Pearls and Perils in the Diagnosis of Sjögren Syndrome

Educational Objectives

The goal of this program is to improve diagnosis of Sjögren syndrome (SS). After hearing and assimilating this program, the clinician will be better able to:

1. Recognize the heterogeneity of clinical presentations of SS.
2. Assess impact to the eyes and salivary glands in patients suspected to have SS.
3. Determine autoimmunity in a patient suspected to have SS.
4. Analyze the current classification criteria for SS.
5. Prevent future complications of SS.

Summary

Background: a presentation by Dr. W.B. Hadden at the Clinical Society of London in 1888 was one of the first to describe a patient with Sjögren syndrome (SS); Dr. Sjögren was the first physician to describe SS in a large group of patients and published detailed studies, noting symptoms including dry eyes, dry mouth, and arthritis (67%); he emphasized the systemic nature of the disease and the interrelationship of the 3 cardinal symptoms (ie, dry eyes, xerostomia, arthritis)

Epidemiology: SS was listed in the database for the National Organization for Rare Disorders; Thomas et al (1998) reported a prevalence of ≤4% in the British population; data from the Women’s Health Study and the Physician’s Health Study suggest that ≤20 million Americans have dry eyes, ≈4.5 million of whom are >50 yr of age and may have clinically significant (ie, severe) dry eyes suggestive of SS; Helmick et al (2008) listed SS as the second most prevalent autoimmune rheumatic disease

Demographics: SS was originally described in a group of Scandinavian women; for many years, the typical patient was a middle-aged Caucasian woman; as knowledge and diagnosis of SS have grown, it has become known that the disease can affect young women of any race or ethnicity, and an increase in cases among men and children has also been observed

Clinical presentation: ≈80% of patients present with some form of sicca syndrome and exhibit insidious onset of, eg, dry eyes (most common presenting manifestation), xerostomia; ≈20% of patients atypically present with internal organ or extraglandular manifestations and without sicca symptoms; they may present with, eg, rheumatoid-like arthritis (without erosions), polymyalgia rheumatica, leukocytoclastic vasculitis, multiple sclerosis, peripheral neuropathy, proximal muscle weakness (with high levels of creatinine phosphokinase), swelling of the salivary glands, rampant dental caries, renal tubular acidosis, fever of unknown origin, chronic fatigue syndrome, interstitial lung disease (ILD), new-onset corneal melt or perforation, abnormal erythrocyte sedimentation rates, unexplained high titer of antinuclear antibodies (ANAs)

Correlation between sicca symptoms and objective testing: diagnosis of SS is possible in the absence of sicca symptoms and entirely based on the results of objective testing; the correlation between symptom severity and the results of objective testing is poor; positive ANA and sicca symptoms may occur in patients with, eg, hepatitis C infection, HIV-induced diffuse infiltrative lymphocytosis syndrome, immunoglobulin G4-related disease; sicca symptoms occur in systemic diseases (eg, sarcoidosis, amyloidosis), neurologic disorders, and dysautonomia (with, eg, orthostatic hypotension, gastroparesis); chronic sialadenitis (CS) — nonautoimmune sicca syndrome; patients report severe dryness (eg, eyes, mouth, whole body); serologic testing is negative, and labial biopsy will not reveal findings characteristic of SS; associated with osteoarthritis in SOX (chronic sialadenitis, osteoarthritis, and xerostomia) syndrome; medications — the most common cause of sicca symptoms in the United States; >500 medications induce symptoms through, eg, anticholinergic effects

Screening for dry eyes

Schirmer testing: a strip of filter paper is placed on the lateral third of the lower eyelid; the degree of wetting during a 5-min period is measured and compared with normal wetting (≥10 mm)

Vital dye staining: vital dyes (eg, fluorescein, rose Bengal, lissamine green) are assimilated by devitalized tissue on the surface of the eye; the combination of fluorescein and lissamine green has the greatest sensitivity; fluorescein is best for revealing corneal abnormalities, and lissamine green is best for revealing conjunctival abnormalities; individuals with significant confluent areas of corneal staining are at a high risk for developing corneal ulcers

Ocular surface staining (OSS) score system (Whitcher et al, 2010): derived from the Sjögren’s International Collaborative Clinical Alliance (SICCA) tissue registry; the density of staining in the parts of the eye (ie, nasal conjunctiva, temporal conjunctiva, cornea) is graded on a 3-point scale; additional points are awarded for, eg, confluent staining, pupillary staining, filamentary keratitis; the maximum score for each eye is 12; an OSS score of ≥3 is clinically significant and positively correlates with the presence of serum autoantibodies and positive labial biopsy

