Precision medicine in Sjögren's disease.

Sjögren's disease is a clinically and pathophysiologically heterogeneous disease to which precision medicine, on the basis of clinical and biological heterogeneity, has been not always applicable. In patients with Sjögren's disease, the relationship between dysregulated biological pathways and symptoms such as fatigue and pain or clinical manifestations is often difficult to establish. This clinical and biological dissociation also poses challenges when defining appropriate clinical endpoints for clinical trials. In the last few years, however, research efforts have been focused on gaining a better understanding of the considerable heterogeneity of Sjögren's disease by developing stratification models aimed at clustering patients with this condition into homogenous subgroups characterised by distinctive molecular signatures, biomarkers, clinical features, and outcomes. In this Review, we discuss current evidence regarding clinical, laboratory, histological, and biomolecular stratification in Sjögren's disease and examine how available stratification data can guide precision medicine and inform the design of future clinical trials.

CD8+ tissue-resident memory T cells are expanded in primary Sjögren's disease and can be therapeutically targeted by CD103 blockade.

OBJECTIVE: Tissue-resident memory cells (Trm) are a subset of T cells residing persistently and long-term within specific tissues that contribute to persistent inflammation and tissue damage. We characterised the phenotype and function of Trm and the role of CD103 in primary Sjogren's syndrome (pSS). METHODS: In both pSS and non-pSS sicca syndrome patients, we examined Trm frequency, cytokine production in salivary glands (SG) and peripheral blood (PB). We also analysed Trm-related gene expression in SG biopsies through bulk and single-cell RNA sequencing (scRNAseq). Additionally, we investigated Trm properties in an immunisation-induced animal model of pSS (experimental SS, ESS) mouse model and assessed the effects of Trm inhibition via intraglandular anti-CD103 monoclonal antibody administration. RESULTS: Transcriptomic pSS SG showed an upregulation of genes associated with tissue recruitment and long-term survival of Trm cells, confirmed by a higher frequency of CD8+CD103+CD69+ cells in pSS SG, compared with non-specific sialadenitis (nSS). In SG, CD8+ CD103+ Trm contributed to the secretion of granzyme-B and interferon-γ, CD8+ Trm cells were localised within inflammatory infiltrates, where PD1+CD8+ T cells were also increased compared with nSS and MALT lymphoma. scRNAseq of PB and pSS SG T cells confirmed expression of CD69, ITGAE, GZMB, GZMK and HLA-DRB1 among CD3+CD8+ SG T cells. In the SG of ESS, CD8+CD69+CD103+ Trm producing Granzyme B progressively expanded. However, intraglandular blockade of CD103 in ESS reduced Trm, reduced glandular damage and improved salivary flow. CONCLUSIONS: CD103+CD8+Trm cells are expanded in the SG of pSS and ESS, participate in tissue inflammation and can be therapeutically targeted.

The effect of anti-TNF drugs on the intestinal microbiota in patients with spondyloarthritis, rheumatoid arthritis, and inflammatory bowel diseases.

Spondyloarthritis (SpA), rheumatoid arthritis (RA), and inflammatory bowel diseases (IBD) are chronic inflammatory autoimmune diseases that are associated with alterations in the composition of the intestinal microbiota (i.e., dysbiosis). For SpA and RA, a gut-joint-enthesis axis is hypothesized and recent data suggests that dysbiosis may contribute directly to initiating and perpetuating joint and spine inflammation. Biologic drugs targeting tumor necrosis factor (TNF) are effective in treating these diseases and have been shown to partially restore the disrupted microbiome. Hence, drugs that affect both the intestinal and joint components of these diseases, such as anti-TNF drugs, may act on the intestinal microbiome. However, despite the remarkable efficacy of anti-TNF-α treatments, non-responders are frequent, and predictors of patient outcomes have not been identified. In this narrative review, we summarize recent research on the downstream effects of anti-TNF drugs on the intestinal microbiota in SpA, RA, and IBD. We also discuss whether these changes could have a role as predictive biomarkers of anti-TNF response.

The bone marrow side of axial spondyloarthritis.

