Mortality risk factors in primary Sjögren syndrome: a real-world, retrospective, cohort study.

Background: What baseline predictors would be involved in mortality in people with primary Sjögren syndrome (SjS) remains uncertain. This study aimed to investigate the baseline characteristics collected at the time of diagnosis of SjS associated with mortality and to identify mortality risk factors for all-cause death and deaths related to systemic SjS activity measured by the ESSDAI score. Methods: In this international, real-world, retrospective, cohort study, we retrospectively collected data from 27 countries on mortality and causes of death from the Big Data Sjögren Registry. Inclusion criteria consisted of fulfilling 2002/2016 SjS classification criteria, and exclusion criteria included chronic HCV/HIV infections and associated systemic autoimmune diseases. A statistical approach based on a directed acyclic graph was used, with all-cause and Sjögren-related mortality as primary endpoints. The key determinants that defined the disease phenotype at diagnosis (glandular, systemic, and immunological) were analysed as independent variables. Findings: Between January 1st, 2014 and December 31, 2023, data from 11,372 patients with primary SjS (93.5% women, 78.4% classified as White, mean age at diagnosis of 51.1 years) included in the Registry were analysed. 876 (7.7%) deaths were recorded after a mean follow-up of 8.6 years (SD 7.12). Univariate analysis of prognostic factors for all-cause death identified eight Sjögren-related variables (ocular and oral tests, salivary biopsy, ESSDAI, ANA, anti-Ro, anti-La, and cryoglobulins). The multivariate CPH model adjusted for these variables and the epidemiological features showed that DAS-ESSDAI (high vs no high: HR = 1.68; 95% CI, 1.27-2.22) and cryoglobulins (positive vs negative: HR = 1.72; 95% CI, 1.22-2.42) were independent predictors of all-cause death. Of the 640 deaths with available information detailing the specific cause of death, 14% were due to systemic SjS. Univariate analysis of prognostic factors for Sjögren-cause death identified five Sjögren-related variables (oral tests, clinESSDAI, DAS-ESSDAI, ANA, and cryoglobulins). The multivariate competing risks CPH model adjusted for these variables and the epidemiological features showed that oral tests (abnormal vs normal results: HR = 1.38; 95% CI, 1.01-1.87), DAS-ESSDAI (high vs no high: HR = 1.55; 95% CI, 1.22-1.96) and cryoglobulins (positive vs negative: HR = 1.52; 95% CI, 1.16-2) were independent predictors of SjS-related death. Interpretation: The key mortality risk factors at the time of SjS diagnosis were positive cryoglobulins and a high systemic activity scored using the ESSDAI, conferring a 2-times increased risk of all-cause and SjS-related death. ESSDAI measurement and cryoglobulin testing should be considered mandatory when an individual is diagnosed with SjS. Funding: Novartis.

Characterization and outcomes of 414 patients with primary SS who developed haematological malignancies.

OBJECTIVE: To characterize 414 patients with primary SS who developed haematological malignancies and to analyse how the main SS- and lymphoma-related features can modify the presentation patterns and outcomes. METHODS: By January 2021, the Big Data Sjögren Project Consortium database included 11 966 patients fulfilling the 2002/2016 classification criteria. Haematological malignancies diagnosed according to the World Health Organization (WHO) classification were retrospectively identified. RESULTS: There were 414 patients (355 women, mean age 57 years) with haematological malignancies (in 43, malignancy preceded at least one year the SS diagnosis). A total of 376 (91%) patients had mature B-cell malignancy, nearly half had extranodal marginal zone lymphoma (MZL) of mucosa-associated lymphoid tissue (MALT lymphoma) (n = 197), followed by diffuse large B-cell lymphoma (DLBCL) (n = 67), nodal MZL lymphoma (n = 29), chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) (n = 19) and follicular lymphoma (FL) (n = 17). Rates of complete response, relapses and death were 80%, 34% and 13%, respectively, with a 5-year survival rate of 86.5% after a mean follow-up of 8 years. There were significant differences in age at diagnosis (younger in MALT, older in CLL/SLL), predominant clinical presentation (glandular enlargement in MALT lymphoma, peripheral lymphadenopathy in nodal MZL and FL, constitutional symptoms in DLBCL, incidental diagnosis in CLL/SLL), therapeutic response (higher in MALT lymphoma, lower in DLBCL) and survival (better in MALT, nodal MZL and FL, worse in DLBCL). CONCLUSION: In the largest reported study of haematological malignancies complicating primary SS, we confirm the overwhelming predominance of B-cell lymphomas, especially MALT, with the salivary glands being the primary site of involvement. This highly-specific histopathological scenario is linked with the overall good prognosis with a 5-year survival rate of nearly 90%.

