Increased Interferon Signalling in Vaginal Tissue of Patients With Primary Sjögren Syndrome.

OBJECTIVE: Vaginal dryness is an important factor influencing sexual function in women with primary Sjögren syndrome (pSS). Previous studies showed a higher degree of inflammation in vaginal biopsies from patients with pSS compared to non-pSS controls. However, the molecular pathways that drive this inflammation remain unclear. Therefore, the aim of this study was to investigate inflammatory pathway activity in the vaginal tissue of patients with pSS. METHODS: Vaginal biopsies of 8 premenopausal patients with pSS experiencing vaginal dryness and 7 age-matched non-pSS controls were included. Expression of genes involved in inflammation and tissue homeostasis was measured using NanoString technology and validated using TaqMan Real-Time PCR. Vaginal tissue sections were stained by immunohistochemistry for myxovirus resistance protein 1 (MxA) and CD123 (plasmacytoid dendritic cells [pDCs]). RESULTS: The most enriched pathway in vaginal biopsies from patients with pSS compared to non-pSS controls was the interferon (IFN) signaling pathway (P < 0.01). Pathway scores for Janus kinase and signal transducer and activator of transcription (JAK-STAT) and Notch signaling were also higher (P < 0.01 for both pathways). Conversely, transforming growth factor-ß signaling and angiogenesis pathway scores were lower in pSS (P = 0.02 and P = 0.04, respectively). Differences in IFN signaling between patients with pSS and non-pSS controls were confirmed by PCR and MxA tissue staining. No CD123+ pDCs were detected in vaginal biopsies. IFN-stimulated gene expression levels correlated positively with CD45+ cell numbers in vaginal biopsies and serum anti-SSA/Ro positivity. CONCLUSION: Upregulation of IFN signaling in vaginal tissue of women with pSS, along with its association with tissue pathology, suggests that IFNs contribute to inflammation of the vaginal wall and potentially also to clinical symptomatology (ie, vaginal dryness).

Histopathological comparison of Sjögren-related features between paired labial and parotid salivary gland biopsies of sicca patients.

OBJECTIVES: To compare focus score (FS) and other histopathological features between paired labial and parotid salivary gland biopsies in a diagnostic cohort of suspected Sjögren's disease (SjD) patients. METHODS: Labial and parotid salivary gland biopsies were simultaneously obtained from patients with sicca complaints, suspected of having SjD. Biopsies were formalin fixed and paraffin embedded. Sections were stained with haematoxylin & eosin (H&E) and for CD3, CD20, CD45, cytokeratin, CD21, Bcl6, activation induced deaminase (AID), and IgA/IgG. FS and other histopathological features characteristic for SjD were analysed. RESULTS: Based on the expert opinion of three experienced rheumatologists, 36 patients were diagnosed as SjD and 63 as non-SjD sicca patients. When taking all patients together, absolute agreement of various histopathological features between labial and parotid biopsies was high and varied between 80% (FS) and 93% ((pre-)lymphoepithelial lesions (LELs)). More labial gland biopsies had a FS ≥ 1 compared with their parotid counterpart. Accordingly, the area of infiltrate was larger in labial gland biopsies. When considering only SjD patients, labial glands contained significantly less B-lymphocytes, GCs/mm2 and less severe LELs compared with parotid glands. CONCLUSION: Labial and parotid glands from SjD patients contain similar histopathological key features, and thus both glands can be used for diagnosis and classification of SjD. However, parotid salivary glands reveal more evident B-lymphocyte related features, while labial glands exhibit more inflammation, which may be partially unrelated to SjD.

Increased Diagnostic Accuracy of the Labial Gland Biopsy in Primary Sjögren Syndrome When Multiple Histopathological Features Are Included.

