| 1. |
- Acar-Denizli, N., et al.
(författare)
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Systemic phenotype related to primary Sjögren's syndrome in 279 patients carrying isolated anti-La/SSB antibodies
- 2020
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Ingår i: Clinical and Experimental Rheumatology. - : CLINICAL & EXPER RHEUMATOLOGY. - 0392-856X .- 1593-098X. ; 38:4; Suppl. 126, s. S85-S94
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To evaluate the systemic phenotype associated with the presence of isolated anti-La/SSB antibodies in a large international registry of patients with primary Sjogren's syndrome (pSS) fulfilling the 2002 classification criteria.Methods: The Big Data Sjogren 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.Conclusion: 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.
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| 3. |
- Khatri, B., et al.
(författare)
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Genome-wide association study identifies Sjogren's risk loci with functional implications in immune and glandular cells
- 2022
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Sjogren's disease is a complex autoimmune disease with twelve established susceptibility loci. This genome-wide association study (GWAS) identifies ten novel genome-wide significant (GWS) regions in Sjogren's cases of European ancestry: CD247, NAB1, PTTG1-MIR146A, PRDM1-ATG5, TNFAIP3, XKR6, MAPT-CRHR1, RPTOR-CHMP6-BAIAP6, TYK2, SYNGR1. Polygenic risk scores yield predictability (AUROC = 0.71) and relative risk of 12.08. Interrogation of bioinformatics databases refine the associations, define local regulatory networks of GWS SNPs from the 95% credible set, and expand the implicated gene list to >40. Many GWS SNPs are eQTLs for genes within topologically associated domains in immune cells and/or eQTLs in the main target tissue, salivary glands. The genetic architecture underlying Sjogren's syndrome is not fully understood. Here, the authors perform a genome-wide association study to identify 10 new genetic risk regions, implicating genes involved in immune and salivary gland function.
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| 5. |
- Retamozo, S., et al.
(författare)
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Influence of the age at diagnosis in the disease expression of primary Sjogren's syndrome : Analysis of 12,753 patients from the Sjogren Big Data Consortium
- 2021
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Ingår i: Clinical and Experimental Rheumatology. - : CLINICAL & EXPER RHEUMATOLOGY. - 0392-856X .- 1593-098X. ; 39:6, s. S166-S174
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Tidskriftsartikel (refereegranskat)abstract
- Objective. To analyse how the main components of the disease phenotype (sicca symptoms, diagnostic tests, immunological markers and systemic disease) can be driven by the age at diagnosis of primary Sjogren's syndrome (pSS).Methods. By January 2021, the participant centres had included 12,753 patients from 25 countries that fulfilled the 2002/2016 classification criteria for pSS. The age at diagnosis was defined as the time when the attending physician confirmed fulfilment of the criteria. Patients were clustered according to age at diagnosis. 50 clusters with more than 100 observations (from 27 to 76 years) were used to study the influence of the age at diagnosis in the disease expression.Results. There was a consistent increase in the frequency of oral dryness according to the age at diagnosis, with a frequency of <90% in patients diagnosed at the youngest ages and >95% in those diagnosed at the oldest ages. The smooth curves that best fitted a linear model were the frequency of dry mouth (adjusted R-2 0.87) and the frequency of abnormal oral tests (adjusted R-2 0.72). Therefore, for each 1-year increase in the age at diagnosis, the frequency of dry mouth increased by 0.13%, and the frequency of abnormal oral diagnostic tests by 0.11%. There was a consistent year-by-year decrease in the frequency of all autoantibodies and immunological markers except for cryoglobulins. According to the linear models, for each 1-year increase in the age at diagnosis, the frequency of a positive result decreased by 0.57% (for anti-Ro antibodies), 0.47% (for RF) and 0.42% (for anti-La antibodies). The ESSDAI domains which showed a more consistent decrease were glandular and lymph node involvement (for each 1-year increase in the age at diagnosis, the frequency of activity decreased by 0.18%), and constitutional, cutaneous, and haematological involvements (the frequency decreased by 0.09% for each 1-year increase). In contrast, other domains showed an ascending pattern, especially pulmonary involvement (for each 1-year increase in the age at diagnosis, the frequency of activity increased by 0.22%), and peripheral nerve involvement (the frequency increased by 0.09% for each 1-year increase).Conclusion. The influence of the age at diagnosis on the key phenotypic features of pSS is strong, and should be considered critical not only for designing a personalised diagnostic approach, but also to be carefully considered when analysing the results of diagnostic tests and immunological parameters, and when internal organ involvement is suspected at diagnosis.
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| 8. |
- Brito-Zeron, P., et al.