Spondyloarthritis (SpA) is characterized by the infiltration of innate and adaptive immune cells into entheses and bone marrow. Molecular, cellular and imaging evidence demonstrates the presence of bone marrow inflammation, a hallmark of SpA. In the spine and the peripheral joints, bone marrow is critically involved in the pathogenesis of SpA. Evidence suggests that bone marrow inflammation is associated with enthesitis and that there are roles for mechano-inflammation and intestinal inflammation in bone marrow involvement in SpA. Specific cell types (including mesenchymal stem cells, innate lymphoid cells and γδ T cells) and mediators (Toll-like receptors and cytokines such as TNF, IL-17A, IL-22, IL-23, GM-CSF and TGFß) are involved in these processes. Using this evidence to demonstrate a bone marrow rather than an entheseal origin for SpA could change our understanding of the disease pathogenesis and the relevant therapeutic approach.

Seronegative rheumatoid arthritis: one year in review 2023.

In the past 20 years, earlier diagnosis and more intensive management have considerably improved the prognosis of rheumatoid arthritis (RA), with milder disease course achieved in particular in seropositive patients. In contrast, seronegative RA has remained largely neglected, and continues to be surrounded by uncertainties regarding its correct diagnosis, clinical phenotype, optimal treatment strategies and relevant outcomes.The purpose of this review is to summarise new insights about the pathogenic, clinical and prognostic peculiarities of seronegative RA that emerged during 2022, and that make this disease subset at least partially different from its seropositive counterpart.

Autoantibody-negative rheumatoid arthritis: still a challenge for the rheumatologist.

Increased research over the past 30 years has greatly improved the understanding of the pathophysiological mechanisms and clinical aspects of autoantibody-positive rheumatoid arthritis, resulting in improved management and outcomes. In contrast, the subset of rheumatoid arthritis that does not have autoantibodies (such as rheumatoid factor and anti-citrullinated protein autoantibodies) remains less well defined in its pathogenic mechanisms. Autoantibody-negative rheumatoid arthritis continues to pose diagnostic challenges, might respond differently to therapies, and appears to be burdened with different comorbidities and outcomes. The clear separation of rheumatoid arthritis according to serotypes is still a subject of uncertainty and controversy, and studies specifically focused on comparing rheumatoid arthritis and rheumatoid arthritis-like arthritides that do not have autoantibodies remain scarce. The purpose of this Review is to summarise the peculiarities that make autoantibody-negative rheumatoid arthritis different from its autoantibody-positive counterpart, with the aim of generating debate and stimulating further research on this challenging condition.

Will fecal microbiota transplantation eventually be an effective therapeutic strategy for systemic lupus erythematosus?

Gut microbiota dysbiosis serves as a potential trigger that may contribute to metabolic and immune dysregulation that underlies the development of autoimmune diseases. Fecal microbiota transplantation (FMT) is restoration of disturbed microbiota by transplanting foreign gut microbiota from healthy individuals into the gastrointestinal tract of diseased individuals. In this issue of the Journal of Autoimmunity, Huang et al. conducted a 12-week, single-arm pilot clinical trial of oral FMT capsules in patients with active SLE. No serious adverse events (AEs) or deaths were observed and the rate of the primary endpoint (SLE Responder Index-4) was 42.12%. Alternations in bacteria, metabolites and immune parameters were linked to FMT treatment and clinical response in SLE patients. This is the first FMT trial in SLE patients and provides supportive evidence that FMT appears to be a safe, feasible and potentially effective treatment modality in SLE. We await future investigations conducting larger, randomized FMT clinical trials with a longer follow-up to confirm the long-term safety, effectiveness, and potential benefits of FMT-based intervention in SLE and to further demonstrate the underlying microbiological mechanisms.

Addressing the clinical unmet needs in primary Sjögren's Syndrome through the sharing, harmonization and federated analysis of 21 European cohorts.