OBJECTIVE: The aim of this study was to evaluate the diagnostic accuracy of the labial salivary gland biopsy based on multiple histopathological features in patients with suspected primary Sjögren syndrome (pSS). METHODS: Patients from a diagnostic sicca cohort with clinically suspected pSS who underwent a labial gland biopsy were included. Patients were categorized as having pSS or non-Sjögren syndrome sicca (non-SS sicca) based on vignettes scored by an expert panel. Labial gland biopsies were analyzed for the presence of four histopathological features: focus score (FS) ≥1, prelymphoepithelial and lymphoepithelial lesions, immunoglobulin G plasma cell shift, and germinal centers. Sensitivity and specificity of histologic features were calculated, and the optimal cutoff value for the number of histopathological features needed to diagnose pSS was determined with receiver operating curve analysis. RESULTS: A total of 38 patients were categorized as having pSS and 65 as having non-SS sicca. In labial gland biopsies of patients with pSS, the prevalence of FS ≥1 was 82%, followed by 68% for pre-lymphoepithelial and lymphoepithelial lesions, 63% for plasma cell shift, and 24% for germinal centers. Although FS ≥1 showed the highest sensitivity for patients with pSS (82%), specificity was higher for the other three features (98%-100%). The presence of two or more (of four) histopathological features had almost comparable sensitivity to FS alone, but specificity increased with 12% to 100%. For fulfillment of American College of Rheumatology/EULAR criteria, specificity increased from 84% to 95% when an abnormal biopsy was defined by the presence of two or more histopathological features instead of FS ≥1 only. CONCLUSION: The diagnostic accuracy of the labial gland biopsy increases when other histopathological features besides FS are taken into account, by reducing the number of false-positive biopsies.

The diagnostic power of salivary electrolytes for Sjögren's disease: a systematic literature review and meta-analysis.

OBJECTIVES: To perform a systematic review and meta-analysis to determine the power of salivary electrolytes for the diagnosis of Sjögren's disease (SjD). METHODS: A literature search was conducted (last search March 2023) using PubMed and Web of Science and completed with a manual search. Articles were screened for reports of human salivary ion concentrations, comparing SjD patients with healthy controls and/or sicca patients. Articles not using the SjD classification criteria or performing the classification as part of the experimental design were excluded. Forest plots were used to present the meta-analyses results for each ion, distinguishing between salivary type (unstimulated and stimulated whole saliva, submandibular/sublingual and parotid saliva). RESULTS: A total of 21 out of 722 articles were eligible for inclusion. For SjD patients a significant increase in salivary ion concentration was observed for sodium, chloride and calcium when comparing to healthy controls. Significant differences between SjD and sicca patients were noted for sodium, chloride, phosphate, calcium, phosphate, nitrite and nitrate. Stimulated whole saliva showed larger variability in results between studies in comparison to other types of saliva (unstimulated whole saliva, submandibular/sublingual saliva and parotid saliva). CONCLUSIONS: Despite differences in saliva type, salivary ion levels could be utilised for the screening for SjD. Making use of chloride in combination with sodium would be most promising for distinguishing SjD patients from healthy controls and adding phosphate to potentially make a distinguishment with sicca patients. Unstimulated whole saliva should be the first choice when testing salivary ion concentrations.

The Effect of Two Years of Secukinumab Treatment on Bone Metabolism in Patients with Radiographic Axial Spondyloarthritis: Results from Daily Clinical Practice.

Background: Our objective was to explore bone-related outcome and bone turnover markers (BTM) during 2 years of secukinumab treatment in patients with radiographic axial spondyloarthritis (r-axSpA) in daily clinical practice. Methods: Included were consecutive r-axSpA outpatients from the Groningen Leeuwarden axSpA (GLAS) cohort treated with secukinumab for 2 years. At baseline and 2 years, spinal radiographic damage was assessed using the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS; 0-72), cervical facet joint involvement according the "de Vlam" scoring method (0-15) and radiographic vertebral fractures (VF) using the "Genant" method (grade 0-3). At all visits, BTM reflecting collagen resorption (serum type I collagen C-telopeptide; sCTX), collagen formation (procollagen type 1 N-terminal peptide; PINP) and bone mineralization (bone-specific alkaline phosphatase; BALP) were measured and expressed in Z-scores to correct for the normal influence of age and gender. Results: 17 r-axSpA patients were included; 53% male, mean age was 47±15 years, mean Ankylosing Spondylitis Disease Activity Score (ASDAS) 3.9±1.2, and 53% was biological naïve. The median 2-year progression rates were 1.1 for mSASSS and 0.5 for facet joints, which was less than the smallest detectable change. One traumatic VF (grade 3) occurred. Serum levels of sCTX and PINP remained stable during secukinumab treatment and BALP decreased significantly after 2 years, with median 0-2 year change in Z-scores of +0.1, -0.4, and -1.2, respectively. Conclusion: This explorative study of r-axSpA patients treated with secukinumab in daily clinical practice showed low radiographic spinal progression during 2 years of follow-up. Collagen resorption and formation markers remained stable, whereas mineralization marker BALP decreased significantly after 2 years. Our results are in line with the results of in vitro studies demonstrating that inhibition of IL17-A resulted in suppression of osteogenic differentiation with significant decrease in mineralization.

