What's New in Sjögren Disease: Update From ACR 2021

Luca Quartuccio, MD, PhD; Sara McCoy, MD; and Robert Fox, MD, PhD


February 10, 2022

Some of the best research presentations on primary Sjögren disease (SJD) at the 2021 American College of Rheumatology Annual Meeting reported progress and insights on the treatment of glandular and extraglandular manifestations (EGMs) of the disease, as well as the impact of having EGMs as initial symptoms, the value of ultrasound vs biopsy of parotid glands, and new evidence for why SJD is the most female-predominant systemic autoimmune disease.

We have chosen to share with you some of the most significant studies in these areas that were presented at ACR 2021. 

Insights Lead to Promising Investigational Treatments for Glandular and Extraglandular Manifestations

For the busy rheumatologist, the first question is generally, "What is new in therapy?" A PubMed search for "double-blind studies of rituximab" will result in over 5000 peer-edited reports; all indicate the drug's benefit for EGMs but little use for the "benign" indications (dryness and fatigue). ACR 2021 featured several abstracts in which therapy improved salivary and tear function or EGMs.

Three studies presented at the meeting show how B-cell depletion mediates a host of functional changes to ductal epithelial cells in salivary glands of patients with SJD. An abstract by van Maurik et al reported a phase 2 study of 86 patients where sequential belimumab after rituximab provided superior depletion of B cells in minor salivary gland biopsies, a larger decrease in circulating memory B cells, and a more extended period of sustained B-cell deficit.

The mechanism of improvement of parotid function by B-cell depletion and B-cell activating factor (BAFF) inhibition was demonstrated in the abstract by Pringle et al of University Medical Center Groningen in the Netherlands, who presented the effect of B-cell "communication" with secretory epithelial cells in SJD by showing that the presence of CD20 B cells in either the minor salivary gland or parotid glands of SJD patients affects the functional location of sodium transporters in ductal cells, which generally reside in the apical portion of the cells.

This abstract extends the study recently published by this group on transcriptomic and proteomics. The major saliva glands (such as parotid) and minor labial glands usually show similar histologic changes; this group points out the histologic and transcriptional changes may be present in a parotid gland biopsy while not occurring in a minor salivary gland biopsy, which is our usual target for biopsy.

To underscore the importance of evaluating the major salivary gland as the critical target for the treatment of oral dryness, it is worth pointing out the recent study reported by the Oklahoma Medical Research Foundation group that shows full glandular and extraglandular SJD manifestations in the SS-A+/SS-B+ patients who have a negative minor salivary gland biopsy. The Groningen group mentioned above is virtually the only research group that obtains open surgical biopsies of the parotid and thus can make these comparisons. However, other diagnostic approaches (ie, ultrasound-guided core needle biopsy) rather than open parotid biopsy could be applied to this end, as two recent studies show.

The multicenter trial of ianalumab presented a new therapy with a dual mechanism of action of blocking BAFF receptors and depleting B cells by a natural killer cell attack on a modified Fc domain. Crucial further information in this abstract was that B-cell depletion was insufficient to restore salivary flow or improve fatigue. Still, the blockage of the BAFF receptor was necessary to achieve these benefits. The full article on this trial was recently published in Lancet Rheumatology.

Taken together, these presentations provide a background framework for understanding epithelial-immune cell interaction. The role of cytokines and metalloproteinase action leads to interruption of neural signal transduction (both sympathetic and parasympathetic pathways). Thus, the failure of the secretory gland to produce saliva or tears is much greater than the relatively small percentage of glandular destruction (about 50% of acini and ducts remain present in patients with longstanding SJD).

Since the objective dryness noted on the exam (or the patient's perception of dryness when measured on global assessment exam) is often quite surprisingly different from biopsy, we must conclude that what counts to the patient is how their brain perceives the level of dryness. Rather than frustrating the rheumatologist (or the person performing an ultrasound), these findings indicate the importance of the central nervous system in processing and interpreting these neural signals from the "periphery."

The promising therapeutic studies with B-cell depletion combined with BAFF blockage indicate that the immune-suppressing interaction between B cells and epithelial cells can be partially reversed to improve dryness and EGMs. The results are promising, but we await further studies to confirm the efficacy and assess safety. After years of serial failures of biologic therapies, the success of even a single study may lead to the recognition of additional pathways that link the immune pathways to secretory pathways in SJD.

Importance of Extraglandular Manifestations as Initial Symptoms

SJD has a significant impact on patients' morbidity and quality of life. An Argentinian cohort of 111 patients presented at ACR 2021 found that an EGM was the initial presentation of SJD in 53%, with articular involvement (70.3%) being the most frequent initial EGM according to ESSDAI domain criteria, followed by biological (32.6%) and pulmonary involvement (23.7%).