For many decades, the clinical unmet needs of primary Sjögren's Syndrome (pSS) have been left unresolved due to the rareness of the disease and the complexity of the underlying pathogenic mechanisms, including the pSS-associated lymphomagenesis process. Here, we present the HarmonicSS cloud-computing exemplar which offers beyond the state-of-the-art data analytics services to address the pSS clinical unmet needs, including the development of lymphoma classification models and the identification of biomarkers for lymphomagenesis. The users of the platform have been able to successfully interlink, curate, and harmonize 21 regional, national, and international European cohorts of 7,551 pSS patients with respect to the ethical and legal issues for data sharing. Federated AI algorithms were trained across the harmonized databases, with reduced execution time complexity, yielding robust lymphoma classification models with 85% accuracy, 81.25% sensitivity, 85.4% specificity along with 5 biomarkers for lymphoma development. To our knowledge, this is the first GDPR compliant platform that provides federated AI services to address the pSS clinical unmet needs.

JAK/STAT Pathway Targeting in Primary Sjögren Syndrome.

Primary Sjögren's syndrome (pSS) is an autoimmune systemic disease mainly affecting exocrine glands and resulting in disabling symptoms, as dry eye and dry mouth. Mechanisms underlying pSS pathogenesis are intricate, involving multiplanar and, at the same time, interlinked levels, e.g., genetic predisposition, epigenetic modifications and the dysregulation of both immune system and glandular-resident cellular pathways, mainly salivary gland epithelial cells. Unravelling the biological and molecular complexity of pSS is still a great challenge but much progress has been made in recent years in basic and translational research field, allowing the identification of potential novel targets for therapy development. Despite such promising novelties, however, none therapy has been specifically approved for pSS treatment until now. In recent years, growing evidence has supported the modulation of Janus kinases (JAK) - signal transducers and activators of transcription (STAT) pathways as treatment strategy immune mediated diseases. JAK-STAT pathway plays a crucial role in autoimmunity and systemic inflammation, being involved in signal pathways of many cytokines. This review aims to report the state-of-the-art about the role of JAK-STAT pathway in pSS, with particular focus on available research and clinical data regarding the use of JAK inhibitors in pSS.

Maladaptive Autophagy in the Pathogenesis of Autoimmune Epithelitis in Sjögren's Syndrome.

OBJECTIVE: Salivary gland epithelial cells (SGECs) are key cellular drivers in the pathogenesis of primary Sjögren's syndrome (SS); however, the mechanisms sustaining SGEC activation in primary SS remain unclear. We undertook this study to determine the role of autophagy in the survival and activation of SGECs in primary SS. METHODS: Primary SGECs isolated from the minor SGs of patients with primary SS or sicca syndrome were evaluated by flow cytometry, immunoblotting, and immunofluorescence to assess autophagy (autophagic flux, light chain 3 IIB [LC3-IIB], p62, LC3-IIB+/lysosome-associated membrane protein 1 [LAMP-1] staining), apoptosis (annexin V/propidium iodide [PI], caspase 3), and activation (intercellular adhesion molecule, vascular cell adhesion molecule). Focus score and germinal center presence were assessed in the SGs from the same patients to assess correlation with histologic severity. Human SG (HSG) cells were stimulated in vitro with peripheral blood mononuclear cells (PBMCs) and serum from primary SS patients in the presence or absence of autophagy inhibitors to determine changes in autophagy and epithelial cell activation. RESULTS: SGECs from primary SS patients (n = 24) exhibited increased autophagy (autophagic flux [P = 0.001]; LC3-IIB [P = 0.02]; p62 [P = 0.064]; and as indicated by LC3-IIB/LAMP-1+ staining), increased expression of antiapoptotic molecules (Bcl-2 [P = 0.006]), and reduced apoptosis (annexin V/PI [P = 0.002]; caspase 3 [P = 0.057]), compared to samples from patients with sicca syndrome (n = 16). Autophagy correlated with histologic disease severity. In vitro experiments on HSG cells stimulated with serum and PBMCs from primary SS patients confirmed activation of autophagy and expression of adhesion molecules, which was reverted upon pharmacologic inhibition of autophagy. CONCLUSION: In primary SS SGECs, inflammation induces autophagy and prosurvival mechanisms, which promote SGEC activation and mirror histologic severity. These findings indicate that autophagy is a central contributor to the pathogenesis of primary SS and a new therapeutic target.

A federated AI strategy for the classification of patients with Mucosa Associated Lymphoma Tissue (MALT) lymphoma across multiple harmonized cohorts.

