Seronegative Sjögren Syndrome: A Forgotten Entity?

As a highly varied disease, Sjögren syndrome (SS; also termed Sjögren disease) is estimated to affect 0.01% to 0.72% of the population, with an overwhelming bias toward the female gender.¹ SS causes a significant burden to the quality of life of patients and inhibits their function. Patients present with a spectrum of clinical manifestations from sicca (dryness) symptoms to potentially severe extraglandular and/or systemic features, such as inflammatory arthritis, interstitial lung disease, neurological dysfunction, cryoglobulinemia, and malignant lymphoma. The hallmark of SS is B cell hyperreactivity and consequently, autoantibodies such as antinuclear antibodies (ANAs; including anti-Ro60/Ro52/La) and rheumatoid factors.² These autoantibodies are present in 45% to 75% of patients.³ When patients lack serum anti-Ro52/Ro60 (SSA/Ro), the diagnosis of SS relies upon meeting internationally defined classification criteria,⁴ which include reduction of measured tear and/or salivary flow, and the finding of focal lymphocytic sialadenitis on minor salivary gland biopsy (MSGB). Patients fulfilling SS criteria who do not express classic serum antibodies are called patients with seronegative SS. However, there is no universally accepted definition of which autoantibodies should define seropositive from seronegative SS. Hence, the proportion of patients with seronegative SS varies in the literature, ranging from 8% to 37% of SS cohorts.^5-7

Because of the lack of SS-associated autoantibody biomarkers, seronegative SS may be missed in the clinic if further investigations such as an MSGB are not performed. It is important to differentiate patients with seronegative SS from other patients who have sicca symptoms due to the potential for serious extraglandular manifestations in the former.⁸ However, undetectable ANA and autoantibodies could be a function of the type of assay used, serum dilutions, and analytical sensitivities. Early immunoassays favored detection of immunoprecipitating autoantibodies, such as anti-Ro60; those patients who are positive only to anti-Ro52 may have been missed on immunoprecipitation assays since anti-Ro52 does not readily precipitate.⁹ ANAs may also be undetectable in patients who are only monopositive for anti-Ro52 as these autoantibodies may not show a positive ANA on indirect immunofluorescent microscopy. Hence, it is important for clinicians to specifically request serum anti-Ro52 antibody testing when SS is suspected so more appropriate assays may be performed by the laboratory.

Further, in patients with seronegative SS, the serum autoantibodies to Ro/La ribonucleoprotein complex autoantigens may be too dilute for assay detection in serum since they likely originate in tissues, such as the salivary glands. As evidence of this, IgG and IgA anti-Ro/La autoantibodies can be detected in the saliva and tears of patients with seronegative SS.^10,11 Moreover, analysis of antibody-secreting B cells in salivary glands of patients with seropositive SS confirm that B cells to classic SS autoantigens (eg, Ro60) are present in these tissues.¹² These data suggest that the term seronegative, in fact, may refer to the inability to detect antibodies in the periphery and that pathology may be localized to exocrine glands. Indeed, further research to elucidate the immunologic basis of seronegative patients compared to seropositive patients would be most informative.

The number of autoantibodies detected in patient serum inversely correlates with the age of diagnosis³; hence, seronegative patients tend to be diagnosed later than their seropositive SS counterparts.¹³ These patients often have a milder clinical phenotype with less lymphadenopathy and peripheral nervous system involvement, but in contrast, have a higher sicca, fatigue, and pain burden.^7,8 Nonetheless, many patients with seronegative SS exhibit considerable and serious systemic features,⁵ and thus, accurate recognition and diagnosis is important for provision of appropriate management and determination of prognosis.

Without readily detectable serum biomarkers, patients with seronegative SS may be overlooked in the clinic and often excluded from clinical trials. In fact, there is a bias of clinical trials to include patients with SS who are seropositive, and some large cohort studies of patients with SS fail to specifically characterize seronegative patients.¹⁴ This may be because patients with seropositive SS are more likely to have extensive systemic disease and higher disease activity,¹⁵ and therefore represent a group more likely to respond to the trial drug. Seropositive patients are also more likely to have a positive MSGB and therefore be included in trials with “definite” SS.¹⁶ A consequence of this selection bias is that the trial results may not be generalizable to the significant percentage of patients with SS who are seronegative. Both patients with seropositive and seronegative SS display the hallmarks of B cell hyperreactivity (such as locally produced autoantibodies and hypergammaglobulinemia).¹⁷ Current and future studies should thus include patients within both SS subsets to determine the effects of therapies targeting B cells, interferons, cytokines, and other potential targets.¹⁸

In summary, clinicians should be suspicious of SS in patients presenting with sicca symptoms or other clinical features typical of SS despite not having the typical SS autoantibodies, since up to a third of patients with SS may lack classic serum autoantibodies. Hence, objective measurement of lacrimal function (eg, Schirmer test) and referral when appropriate for MSGB, should be part of the diagnostic armamentarium of physicians caring for these patients. Salivary gland imaging, such as ultrasound, may also contribute to diagnostic likelihood; a normal salivary gland ultrasound has a high negative predictive value for seronegative SS and may circumvent an MSGB.¹⁹ However, it is important to acknowledge the converse, whereby seronegative patients without SS are inappropriately labeled as having SS. This may arise from inconsistent agreement and reporting of MSGB among pathologists.²⁰ Since a biopsy is central in the diagnosis of patients with seronegative SS, consultation of experienced pathologists familiar with international SS histology reporting guidelines is recommended to avoid overdiagnosing patients with SS.

The importance of early recognition, diagnosis, and management of SS is reflected by patients presenting with late and/or serious complications, such as severe dental caries, interstitial pneumonitis and pulmonary fibrosis, cryoglobulinemic nephritis, lymphoma, reduced quality of life, and increased health service utilization. Appropriate serological phenotyping of patients with SS may be instrumental in prognosticating patients.⁶ Patients with seropositive SS have an increased lymphomagenesis risk and may have worse quality of life over seronegative patients, yet suffer lower pain and fatigue complaints.^1,7 Indeed, further work is required to better understand how serological classification of patients may assist in predicting clinical and patient outcomes in patients with SS. On a research level, understanding why a subset of patients with SS do not produce serum autoantibodies against the Ro/La ribonucleoprotein complex would be instrumental in understanding the immunopathology of autoantibody-associated diseases like SS, and perhaps be contributory to the development of targeted therapeutic interventions.

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