This rate of EGM at the initial presentation of SJD is much higher than in similar reports in American cohorts. An important caveat in the analysis of the percentage of patients with EGM at onset is the need to check whether the ANA and SS-A laboratory tests are submitted by a primary care physician, who may usually perform them as a screen for fatigue or vague neurologic symptoms and then refer the patient to a rheumatologist.

Alternatively, in other healthcare systems, a patient is selected based on EGM for referral to a rheumatologist to determine if the EGM results from systemic autoimmunity. In the healthcare system of Argentina (or Japan or China, for example), ANA and SS-A tests can only be ordered by a rheumatologist to support their diagnosis of an autoimmune basis for the EGM. 

Thus, in comparing studies from different countries, we must be aware that a higher ESSDAI score (ie, more EGM) and the different long-term prognosis it carries for patients with SJD depends on which physician ordered the tests.

In the Argentinian study, patients with EGM as initial symptoms were younger at diagnosis than those who started with sicca symptoms (46.3 vs. 51.4 years; P = .042). This may reflect the tendency of physicians to take the complaints of younger patients more seriously than older patients. When comparing patient clinical characteristics and outcomes, both biases must be considered (ie, health policy for drawing labs and age bias).

Cardiac involvement is not mentioned among the ESSDAI domains because of its rarity as an initial clinical manifestation. However, cardiovascular risk increases in SJD and cardiac disease is the most common cause of death in SJD. Kobayashi and colleagues from Japan studied 52 patients with SJD who underwent noncontrast feature tracking cardiac MRI (FT-CMR) and late gadolinium enhancement (LGE) protocol to evaluate myocardial fibrosis. Abnormal LGE was seen in 10/52 subjects (19%), which means a substantial number of patients could be affected by silent myocardial fibrosis. Thus, CMR should be done in the case of heart failure in SJD to rule out fibrosis as the underlying cause of heart failure.

Ultrasound Does Not Replace Diagnostic Value of Biopsy

There is great interest among rheumatologists in using salivary gland ultrasound to diagnose SJD. Still, a new study by van Ginkel and colleagues at University Medical Center Groningen in the Netherlands indicates a poor correlation between glandular ultrasound and parotid histopathology in patients with SJD.

However, another study from ACR 2021 suggests ultrasound might have a role in assessing risk for MALT lymphoma. Lymphoma risk is also elevated in patients with SJD who have leukopenia and lymphopenia. A case-control study of 1017 patients with SJD who were followed at three centers in Greece confirmed the role of leukopenia and lymphopenia in predicting lymphoma risk, in which leukopenia is defined as an absolute lymphocyte count <1000/mm3 and white blood cell count <4000/mm3, detected in at least three consecutive visits within 1 year after SJD diagnosis.

New Insights Arise About Female Predominance of SJD

SJD is the most female-predominant systemic autoimmune disease. Prior studies had suggested that this might result from Toll receptors 7 and 8 located on the X chromosome. Previous studies in males with SJD identified increased frequency of 47,XXY and 47,XXX among patients with SJD, compared with healthy controls, implicating X chromosome-linked genes as contributors to the striking female bias of SJD.

Data presented at ACR 2021 by Shaw and colleagues extended previous studies about escape from X chromosome inactivation and the female predominance in autoimmune disease by showing that all mesenchymal stromal cells from women with SJD had skewed expression of X-linked genes that escaped X-chromosome inactivation.

In contrast, mesenchymal stromal cells from women with sicca symptoms but without clinical or laboratory features of autoimmunity demonstrated balanced escapee expression. The researchers found that the skewed escapees were enriched in genes responsible for chromatin modification. They also reported that X-inactive-specific transcript (XIST) was decreased in SJD compared with controls. XIST is a non-coding RNA on the X chromosome that acts as a major effector of the X-inactivation process.

Thus, patients with SJD exhibit a mechanism of X-chromosome escape that might serve as a novel mechanism to explain the female bias by perhaps altering hormone-activated genes, Toll-like receptors, or maybe an entirely new class of immune-active genes.

Summary Remarks

Even though the 2021 ACR was a virtual meeting, we shared new developments in SJD pathogenesis and treatment. The finding of selected inactivation of the X-chromosome in SJD may provide a generation of therapeutic targets. The combination of B-cell depletion and BAFF inhibition appears promising for treating dryness and EGMs, although further studies are needed. One report suggested that myocardial involvement may be more frequent than expected.

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