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- Huang, X. F., et al.
(författare)
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Genomewide Association Study of Acute Anterior Uveitis Identifies New Susceptibility Loci
- 2020
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Ingår i: Investigative Ophthalmology & Visual Science. - : Association for Research in Vision and Ophthalmology (ARVO). - 0146-0404 .- 1552-5783. ; 61:6
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE. Acute anterior uveitis (AAU) is a common intraocular inflammatory disease. AAU occurs in 30% to 50% of patients with ankylosing spondylitis (AS), and both conditions are strongly associated with human leukocyte antigen (HLA)-B 27 , implying a shared etiology. This study aims to apply genomewide association study (GWAS) to characterize the genetic associations of AAU and their relationship to the genetics of AS. METHODS. We undertook the GWAS analyses in 2752 patients with AS with AAU (cases) and 3836 patients with AS without AAU (controls). There were 7,436,415 single-nucleotide polymorphisms (SNPs) available alter SNP microarray genotyping, imputation, and quality-control filtering. RESULTS. We identified one locus associated with AAU at genomewide significance: rs9378248 (P = 2.69 x 10(-8), odds ratio [OR] = 0.78), lying close to HLA-B. Suggestive association was observed at 11 additional loci, including previously reported AS loci ERAP1 (rs27529, P = 2.19 x 10(-7), OR = 1.22) and NOS2 (rs2274894, P = 8.22 x 10(-7), OR = 0.83). Multiple novel suggestive associations were also identified, including MERTK (rsl0171979, P = 2.56 x 10(-6), OR = 1.20), KIFAP3 (rs508063, P = 5.64 x 10(-7), OR = 1.20), CLCN7 (rs67412457, P = 1.33 x 10(-6), OR = 1.25), ACAA2 (rs9947182, P = 9.70 x 10(-7), OR = 1.37), and 5 intergenic loci. The SNP-based heritability is approximately 0.5 for AS alone, and is much higher (approximately 0.7) for AS with AAU. Consistent with the high heritability, a genomewide polygenic risk score shows strong power in identifying individuals at high risk of either AS with AAU or AS alone. CONCLUSIONS. We report here the first GWAS for AAU and identify new susceptibility loci. Our findings confirm the strong overlap in etiopathogenesis of AAU with AS, and also provide new insights into the genetic basis of AAU.
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| 2. |
- 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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| 4. |
- Frisell, T, et al.
(författare)
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SAFETY OF B/TSDMARDS FOR RA AS USED IN CLINICAL PRACTICE - RESULTS FROM THE LAST DECADE OF THE ARTIS PROGRAM
- 2022
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Ingår i: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 81, s. 587-588
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- While the relative efficacy of treatments can be demonstrated in relatively small studies with limited follow-up, most safety concerns are infrequent, requiring longer follow-up and larger populations. This is recognized by the regulatory framework, where data from pivotal randomized controlled trials are usually considered sufficient for demonstrating efficacy and non-toxicity, but post-approval safety studies are required for many years to fully evaluate drug-associated risks. Though such regulatory safety-studies often focus on one drug (vs. all others), clinical decision-making requires data across all available treatment options. Long-standing longitudinal clinical registries, like the Anti-Rheumatic Therapies in Sweden (ARTIS) database, thus have a key role in assessing the relative safety of b/tsDMARDs, allowing simultaneous comparison of all drugs used in clinical practice, with consistent definitions of treatment cohorts, follow-up, and outcomes.ObjectivesTo assess incidence rates of critical safety endpoints for individual b/tsDMARDs used to treat RA, updating previously published reports and including more recently introduced treatments.MethodsNationwide register-based cohort study including all RA patients in Sweden registered as starting any b/tsDMARD between Jan 1st 2010 and Dec 31st 2019, and followed until Dec 31st 2020. The incidence rates of selected outcomes, identified through national healthcare registers, were compared between individual b/tsDMARDs while adjusting for a range of potential confounders (covering demographics, RA-related characteristics and disease activity, and comorbidity) using Inverse Probability of Treatment Weighting. Probabilities were predicted by multinomial logistic regression, regressing all covariates on treatment status. Exposure time was counted from treatment start until stop (+90 days’ lag time), censored at emigration and death.ResultsThere were clear differences between patients starting individual b/tsDMARDs, in particular with TNF inhibitors more often used as a first line b/tsDMARD; sarilumab, baricitinib, and tofacitinib predominantly used