(författare)
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How immunological profile drives clinical phenotype of primary Sjögren's syndrome at diagnosis : analysis of 10,500 patients (Sjögren Big Data Project)
- 2018
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Ingår i: Clinical and Experimental Rheumatology. - : CLINICAL & EXPER RHEUMATOLOGY. - 0392-856X .- 1593-098X. ; 36:3, s. S102-S112
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To evaluate the influence of the main immunological markers on the disease phenotype at diagnosis in a large international cohort of patients with primary Sjogren's syndrome (SjS).Methods: The Big Data Sjogren Project Consortium is an international, multicentre registry created in 2014. As a first step, baseline clinical information from leading centres on clinical research in SjS of the 5 continents was collected. The centres shared a harmonised data architecture and conducted cooperative online efforts in order to refine collected data under the coordination of a big data statistical team. Inclusion criteria were the fulfillment of the 2002 classification criteria. Immunological tests were carried out using standard commercial assays.Results: By January 2018, the participant centres had included 10,500 valid patients from 22 countries. The cohort included 9,806 (93%) women and 694 (7%) men, with a mean age at diagnosis of primary SjS of 53 years, mainly White (78%) and included from European countries (71%). The frequency of positive immunological markers at diagnosis was 79.3% for ANA, 73.2% for anti-Ro, 48.6% for RF, 45.1% for anti-La, 13.4% for low C3 levels, 14.5% for low C4 levels and 7.3% for cryoglobulins. Positive autoantibodies (ANA, Ro, La) correlated with a positive result in salivary gland biopsy, while hypocomplementaemia and especially cryoglobulinaemia correlated with systemic activity (mean ESSDAI score of 17.7 for ctyoglobulins, 11.3 for low C3 and 9.2 for low C4, in comparison with 3.8 for negative markers). The immunological markers with a great number of statistically-significant associations (p<0.001) in the organ-by-organ ESSDAI evaluation were cryoglobulins (9 domains), low C3 (8 domains), anti-La (7 domains) and low C4 (6 domains).Conclusion: We confirm the strong influence of immunological markers on the phenotype of primary SjS at diagnosis in the largest multi-ethnic international cohort ever analysed, with a greater influence for cryoglobulinaemic-related markers in comparison with Ro/La autoantibodies and ANA. Immunological patterns play a central role in the phenotypic expression of the disease already at the time of diagnosis, and may guide physicians to design a specific personalised management during the follow-up of patients with primary SjS.
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| 16. |
- Haldorsen, K., et al.
(författare)
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No association of primary Sjogren's syndrome with Fc gamma receptor gene variants
- 2013
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Ingår i: Genes and Immunity. - : Springer Science and Business Media LLC. - 1476-5470 .- 1466-4879. ; 14:4, s. 234-237
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Tidskriftsartikel (refereegranskat)abstract
- The genetic background of primary Sjogren's syndrome (pSS) is partly shared with systemic lupus erythematosus (SLE). Immunoglobulin G Fc receptors are important for clearance of immune complexes. Fcg receptor variants and gene deletion have been found to confer SLE risk. In this study, four Fc gamma receptor single-nucleotide polymorphisms (SNPs) and one copy number variation (CNV) were studied. Swedish and Norwegian pSS patients (N = 527) and controls (N = 528) were genotyped for the Fc gamma receptor gene variant FCGR2A H131R (rs1801274) by the Illumina GoldenGate assay. FCGR3A F158V (rs396991) was analysed in 488 patients and 485 controls, FCGR3B rs447536 was analysed in 471 patients and 467 controls, and FCGR3B rs448740 was analysed in 478 cases and 455 controls, using TaqMan SNP genotyping assays. FCGR3B CNV was analysed in 124 patients and 139 controls using a TaqMan copy number assay. None of the SNPs showed any association with pSS. Also, no FCGR3B CNV association was detected. The lack of association of pSS with Fc gamma receptor gene variants indicates that defective immune complex clearance may not be as important in pSS pathogenesis as in SLE, and may point to important differences between SLE and pSS.
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| 18. |
- Kvarnstrom, M, et al.
(författare)
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Autoantibodies to the functionally active RING-domain of Ro52/SSA are associated with disease activity in patients with lupus
- 2013
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Ingår i: Lupus. - : SAGE Publications. - 1477-0962 .- 0961-2033. ; 22:5, s. 477-485
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Tidskriftsartikel (refereegranskat)abstract
- The Ro52 protein of the Ro/SSA antigen was recently defined as an E3 ligase controlling cytokine production. Autoantibodies from systemic lupus erythematosus (SLE) patients targeting the Ro52-RING domain, containing the E3 ligase activity, have been shown to inhibit the E3 ligase activity of Ro52. The objective of the present study was to investigate correlations between clinical parameters in patients with SLE and levels of Ro/SSA (Ro52 and Ro60) and La/SSB autoantibodies, including autoantibodies directed towards the functional RING and B-box domains of the Ro52 protein. SLE patients ( n = 232) were clinically examined and disease activity indices collected concurrently to blood sampling. The samples were analyzed for immunological parameters including autoantibodies. Ro52 autoantibody levels were associated with more variables than the other analyzed antibodies and were significantly associated with several individual items related to sSS and the diagnosis of sSS itself ( p = 0.004). Other associated variables were high sedimentation rate ( p = 0.0003), levels of immunoglobulins ( p = 0.0003), and an inverse correlation with levels of lymphocytes ( p = 0.003) and leukocytes ( p = 0.01). Antibodies to the RING domain of Ro52, which is the functionally active domain with E3 ligase activity, were significantly correlated with disease activity as measured by the SLAM score. We conclude that autoantibodies against Ro52 and in particular its functional RING domain are important in lupus patients and associated with several clinical and laboratory features of the disease. The impact on disease activity of Ro52-RING specific antibodies was especially noted, and could imply a functional role for these autoantibodies in inhibiting Ro52 activity, which is important for the control of proinflammatory cytokine production, including type 1 interferons.
