Identification of distinct subgroups of Sjögren's disease by cluster analysis based on clinical and biological manifestations: data from the cross-sectional Paris-Saclay and the prospective ASSESS cohorts.

BACKGROUND: Sjögren's disease is a heterogenous autoimmune disease with a wide range of symptoms-including dryness, fatigue, and pain-in addition to systemic manifestations and an increased risk of lymphoma. We aimed to identify distinct subgroups of the disease, using cluster analysis based on subjective symptoms and clinical and biological manifestations, and to compare the prognoses of patients in these subgroups. METHODS: This study included patients with Sjögren's disease from two independent cohorts in France: the cross-sectional Paris-Saclay cohort and the prospective Assessment of Systemic Signs and Evolution of Sjögren's Syndrome (ASSESS) cohort. We first used an unsupervised multiple correspondence analysis to identify clusters within the Paris-Saclay cohort using 26 variables comprising patient-reported symptoms and clinical and biological manifestations. Next, we validated these clusters using patients from the ASSESS cohort. Changes in disease activity (measured by the European Alliance of Associations for Rheumatology [EULAR] Sjögren's Syndrome Disease Activity Index [ESSDAI]), patient-acceptable symptom state (measured by the EULAR Sjögren's Syndrome Patient Reported Index [ESSPRI]), and lymphoma incidence during follow-up were compared between clusters. Finally, we compared our clusters with the symptom-based subgroups previously described by Tarn and colleagues. FINDINGS: 534 patients from the Paris-Saclay cohort (502 [94%] women, 32 [6%] men, median age 54 years [IQR 43-64]), recruited between 1999 and 2022, and 395 patients from the ASSESS cohort (370 [94%] women, 25 [6%] men, median age 53 years [43-63]), recruited between 2006 and 2009, were included in this study. In both cohorts, hierarchical cluster analysis revealed three distinct subgroups of patients: those with B-cell active disease and low symptom burden (BALS), those with high systemic disease activity (HSA), and those with low systemic disease activity and high symptom burden (LSAHS). During follow-up in the ASSESS cohort, disease activity and symptom states worsened for patients in the BALS cluster (67 [36%] of 186 patients with ESSPRI score <5 at month 60 vs 92 [49%] of 186 at inclusion; p<0·0001). Lymphomas occurred in patients in the BALS cluster (five [3%] of 186 patients; diagnosed a median of 70 months [IQR 42-104] after inclusion) and the HSA cluster (six [4%] of 158 patients; diagnosed 23 months [13-83] after inclusion). All patients from the Paris-Saclay cohort with a history of lymphoma were in the BALS and HSA clusters. This unsupervised clustering classification based on symptoms and clinical and biological manifestations did not correlate with a previous classification based on symptoms only. INTERPRETATION: On the basis of symptoms and clinical and biological manifestations, we identified three distinct subgroups of patients with Sjögren's disease with different prognoses. Our results suggest that these subgroups represent different heterogeneous pathophysiological disease mechanisms, stages of disease, or both. These findings could be of interest when stratifying patients in future therapeutic trials. FUNDING: Fondation pour la Recherche Médicale, French Ministry of Health, French Society of Rheumatology, Innovative Medicines Initiative 2 Joint Undertaking, Medical Research Council UK, and Foundation for Research in Rheumatology.

Comparison between primary Sjögren's disease patients with high or low level of dryness.

OBJECTIVES: To describe primary Sjögren's disease (SjD) patients presenting no or low level of dryness and to compare them with SjD patients with oral or ocular dryness features. METHODS: All patients diagnosed with SjD according to AECG or ACR/EULAR criteria in our tertiary reference centre were included. Patients with high or low subjective symptoms or objective signs of dryness were compared. RESULTS: Overall, 509 patients were included for the comparison of patients with high (n=456) or low (n=53) level of subjective dryness and 472 for the comparison of patients with (n=359) or without (n=113) high objective dryness. Compared with patients with subjective dryness, patients without high subjective dryness were significantly younger (median 49 (39-62) years vs 58 (47-67) years, p<0.01), diagnosed earlier (median time from first symptoms to diagnosis 2 (0.5-4.5) years vs 4 (1-9.25), p=0.0056), more frequently anti-SSA positive ((83% vs 64%, p=0.008) and had less focal sialadenitis in minor salivary gland biopsy (69% vs 83%, p=0.02).The patients without high level of objective dryness (n=113) were also younger (51 (41-60) vs 58 (47-67) years, p<0.001) and were more frequently anti-SSA positive (79% vs 63%, p=0.002).In both groups, no difference was observed regarding disease activity. CONCLUSIONS: Among the patients with SjD, those without high subjective or objective dryness features had a younger profile, a faster diagnosis which may result from a more acute onset, were more frequently anti-SSA positive than patients with high dryness features.

Associations between ocular and extra-ocular assessment in primary Sjögren's syndrome.