The Imbalance of Circulating Follicular T Helper Cell Subsets in Primary Sjögren's Syndrome Associates With Serological Alterations and Abnormal B-Cell Distribution.

Since B-cell hyperactivity and pathologic antibody response are key features in the immunopathogenesis of primary Sjögren's syndrome (pSS), the role of follicular T helper (TFH) cells as efficient helpers in the survival and differentiation of B cells has emerged. Our aim was to investigate whether a change in the balance of circulating (c)TFH subsets and follicular regulatory T (TFR) cells could affect the distribution of B cells in pSS. Peripheral blood of 38 pSS patients and 27 healthy controls was assessed for the frequencies of cTFH cell subsets, TFR cells, and certain B cell subpopulations by multicolor flow cytometry. Serological parameters, including anti-SSA, anti-SSB autoantibodies, immunoglobulin, and immune complex titers were determined as part of the routine diagnostic evaluation. Patients with pSS showed a significant increase in activated cTFH cell proportions, which was associated with serological results. Frequencies of cTFH subsets were unchanged in pSS patients compared to healthy controls. The percentages and number of cTFR cells exhibited a significant increase in autoantibody positive patients compared to patients with seronegative pSS. The proportions of transitional and naïve B cells were significantly increased, whereas subsets of memory B cells were significantly decreased and correlated with autoantibody production. Functional analysis revealed that the simultaneous blockade of cTFH and B cell interaction with anti-IL-21 and anti-CD40 antibodies decreased the production of IgM and IgG. Imbalance in TFH subsets and TFR cells indicates an ongoing over-activated humoral immune response, which contributes to the characteristic serological manifestations and the pathogenesis of pSS.

Regulation of RLR-Mediated Antiviral Responses of Human Dendritic Cells by mTOR.

To detect replicating viruses, dendritic cells (DCs) utilize cytoplasmic retinoic acid inducible gene-(RIG) I-like receptors (RLRs), which play an essential role in the subsequent activation of antiviral immune responses. In this study, we aimed to explore the role of the mammalian target of rapamycin (mTOR) in the regulation of RLR-triggered effector functions of human monocyte-derived DCs (moDCs) and plasmacytoid DCs (pDCs). Our results show that RLR stimulation increased the phosphorylation of the mTOR complex (mTORC) 1 and mTORC2 downstream targets p70S6 kinase and Akt, respectively, and this process was prevented by the mTORC1 inhibitor rapamycin as well as the dual mTORC1/C2 kinase inhibitor AZD8055 in both DC subtypes. Furthermore, inhibition of mTOR in moDCs impaired the RLR stimulation-triggered glycolytic switch, which was reflected by the inhibition of lactate production and downregulation of key glycolytic genes. Blockade of mTOR diminished the ability of RLR-stimulated moDCs and pDCs to secret type I interferons (IFNs) and pro-inflammatory cytokines, while it did not affect the phenotype of DCs. We also found that mTOR blockade decreased the phosphorylation of Tank-binding kinase 1 (TBK1), which mediates RLR-driven cytokine production. In addition, rapamycin abrogated the ability of both DC subtypes to promote the proliferation and differentiation of IFN-y and Granzyme B producing CD8 + T cells. Interestingly, AZD8055 was much weaker in its ability to decrease the T cell proliferation capacity of DCs and was unable to inhibit the DC-triggered production of IFN-y and Granyzme B by CD8 + T cells. Here we demonstrated for the first time that mTOR positively regulates the RLR-mediated antiviral activity of human DCs. Further, we show that only selective inhibition of mTORC1 but not dual mTORC1/C2 blockade suppresses effectively the T cell stimulatory capacity of DCs that should be considered in the development of new generation mTOR inhibitors and in the improvement of DC-based vaccines.