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| 22. |
- Lundtoft, Christian, et al.
(författare)
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Strong Association of Combined Genetic Deficiencies in the Classical Complement Pathway With Risk of Systemic Lupus Erythematosus and Primary Sjogren's Syndrome
- 2022
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Ingår i: Arthritis & Rheumatology. - : Wiley. - 2326-5191 .- 2326-5205. ; 74:11, s. 1842-1850
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Tidskriftsartikel (refereegranskat)abstract
- Objective Complete genetic deficiency of the complement component C2 is a strong risk factor for monogenic systemic lupus erythematosus (SLE), but whether heterozygous C2 deficiency adds to the risk of SLE or primary Sjogren's syndrome (SS) has not been studied systematically. This study was undertaken to investigate potential associations of heterozygous C2 deficiency and C4 copy number variation with clinical manifestations in patients with SLE and patients with primary SS. Methods The presence of the common 28-bp C2 deletion rs9332736 and C4 copy number variation was examined in Scandinavian patients who had received a diagnosis of SLE (n = 958) or primary SS (n = 911) and in 2,262 healthy controls through the use of DNA sequencing. The concentration of complement proteins in plasma and classical complement function were analyzed in a subgroup of SLE patients. Results Heterozygous C2 deficiency-when present in combination with a low C4A copy number-substantially increased the risk of SLE (odds ratio [OR] 10.2 [95% confidence interval (95% CI) 3.5-37.0]) and the risk of primary SS (OR 13.0 [95% CI 4.5-48.4]) when compared to individuals with 2 C4A copies and normal C2. For patients heterozygous for rs9332736 with 1 C4A copy, the median age at diagnosis was 7 years earlier in patients with SLE and 12 years earlier in patients with primary SS when compared to patients with normal C2. Reduced C2 levels in plasma (P = 2 x 10(-9)) and impaired function of the classical complement pathway (P = 0.03) were detected in SLE patients with heterozygous C2 deficiency. Finally, in a primary SS patient homozygous for C2 deficiency, we observed low levels of anti-Scl-70, which suggests a risk of developing systemic sclerosis or potential overlap between primary SS and other systemic autoimmune diseases. Conclusion We demonstrate that a genetic pattern involving partial deficiencies of C2 and C4A in the classical complement pathway is a strong risk factor for SLE and for primary SS. Our results emphasize the central role of the complement system in the pathogenesis of both SLE and primary SS.
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| 27. |
- Retamozo, S., et al.
(författare)
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Systemic manifestations of primary Sjogren's syndrome out of the ESSDAI classification : prevalence and clinical relevance in a large international, multi-ethnic cohort of patients
- 2019
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Ingår i: Clinical and Experimental Rheumatology. - : CLINICAL & EXPER RHEUMATOLOGY. - 0392-856X .- 1593-098X. ; 71
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: To analyse the frequency and characterise the systemic presentation of primary Sjogren's syndrome (SS) out of the ESSDAI classification in a large international, multi-ethnic cohort of patients. Methods: The Big Data Sjogren 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.
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| 28. |
- Sepulveda, Jorge I. Ramirez, et al.
(författare)
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Long-term follow-up in primary Sjögren's syndrome reveals differences in clinical presentation between female and male patients
- 2017
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Ingår i: Biology of Sex Differences. - : BioMed Central. - 2042-6410. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Background: Despite men being less prone to develop autoimmune diseases, male sex has been associated with a more severe disease course in several systemic autoimmune diseases. In the present study, we aimed to investigate differences in the clinical presentation of primary Sjogren's syndrome (pSS) between the sexes and establish whether male sex is associated with a more severe form of long-term pSS. Methods: Our study population included 967 patients with pSS (899 females and 68 males) from Scandinavian clinical centers. The mean follow-up time (years) was 8.8 +/- 7.6 for women and 8.5 +/- 6.2 for men (ns). Clinical data including serological and hematological parameters and glandular and extraglandular manifestations were compared between men and women. Results: Male patient serology was characterized by more frequent positivity for anti-Ro/SSA and anti-La/SSB (p = 0. 02), and ANA (p = 0.02). Further, men with pSS were more frequently diagnosed with interstitial lung disease (p = 0. 008), lymphadenopathy (p = 0.04) and lymphoma (p = 0.007). Conversely, concomitant hypothyroidism was more common among female patients (p = 0.009). Conclusions: We observe enhanced serological responses and higher frequencies of lymphoma-related extraglandular manifestations in men with pSS. Notably, lymphoma itself was also significantly more common in men. These observations may reflect an aggravated immune activation and a more severe pathophysiological state in male patients with pSS and indicate a personalized managing of the disease due to the influence of the sex of patients with pSS.
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