| 1. |
- 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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| 2. |
- 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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| 3. |
- Bengtsson, K, et al.
(författare)
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RISK FACTORS FOR NON-VERTEBRAL FRACTURES IN ANKYLOSING SPONDYLITIS
- 2022
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Ingår i: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 81, s. 785-786
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Osteoporosis is common in patients with ankylosing spondylitis (AS) and a risk factor for fragility fractures. Additional established risk factors for fractures in the general population include higher age, female sex, previous fracture, fall tendency, glucocorticoid treatment, insulin dependent diabetes, smoking and high alcohol consumption.ObjectivesTo estimate the influence of established risk factors for fragility fractures on the development of non-vertebral fractures in AS and population controls.MethodsThrough linkage of national population and health care registers 2001-2016, patients with AS (n=11611, 65.5% men, mean age 48 years) and age-, sex- and geography-matched population controls (n=58050) were identified and from 1 January 2007 (or 3 months after the first registered AS diagnosis if this occurred later) followed prospectively until the time of a non-vertebral fracture, death, emigration or end of study (30 December 2016). Occurrence of established risk factors for a fracture and AS related characteristics at start of follow-up were identified in the National Patient and Prescribed Drug Registers using ICD-10 and ATC codes. Smoking status and anthropometric measurements are not available in these registers. Chi-square, Fischer’s exact test and T tests were used to compare between subjects with and without a non-vertebral fracture during follow-up, separately for AS and controls. Multivariable Poisson regression was used to estimate the influence of each established risk factor in AS and controls. Risk factors for which there were ≤20 observed events in the AS cohort were not included. Results are presented as incidence rate ratios (IRR) with 95% confidence intervals.ResultsIn total 974 (8.4%) patients with AS and 4106 (7.1%) of their controls were registered with a non-vertebral fracture during the study period. The characteristics of the patients and controls at start of follow-up are presented in Table 1 stratified by fracture status during follow-up. Figure 1 displays the results from the Poisson regression.Table 1.ASControlsNo fracture (n=10637)Fracture (n=974)P-valueNo fracture (n=53944)Fracture (n=4106)P-valueMale sex7002 (65.8)603 (61.9)0.01435448 (65.7)2572 (62.6)<0.001Mean age (SD)47.6 (14.7)53.8 (14.8)<0.00147.8 (14.7)53.0 (15.0)<0.001Prior fracture667 (6.3)140 (14.4)<0.0012715 (5.0)486 (11.8)<0.001Osteoporosis*359 (3.4)83 (8.5)<0.001367 (0.7)85 (2.1)<0.001Fall injury without fracture714 (6.7)97 (10.0)<0.0013205 (5.9)350 (8.5)<0.001Harmful use of alcohol158 (1.5)26 (2.7)0.005889 (1.6)171 (4.2)<0.001Hyperthyroidism39 (0.4)7 (0.7)0.105180 (0.3)19 (0.5)0.173Diabetes type 1178 (1.7)30 (3.1)0.002651 (1.2)80 (1.9)<0.001Liver disease66 (0.6)10 (1.0)0.132197 (0.4)32 (0.8)<0.001Malnutrition8 (0.1)3 (0.3)0.05816 (0.0)2 (0.0)0.367Hypogonadism or premature menopause11 (0.1)1 (0.1)1.00033 (0.1)0 (0.0)0.169Use of oral glucocorticoids#1531 (14.4)152 (15.6)0.304839 (1.6)97 (2.4)<0.001Anterior uveitis2168 (20.4)204 (20.9)0.677317 (0.6)32 (0.8)0.126Psoriasis316 (3.0)34 (3.5)0.364605 (1.1)58 (1.4)0.091Inflammatory bowel disease675 (6.3)64 (6.6)0.783441 (0.8)35 (0.9)0.811Use of any DMARD¤3411 (32.1)266 (27.3)0.002465 (0.9)52 (1.3)0.008Use of TNF inhibitor¤1539 (14.5)109 (11.2)0.00543 (0.1)4 (0.1)0.573The data is presented as number (%) if not stated otherwise. *Diagnosed osteoporosis and/or use of osteoporosis medication. #Prednisolone equivalent cumulative dose of ≥450 mg within the last year before start of follow-up. ¤Use within the last year before start of follow-up.Figure 1.Multivariable Poisson regression analyses for a non-vertebral fracture during follow-up, with results presented for each included baseline variable as IRR with 95% CI, separately for AS and controls.ConclusionThe influence of established risk factors for fragility fractures in AS is similar to that in the general population; in both populations with advanced age, prior fracture and harmful use of alcohol being the strongest risk factors.Disclosure of InterestsKarin Bengtsson: None declared, Johan Askling Grant/research support from: AbbVie, AstraZeneca, Bristol Myers Squibb, Eli Lilly, Janssen, Merck, Pfizer, Roche, Samsung Bioepis, Sanofi, and UCB, Mattias Lorentzon: None declared, Björn Rosengren: None declared, Anna Deminger: None declared, Eva Klingberg: None declared, Lennart T.H. Jacobsson Speakers bureau: Lecture and consulting fees from Novartis, Eli Lilly and Janssen, Helena Forsblad-d’Elia: None declared
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| 4. |
- Deminger, Anna, 1973, et al.
(författare)
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Factors associated with changes in volumetric bone mineral density and cortical area in men with ankylosing spondylitis : a 5-year prospective study using HRpQCT
- 2022
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Ingår i: Osteoporosis International. - : Springer. - 0937-941X .- 1433-2965. ; 33:1, s. 205-216
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Tidskriftsartikel (refereegranskat)abstract
- Summary: Patients with ankylosing spondylitis (AS) have impaired volumetric bone mineral density (vBMD) assessed with high-resolution peripheral computed tomography (HRpQCT). This first longitudinal HRpQCT study in AS shows that cortical and trabecular vBMD decreased at tibia and that signs of inflammation were associated with cortical bone loss at tibia and radius.Introduction: Patients with ankylosing spondylitis (AS) have reduced volumetric bone mineral density (vBMD) in the peripheral skeleton assessed with high-resolution peripheral quantitative computed tomography (HRpQCT). The aims were to investigate longitudinal changes in vBMD, cortical area, and microarchitecture and to assess factors associated with changes in vBMD and cortical area in men with AS.Methods: HRpQCT of radius and tibia was performed in 54 men with AS at baseline and after 5 years. Univariate and multivariable linear regression analyses were used.Results: At tibia, there were significant decreases exceeding least significant changes (LSC) in cortical and trabecular vBMD, mean (SD) percent change −1.0 (1.9) and −2.7 (5.0) respectively (p<0.001). In multivariable regression analyses, increase in disease activity measured by ASDAS_CRP from baseline to follow-up was associated with decreases in cortical vBMD (β −0.86, 95% CI −1.31 to −0.41) and cortical area (β −1.66, 95% CI −3.21 to −0.10) at tibia. At radius, no changes exceeded LSC. Nonetheless, increase in ASDAS_CRP was associated with decreases in cortical vBMD, and high time-averaged ESR was associated with decreases in cortical area. Treatment with TNF inhibitor ≥ 4 years during follow-up was associated with increases in cortical vBMD and cortical area at tibia, whereas exposure to bisphosphonates was associated with increases in cortical measurements at radius. No disease-related variables or treatments were associated with changes in trabecular vBMD.Conclusion: The findings in this first longitudinal HRpQCT study in patients with AS strengthen the importance of controlling disease activity to maintain bone density in the peripheral skeleton.
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