Systemic manifestations of primary Sjögren's syndrome out of the ESSDAI classification: prevalence and clinical relevance in a large international, multi-ethnic cohort of patients.

OBJECTIVES: To analyse the frequency and characterise the systemic presentation of primary Sjögren's syndrome (SS) out of the ESSDAI classification in a large international, multi-ethnic cohort of patients. METHODS: The Big Data Sjögren Project Consortium is an international, multicentre registry based on world-wide data-sharing and cooperative merging of pre-existing clinical SS databases from leading centres in clinical research in SS from the five continents. A list of 26 organ-by-organ systemic features not currently included in the ESSDAI classification was defined according to previous studies; these features were retrospectively recorded. RESULTS: Information about non-ESSDAI features was available in 6331 patients [5,917 female, mean age at diagnosis 52 years, mainly White (86.3%)]. A total of 1641 (26%) patients had at least one of the ESSDAI systemic features. Cardiovascular manifestations were the most frequent organ-specific group of non-ESSDAI features reported in our patients (17% of the total cohort), with Raynaud's phenomenon being reported in 15%. Patients with systemic disease due to non-ESSDAI features had a lower frequency of dry mouth (90.7% vs. 94.1%, p<0.001) and positive minor salivary gland biopsy (86.7% vs. 89%, p=0.033), a higher frequency of anti-Ro/SSA (74.7% vs. 68.7%, p<0.001), anti-La/SSB antibodies (44.5% vs. 40.4%, p=0.004), ANA (82.7% vs. 79.5%, p=0.006), low C3 levels (17.4% vs. 9.7%, p<0.001), low C4 levels (14.4% vs. 9.6%, p<0.001), and positive serum cryoglobulins (8.6% vs. 5.5%, p=0.001). Systemic activity measured by the ESSDAI, clinESSDAI and DAS was higher in patients with systemic disease out of the ESSDAI in comparison with those without these features (p<0.001 for all comparisons). CONCLUSIONS: More than a quarter of patients with primary SS may have systemic manifestations not currently included in the ESSDAI classification, with a wide variety of cardiovascular, digestive, pulmonary, neurological, ocular, ENT (ear, nose, and throat), cutaneous and urological features that increase the scope of the systemic phenotype of the disease. However, the individual frequency of each of these non-ESSDAI features was very low, except for Raynaud's phenomenon.

[Differential diagnosis of Graves' orbitopathy. Case report]. / Az endokrin orbitopathia differenciáldiagnosztikája.

Graves' orbitopathy is the extrathyroidal manifestation of Graves' disease, which is the most common cause of exophthalmos. As eye symptoms usually coincide with the development of thyrotoxicosis, the diagnosis of the disease is rarely difficult. The aim of the authors was to summarize the differential diagnosis of Graves' orbitopathy based on literature review and presentation of their own four problematic cases on this topic. They conclude that symptoms similar to endocrine orbitopathy are present in other disorders. Endocrinologists need to be aware of these other conditions to avoid treatment failures.

Characterization and Comparison of Patient Subgroups Suspicious for IgG4-Related Disease and Malignant Lymphoma in Patients Followed-up for Sjögren's Syndrome.

Differential diagnosis of patients with Sjögren's syndrome (SS), IgG4-related disease (IgG4-RD) and SS patients having high risk for lymphoma (LHR) can be challenging. Some patients with IgG4-RD might be misdiagnosed as having SS. There are special symptoms of SS that raise the possibility of IgG4-RD whereas other symptoms identify patients as having LHR. The purpose of this study was to characterize and compare patients with SS, possible IgG4-RD and SS patients with LHR. Sixty-five SS patients were divided into 4 subgroups according to having possible IgG4-RD (n = 15), LHR (n = 16), eligible for both aforementioned groups (n = 20) and not eligible for either group (n = 14), respectively. Four patients fulfilled the diagnostic criteria for IgG4-RD. The serum levels of IgG4 were significantly higher in patients suspicious for IgG4-RD compared to that of LHR patients (0.46 g/l vs. 0.12 g/l, p = 0.032). Shared features of the patient groups (salivary gland swelling (SGS) and lymphadenopathy), were separately analysed: SGS patients had higher IgG4/IgG ratio (p = 0.036), lymphadenopathic patients had higher IgG4 levels (p = 0.042). Some patients may be "hidden" under the diagnosis of SS. Although patients with LHR and patients with possible IgG4-RD share some symptoms, they differ significantly regarding IgG4 levels and IgG4/IgG ratio.