Longitudinal evaluation of major salivary gland functioning in Sjögren's disease patients in a prospective standard-of-care cohort.

OBJECTIVES: To evaluate changes in major salivary gland functioning over time using salivary gland ultrasonography (SGUS), salivary flow measurements (sialometry), and patient-reported outcome measures (PROMs) in patients diagnosed with primary Sjögren's disease (SjD). METHODS: Consecutive outpatients from the ongoing prospective REgistry of Sjögren Syndrome LongiTudinal (RESULT) cohort, all fulfilling the ACR-EULAR classification criteria for SjD, were included. SGUS images assessed with the Hocevar and OMERACT scoring system, unstimulated and stimulated whole saliva (UWS/SWS), unstimulated and stimulated submandibular/sublingual saliva (uSMSLS/sSMSLS) and parotid saliva, EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) general dryness, oral dryness, and Xerostomia Inventory were assessed at baseline (BL), 2-year (Y2) and 5-year (Y5) follow-up. RESULTS: In total, BL and Y2 data were available for 253 patients and 75 patients had already reached Y5. At group level, SGUS Hocevar (i.e., mean±SD: 22±10 at BL, 22±10 at Y2 and 23±10 at Y5), OMERACT scores, UWS, SWS and PROMs remained stable over time (all p>0.05). Slightly decreased uSMSLS (p=0.025) and sSMSLS (p=0.004) were observed at Y5. At individual patient level, a similar proportion showed an increase or decrease of ≥25% for Hocevar, UWS and SWS. At baseline, poor associations were observed between SGUS and PROMs and fair associations between sialometry and PROMs. Over time, changes in objective assessments did not correlate with changes in PROMs. CONCLUSIONS: Overall, major salivary gland functioning assessed with SGUS, sialometry and PROMs did not change significantly up to 5 years of follow-up in a standard-of-care cohort of SjD patients from daily clinical practice.

Why do drug treatments fail in Sjögren's disease? Considerations for treatment, trial design and interpretation of clinical efficacy.

INTRODUCTION: Despite ongoing efforts to develop effective therapeutics, no disease-modifying drugs have been officially licensed for the indication of Sjögren's disease (SjD). This is partly due to heterogeneity in disease manifestations, which complicates drug target selection, trial design and interpretation of clinical efficacy in SjD. AREAS COVERED: Here, we summarize developments and comment on challenges in 1) identifying the right target for treatment, 2) selection of the primary study endpoint for trials and definition of clinically relevant response to treatment, 3) inclusion criteria and patient stratification, 4) distinguishing between disease activity and damage and 5) establishing the effect of treatment considering measurement error, natural variation, and placebo or nocebo responses. EXPERT OPINION: Targets that are involved in both the immune cell response and dysregulation of glandular epithelial cells (e.g. B-lymphocytes, type-I interferon) are of particular interest to treat both glandular and extra-glandular manifestations of SjD. The recent development of composite study endpoints (CRESS and STAR) may be a crucial step forward in the search for clinically effective systemic treatment of patients with SjD. Important additional areas for future research are symptom-based and/or molecular pathway-based patient stratification, prevention of irreversible damage, and establishing the effect of treatment.

Targeting plasma cells in systemic autoimmune rheumatic diseases - Promises and pitfalls.

