≥1 symptoms of ocular or oral dryness (based on American-European Consensus Group questions), or suspicion of SS from European League Against Rheumatism Sjögren’s Syndrome Disease Activity Index questionnaire items.5
Other baseline diagnostic testing may include complete blood count with differential, erythrocyte sedimentation rate, total globulins, basic metabolic panel, and urinalysis. Patients can test positive for antinuclear antibodies, anti-Ro (note that anti-La is not included in the recent criteria), and rheumatoid factor.4 Negative anti-Ro confers a protective status for progression to lymphoma in primary SS.6
All patients should be evaluated by an ophthalmologist for scoring ocular surface staining. Minor salivary gland biopsy is also an important diagnostic test. A focus score is a semiquantitative assessment of severity of focal lymphocytic sialadenitis per 4 mm2 of glandular tissue. In a recent clinical trial, a focus score of >3 was associated with reduced survival and increased hazard ratio for non-Hodgkin’s lymphoma (NHL), when adjusted for autoantibody profile and immunoglobulin (Ig) G level.7
Recent evidence has also supported the use of salivary gland ultrasound, which is a noninvasive tool with high sensitivity and specificity, in the diagnosis and classification of SS.8
VBCR: Which symptoms indicate a possible progression to lymphoma?
Dr Hasan: Eventually, 5% to 10% of all patients with primary SS will develop a B-cell NHL. The most frequently diagnosed NHL in these patients is mucosa-associated lymphoid tissue lymphoma, which typically occurs in the salivary glands, but may also affect other moisture-producing tissues, including those in the eyes, lungs, and gastrointestinal tract.9 Other subtypes of NHL seen in patients with primary SS include diffuse large B-cell lymphoma and marginal zone lymphoma.10
There are certain clues to look for regarding progression to mucosa-associated lymphoid tissue. Patients may have more persistent salivary gland involvement or a mass, and certain extraglandular signs, such as palpable purpura, low C4, cryoglobulinemia, and a monoclonal component in serum or urine.9
VBCR: What strategies are used to manage symptoms associated with SS?
Dr Hasan: Patients with xerostomia may experience dental caries, periodontal disease, halitosis, salivary gland calculi, or oral candidiasis. Management strategies may include artificial saliva containing carboxymethylcellulose, muscarinic agonists (eg, pilocarpine and cevimeline), good hydration, and avoidance of oral irritants and/or medications, which can aggravate oral dryness.11
Xerophthalmia is generally managed by an ophthalmologist, who may use artificial tears, punctual plugs, and anti-inflammatory ophthalmic drops, such as cyclosporine.11
Studies have been conducted to evaluate the efficacy of systemic immunosuppressive therapy for the management of patients with SS. Hydroxychloroquine has shown mixed results for xerostomia. Clinical trials assessing biologic agents, such as infliximab, etanercept, and baminercept, have not met the primary outcome measures.11,12 In an open-label study of belimumab (n = 60), 60% of patients with primary SS achieved the primary end point at 28 weeks, which was improvement in parotid swelling, IgG levels, rheumatoid factor, and cryoglobulins. However, there was no improvement in pain and visual analog scale scores.13
In current research models for autoimmune diseases, beneficial effects from proteasome inhibitors, such as bortezomib, are also being evaluated.14
VBCR: Are there any promising new biomarkers for SS?
Dr Hasan: There is a need to define robust and reproducible biomarkers to improve our understanding of the pathologic processes of the disease, and to measure a patient’s response to various therapies. A study of 78 patients identified anticarbamilate protein, which is positively correlated with IgG/IgM rheumatoid factor and a focus score >3.15 In a second study, authors analyzed sera from 235 patients and noted that anti-TRIM38 was associated with higher ocular surface staining scores, lower Schirmer test scores, and lower labial salivary gland biopsy focus scores of ≥3.16 However, further studies will need to be conducted to assess the clinical significance of these antibodies as diagnostic and assessment tools in SS.
SS remains a complex and heterogeneous condition. Therefore, it is critical to follow recommended guidelines for the diagnosis and classification of SS and to focus on the development of novel, targeted treatments that can modify the course of the disease and minimize complications.
- Kuo CF, Grainge MJ, Valdes AM, et al. Familial risk of Sjögren’s syndrome and co-aggregation of autoimmune diseases in affected families: a nationwide population study. Arthritis Rheumatol. 2015;67:1904-1912.
- Harris VM, Sharma R, Cavett J, et al. Klinefelter’s syndrome (47,XXY) is in excess among men with Sjögren’s syndrome. Clin Immunol. 2016;168:25-29.
- Shiboski SC, Shiboski CH, Criswell L, et al; for the Sjögren’s International Collaborative Clinical Alliance (SICCA) Research Groups. American College of Rheumatology classification criteria for Sjögren’s syndrome: a data-driven, expert consensus approach in the Sjögren’s International Collaborative Clinical Alliance cohort. Arthritis Care Res (Hoboken). 2012;64:475-487.
- Patel R, Shahane A. The epidemiology of Sjögren’s syndrome. Clin Epidemiol. 2014;6:247-255.
- Shiboski CH, Shiboski SC, Seror R, et al; for the International Sjögren’s Syndrome Criteria Working Group. 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. Arthritis Rheumatol. 2017;69:35-45.
- Quartuccio L, Baldini C, Bartoloni E, et al. Anti-SSA/SSB-negative Sjögren’s syndrome shows a lower prevalence of lymphoproliferative manifestations, and a lower risk of lymphoma evolution. Autoimmun Rev. 2015;14:1019-1022.
- Risselada AP, Kruize AA, Goldschmeding R, et al. The prognostic value of routinely performed minor salivary gland assessments in primary Sjögren’s syndrome. Ann Rheum Dis. 2014;73:1537-1540.
- Baldini C, Luciano N, Tarantini G, et al. Salivary gland ultrasonography: a highly specific tool for the early diagnosis of primary Sjögren’s syndrome. Arthritis Res Ther. 2015;17:146.
- Yachoui R, Leon C, Sitwala K, Kreidy M. Pulmonary MALT lymphoma in patients with Sjögren’s syndrome. Clin Med Res. 2017 May 9. Epub ahead of print.
- Brito-Zerón P, Kostov B, Fraile G, et al; for the SS Study Group GEAS-SEMI. Characterization and risk estimate of cancer in patients with primary Sjögren syndrome. J Hematol Oncol. 2017;10:90.
- Vitali C, Palombi G, Cataleta P. Treating Sjögren’s syndrome: insights for the clinician. Ther Adv Musculoskel Dis. 2010;2:155-166.
- Holdgate N, St Clair EW. Recent advances in primary Sjögren’s syndrome. F1000Res. 2016;5:F1000 Faculty Rev-1412.
- Mariette X, Seror R, Quartuccio L, et al. Efficacy and safety of belimumab in primary Sjögren’s syndrome: results of the BELISS open-label phase II study. Ann Rheum Dis. 2015;74:526-531.
- Verbrugge SE, Scheper RJ, Lems WF, et al. Proteasome inhibitors as experimental therapeutics of autoimmune diseases. Arthritis Res Ther. 2015;7:17-26.
- Bergum B, Koro C, Delaleu N, et al. Antibodies against carbamylated proteins are present in primary Sjögren’s syndrome and are associated with disease severity. Ann Rheum Dis. 2016;75:1494-1500.
- Wolska N, Rybakowska P, Rasmussen A, et al. Brief report: patients with primary Sjögren’s syndrome who are positive for autoantibodies to tripartite motif-containing protein 38 show greater disease severity. Arthritis Rheumatol. 2016;68:724-729.