Lack of association of vitamin D receptor gene polymorphisms/haplotypes in Sjögren's syndrome.

The vitamin D is involved in a wide variety of biological processes including bone metabolism, modulation of the immune response, and regulation of cell proliferation and differentiation. Vitamin D has several immunomodulatory effects through vitamin D receptor (VDR). A series of common single-nucleotide polymorphisms (SNPs) in the vitamin D receptor gene have been linked to numerous of diseases, including osteoarthritis, diabetes, cancer, cardiovascular diseases, tuberculosis, virus infections, urinary stones, and periodontitis. Several studies have reported that genetic variations of VDR might be a risk factor for the development of autoimmune diseases such as systemic lupus erythematosus (SLE), multiple sclerosis (MS), psoriasis, and autoimmune thyroid diseases (AITD). However, no data is available on the possible relationship between primary Sjögren's syndrome and VDR gene polymorphisms. Our aim was to determine VDR gene BsmI, ApaI, TaqI, and FokI polymorphism genotypes in pSS patients and healthy controls to analyze whether a relationship exists between polymorphisms in the VDR gene and susceptibility to Sjögren's syndrome. In the current study, 105 patients with pSS and 93 healthy controls were tested for VDR gene polymorphisms (BsmI, ApaI, TaqI, and FokI) genotypes. There were no statistical differences in the distribution of BsmI, TaqI, ApaI, and FokI genotypes and the common haplotypes between pSS patients and healthy controls. We hypothesized that the TaqI, BsmI, ApaI, and FokI polymorphisms of the VDR gene are not associated with the development of primary Sjögren's syndrome in the Hungarian population studied.

Clinical course, prognosis, and cause of death in primary Sjögren's syndrome.

The aim of this retrospective, single-centre study was to investigate the clinical and laboratory features and disease outcomes of 547 patients diagnosed with primary Sjögren's syndrome (pSS) between 1975 and 2010. The patients were followed up for 11.4±6.2 years. We evaluated the clinical and laboratory features, and assessed their influence on the time of diagnosis, survival, and mortality ratios, and compared them within subgroups defined by gender, glandular and extraglandular manifestations (EGMs), associated diseases, and immunoserological abnormalities. The most frequent EGMs were polyarthritis, Raynaud's phenomenon, and vasculitis among our patients; the most common associated disease was thyroiditis. During the follow-up period, 51 patients died; the median survival time was 33.71 years. Our results revealed a negative effect of cryoglobulinemia on survival ratios; additionally, the presence of vasculitis and lymphoproliferative diseases at the time of diagnosis increased the risk of mortality. The development of vasculitis was the most powerful predictor of mortality. Mortality in the group of patients with extraglandular symptoms was two- to threefold higher than in the glandular group. Attention is drawn to the importance of close monitoring and targeted diagnostic approaches in those pSS subgroups with obviously increased mortality risk.

Autoimmune thyroid diseases in a large group of Hungarian patients with primary Sjögren's syndrome.

BACKGROUND: Previous studies on relatively small populations of patients with primary Sjögren's syndrome (pSS) suggested an association between pSS and Hashimoto's thyroiditis (HT). As some findings in the literature regarding the relationship between pSS and thyroid disease are contradictory, and there is little information on the sequence of pSS and HT, we conducted a study with a population of patients with pSS that was about three times larger than previously studied populations. Our objective was to determine the prevalence of HT and Graves' disease (GD) in patients with pSS and to assess the sequence of pSS and autoimmune thyroid diseases. METHODS: A total of 479 patients with pSS were retrospectively studied. Thyroid ultrasound and scintigraphy were performed, and serum thyrotropin, free triiodothyronine, free thyroxine, antithyroid peroxidase antibody (TPOAb), and anti-thyroglobulin autoantibody (TgAb) measurements were carried out. Solitary thyroid nodules were investigated by fine-needle aspiration biopsy. RESULTS: Thyroid dysfunction was found in 95 patients (21.25%). Thirty of these patients had HT and 18 had GD. HT predated pSS in eight patients, developed at approximately the same time in seven patients, and followed pSS in 15 patients. Almost all (90%) patients with HT had persistently elevated serum TgAb or TPOAb titers. CONCLUSIONS: An association between HT and pSS was found based on the fact that the frequency of HT was greater among pSS patients (6.26%) than in the general population (1-2%). In contrast, no association between GD and pSS was found. We noted that both HT and GD can appear either before or after the onset of pSS. Since most cases of pSS predate the appearance of autoimmune thyroid diseases it is important to determine if pSS is a predisposing factor for the development of autoimmune thyroiditis.