Plasma cells are the antibody secretors of the immune system. Continuous antibody secretion over years can provide long-term immune protection but could also be held responsible for long-lasting autoimmunity in case of self-reactive plasma cells. Systemic autoimmune rheumatic diseases (ARD) affect multiple organ systems and are associated with a plethora of different autoantibodies. Two prototypic systemic ARDs are systemic lupus erythematosus (SLE) and Sjögren's disease (SjD). Both diseases are characterized by B-cell hyperactivity and the production of autoantibodies against nuclear antigens. Analogues to other immune cells, different subsets of plasma cells have been described. Plasma cell subsets are often defined dependent on their current state of maturation, that also depend on the precursor B-cell subset from which they derived. But, a universal definition of plasma cell subsets is not available so far. Furthermore, the ability for long-term survival and effector functions may differ, potentially in a disease-specific manner. Characterization of plasma cell subsets and their specificity in individual patients can help to choose a suitable targeting approach for either a broad or more selective plasma cell depletion. Targeting plasma cells in systemic ARDs is currently challenging because of side effects or varying depletion efficacies in the tissue. Recent developments, however, like antigen-specific targeting and CAR-T-cell therapy might open up major benefits for patients beyond current treatment options.

Targeting alarmin release reverses Sjogren's syndrome phenotype by revitalizing Ca2+ signalling.

BACKGROUND: Primary Sjogren's syndrome (pSS) is a systemic autoimmune disease that is embodied by the loss of salivary gland function and immune cell infiltration, but the mechanism(s) are still unknown. The aim of this study was to understand the mechanisms and identify key factors that leads to the development and progression of pSS. METHODS: Immunohistochemistry staining, FACS analysis and cytokine levels were used to detect immune cells infiltration and activation in salivary glands. RNA sequencing was performed to identify the molecular mechanisms involved in the development of pSS. The function assays include in vivo saliva collection along with calcium imaging and electrophysiology on isolated salivary gland cells in mice models of pSS. Western blotting, real-time PCR, alarmin release, and immunohistochemistry was performed to identify the channels involved in salivary function in pSS. RESULTS: We provide evidence that loss of Ca2+ signaling precedes a decrease in saliva secretion and/or immune cell infiltration in IL14α, a mouse model for pSS. We also showed that Ca2+ homeostasis was mediated by transient receptor potential canonical-1 (TRPC1) channels and inhibition of TRPC1, resulting in the loss of salivary acinar cells, which promoted alarmin release essential for immune cell infiltration/release of pro-inflammatory cytokines. In addition, both IL14α and samples from human pSS patients showed a decrease in TRPC1 expression and increased acinar cell death. Finally, paquinimod treatment in IL14α restored Ca2+ homeostasis that inhibited alarmin release thereby reverting the pSS phenotype. CONCLUSIONS: These results indicate that loss of Ca2+ signaling is one of the initial factors, which induces loss of salivary gland function along with immune infiltration that exaggerates pSS. Importantly, restoration of Ca2+ signaling upon paquinimod treatment reversed the pSS phenotype thereby inhibiting the progressive development of pSS.

Rheumatoid factor autoantibody repertoire profiling reveals distinct binding epitopes in health and autoimmunity.

BACKGROUND: Rheumatoid factors (RF) are one of the hallmark autoantibodies characteristic of rheumatoid arthritis (RA), and are frequently observed in other diseases and in healthy individuals. RFs comprise multiple subtypes with different specificities towards the constant region of human IgG. Studies indicate that these patterns differ between naturally occurring RFs and RFs associated with disease. However, individual specificities characteristic of either have not been clearly defined. METHODS: In this study, we developed an extended set of engineered IgG-fragment crystallisable (Fc) targets with preferential RF binding to specific (conformational) epitopes, which was subsequently used for profiling of RF binding patterns in a compiled exploration cohort, consisting of sera from healthy donors with measurable RF and patients with RA, primary Sjögren's syndrome (pSS) and seropositive arthralgia. RESULTS: We identified an epitope that is strongly associated with RA, which was targeted by both IgM-RF and IgA-RF. We also identified an epitope that is preferentially targeted by healthy donor (IgM) RFs. IgM-RFs derived from healthy donors and patients with RA and pSS all target distinct regions on the IgG-Fc, whereas overall, the IgA-RF repertoire is largely restricted to pathology-associated specificities. Using monoclonal RFs with different specificities, we furthermore demonstrate that the capacity to activate complement or even inhibit IgG-mediated complement activation varies according to the epitopes to which RFs bind. CONCLUSIONS: Our results demonstrate both the need and feasibility to redefine 'RF' into pathological and physiological autoantibody subtypes.

