| 1. |
- Acar-Denizli, N., et al.
(author)
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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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In: Clinical and Experimental Rheumatology. - : CLINICAL & EXPER RHEUMATOLOGY. - 0392-856X .- 1593-098X. ; 38:4; Suppl. 126, s. S85-S94
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Journal article (peer-reviewed)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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| 2. |
- Arvidsson, Gustav, et al.
(author)
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Multimodal Single-Cell Sequencing of B Cells in Primary Sjögren's Syndrome
- 2024
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In: Arthritis & Rheumatology. - 2326-5191 .- 2326-5205. ; 76:2, s. 255-267
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Journal article (peer-reviewed)abstract
- Objective. B cells are important in the pathogenesis of primary Sjögren's syndrome (pSS). Patients positive for Sjögren's syndrome antigen A/Sjögren syndrome antigen B (SSA/SSB) autoantibodies are more prone to systemic disease manifestations and adverse outcomes. We aimed to determine the role of B cell composition, gene expression, and B cell receptor usage in pSS subgroups stratified for SSA/SSB antibodies.Methods. Over 230,000 B cells were isolated from peripheral blood of patients with pSS (n = 6 SSA−, n = 8 SSA+ single positive and n = 10 SSA/SSB+ double positive) and four healthy controls and processed for single-cell RNA sequencing (scRNA-seq) and single-cell variable, diversity, and joining (VDJ) gene sequencing (scVDJ-seq).Results. We show that SSA/SSB+ patients present the highest and lowest proportion of naïve and memory B cells, respectively, and the highest up-regulation of interferon-induced genes across all B cell subtypes. Differential usage of IGHV showed that IGHV1-69 and IGHV4-30-4 were more often used in all pSS subgroups compared with controls. Memory B cells from SSA/SSB+ patients displayed a higher proportion of cells with unmutated VDJ transcripts compared with other pSS patient groups and controls, indicating altered somatic hypermutation processes. Comparison with previous studies revealed heterogeneous clonotype pools, with little overlap in CDR3 sequences. Joint analysis using scRNA-seq and scVDJ-seq data allowed unsupervised stratification of patients with pSS and identified novel parameters that correlated to disease manifestations and antibody status.Conclusion. We describe heterogeneity and molecular characteristics in B cells from patients with pSS, providing clues to intrinsic differences in B cells that affect the phenotype and outcome and allowing stratification of patients with pSS at improved resolution.
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| 3. |
- Berry, Joe Scott, et al.
(author)
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Examining the biological pathways underlying clinical heterogeneity in Sjogren's syndrome : proteomic and network analysis
- 2024
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In: Annals of the Rheumatic Diseases. - : BMJ Publishing Group Ltd. - 0003-4967 .- 1468-2060. ; 83:1, s. 88-95
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Journal article (peer-reviewed)abstract
- Objectives: Stratification approaches are vital to address clinical heterogeneity in Sjogren's syndrome (SS). We previously described that the Newcastle Sjogren's Stratification Tool (NSST) identified four distinct clinical subtypes of SS. We performed proteomic and network analysis to analyse the underlying pathobiology and highlight potential therapeutic targets for different SS subtypes.Method: We profiled serum proteins using O-link technology of 180 SS subjects. We used 5 O-link proteomics panels which included a total of 454 unique proteins. Network reconstruction was performed using the ARACNE algorithm, with differential expression estimates overlaid on these networks to reveal the key subnetworks of differential expression. Furthermore, data from a phase III trial of tocilizumab in SS were reanalysed by stratifying patients at baseline using NSST.Results: Our analysis highlights differential expression of chemokines, cytokines and the major autoantigen TRIM21 between the SS subtypes. Furthermore, we observe differential expression of several transcription factors associated with energy metabolism and redox balance namely APE1/Ref-1, FOXO1, TIGAR and BACH1. The differentially expressed proteins were inter-related in our network analysis, supporting the concept that distinct molecular networks underlie the clinical subtypes of SS. Stratification of patients at baseline using NSST revealed improvement of fatigue score only in the subtype expressing the highest levels of serum IL-6.Conclusions: Our data provide clues to the pathways contributing to the glandular and non-glandular manifestations of SS and to potential therapeutic targets for different SS subtypes. In addition, our analysis highlights the need for further exploration of altered metabolism and mitochondrial dysfunction in the context of SS subtypes.
