What's New in Ocular and Oral Aspects of Sjögren's Syndrome and Do New Treatments Work?

Nurhan Sutcliffe; Alberto Recchioni; Shireen Hilmi; Saaeha Rauz; Anwar R. Tappuni


Rheumatology. 2021;60(3):1034-1041. 

In This Article

New Investigations for Diagnosis in SS: Oral and Salivary Gland Involvement

The oral signs and symptoms are integral to the diagnosis of SS. Minor labial salivary gland biopsy is an important element of both the AECG and ACR–EULAR classification criteria.[4,5] Current practice includes taking a minor salivary gland biopsy, usually from the lip, as it is less invasive and associated with less risk compared with biopsying a major salivary gland. However, a labial gland biopsy (LGBx) is still associated with significant side effects. A recent meta-analysis found that the risk of temporary paraesthesia associated with LGBx is 11.7% and the risk of permanent paraesthesia is 6%.[46] Additionally, variability in the specificity and sensitivity of histological findings and high operator dependency of both the surgeon and histopathologist are issues that have been recognized. There have been attempts to provide guidance and standardize labial salivary gland histopathology reporting in the classification of pSS, but the evidence to support this guidance is still lacking and further research is needed.[47]

Recently, studies have shown that salivary gland ultrasonography (SGUS) has a major advantage over salivary gland biopsy—being less invasive, cheaper, with far fewer risks and side effects, including less postoperative pain and swelling and no risk of neurological damage.[46] There are recognizable features on the SGUS indicative of SS. It is more reproducible than surgical biopsies and, as such, it is more suited for long-term monitoring and follow-up investigations. Recent studies have advocated the inclusion of SGUS in the diagnostic criteria of SS, due to its desirable qualities. A retrospective study by Astorri et al.[48] and a prospective study by Mossel et al.[49] found that a positive SGUS combined with anti-SSA/Ro antibodies provides a high predictive value for the diagnosis of pSS based on the ACR, AECG and ACR–EULAR classification systems, potentially negating the need for an invasive biopsy in these cases. Importantly, however, a negative SGUS with negative anti-SSA/Ro antibodies cannot reliably exclude pSS, and in these cases, salivary gland biopsy may be indicated in order to definitively exclude pSS in the presence of strong clinical signs, i.e. abnormal Schirmer or unstimulated salivary flow rates.[49] Furthermore, other studies have shown that when LGBx or serum antibody testing is replaced with SGUS in the ACR–EULAR criteria, the accuracy of the classification criteria is significantly reduced, indicating the strength of histological and serum testing in the diagnosis of pSS. The strength of SGUS was shown to be comparable to clinical unstimulated saliva flow testing or the Schirmer test when replacing these in the ACR–EULAR criteria.[50] These two studies demonstrate the importance of utilizing multiple diagnostic tools in the diagnosis of pSS and perhaps an approach to add SGUS to the current diagnostic criteria rather than as a replacement of serological testing or LGBx. As such, where less-invasive clinical markers accrue sufficient numbers of points for a positive diagnosis, LGBx can then be reserved for patients where the diagnosis is more challenging.[50] Nogal et al.[51] demonstrated similar findings, where SGUS was shown to provide comparable sensitivity to LGBx, but with a lower specificity; therefore, again, reaffirming that SGUS is a useful adjunct to existing diagnostic tools and may negate the need for biopsy in selected patients with strong clinical signs and positive serological testing.

It is noteworthy, however, that SGUS is highly technique sensitive and operator dependent and that there are no agreed upon gold standards for ultrasound features diagnostic of SS. Vukicevic et al.[52] investigated the use of radiomics-based assessment of this group of patients and speculated that this is further complicated by a relative lack of skilled sonographers to interpret the images. These drawbacks make this modality less suitable for wider use, but further research to provide solid evidence for the inclusion of SGUS as a mainstay of clinical diagnosis should be encouraged, as this modality has obvious benefits for patients.

Promising research is emerging regarding another non-invasive technique. A recent study investigated impression cytology (IC), which is commonly used for ocular testing. Hao et al.[53] applied a cellulose acetate filter on the labial mucosa to capture the superficial layers of cells of the epithelium for histological analysis. In the same study, in vivo confocal microscopy (CM), was used to observe the microstructure of the labial mucosa. The authors noted that both the IC and CM can identify patterns present in SS patients specifically when compared with controls.

While research into non-invasive procedures as alternatives to LGBx is increasing, there is emerging data showing that histological investigations still have a place in predicting the prognosis and progressions of pSS, for example, the correlation between focus scores and extraglandular manifestations of pSS, including interstitial lung disease.[54] Higher focus scores, as well as the histological detection of germinal centre-like structures in minor salivary glands, have been linked to a higher risk of developing non-Hodgkin lymphoma and systemic disease. Specifically, studies have demonstrated that focus scores ≥4 are associated with a risk of developing interstitial lung disease in patients with pSS, potentially underlining a need for routinely performing minor salivary gland biopsies even in patients who are seropositive.[54] It has been recognized, however, that operator-dependent variations in interpretation of biopsy samples may lead to over -or underestimating the risk of such histological findings, therefore more research into this area is still necessary.