After an initial balance favoring collagen formation and mineralization, bone turnover markers return to pre-treatment levels during long-term TNF-α inhibition in patients with ankylosing spondylitis.

BACKGROUND: Bone turnover balance favors bone formation, especially mineralization, during the first 3 years of treatment with TNF-α inhibitors (TNFi). Our aim was to evaluate the course of serum bone turnover markers (BTM) and to investigate if facilitation of mineralization reflected by BTM BALP continues to increase during 6 years of TNFi treatment in patients with ankylosing spondylitis (AS) in daily clinical practice. METHODS: Included were outpatients from the University Medical Center Groningen (UMCG) participating in the Groningen Leeuwarden Axial SpA (GLAS) cohort who were treated with TNFi for at least 6 years. Serum markers of collagen resorption, bone regulation, collagen formation and facilitator of bone mineralization (sCTX, OC, PINP and BALP, respectively) were measured at baseline, 3 and 6 months, 1, 2, 4 and 6 years. Z-scores were calculated to correct for age and gender. RESULTS: 53 AS patients were eligible for analyses (66% male, mean age 39±11 years). Disease activity showed rapid and sustained improvement after start of TNFi. Evaluating BTM, sCTX did not significantly change during 6 years of treatment. OC was only significantly increased at 3 months compared to baseline, with median change in Z-score of +0.5. PINP significantly increased at 3 and 6 months and 2 years of treatment, with maximum median change in Z-score of +0.3. Interestingly, BALP was significantly increased at all time points up to and including 2 years of TNFi treatment, with maximum change in median Z-score of +1.2, and decreased thereafter. CONCLUSION: In AS patients receiving long-term TNFi, bone turnover balance favored collagen formation and facilitation of mineralization during the first 2 years of treatment. Thereafter, at 4 and 6 years of follow-up, BTM Z-scores returned to pre-treatment levels.

FDG-PET/CT discriminates between patients with and without lymphomas in primary Sjögren's syndrome.

OBJECTIVES: To assess the usefulness of [18F]-fluorodeoxyglucose (FDG)-PET/CT (i) to discriminate between primary SS (pSS) patients with and without lymphomas and (ii) to evaluate systemic disease activity in pSS. METHODS: ACR-EULAR-positive pSS patients who underwent FDG-PET/CT were included. Scans were visually evaluated and quantitative analysis was performed by measuring standardized uptake values (SUV) of salivary and lacrimal glands and systemic regions. Receiver operating characteristic curve analyses were performed to find SUV cut-off values to discriminate between lymphoma and non-lymphoma. RESULTS: Of the 70 included patients, 26 were diagnosed with a pSS-associated lymphoma, mostly of the mucosa-associated lymphoid tissue type (23/26). Lymphoma patients showed higher FDG uptake in the parotid and submandibular glands, and more frequently showed presence of nodular lung lesions, compared with non-lymphoma patients. The accuracy of the maximum SUV (SUVmax) in the parotid and submandibular gland to predict lymphoma diagnosis was good, with optimal cut-off points of 3.1 and 2.9. After combining these three visual and quantitative findings (nodular lung lesions, parotid SUVmax > 3.1 and submandibular SUVmax > 2.9), sensitivity was 92% when at least one of the three features were present, and specificity was 91% in case at least two features were present. Furthermore, FDG-PET/CT was able to detect systemic manifestations in pSS patients, mostly involving lymph nodes, entheses and lungs. CONCLUSIONS: FDG-PET/CT can assist in excluding pSS-associated lymphomas in patients without PET abnormalities, possibly leading to a decrease of invasive biopsies in suspected lymphoma patients. Furthermore, FDG-PET/CT is able to detect systemic manifestations in pSS and can guide to the best biopsy location.

Association of Circulating Antibody-Secreting Cell Maturity With Disease Features in Primary Sjögren's Syndrome.