OBJECTIVES: To assess associations between ophthalmological features and the main systemic biomarkers of primary Sjögren's Syndrome (pSS), and to identify systemic biomarkers associated with severe keratoconjunctivitis sicca (KCS) in pSS patients. METHODS: In this cross-sectional study, data was retrospectively extracted from the monocentric cohort of the French reference centre for pSS. We analysed data from the initial visit of patients admitted for suspicion of pSS and included patients validating pSS ACR/EULAR classification criteria. Ophthalmological assessment included Schirmer's test, tear break-up time, ocular staining score (OSS), and visual analogue scale (DED-VAS) for dry eye disease (DED) symptoms. Results of minor salivary gland biopsy, unstimulated whole salivary flow rate, anti-SSA/Ro antibodies, anti-SSB/La antibodies, and rheumatoid factor (RF) were collected. RESULTS: A total of 253 patients (245 females) with confirmed pSS, aged 56.6±13.0 years, were included, among which 37% had severe KCS. Multivariate analysis showed that the presence of anti-SSA/Ro antibodies, anti-SSB/La antibodies and RF were associated with conjunctival OSS (odds ratio-OR-=1.25 per OSS unit increase; confidence interval-CI-95%=1.05-1.49; P=0.01; OR=1.31 per OSS unit increase; CI95%=1.09-1.58, P=0.002, and OR=1.34 per OSS unit increase; CI95%=1.12-1.59; P=0.001, respectively). Both anti-SSB/La antibodies and DED-VAS ≥ 5 were significantly associated with severe KCS (OR=2.03; CI95%=1.03-4.00; P<0.05 and OR=2.52, CI95%=1.31-4.90; P<0.01, respectively). CONCLUSION: Association between conjunctival OSS and systemic biomarkers of pSS indicate the crucial importance of conjunctival staining when pSS is suspected as a cause of DED. Conversely, patients with anti-SSB and DED-VAS ≥ 5 features should be prioritized for extensive evaluation by an ophthalmologist due to their association with severe KCS.

Brief Report: Monoclonal Gammopathy and Risk of Lymphoma and Multiple Myeloma in Patients With Primary Sjögren's Syndrome.

OBJECTIVE: To assess the link between monoclonal gammopathy (MG), disease activity, and incidence of malignant hematologic disorders (MHDs), including lymphoma and multiple myeloma (MM), in patients with primary Sjögren's syndrome (SS). METHODS: Screening for the presence of MG was performed in 352 primary SS patients. Each patient with MG was paired with 2 age- and sex-matched primary SS controls without MG. Their characteristics were compared for the presence of risk factors for MG and for the relationship between MG and MHD. RESULTS: Twenty-six of the 352 primary SS patients (7.4%) had MG; 88% were women, with a median age of 62.7 years (interquartile range [IQR] 50.3-69.1 years) and a median disease duration of 7.8 years (IQR 3.6-12.8 years). The parameters associated with MG on multivariate analysis were higher disease activity, as measured by either the European League Against Rheumatism Sjögren's Syndrome Disease Activity Index (ESSDAI; adjusted odds ratio [OR] 9.7, P = 0.0002) or the Clinical ESSDAI (adjusted OR 6.7, P = 0.001), and low C4 level (adjusted OR 3.4, P = 0.04). After a median follow-up of 6.3 years (IQR 3.1-9.5 years), 10 patients with MG had developed an MHD (38.5%; 4 had lymphomas and 6 had MM), as compared with 4 patients in the control group (7.7%; all had lymphomas) (OR 7.5, P = 0.002). The only factor associated with the risk of MHDs was the presence of MG (adjusted OR 5.5, P = 0.02), which was principally associated with an increased risk of MM (23% versus 0%; P = 0.0009), but not lymphoma (15% versus 8%; P = 0.3). CONCLUSION: The presence of MG was associated with higher disease activity and an increased risk of MHD in primary SS. In the presence of MG, the risk of MM was even higher than the risk of lymphoma. These results suggest that regular monitoring of primary SS patients with MG for the emergence of both lymphoma and MM is necessary.

Low numbers of blood and salivary natural killer cells are associated with a better response to belimumab in primary Sjögren's syndrome: results of the BELISS study.