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| 4. |
- Björk, Albin, et al.
(author)
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Protein and DNA methylation-based scores as surrogate markers for interferon system activation in patients with primary Sjögren's syndrome
- 2020
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In: RMD Open. - : BMJ PUBLISHING GROUP. - 2056-5933. ; 6:1
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Journal article (peer-reviewed)abstract
- Objective: Standard assessment of interferon (IFN) system activity in systemic rheumatic diseases depends on the availability of RNA samples. In this study, we describe and evaluate alternative methods using plasma, serum and DNA samples, exemplified in the IFN-driven disease primary Sjogren's syndrome (pSS).Methods: Patients with pSS seropositive or negative for anti-SSA/SSB and controls were included. Protein-based IFN (pIFN) scores were calculated from levels of PD-1, CXCL9 and CXCL10. DNA methylation-based (DNAm) IFN scores were calculated from DNAm levels at RSAD2, IFIT1 and IFI44L. Scores were compared with mRNA-based IFN scores measured by quantitative PCR (qPCR), Nanostring or RNA sequencing (RNAseq).Results: mRNA-based IFN scores displayed strong correlations between B cells and monocytes (r=0.93 and 0.95, p<0.0001) and between qPCR and Nanostring measurements (r=0.92 and 0.92, p<0.0001). The pIFN score in plasma and serum was higher in patients compared with controls (p<0.0001) and correlated well with mRNA-based IFN scores (r=0.62-0.79, p<0.0001), as well as with each other (r=0.94, p<0.0001). Concordance of classification as 'high' or 'low' IFN signature between the pIFN score and mRNA-based IFN scores ranged from 79.5% to 88.6%, and the pIFN score was effective at classifying patients and controls (area under the curve, AUC=0.89-0.93, p<0.0001). The DNAm IFN score showed strong correlation to the RNAseq IFN score (r=0.84, p<0.0001) and performed well in classifying patients and controls (AUC=0.96, p<0.0001).Conclusions: We describe novel methods of assessing IFN system activity in plasma, serum or DNA samples, which may prove particularly valuable in studies where RNA samples are not available.
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| 5. |
- Bolin, Karin
(author)
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Lupus Nephritis – Genetic Impact on Clinical Phenotypes, Disease Severity and Renal Outcome
- 2020
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Doctoral thesis (other academic/artistic)abstract
- Systemic lupus erythematosus (SLE) is an autoimmune inflammatory disease that can affect every organ system. Lupus nephritis (LN) is one of the more serious SLE manifestations. Whilst the genetic background of SLE has been thoroughly investigated, less is known about the background of LN. The aim of this thesis was to further elucidate the genetic background of LN, its subtypes and outcome.In paper I, we analysed genetic variations for association with LN, its severe form proliferative nephritis and renal outcome, in two SLE cohorts. Patients and controls were genotyped and association analyses were performed for patients versus controls and for patients with or without a specific clinical manifestation. In the case-control analysis of cohort I, four highly linked risk alleles in the STAT4 gene were associated with LN with genome-wide significance. In the case-only meta-analysis of the two cohorts, a STAT4 risk allele was associated with severe renal insufficiency. We conclude that genetic variations in STAT4 predispose to LN and a worse outcome with severe renal insufficiency.In paper II, we describe a case of severe SLE on the basis of C1q deficiency. By sequencing, a mutation in the C1qC gene leading to a premature stop codon was found. The patient was also found to carry risk alleles in several SLE-associated variants. Interferon alpha (IFN-α) levels were analysed over time in patient serum, and were found to correlate with disease activity. The patient’s serum had a strong interferogenic capacity when stimulating peripheral blood mononuclear cells from healthy individuals. With this study, we further emphasise the role of IFN-α in C1q deficiency and highlight the need to consider inherited impairments in the complement system in SLE with childhood onset.In paper III, we studied the impact of sex on disease manifestations in SLE. Female SLE patients more often presented with malar rash, photosensitivity, oral ulcers and arthritis, whilst the frequency of serositis, renal disorder and immunologic disorder were higher among male patients. Women were younger at LN onset, whereas men had a higher risk for progression into end-stage renal disease.In paper IV, we analysed genetic variations for association with LN and its subtypes in three SLE cohorts. Patients were genotyped and association analyses were performed for patients with versus without different phenotypes. We found genetic variations in the BANK1 gene to be associated with LN.In conclusion, this thesis provides further insight into the genetic background of renal manifestations in patients with SLE.