Salivary gland involvement

Sialometry: the patient swallows once, then expectorates into a container for 15 min; the volume of saliva is measured before and after collection; salivary flow rate (SFR) is calculated (normal SFR is 0.3-0.5 mL/min)

Imaging: nuclear medicine salivary gland scan — identifies defects in saliva formation and excretion; parotid duct sialography — water-soluble contrast dye is injected through the Stenson duct to detect structural abnormalities in the parotid ductal system; ultrasonography — identifies areas of parenchymal inhomogeneity or hypoechogenicity (represented by dark circles)

Autoimmunity: demonstrate the presence of anti-Sjögren-syndrome-related antigen A (anti-SSA) antibodies in the blood (preferable) or positive labial minor salivary gland biopsy (MSGB); autoantibodies for ANA and rheumatoid factor (RF) are most prevalent; anti-SSA and anti-SSB antibodies are most specific but only occur in ≤60% of patients (thus, perform MSGB in patients without these antibodies to avoid missed diagnosis); presence of anti-cyclic citrullinated peptide antibodies is associated with increased risk of synovitis and features that overlap with rheumatoid arthritis; anticentromere antibodies are observed in a subset of patients with features that overlap with limited scleroderma; some patients who meet criteria for SS also develop calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia (CREST) syndrome; Shen et al (2012) discovered antibodies to carbonic anhydrase 6, salivary gland protein 1, and parotid secretory protein in murine models that appeared prior to anti-SSA and anti-SSB antibodies; they were also discovered in the serum of seronegative humans with MSGB results diagnostic for SS; it was hypothesized that the antibodies could be used as an early diagnostic marker; a commercial diagnostic kit (the early SS profile) was developed and marketed; assays were originally performed using Western blotting and are now performed using enzyme-linked immunosorbent assay (ELISA); the tests are not routinely recommended, as studies demonstrate no significant differences in sensitivity and specificity when performed in healthy controls, compared with patients with SS or other autoimmune diseases

Labial MSGB: 5- to 10-min procedure performed under local anesthesia; 1 to 2 cm incision is made in the lower lip on one side of normally-appearing mucosa; a pathology report revealing ≥4 minor salivary glands or tissue surface area ≥8 mm² confirms adequate tissue sampling; biopsy reveals the presence of focal lymphocytic sialadenitis, a pattern of lymphoepithelial lesions (LELs; ie, aggregates of mononuclear cells clustered around the acini or salivary ducts; typically contain cluster of differentiation 4+ T-lymphocytes) diagnostic for SS; pathologists count the number of foci (LELs consisting of ≥50 mononuclear cells) in the specimen and divide it by the surface area of normal-appearing tissue to obtain the focus score (FS; reflects the density of inflammation in the glands); FS ≥1 focus per 4 mm² is considered a positive biopsy result)

Erroneous diagnosis: Vivino et al (2002) found that ≈50% of initial biopsy results from outside institutions were misread, resulting in misdiagnosis; a second review changed the diagnosis; common errors included failure to calculate the FS or cite inadequate tissue sampling for initial negative biopsy results; histologic changes suggestive of CS were overlooked

Classification criteria

American-European Consensus Group (Vitali et al [2002]): include subjective and objective findings; the presence of anti-SSA or anti-SSB antibodies is accepted as proof of autoimmunity; heavily criticized for reliance on symptoms for classification

American College of Rheumatology (ACR; Shiboski et al [2012]): solely based on objective testing; the only permitted eye testing is OSS; presence of anti-SSA or anti-SSB antibodies is accepted as proof of autoimmunity, in addition to ANA or RF titer positivity

ACR and the European League Against Rheumatism (EULAR; Shiboski et al [2017]): fully based on objective testing; presence of anti-SSA antibodies is considered proof of serologic autoimmunity; Baer et al (2015) — found that patients in the SICCA tissue registry (tested with ELISA or multiplex flow immunoassay [MFI; permits batch testing with quicker turnaround times, compared with ELISA]) with isolated anti-SSB seropositivity (group B) more closely pathologically resemble patients with full seronegativity (group C; unlikely to have SS) than patients with anti-SSA seropositivity with or without anti-SSB seropositivity (group A; likely to have SS); patient symptoms were similar among all groups; labial MSGB was positive in ≈75% of patients in group A, compared with 25% in groups B and C; it was concluded that most patients with isolated anti-SSB seropositivity may erroneously be diagnosed with SS and do not exhibit the key phenotypic features for SS; the prevalence of isolated anti-SSB antibodies increased 10-fold with use of MFI, compared with ELISA; it is recommended to interpret isolated anti-SSB seropositivity with caution and advise MSGB prior to diagnosis