Mucosa Associated Lymphoma Tissue (MALT) type is an extremely rare type of lymphoma which occurs in less than 3% of patients with primary Sjögren's Syndrome (pSS). No reported studies so far have been able to investigate risk factors for MALT development across multiple cohort databases with sufficient statistical power. Here, we present a generalized, federated AI (artificial intelligence) strategy which enables the training of AI algorithms across multiple harmonized databases. A case study is conducted towards the development of MALT classification models across 17 databases on pSS. Advanced AI algorithms were developed, including federated Multinomial Naïve Bayes (FMNB), federated gradient boosting trees (FGBT), FGBT with dropouts (FDART), and the federated Multilayer Perceptron (FMLP). The FDART with dropout rate 0.3 achieved the best performance with sensitivity 0.812, and specificity 0.829, yielding 8 biomarkers as prominent for MALT development.

Shared Pathogenetic Features Between Common Variable Immunodeficiency and Sjögren's Syndrome: Clues for a Personalized Medicine.

Common variable immunodeficiency disorders (CVID) are a group of rare diseases of the immune system and the most common symptomatic primary antibody deficiency in adults. The "variable" aspect of CVID refers to the approximately half of the patients who develop non-infective complications, mainly autoimmune features, in particular organ specific autoimmune diseases including thyroiditis, and cytopenias. Among these associated conditions, the incidence of lymphoma, including mucosal associated lymphoid tissue (MALT) type, is increased. Although these associated autoimmune disorders in CVID are generally attributed to Systemic Lupus Erythematosus (SLE), we propose that Sjogren's syndrome (SS) is perhaps a better candidate for the associated disease. SS is an autoimmune disorder characterized by the lymphocytic infiltrates of lacrimal and salivary glands, leading to dryness of the eyes and mouth. Thus, it is a lymphocyte aggressive disorder, in contrast to SLE where pathology is generally attributed to auto-antibody and complement activation. Although systemic lupus erythematosus (SLE) shares these features with SS, a much higher frequency of MALT lymphoma distinguishes SS from SLE. Also, the higher frequency of germ line encoded paraproteins such as the monoclonal rheumatoid factor found in SS patients would be more consistent with the failure of B-cell VDJ switching found in CVID; and in contrast to the hypermutation that characterizes SLE autoantibodies. Thus, we suggest that SS may fit as a better "autoimmune" association with CVID. Examining the common underlying biologic mechanisms that promote lymphoid infiltration by dysregulated lymphocytes and lymphoma in CVID may provide new avenues for treatment in both the diseases. Since the diagnosis of SLE or rheumatoid arthritis is usually based on specific autoantibodies, the associated autoimmune features of CVID patients may not be recognized in the absence of autoantibodies.

A biomarker for lymphoma development in Sjogren's syndrome: Salivary gland focus score.

The aim of this study is to explore the role of labial minor salivary gland (LMSG) focus score (FS) in stratifying Sjögren's Syndrome (SS) patients, lymphoma development prediction and to facilitate early lymphoma diagnosis. Ιn an integrated cohort of 1997 patients, 618 patients with FS ≥ 1 and at least one-year elapsing time interval from SS diagnosis to lymphoma diagnosis or last follow up were identified. Clinical, laboratory and serological features were recorded. A data driven logistic regression model was applied to identify independent lymphoma associated risk factors. Furthermore, a FS threshold maximizing the difference of time interval from SS until lymphoma diagnosis between high and low FS lymphoma subgroups was investigated, to develop a follow up strategy for early lymphoma diagnosis. Of the 618 patients, 560 were non-lymphoma SS patients while the other 58 had SS and lymphoma. FS, cryoglobulinemia and salivary gland enlargement (SGE) were proven to be independent lymphoma associated risk factors. Lymphoma patients with FS ≥ 4 had a statistically significant shorter time interval from SS to lymphoma diagnosis, compared to those with FS < 4 (4 vs 9 years, respectively, p = 0,008). SS patients with FS ≥ 4 had more frequently B cell originated manifestations and lymphoma, while in patients with FS < 4, autoimmune thyroiditis was more prevalent. In the latter group SGE was the only lymphoma independent risk factor. A second LMSG biopsy is patients with a FS ≥ 4, 4 years after SS diagnosis and in those with FS < 4 and a history of SGE, at 9-years, may contribute to an early lymphoma diagnosis. Based on our results we conclude that LMSG FS, evaluated at the time of SS diagnosis, is an independent lymphoma associated risk factor and may serve as a predictive biomarker for the early diagnosis of SS-associated lymphomas.