Intrapulmonary rheumatoid nodules in a patient with long-standing rheumatoid arthritis treated with leflunomide.

Rheumatoid nodules are well established manifestations of rheumatoid arthritis but in the lungs they are very rare according to the literature. In our study we present the case of a 34-year-old woman with rheumatoid arthritis and secondary Sjögren's syndrome who developed multiplex rheumatoid nodules in the lungs 3 years after initiating leflunomide therapy. During leflunomide therapy we did not detect inflammation in the joints. Surprisingly, in November 2005 she started to cough, had low grade fever and low back pain. On the chest X-ray there were multiplex necrobiotic nodules in the lungs. All bacteriological, viral and fungal investigations including tuberculosis, serological tests and cytology were negative. The X-ray, video-associated thoracoscopy and repeated biopsy of the lung followed by histology of the samples proved intrapulmonary rheumatoid nodules, caused by leflunomide.

[Severe necrotising primary vasculitis--case report]. / Súlyos nekrotizáló primer vasculitis.

INTRODUCTION: Vasculitis is an inflammatory disorder of the vessels, often associates with necrosis. The primary (idiopathic) form caused by distinct immunological mechanisms, the secondary form caused by infection, tumor, drugs or systemic autoimmune disease. CASE REPORT: 57-year-old smoking female patient with a medical history of the left ankle fracture. Four days earlier had sore throat, at admission was febrile and generally weak and had severe pain in her lower extremities. Physical examination revealed numerous livid alterations in both lower extremities, necrotic change of some toes and new onset of diastolic hypertension. Elevated serum transaminase levels, severe thrombopenia, anemia, leukocytosis suggested the possibility of thrombotic thrombocytopenic purpura and vasculitis. Tests ruled out septic embolism, therefore we applied high dose steroid treatment and plasma exchange. Meanwhile the results fulfilled the classification criteria of polyarteritis nodosa (vasculitis, livedo reticularis, polyneuropathia and new onset of diastolic hypertension), accordingly we synchronized the treatment with fractionally administered intravenous cyclophosphamide. The process revealed responsive to therapy and the substantive function of the legs remained after surgical removal of the necrotic areas. CONCLUSIONS: Early rapid diagnosis of vasculitis is fundamental and we emphasize the significance of the efficient treatment.

[Association of systemic lupus erythematosus and Sjögren's syndrome]. / Szisztémás lupus erythematosus es Sjögren-szindróma társult eseteinek elemzése.

INTRODUCTION: Systemic lupus erythematosus and Sjögren's syndrome are multisystemic autoimmune diseases which can be associated to each other. OBJECTIVE: To investigate if there are any distinct clinical, laboratory or serologic features due to the association of the two diseases that can influence the follow up of these patients. PATIENTS AND METHODS: The authors proved the association of these two autoimmune diseases in 56 patients, and these patients' clinical, laboratory and immunoserologic alterations. 50 patients with Sjögren's syndrome and 50 patients with systemic lupus erythematosus were used as control groups. RESULTS: Compared with Sjögren's syndrome alone, in the cases of the association of the diseases, rheumatoid factor was present less frequently, Ro/SS-A, La/SS-B and DNA antibodies were present more frequently, such as antiphospholipid autoantibodies and antiphospholipid syndrome. Anaemia, leukopenia and lymphopenia were detected more often and the patients were younger than in Sjögren's syndrome. Also, affection of the lung, kidney, skin, central nervous system and serous membranes are more common. The group with systemic lupus erythematosus differs in being older, having thyroiditis, Ro/SS-A, La/SS-B and DNA more frequently. CONCLUSION: Definitive clinical, laboratory and serological features make the difference between the association of the two diseases and the diseases observed alone.