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| 6. |
- Bolin, Karin, et al.
(author)
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Variants in BANK1 are associated with lupus nephritis of European ancestry
- 2021
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In: Genes and Immunity. - : Springer Nature. - 1466-4879 .- 1476-5470. ; 22:3, s. 194-202
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Journal article (peer-reviewed)abstract
- The genetic background of lupus nephritis (LN) has not been completely elucidated. We performed a case-only study of 2886 SLE patients, including 947 (33%) with LN. Renal biopsies were available from 396 patients. The discovery cohort (Sweden, n = 1091) and replication cohort 1 (US, n = 962) were genotyped on the Immunochip and replication cohort 2 (Denmark/Norway, n = 833) on a custom array. Patients with LN, proliferative nephritis, or LN with end-stage renal disease were compared with SLE without nephritis. Six loci were associated with LN (p < 1 × 10−4, NFKBIA, CACNA1S, ITGA1, BANK1, OR2Y, and ACER3) in the discovery cohort. Variants in BANK1 showed the strongest association with LN in replication cohort 1 (p = 9.5 × 10−4) and proliferative nephritis in a meta-analysis of discovery and replication cohort 1. There was a weak association between BANK1 and LN in replication cohort 2 (p = 0.052), and in the meta-analysis of all three cohorts the association was strengthened (p = 2.2 × 10−7). DNA methylation data in 180 LN patients demonstrated methylation quantitative trait loci (meQTL) effects between a CpG site and BANK1 variants. To conclude, we describe genetic variations in BANK1 associated with LN and evidence for genetic regulation of DNA methylation within the BANK1 locus. This indicates a role for BANK1 in LN pathogenesis.
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| 7. |
- Brito-Zerón, Pilar, et al.
(author)
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SARS-CoV-2 infection in patients with primary Sjögren syndrome : characterization and outcomes of 51 patients.
- 2021
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In: Rheumatology. - : Oxford University Press. - 1462-0324 .- 1462-0332. ; 60:6, s. 2946-2957
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Journal article (peer-reviewed)abstract
- OBJECTIVE: To analyse the prognosis and outcomes of SARS-CoV-2 infection in patients with primary SS.METHODS: We searched for patients with primary SS presenting with SARS-CoV-2 infection (defined following and according to the European Centre for Disease Prevention and Control guidelines) among those included in the Big Data Sjögren Registry, an international, multicentre registry of patients diagnosed according to the 2002/2016 classification criteria.RESULTS: A total of 51 patients were included in the study (46 women, mean age at diagnosis of infection of 60 years). According to the number of patients with primary SS evaluated in the Registry (n = 8211), the estimated frequency of SARS-CoV-2 infection was 0.62% (95% CI 0.44, 0.80). All but two presented with symptoms suggestive of COVID-19, including fever (82%), cough (57%), dyspnoea (39%), fatigue/myalgias (27%) and diarrhoea (24%), and the most frequent abnormalities included raised lactate dehydrogenase (LDH) (88%), CRP (81%) and D-dimer (82%) values, and lymphopenia (70%). Infection was managed at home in 26 (51%) cases and 25 (49%) required hospitalization (five required admission to ICU, four died). Compared with patients managed at home, those requiring hospitalization had higher odds of having lymphopenia as laboratory abnormality (adjusted OR 21.22, 95% CI 2.39, 524.09). Patients with comorbidities had an older age (adjusted OR 1.05, 95% CI 1.00, 1.11) and showed a risk for hospital admission six times higher than those without (adjusted OR 6.01, 95% CI 1.72, 23.51) in the multivariate analysis.CONCLUSION: Baseline comorbidities were a key risk factor for a more complicated COVID-19 in patients with primary SS, with higher rates of hospitalization and poor outcomes in comparison with patients without comorbidities.
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| 8. |
- Cunningham, Janet L., et al.