OBJECTIVE: B cell hyperactivity plays an important role in primary Sjögren's syndrome (SS). We undertook this study to better understand the B cell effector branch, namely antibody-secreting cells (ASCs) in primary SS, and to examine the quantity, maturity, and inflammatory properties of ASCs in primary SS patients. METHODS: Circulating ASCs, defined as CD3-CD14-CD27+CD38++ cells, from 21 primary SS patients and 10 healthy controls were assessed using spectral flow cytometry. Expression levels of relevant ASC markers relating to maturity, survival, and inflammatory status were analyzed using a t-distributed stochastic neighbor embedding approach. Correlation of ASC properties with primary SS disease parameters was assessed. RESULTS: ASCs were more abundant in peripheral blood from primary SS patients than from healthy controls (mean ± SD 3.1 ± 5.1 cells/µl versus 1.1 ± 1.0 cells/µl, respectively; P = 0.048) and displayed a more mature phenotype (mean ± SD CD19- ASCs 0.37 ± 1.21 cells/µl versus 0.06 ± 0.11 cells/µl, respectively; P = 0.005). An inflammatory CXCR3+ phenotype of ASCs correlated positively with our newly developed ASC maturity index (r = 0.568, P = 0.007) but correlated negatively with antiinflammatory interleukin-10 expression (r = -0.769, P < 0.001). ASCs with a higher maturity index also demonstrated higher levels of the pro-survival protein myeloid cell leukemia 1 (r = 0.567, P = 0.007). Frequency and/or maturity of ASCs correlated with several primary SS disease parameters, such as antinuclear antibody and anti-La/SSB titers, salivary gland focus scores, and ocular staining scores. CONCLUSION: Quantity and maturity of ASCs in primary SS patients are increased and correlate with disease parameters. A higher maturity index of ASCs marks a pro-survival and proinflammatory phenotype. Altogether, B cell hyperactivity in primary SS extends to the peripheral ASC compartment, raising potential for ASCs as future biomarkers or targets for primary SS treatment.

Patient Acceptable Symptom State (PASS) in patients with primary Sjögren's syndrome in daily clinical practice.

OBJECTIVES: To explore Patient Acceptable Symptom State (PASS) in a standard of care cohort of patients with primary Sjögren's syndrome (pSS) and to compare patient characteristics including EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) between PASS and non-PASS groups. METHODS: All pSS patients fulfilling ACR/EULAR classification criteria from the Registry of Sjögren's Syndrome LongiTudinal (RESULT) cohort, who had available PASS data at baseline were included. Patient-reported outcomes included the PASS question: "Considering all the different ways your disease is affecting you, if you were to stay in this state for the next few months, do you consider your current state satisfactory?"; yes: PASS / no: non-PASS. RESULTS: Of the 278 included pSS patients, 199 (72%) had an acceptable symptom state according to the PASS question, and median ESSPRI was 6 (IQR 4-7). In the PASS group, 118 (59%) patients had an unacceptable symptom state according to ESSPRI (score ≥5). In multivariable regression analyses, ESSPRI and disease duration were independently associated with presence of PASS. The accuracy of ESSPRI to predict PASS was fair (AUC of 0.78). The cut-off point of ESSPRI for presence of PASS with the highest Youden's index was 7.2 (sensitivity 85%, specificity 56%), followed by 5.2 (sensitivity 48%, specificity 90%). CONCLUSIONS: The majority of pSS patients reported being in an acceptable symptom state according to the PASS question, despite high ESSPRI scores. In our standard of care cohort, the optimal cut-off point of ESSPRI to predict PASS is different when focusing on sensitivity (±7) or specificity (±5).

The lacrimal gland in Sjögren's syndrome: can we unravel its mystery using ultrasound?