later in the treatment course; rituximab used more often for older patients, and non-TNFi generally used more frequently for patients with higher disease activity or comorbidity. Expectedly, these differences translated into differences in the crude rate of safety endpoints.Several differences remained after confounder-adjustment (Table 1), including a higher rate of treatment discontinuation due to adverse events on baricitinib, tofacitinib, and sarilumab. Rituximab was associated with higher rates of several outcomes, but the confounder-adjustment markedly reduced risks and residual confounding likely explain part of the remaining increase. Baricitinib and tofacitinib were associated with higher rates of hospitalised herpes zoster, but not with similarly elevated rates of other serious infections. There were no clear differences in the rate of cardiovascular events or severe depression. Low number of events limit the comparison, in particular for sarilumab and tofacitinib.Table 1.Weighted incidence rate per 1,000 person-years of selected safety outcomes.DMARDNDiscont. due to. adverse eventACSStrokeLiver diseaseHosp. infectionHosp. Herpes zosterHosp. depressionAny hosp.All-cause mortalityETA8244456.24.51.4322.92.315610.8ADA5069465.95.61.1363.51.51669.5INF2832508.25.83.1433.22.019712.7CER2072546.47.02.5343.61.717211.0GOL1796515.96.8-322.8-15411.5ABA3254567.34.71.9362.31.617213.9RTX3990318.46.22.2413.32.419415.1TCZ2619305.75.02.1312.91.616315.7SAR271100---18--298-BARI1665693.04.21.4378.82.617316.7TOFA39282---3212.9-129-Note: Rates based on <5 events set to ‘-‘.ConclusionWe found large differences in the rate of treatment discontinuations due to adverse events across b/tsDMARDs, which were not generally mirrored by corresponding differences in the rates for specific serious adverse events.ReferencesN/AAcknowledgementsARTIS has been or is currently supported by agreements with Abbvie, BMS, Eli Lilly, MSD, Pfizer, Roche, Samsung Bioepis, and Sanofi.Disclosure of InterestsThomas Frisell: None declared, Hannah Bower: None declared, Eva Baecklund: None declared, Daniela Di Giuseppe: None declared, Bénédicte Delcoigne: None declared, Nils Feltelius Employee of: NF is employed by the Medical Products Agency (MPA), which is a governmental body. The views in this abstract may not represent the views of the MPA, Helena Forsblad-d’Elia: None declared, Elisabet Lindqvist: None declared, Ulf Lindström: None declared, Johan Askling Grant/research support from: Karolinska Institutet has entered into agreements with the following companies, with JA as PI: Abbvie,BMS, Eli Lilly, Galapagos, Janssen, Pfizer, Roche, Samsung Bioepis and Sanofi.
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| 8. |
- Klingberg, E., et al.
(författare)
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Gut dysbiosis in ankylosing spondylitis is associated with increased fecal calprotectin
- 2018
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Ingår i: Clinical and Experimental Rheumatology. - : Clinical and Experimental Rheumatology. - 0392-856X .- 1593-098X. ; 36:4, s. 696-696
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Introduction/Aims: Intestinal dysbiosis may be involved in the pathogenesis of ankylosing spondylitis (AS). We aimed to define differences in the gut microbiota composition between patients with AS, ulcerative colitis (UC) and healthy controls (HC) and determine the relations between gut microbiota, fecal calprotectin (FCal) and disease related variables in AS.Methods: Fecal microbiota was analyzed in patients with AS(N=150), UC(N=18) and HC(N=17) using 16S rRNA sequence technique in a targeted approach. Fecal bacterial abundance and profile was also compared with a healthy reference group creating a Dysbiosis Index score (DI 1-5). The AS patients were assessed with questionnaires, back-mobility tests, FCal, ESR and CRP.Results: Principal component analysis showed highly separate clustering of the microbiota in stool samples from patients with AS, UC and HC. We found an expansion of Proteobacteria and a contraction of Bacteroidetes and Lachnospiraceae in AS. Dysbiosis (defined as DI≥3) was found in 88% of AS and an elevated DI correlated with increased FCal (rS=0.303; p<0.001). Samples from AS patients with FCal<50 (n=57) and >200 mg/kg (n=36) clustered separately in multivariate analysis. The patients with a FCal>200 mg/kg had lower abundance of bacteria with anti-inflammatory effects such as Faecalibacterium prausnitzii and Clostridium and higher abundance of various types of Streptococci. No clear association was found between the overall fecal microbiota composition and HLAB-27 status, disease activity, function or medication.Conclusions: The fecal microbiota signature differed greatly between patients with AS, UC and HC. An increased FCal, suggestive of intestinal inflammation, was associated with aberrations in the microbiota composition and increased dysbiosis.
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| 10. |
- Barbulescu, A, et al.