Ultrasound and Bioptic Investigation of Patients with Primary Sjögren's Syndrome.

Primary Sjögren's syndrome (pSS) is a chronic and heterogeneous disorder characterized by a wide spectrum of glandular and extra-glandular features. The hallmark of pSS is considered to be the immune-mediated involvement of the exocrine glands and B-cell hyperactivation. This leads pSS patients to an increased risk of developing lymphoproliferative diseases, and persistent (>2 months) major salivary gland enlargement is a well-known clinical sign of possible involvement by B cell lymphoma. Better stratification of the patients may improve understanding of the mechanism underlying the risk of lymphoproliferative disorder. Here, we summarize the role of different imaging techniques and a bioptic approach in pSS patients, focusing mainly on the role of salivary gland ultrasonography (SGUS) and a US-guided core needle biopsy (Us-guided CNB) as diagnostic and prognostic tools in pSS patients with persistent parotid swelling.

Peripheral Nervous System Involvement in Sjögren's Syndrome: Analysis of a Cohort From the Italian Research Group on Sjögren's Syndrome.

Purpose: The prevalence of peripheral nervous system (PNS) involvement in primary Sjögren's syndrome (pSS) has been reported to range from 2% to over 50%. Bias in study designs, including low number of patients and unclearly defined rheumatological and neurological diagnosis could explain such variability. Consequently, the exact depiction of PNS involvement in pSS is still lacking. This study aimed at analyzing the prevalence and the clinical and laboratory factors associated with PNS involvement in a very large cohort of well-characterized pSS patients with a clearly defined neurological diagnosis. Methods: Clinical and serological data of 1,695 pSS patients with specific and accurate information on PNS involvement were analyzed. Comparisons between patients with and without PNS involvement and between patients with distinct subsets of PNS manifestations were performed. Results: Prevalence of PNS involvement was 3.7%. The most frequent types observed were pure sensory neuropathies and axonal sensorimotor polyneuropathies (SMP). Patients with PNS involvement exhibited a more active disease profile and were more frequently treated with immunosuppressants. Intriguingly, clinical and serological negative prognostic factors, including purpura, extra-glandular manifestations, leukopenia, low complement and cryoglobulinemia, principally characterized patients with SMP, while subjects with pure sensory neuropathy displayed a milder phenotype. Conclusion: Our results highlight that PNS involvement is rather rare, but prognostically relevant in pSS. Main adverse prognostic features characterize patients with SMP, while pure sensory neuropathies are usually associated with a mild clinical picture. These findings, useful for patient stratification, may suggest protean pathogenic pathways underlying different types of PNS manifestations in pSS.

Childhood-onset of primary Sjögren's syndrome: phenotypic characterization at diagnosis of 158 children.

OBJECTIVES: To characterize the phenotypic presentation at diagnosis of childhood-onset primary SS. METHODS: The Big Data Sjögren Project Consortium is an international, multicentre registry using worldwide data-sharing cooperative merging of pre-existing clinical SS databases from the five continents. For this study, we selected those patients in whom the disease was diagnosed below the age of 19 years according to the fulfilment of the 2002/2016 classification criteria. RESULTS: Among the 12 083 patients included in the Sjögren Big Data Registry, 158 (1.3%) patients had a childhood-onset diagnosis (136 girls, mean age of 14.2 years): 126 (80%) reported dry mouth, 111 (70%) dry eyes, 52 (33%) parotid enlargement, 118/122 (97%) positive minor salivary gland biopsy and 60/64 (94%) abnormal salivary US study, 140/155 (90%) positive ANA, 138/156 (89%) anti-Ro/La antibodies and 86/142 (68%) positive RF. The systemic EULAR Sjögren's syndrome disease activity index (ESSDAI) domains containing the highest frequencies of active patients included the glandular (47%), articular (26%) and lymphadenopathy (25%) domains. Patients with childhood-onset primary SS showed the highest mean ESSDAI score and the highest frequencies of systemic disease in 5 (constitutional, lymphadenopathy, glandular, cutaneous and haematological) of the 12 ESSDAI domains, and the lowest frequencies in 4 (articular, pulmonary, peripheral nerve and CNS) in comparison with patients with adult-onset disease. CONCLUSIONS: Childhood-onset primary SS involves around 1% of patients with primary SS, with a clinical phenotype dominated by sicca features, parotid enlargement and systemic disease. Age at diagnosis plays a key role in modulating the phenotypic expression of the disease.