INTRODUCTION: In this study, we sought to address changes in blood lymphocyte subpopulations and labial salivary gland (LSG) inflammation after belimumab treatment in patients with primary Sjögren's syndrome (pSS) and to identify predictors of response to treatment. METHODS: Sequential blood lymphocyte subsets and LSG biopsies were analysed between week 0 (W0) and W28 in 15 patients with pSS treated with belimumab. Systemic response to treatment was defined as a decrease in the European League Against Rheumatism Sjögren's Syndrome Disease Activity Index score of ≥3 points at W28. RESULTS: After belimumab, we observed a decrease in blood B lymphocytes primarily involving CD27-negative/immunoglobulin D-positive naïve B cells (p=0.008). Lymphocytic sialadenitis (focus score >1) that was present in 12 patients (80.0 %) before belimumab treatment became negative in 5 of them after treatment (p=0.03). The median (interquartile range) LSG B-cell/T-cell ratio decreased from 0.58 (0.5-0.67) to 0.50 (0.5-0.5) (p=0.06). B-cell activating factor (BAFF) staining was detected in 11 (78.6 %) of 14 patients before belimumab treatment compared with 7 (50.0 %) of 14 after belimumab therapy (p=0.10). The median percentage of BAFF-positive cells in foci significantly decreased from 27.5 % (10-40) to 5 % (0-20) (p=0.03). A systemic response was achieved in six patients (40 %). The only predictor of response was the presence of a low number of natural killer (NK) cells, both in blood (8.5 % [7-10] vs 11 % [9-21]; p=0.04) and in LSG (20.6/mm(3) [20.0-21.4] vs 30.0/mm(3) [25.0-100.0], p=0.003). Serum BAFF levels did not influence response to treatment. CONCLUSIONS: Low blood and salivary NK cell numbers are associated with a better response to belimumab. This suggests that two distinct subsets of pSS may exist: one with a predominant type I interferon (IFN)-BAFF-B-cell axis, representing good responders to belimumab; and one with a predominant type II IFN-NK cell axis, representing non-responders. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01160666 . Registered 9 July 2010.

Efficacy and safety of belimumab in primary Sjögren's syndrome: results of the BELISS open-label phase II study.

BACKGROUND: Increased expression of B cell activating factor (BAFF or B lymphocyte stimulator) may explain the B cell activation characteristic of primary Sjögren's syndrome (pSS). OBJECTIVES: To evaluate the efficacy and safety of belimumab, targeting BAFF, in patients with pSS. METHODS: Patients were included in this bi-centric prospective 1-year open-label trial if they fulfilled American European Consensus group criteria, were anti-Sjögren's syndrome A-positive and had current systemic complications or salivary gland enlargement, or early disease (<5 years), or biomarkers of B cell activation. They received belimumab, 10 mg/kg, at weeks 0, 2 and 4 and then every 4 weeks to week 24. The primary end-point, assessed at week 28, was improvement in two of five items: reduction in ≥30% in dryness score on a visual analogue scale (VAS), ≥30% in fatigue VAS score, ≥30% in VAS pain score, ≥30% in systemic activity VAS assessed by the physician and/or >25% improvement in any B cell activation biomarker values. RESULTS: Among 30 patients included, the primary end-point was achieved in 18 (60%). The mean (SD) European League Against Rheumatism (EULAR) Sjögren's Syndrome Disease Activity Index decreased from 8.8 (7.4) to 6.3 (6.6) (p=0.0015) and EULAR) Sjögren's Syndrome Patient Reported Index from 6.4 (1.1) to 5.6 (2.0) (p=0.0174). The mean dryness, fatigue and pain VAS varied from 7.8 (1.8) to 6.2 (2.9) (p=0.0021), 6.9 (1.8) to 6.0 (2.2) (p=0.0606) and 4.6 (2.6) to 4.7 (2.4) (p=0.89), respectively. Salivary flow and Schirmer's test did not change. CONCLUSIONS: These encouraging results justify future randomised controlled trials of belimumab in a selected target population of pSS patients most likely to benefit from treatment.

Anticentromere antibodies identify patients with Sjögren's syndrome and autoimmune overlap syndrome.

OBJECTIVE: To assess the prevalence and clinical and immunological significance of anticentromere antibodies (ACA) in patients with primary Sjögren's syndrome (pSS). METHODS: We retrospectively investigated the prevalence of ACA in patients with SS. We compared ACA-positive SS patients with ACA-negative pSS patients. RESULTS: The prevalence of ACA among patients with pSS was 4.7% (10/212). Among the patients with SS and an associated autoimmune disease, 10 patients had ACA and limited cutaneous sclerosis (SSc). Clinical and immunological patterns did not differ between the 10 pSS patients with ACA alone and the 10 SS patients with ACA and SSc, except for presence of limited cutaneous SSc (lcSSc). Moreover, all ACA-positive sera recognized centromere protein-B on ELISA, regardless of the presence of SSc. The entire SS-ACA group (n = 20) showed greater frequency of Raynaud's phenomenon, objective xerophthalmia, peripheral neuropathy, and additional autoimmune disorders, especially primary biliary cirrhosis, compared to pSS patients without ACA (p = 0.005, p = 0.04, p = 0.001, p = 0.05, p < 0.0001, respectively). SS patients with ACA less frequently showed anti-SSA or anti-SSB antibodies than those without ACA (p = 0.0002, p = 0.01, respectively) but greater prevalence of autoantibodies other than anti-SSA/SSB or ACA (p = 0.001). CONCLUSION: Clinical and immunological features of SS were largely similar among SS patients with ACA with and without SSc. However, the presence of ACA among patients with SS allows identification of a subset of patients with "SS overlap syndrome," who show a wide diversity of autoimmunity, encompassing but not limited to SSc.