(author)
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Experiences in implementing immunopsychiatry in real life
- 2023
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In: Journal of Affective Disorders Reports. - : Elsevier. - 2666-9153. ; 13
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Journal article (peer-reviewed)abstract
- Immunological mechanisms, both alone and in combination, are associated with a broad range of psychiatric disorders encompassing autoimmune, autoinflammatory disorders but also genetic, metabolic, or other immunological disorders. Early treatment improves the outcome for autoimmune disorders, but early diagnosis is more difficult when isolated psychiatric symptoms are manifestations of autoimmunity. Treatment of these cases must encompass integrated models of disease, as both systemic autoimmunity and psychological processes influence mental health. Several challenges need to be overcome to efficiently merge psychiatric and somatic disease paradigms and medical care ranging from language and conceptual barriers to organizational barriers. Since 2015, the Immunopsychiatry team at Uppsala University has developed a collaborative multidisciplinary approach to improve and integrate care for patients with moderate to severe psychiatric disorders. Based on this experience, we have outlined the obstacles to be overcome in taking steps forward to achieve the long-term goal of understanding and early detection and identification of treatable immunological conditions within the psychiatric patient population; the described framework of evaluations and work-flow may serve as a model for other centers.
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| 9. |
- Diaz-Gallo, Lina-Marcela, et al.
(author)
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Four Systemic Lupus Erythematosus Subgroups, Defined by Autoantibodies Status, Differ Regarding HLA-DRB1 Genotype Associations and Immunological and Clinical Manifestations
- 2022
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In: ACR Open Rheumatology. - : John Wiley & Sons. - 2578-5745. ; 4:1, s. 27-39
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Journal article (peer-reviewed)abstract
- Objective: The heterogeneity of systemic lupus erythematosus (SLE) constitutes clinical and therapeutical challenges. We therefore studied whether unrecognized disease subgroups can be identified by using autoantibody profiling together with HLA-DRB1 alleles and immunological and clinical data.Methods: An unsupervised cluster analysis was performed based on detection of 13 SLE-associated autoantibodies (double-stranded DNA, nucleosomes, ribosomal P, ribonucleoprotein [RNP] 68, RNPA, Smith [Sm], Sm/RNP, Sjögren's syndrome antigen A [SSA]/Ro52, SSA/Ro60, Sjögren's syndrome antigen B [SSB]/La, cardiolipin [CL]-Immunoglobulin G [IgG], CL-Immunoglobulin M [IgM], and β2 glycoprotein I [β2 GPI]-IgG) in 911 patients with SLE from two cohorts. We evaluated whether each SLE subgroup is associated with HLA-DRB1 alleles, clinical manifestations (n = 743), and cytokine levels in circulation (n = 446).Results: Our analysis identified four subgroups among the patients with SLE. Subgroup 1 (29.3%) was dominated by anti-SSA/Ro60/Ro52/SSB autoantibodies and was strongly associated with HLA-DRB1*03 (odds ratio [OR] = 4.73; 95% confidence interval [CI] = 4.52-4.94). Discoid lesions were more common for this disease subgroup (OR = 1.71, 95% CI = 1.18-2.47). Subgroup 2 (28.7%) was dominated by anti-nucleosome/SmRNP/DNA/RNPA autoantibodies and associated with HLA-DRB1*15 (OR = 1.62, 95% CI = 1.41-1.84). Nephritis was most common in this subgroup (OR = 1.61, 95% CI = 1.14-2.26). Subgroup 3 (23.8%) was characterized by anti-ß2 GPI-IgG/anti-CL-IgG/IgM autoantibodies and a higher frequency of HLA-DRB1*04 compared with the other patients with SLE. Vascular events were more common in Subgroup 3 (OR = 1.74, 95% CI = 1.2-2.5). Subgroup 4 (18.2%) was negative for the investigated autoantibodies, and this subgroup was not associated with HLA-DRB1. Additionally, the levels of eight cytokines significantly differed among the disease subgroups.Conclusion: Our findings suggest that four fairly distinct subgroups can be identified on the basis of the autoantibody profile in SLE. These four SLE subgroups differ regarding associations with HLA-DRB1 alleles and immunological and clinical features, suggesting dissimilar disease pathways.
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