Applicability of ACR-EULAR criteria: important for clinical trials and studies and apply to patients with sicca symptoms or extraglandular manifestations consistent with SS; the tests are weighted based on perceived order of importance (MSGB and anti-SSA antibody testing are most important); a EULAR/ACR score ≥4 is considered clinically significant, though a score of 9 is possible with abnormal Schirmer testing and SFR

Use of classification criteria vs diagnostic criteria: the use of classification criteria for diagnosis is not always appropriate; classification criteria are created to fulfill research protocol and sacrifice sensitivity to optimize specificity; classification criteria are often compared with the physician’s opinion (ie, gold standard); strict reliance on classification criteria may lead to a missed diagnosis (eg, SFR ≤0.1 mL/min, but not 0.1-0.3 mL/min, is diagnostic for SS); the ACR-EULAR criteria omit the use of imaging; the ACR-EULAR criteria recommend a stringent cutoff for positive Schirmer testing of ≤5 mm in 5 min; the cutoff OSS was arbitrarily changed to ≥5 in the ACR-EULAR criteria (vs≥3 in the ACR criteria); a more liberal definition of SS is used in the clinic to increase sensitivity and increase the chance for early diagnosis; the physician’s gold standard for diagnosis of SS is satisfaction of ≥3 criteria (ie, objective evidence of dry eyes, salivary gland involvement, anti-SSA positivity, positive MSGB); sensitivity and specificity of criteria are 90% to 95%

Outcomes and complications: SS is associated with higher morbidity than previously thought; results of various studies show patients with SS have poor quality of life and high annual costs for prescription drugs and medical and dental care; serious complications include corneal melts and ulcers and rampant dental caries (leads to tooth loss); cardiovascular manifestations are rare; lymphoma — the most significant and dreaded complication; 5% to 7% of patients develop some type of lymphoma within 10 to 15 yr of diagnosis, most commonly non-Hodgkin B-cell lymphoma with nodal and extranodal presentations; a small number of patients have B-cell symptoms, most commonly including persistent swelling of the salivary gland (nodular or indurated on palpation); ≈50% of patients exhibit mucosa-associated lymphoid tissue (MALT) lymphoma of the marginal zone B-cell variety; MALT lymphoma can progress to diffuse large B-cell lymphoma over time; the mortality rate is ≤30%

Questions and answers: ILD — patients who present with ILD receive workup for SS; 20% to 30% of patients with SS may later develop an internal organ manifestation of SS; patients respond well to immunosuppressive therapy (eg, azathioprine); prevention of disease progression and complications — hydroxychloroquine and an anti-inflammatory diet are currently recommended and may induce disease remission; aggressive treatment of the eyes and mouth can help prevent complications; congenital heart block (CHB) in pregnant women with isolated anti-SSB seropositivity without sicca symptoms — full workup with MSGB is recommended to confirm maternal diagnosis of SS; mothers with anti-SSA or anti-SSB seropositivity have a greater likelihood for giving birth to babies with complications of neonatal lupus syndrome (including CHB), compared with mothers with seronegativity; the incidence of CHB is greater among babies born to mothers with lupus, compared with mothers with SS; dietary modification — anti-inflammatory diet incorporates reduction of sources with saturated fatty acids and increasing sources with omega-3 and omega-6 fatty acids (eg, oily fish); patients with adverse reactions to gluten should follow a diet low in gluten; all patients should avoid processed foods and increase intake of colorful fruits and vegetables