Primary Sjögren's Syndrome of Early and Late Onset: Distinct Clinical Phenotypes and Lymphoma Development.

Objectives: To study the clinical, serological and histologic features of primary Sjögren's syndrome (pSS) patients with early (young ≤35 years) or late (old ≥65 years) onset and to explore the differential effect on lymphoma development. Methods: From a multicentre study population of 1997 consecutive pSS patients, those with early or late disease onset, were matched and compared with pSS control patients of middle age onset. Data driven analysis was applied to identify the independent variables associated with lymphoma in both age groups. Results: Young pSS patients (19%, n = 379) had higher frequency of salivary gland enlargement (SGE, lymphadenopathy, Raynaud's phenomenon, autoantibodies, C4 hypocomplementemia, hypergammaglobulinemia, leukopenia, and lymphoma (10.3% vs. 5.7%, p = 0.030, OR = 1.91, 95% CI: 1.11-3.27), while old pSS patients (15%, n = 293) had more frequently dry mouth, interstitial lung disease, and lymphoma (6.8% vs. 2.1%, p = 0.011, OR = 3.40, 95% CI: 1.34-8.17) compared to their middle-aged pSS controls, respectively. In young pSS patients, cryoglobulinemia, C4 hypocomplementemia, lymphadenopathy, and SGE were identified as independent lymphoma associated factors, as opposed to old pSS patients in whom SGE, C4 hypocomplementemia and male gender were the independent lymphoma associated factors. Early onset pSS patients displayed two incidence peaks of lymphoma within 3 years of onset and after 10 years, while in late onset pSS patients, lymphoma occurred within the first 6 years. Conclusion: Patients with early and late disease onset constitute a significant proportion of pSS population with distinct clinical phenotypes. They possess a higher prevalence of lymphoma, with different predisposing factors and lymphoma distribution across time.

Systemic phenotype related to primary Sjögren's syndrome in 279 patients carrying isolated anti-La/SSB antibodies.

OBJECTIVES: To evaluate the systemic phenotype associated with the presence of isolated anti-La/SSB antibodies in a large international registry of patients with primary Sjögren's syndrome (pSS) fulfilling the 2002 classification criteria. METHODS: The Big Data Sjögren Project Consortium is an international, multicentre registry created in 2014. Baseline clinical information from leading centres on clinical research in SS of the 5 continents was collected. Combination patterns of anti-Ro/SSA-La/SSB antibodies at the time of diagnosis defined the following four immunological phenotypes: double positive (combined Ro/SSA and La/SSB,) isolated anti-Ro/SSA, isolated anti-La/SSB, and immunonegative. RESULTS: The cohort included 12,084 patients (11,293 females, mean 52.4 years) with recorded ESSDAI scores available. Among them, 279 (2.3%) had isolated anti-La/SSB antibodies. The mean total ESSDAI score at diagnosis of patients with pSS carrying isolated anti-La/SSB was 6.0, and 80.4% of patients had systemic activity (global ESSDAI score ≥1) at diagnosis. The domains with the highest frequency of active patients were the biological (42.8%), glandular (36.8%) and articular (31.2%) domains. Patients with isolated anti-La/SSB showed a higher frequency of active patients in all ESSDAI domains but two (articular and peripheral nerve) in comparison with immune-negative patients, and even a higher absolute frequency in six clinical ESSDAI domains in comparison with patients with isolated anti-Ro/SSA. In addition, patients with isolated anti-La/SSB showed a higher frequency of active patients in two ESSDAI domains (pulmonary and glandular) with respect to the most active immunological subset (double-positive antibodies). Meanwhile, systemic activity detected in patients with isolated anti-La/SSB was overwhelmingly low. Even in ESSDAI domains where patients with isolated anti-La/SSB had the highest frequencies of systemic activity (lymphadenopathy and muscular), the percentage of patients with moderate or high activity was lower in comparison with the combined Ro/SSA and La/SSB group. CONCLUSIONS: Patients carrying isolated La/SSB antibodies represent a very small subset of patients with a systemic SS phenotype characterised by a significant frequency of active patients in most clinical ESSDAI domains but with a relative low frequency of the highest severe organ-specific involvements. Primary SS still remains the best clinical diagnosis for this subset of patients.