(författare)
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COMPARATIVE EFFECTIVENESS OF JAKI VERSUS BDMARDS; A NATIONWIDE STUDY IN RA
- 2021
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Ingår i: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 80, s. 68-68
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- The Janus kinase inhibitors (JAKi) have been increasingly used for the treatment of rheumatoid arthritis (RA) in Sweden, with baricitinib representing ~80% of prescriptions. Evidence regarding the comparative effectiveness of JAKis versus biologics (bDMARDs), and in particular non- tumour-necrosis-factor inhibitor (TNFi) bDMARDs, in real-life is limited.Objectives:To compare RA patients treated with bDMARDs and JAKi in Sweden, in terms of: (1) patient characteristics at treatment start; (2) proportions of patients remaining on therapy, and response rates, at 12 months.Methods:RA patients starting treatment in 2017 and 2018 with either a TNFi, rituximab, abatacept, interleukin 6 inhibitors (IL6i) or a JAKi as different lines of treatment were identified in the Swedish Rheumatology Quality Register. One patient could contribute with more than one treatment episode.Treatment response at 12 months was measured as EULAR good response, HAQ improvement >0.2 units, DAS28 and CDAI remission, and as 0 tender and swollen joint counts (28JC). Patients were classified as non-responders if they stopped treatment before evaluation due to safety or inefficacy. Responses for patients who stopped treatment due to pregnancy or death and patients on treatment but with missing response were imputed using multiple imputation.Proportions of responders and differences in proportions between treatment groups, adjusted using inverse probability of treatment weighting, were estimated using linear regression with robust standard errors.Results:JAKi were often used after bDMARDs, and less frequently prescribed in combination with methotrexate. Measured comorbidities were less frequent among JAKi initiators than among non-TNFi biologic initiators, but RA activity was similar (Table).Table 1.Patient characteristics at treatment initiationCharacteristicMedian (IQR) or N (%)AbataceptIL6iRituximabTNFiJAKiTreatment Starts6945346923497905Age63 (53-71)59 (48-70)65 (54-73)59 (47-68)60 (51-70)Female543 (78)441 (83)519 (75)2739 (78)759 (84)RA duration (years)13 (5-21)10 (5-18)12 (6-22)9 (3-17)13 (7-22)Rheum. factor535 (79)385 (73)588 (87)2405 (70)686 (77)DAS284.8 (3.9-5.6)4.9 (4.0-5.7)4.7 (3.8-5.5)4.4 (3.4-5.3)4.7 (3.9-5.7)HAQ1.3 (0.8-1.6)1.3 (0.8-1.8)1.3 (0.8-1.8)1.0 (0.5-1.4)1.3 (0.8-1.8)Tender joints5 (2-9)6 (3-10)5 (2-9)4 (2-8)6 (2-10)Swollen joints4 (2-6)4 (2-7)4 (2-7)3 (1-6)4 (2-7)ts/bDMARD line3 (2-4)3 (2-4)2 (1-4)1 (1-2)4 (2-6)At least one prev. TNFi539 (78)442 (83)457 (66)1448 (41)770 (85)At least one prev. non-TNFi271 (39)220 (41)243 (35)441 (13)584 (65)Methotrexate co-treatment264 (50)172 (40)286 (53)1708 (62)296 (40)Glucocorticoids co-treatment247 (47)186 (43)275 (51)1126 (41)389 (53)Cancer*90 (2.8)64 (2.3)363 (7.7)410 (1.8)20 (2.2)Cardio-vascular dis.*245 (7.5)123 (4.4)322 (6.8)749 (3.4)41 (4.4)Chronic respiratory dis.*303 (9.3)140 (5.0)473 (10.0)721 (3.2)50 (5.4)Diabetes*324 (9.9)216 (7.7)456 (9.7)1479 (6.7)69 (7.5)* any diagnosis within 5 years before start Adjusted differences in proportion with each response outcomeIn a crude comparison, 65% (61%-68%) of JAKi, 62% (59%-66%) of abatacept, 58% (53%-62%) of IL6i, 80% (77%-83%) of rituximab and 68% (67%-70%) of TNFi initiators remained on treatment at 12 months after start. Also, JAKi showed lower overall responder proportions than TNFi, rituximab and IL6i.After adjustment for demographic and socio-economic factors, RA disease activity, previous use of ts/bDMARDs, co-medication with glucocorticoids and methotrexate and comorbidities at baseline, no significant differences in responder proportions between JAKi and bDMARDs remained (Figure). Furthermore, the adjusted proportions of patients on treatment were higher for JAKi and rituximab than for the other bDMARDs.Conclusion:This preliminary analysis of patients treated in clinical practice found no statistically significant difference in effectiveness between JAKi and bDMARDs.Disclosure of Interests:Andrei Barbulescu: None declared, Johan Askling Grant/research support from: Abbvie, Astra-Zeneca, BMS, Eli Lilly, MSD, Pfizer, Roche, Samsung Bioepis, Sanofi, and UCB. These entities have entered into agreements with Karolinska Institutet with JA as principal investigator, mainly in the context of safety monitoring of biologics via the ARTIS national safety monitoring system, Katerina Chatzidionysiou Speakers bureau: Eli Lilly, Abbvie and Pfizer, Consultant of: Eli Lilly, Abbvie and Pfizer, Helena Forsblad-d’Elia: None declared, Alf Kastbom Employee of: Sanofi, Ulf Lindström: None declared, Carl Turesson Speakers bureau: Abbvie, Bristol-Myers Squibb, Medac, Pfizer, Roche, Consultant of: Roche, Grant/research support from: Bristol-Myers Squibb, Thomas Frisell: None declared
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