Readings

Akpek EK, Bunya VY, Saldanha IJ. Sjögren’s syndrome: more than just dry eye. Cornea. 2019;38(5):658-661. doi:10.1097/ICO.0000000000001865; Atzeni F, Sarzi-Puttini P, Lama N, et al. Anti-cyclic citrullinated peptide antibodies in primary Sjögren syndrome may be associated with non-erosive synovitis. Arthritis Res Ther. 2008;10(3):R51. doi:10.1186/ar2420; Baer AN, McAdams DeMarco M, Shiboski SC, et al. The SSB-positive/SSA-negative antibody profile is not associated with key phenotypic features of Sjögren’s syndrome. Ann Rheum Dis. 2015;74(8):1557-1561. doi:10.1136/annrheumdis-2014-206683; Daniels TE, Cox D, Shiboski CH, et al. Associations between salivary gland histopathologic diagnoses and phenotypic features of Sjögren’s syndrome among 1,726 registry participants. Arthritis Rheum. 2011;63(7):2021-30. doi: 10.1002/art.30381; Helmick CG, Felson DT, Lawrence RC, et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part I. Arthritis Rheum. 2008;58(1):15-25. doi:10.1002/art.23177; Kassimos DG, Shirlaw PJ, Choy EH, et al. Chronic sialadenitis in patients with nodal osteoarthritis. Br J Rheumatol. 1997;36(12):1312-7. Doi: 10.1093/rheumatology/36.12.1312; Kroese FGM, Haacke EA, Bombardieri M. The role of salivary gland histopathology in primary Sjögren’s syndrome: promises and pitfalls. Clin Exp Rheumatol. 2018;36 Suppl 112(3):222-233; Malicka B, Kaczmarek U, Skośkiewicz-Malinowska K. Prevalence of xerostomia and the salivary flow rate in diabetic patients. Adv Clin Exp Med. 2014;23(2):225–33; Melissaropoulos K, Bogdanos D, Dimitroulas T, et al. Primary Sjögren's syndrome and cardiovascular disease. Curr Vasc Pharmacol. 2020;18(5):447-454. doi:10.2174/1570161118666200129125320; Pedersen AM, Bardow A, Nauntofte B. Salivary changes and dental caries as potential oral markers of autoimmune salivary gland dysfunction in primary Sjögren’s syndrome. BMC Clin Pathol. 2005;5(1):4. Doi:10.1186/1472-6890-5-4; Shen L, Suresh L, Lindemann M, et al. Novel autoantibodies in Sjögren’s syndrome. Clin Immunol. 2012;145(3):251-5. doi: 10.1016/j.clim.2012.09.013; Shiboski SC, Shiboski CH, Criswell L, et al. 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(4):475-87. doi: 10.1002/acr.21591; Shiboski CH, Shiboski SC, Seror R, et al. 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(1):35-45. doi: 10.1002/art.39859; Suresh L, Malyavantham K, Shen L, et al. Investigation of novel autoantibodies in Sjögren’s syndrome utilizing sera from the Sjögren’s International Collaborative Clinical Alliance cohort. BMC Ophthalmol. 2015;15:38. doi: 10.1186/s12886-015-0023-1; Vinet E, Pineau CA, Scott S, et al. Increased congenital heart defects in children born to women with systemic lupus erythematosus: results from the offspring of systemic lupus erythematosus mothers registry study. Circulation. 2015;131:149-156. doi:10.1161/CIRCULATIONAHA.114.010027; Vitali C, Bombardieri S, Jonsson R, et al. Classification criteria for Sjögren’s syndrome: a revised version of the European criteria proposed by the American-European Consensus Group. Ann Rheum Dis. 2002;61(6):554-558. doi:10.1136/ard.61.6.554; Vivino FB, Gala I, Hermann GA. Change in final diagnosis on second evaluation of labial minor salivary gland biopsies. J Rheumatol. 2002;29(5):938-44; Vivino FB. Sjögren’s syndrome: clinical aspects. Clin Immunol. 2017;182:48-54. doi: 10.1016/j.clim.2017.04.005; Whitcher JP, Shiboski CH, Shiboski SC, et al. A simplified quantitative method for assessing keratoconjunctivitis sicca from the Sjögren’s Syndrome International Registry. Am J Ophthalmol. 2010;149(3):405-415. doi:10.1016/j.ajo.2009.09.013.

Disclosures

Dr. Vivino reported nothing relevant to disclose. For this program, members of the faculty and planning committee reported nothing relevant to disclose.

Acknowledgements

Dr. Vivino was recorded at Congress of Clinical Rheumatology East, held May 12-15, 2022, in Destin, FL, and presented by Congress of Clinical Rheumatology. For information about upcoming CME activities from this presenter, please visit https://www.ccrheumatology.com. Audio Digest thanks Dr. Vivino and the Congress of Clinical Rheumatology for their cooperation in the production of this program.

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