Validation of thymic stromal lymphopoietin as a biomarker of primary Sjögren's syndrome and related lymphoproliferation: results in independent cohorts.

OBJECTIVES: Thymic stromal lymphopoietin (TSLP) has been implicated in primary Sjögren's syndrome (pSS) and related B-cell lymphoproliferation and lymphoma (NHL) by studies on salivary pathologic tissues and serum. The purpose of this work was to validate serum TSLP as biomarker of pSS and related lymphoproliferation by the study of two additional independent cohorts. METHODS: Serum TSLP was measured by ELISA in the original published Cohort-1 from Udine, Italy, including 91 patients. Two additional cohorts were then studied for validation: Cohort-2, including 4 sub-cohorts comprising 125 patients from the Universities of Roma, L'Aquila, Pisa and Perugia, belonging to the Italian SS Study Group (GRISS), and Cohort-3, including 59 patients from the University of Athens, Greece. Overall, 159 control subjects were enrolled. Active pSS-NHL, as well as pre-lymphomatous conditions, i.e. persistent salivary gland swelling and mixed cryoglobulinaemia, were investigated in detail. In addition, serum samples from pSS-NHL in complete remission were analysed (n=27). RESULTS: TSLP serum levels were confirmed to be significantly higher in pSS compared to controls in both Cohort-2 and Cohort-3, in particular in patients with lymphoproliferation. Serum TSLP was much higher in pSS pre-lymphomatous conditions. Finally, active NHL showed the highest TSLP serum levels, while in NHL in remission TSLP resulted undetectable or significantly lower than in benign pSS. CONCLUSIONS: By the study of independent cohorts, it was again demonstrated that serum TSLP levels are increased in pSS, above all in more advanced B-cell lymphoproliferation and NHL. Serum TSLP can therefore represent a novel biomarker for pSS-related lymphoproliferation.

Sjögren's Syndrome: The Clinical Spectrum of Male Patients.

BACKGROUND: To compare the clinical, serological and histologic features between male and female patients with Sjögren's syndrome (SS) and explore the potential effect of gender on lymphoma development. METHODS: From a multicenter population (Universities of Udine, Pisa and Athens, Harokopion and Ioannina (UPAHI)) consisting of consecutive SS patients fulfilling the 2016 ACR/EULAR criteria, male patients were identified, matched and compared with female controls. Data-driven multivariable logistic regression analysis was applied to identify independent lymphoma-associated factors. RESULTS: From 1987 consecutive SS patients, 96 males and 192 matched female controls were identified and compared. Males had a higher frequency of lymphoma compared to females (18% vs. 5.2%, OR = 3.89, 95% CI: 1.66 to 8.67; p = 0.0014) and an increased prevalence of serum anti-La/SSB antibodies (50% vs. 34%, OR = 1.953, 95% CI: 1.19 to 3.25; p = 0.0128). No differences were observed in the frequencies of lymphoma predictors between the two genders. Data-driven multivariable logistic regression analysis revealed negative association of the female gender with lymphoma and positive association with lymphadenopathy. CONCLUSION: Male SS patients carry an increased risk of lymphoma development. Although statistics showed no difference in classical lymphoma predictors compared to females, data-driven analysis revealed gender and lymphadenopathy as independent lymphoma-associated features.