According to a recent survey of patients with the autoimmune disease primary Sjögren's syndrome (pSS), dry eye symptoms are present in 95-98% of pSS patients. As one of the most disabling symptoms mentioned by pSS patients, dry eyes have demonstrable effects on quality of their life, leading to eye dryness, itching, and pain, with some patients describing as a recurrent sensation of sand or gravel in the eyes. The symptoms are matched only in prevalence by dry mouth and chronic fatigue. In contrast to the prevalence of dry eye symptoms in pSS and their burden on pSS patients, our comprehension of dry eye disease development is minimal; specifically how function of the tear-fluid producing gland the lacrimal gland (LG), manifests. The comparison becomes stronger again when we consider what we know about dysfunction of the salivary gland (SG) in pSS, for example the appreciation of the transcriptome of 'innately activated' B cells invading the SG, their complicity in formation of lymphoepithelial lesions, and the ability of the SG epithelium to actively contribute to the inflammatory milieu. The exploration of ultrasound imaging as an additional modality to garner information about SG dysfunction in pSS has opened many doors for non-invasive, repeatable imaging in pSS. Here we summarise SG histology and ultrasound phenotype briefly and then juxtapose this with available studies examining LG pathology and ultrasound, and our understanding of LG dysfunction in pSS.

Lymphoepithelial lesions in the salivary glands of primary Sjögren's syndrome patients: the perfect storm?

In patients with primary Sjögren's syndrome (pSS), inflamed salivary gland (SG) tissue may contain lymphoepithelial lesions (LELs). LELs are histopathological phenomena whereby B cells are present in hyperplastic ductal epithelium of the SG. Despite the potential role of LELs in pSS pathogenesis, studies on their formation, detection, and prevalence in benign lesions (not complicated with lymphoma) are scarce. Recent evidence however shows that LELs are present in approximately half of the patients with pSS, both in minor and major SGs. Migration of a small number of B cells into the epithelium appears to be a critical initial step in LEL formation. These intra-epithelial B cells are proliferative, exhibit an innate-like phenotype, and may be linked to MALT lymphoma development. Alongside intra-epithelial B cells, the hyperplastic epithelial partner in LELs also engages in the local immune reaction. Epithelial cells are a source of cytokines and chemokines, with CXCL10 in particular playing a potential role in LEL formation. Importantly, LELs also have a negative impact on the maintenance of SG homeostasis by SG progenitor cell (SGPC) populations, likely due to dysregulation of SGPC lineage commitment or induction of plasticity. In conclusion, LEL formation mirrors a perfect storm of B and epithelial cell interaction culminating in increased risk of B cell derailment and SGPC dysregulation in pSS patients. We therefore argue that attenuation of LEL formation is an important treatment goal to preserve SG function and prevent B cell derailment in pSS.

Fatigue in primary Sjögren's syndrome is associated with an objective decline in physical performance, pain and depression.

OBJECTIVES: Fatigue is a major complaint in primary Sjögren's syndrome (pSS). To acquire a better understanding of fatigue in pSS, we investigated objective measures of performance decline (performance fatigability). Furthermore, we evaluated the relationship of self-reported fatigue with performance fatigability and factors modulating perceptions of fatigability (perceived fatigability). METHODS: Thirty-nine pSS patients and 27 healthy controls were included. To assess performance fatigability, force decline was measured during a sustained (124s) maximal voluntary contraction (MVC) with the index finger abductor muscle, and voluntary muscle activation was indexed using peripheral nerve stimulation. Self-reported fatigue was quantified using the Fatigue Severity Scale (FSS) and Modified Fatigue Impact Scale (MFIS). Pain, depression, and anxiety assessed using questionnaires and inflammatory biomarkers measured in blood were used as factors relating to perceived fatigability. RESULTS: Voluntary muscle activation was reduced in pSS (p=0.030), but force decline during the sustained MVC did not differ between groups. Self-reported fatigue was significantly higher in pSS than in controls (FSS: 4.4 vs. 2.6, p<0.001). Multivariable linear regression showed that both performance fatigability (force decline) and perceived fatigability (pain and depression) were associated with the MFIS physical domain in pSS (total explained variance of 47%). Negative associations with fatigue were observed for two interferon-associated proteins: MxA and CXCL10. CONCLUSIONS: This study demonstrates that performance fatigability in pSS was compromised by a reduced capacity of the central nervous system to drive the muscle. Furthermore, self-reported fatigue is a multifactorial symptom associated with both performance fatigability and perceived fatigability in patients with pSS.