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- Saevarsdottir, S., et al.
(författare)
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Multiomics analysis of rheumatoid arthritis yields sequence variants that have large effects on risk of the seropositive subset
- 2022
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 81:8
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Tidskriftsartikel (refereegranskat)abstract
- Objectives To find causal genes for rheumatoid arthritis (RA) and its seropositive (RF and/or ACPA positive) and seronegative subsets. Methods We performed a genome-wide association study (GWAS) of 31 313 RA cases (68% seropositive) and similar to 1 million controls from Northwestern Europe. We searched for causal genes outside the HLA-locus through effect on coding, mRNA expression in several tissues and/or levels of plasma proteins (SomaScan) and did network analysis (Qiagen). Results We found 25 sequence variants for RA overall, 33 for seropositive and 2 for seronegative RA, altogether 37 sequence variants at 34 non-HLA loci, of which 15 are novel. Genomic, transcriptomic and proteomic analysis of these yielded 25 causal genes in seropositive RA and additional two overall. Most encode proteins in the network of interferon-alpha/beta and IL-12/23 that signal through the JAK/STAT-pathway. Highlighting those with largest effect on seropositive RA, a rare missense variant in STAT4 (rs140675301-A) that is independent of reported non-coding STAT4-variants, increases the risk of seropositive RA 2.27-fold (p=2.1x10(-9)), more than the rs2476601-A missense variant in PTPN22 (OR=1.59, p=1.3x10(-160)). STAT4 rs140675301-A replaces hydrophilic glutamic acid with hydrophobic valine (Glu128Val) in a conserved, surface-exposed loop. A stop-mutation (rs76428106-C) in FLT3 increases seropositive RA risk (OR=1.35, p=6.6x10(-11)). Independent missense variants in TYK2 (rs34536443-C, rs12720356-C, rs35018800-A, latter two novel) associate with decreased risk of seropositive RA (ORs=0.63-0.87, p=10(-9)-10(-27)) and decreased plasma levels of interferon-alpha/beta receptor 1 that signals through TYK2/JAK1/STAT4. Conclusion Sequence variants pointing to causal genes in the JAK/STAT pathway have largest effect on seropositive RA, while associations with seronegative RA remain scarce.
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- Frisell, T, et al.
(författare)
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Comparative analysis of first-year fingolimod and natalizumab drug discontinuation among Swedish patients with multiple sclerosis
- 2016
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Ingår i: Multiple sclerosis (Houndmills, Basingstoke, England). - : SAGE Publications. - 1477-0970 .- 1352-4585. ; 22:1, s. 85-93
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Tidskriftsartikel (refereegranskat)abstract
- Natalizumab (NTZ) and fingolimod (FGL) are mainly used second line in relapsing–remitting multiple sclerosis (MS), although pivotal trials included mainly treatment-naïve patients. Objective: This study aims to provide real-world data on safety and discontinuation rates. Methods: Using IMSE, a drug monitoring registry for all newer MS drugs in Sweden, we analysed differences in baseline characteristics and 1-year drug survival for patients registered 2011–2013, initiating treatment with NTZ ( n=640) or FGL ( n=876). Among FGL initiators, n=383 (44%) had previously used NTZ (FGLafterNTZ). Results: Compared with NTZ, the FGL cohort was older and more often male (36/38 years, 24%/33% males). Baseline Expanded Disability Status Scale was similar across groups, but MS Severity Score was higher in NTZ patients, and Symbol Digit Modalities Test and MS Impact Scale (MSIS-29) was higher in FGLafterNTZ versus FGLNTZ-naïve patients. Proportion on drug after 1 year was high, NTZ=87%, FGLNTZ-naïve=83% and FGLafterNTZ=76%. Adverse events was the most frequent reason for discontinuing FGL (FGLNTZ-naïve=9%, FGLafterNTZ=12%), and was significantly higher than on NTZ (3%). In contrast, the proportion of patients stopping treatment due to lack of effect was more similar: NTZ=4%, FGLNTZ-naïve=3%, FGLafterNTZ=8%. Conclusion: FGL and NTZ were both well tolerated, but FGL less so than NTZ, especially in patients switching to FGL from NTZ. Group differences were not explained by differences in recorded baseline characteristics.
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- Hagman, J, et al.
(författare)
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THE EFFECT OF UV-B RADIATION EXPOSURE ON THE RISK OF DEVELOPING RHEUMATOID ARTHRITIS
- 2021
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Ingår i: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 80, s. 145-145
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- UV-B radiation has known immunomodulatory properties, but to what extent UV-B radiation exposure might affect the occurrence of rheumatoid arthritis (RA) has been relatively little studied, and with partially contradictory results.Objectives:To investigate the association between sun- and travel habits, as proxy markers for UV-B radiation exposure, and risk of incident RA, overall and by RA subtype.Methods:We performed a matched case-control study of 1151 incident cases with new-onset RA and 2374 population controls from the Swedish Epidemiological Investigation of Rheumatoid Arthritis (EIRA) study, recruited between 2006 and 2017. The association between sunbathing frequency, solarium use, and frequency of travels to sunnier countries than Sweden (exposures) and risk of RA (outcome) were assessed as odds ratios (OR) with 95 % confidence intervals (CI) through logistic regression, and adjusted for age, sex, residential region, year of study entry, body mass index, education, income, smoking and alcohol consumption. We further assessed effect modification by self-reported skin type, income and education, and by rheumatoid factor (RF) serostatus.Results:Overall, the frequency of sunbathing, and solarium use, were similar among RA cases and controls: ‘never doing sunbathing’ amongst RA cases vs. controls: 22% vs. 21 %, ‘sunbathing daily when possible’: 10% vs. 12%, and solarium use 13% vs. 12%. The proportion of ‘not travelled abroad to a sunnier country than Sweden during the past 5 years’ was higher for RA cases than controls: 27% vs. 23%, and ‘travelling abroad more than once a year’ was less common among RA cases: 15% vs. 20%.Sunbathing frequency was not linked to risk of RA (OR 0.91, 95% CI 0.69-1.20), nor was solarium use (OR 1.07, 95% CI 0.85-1.35). Stratification by skin type revealed no major effect modification, nor did stratification by RF status. In contrast, frequency of travel to sunnier countries than Sweden was inversely associated with RA risk comparing the most to least frequent travelers (OR 0.68, 95% CI 0.54-0.87). When stratified by educational level, this association was confined to individuals with medium (OR 0.69, 95% CI 0.48-0.98) or high (OR 0.60, 95% CI 0.50-0.91) and absent among subjects with low education (OR 1.10, 95% CI 0.56-1.99). No such interaction was observed between travel habits and income.Table 1.RA cases and controls with adjusted odds ratios and confidence intervals for overall risk of RA and by RA serostatus.NOR* for RA (95% CI)Exposure variableRA casesControlsRF+RF-All RARF+RF-SunbathingaNever24949516185refrefrefAt least once a month3988442651241.05 (0.85-1.29)1.07 (0.84-1.36)0.98 (0.72-1.34)At least once a week3767512391301.11 (0.90-1.38)1.07 (0.83-1.37)1.21 (0.88-1.66)Daily12027875430.91 (0.69-1.20)0.86 (0.62-1.20)0.96 (0.64-1.46)TravelbNever314537208103refrefRefSeldom294568193970.98 (0.79-1.21)0.98 (0.77-1.25)0.98 (0.71-1.35)Once a year3598052271210.82 (0.67-1.01)0.80 (0.63-1.02)0.83 (0.61-1.13)More than once a year176463112610.68 (0.54-0.87)0.68 (0.51-0.91)0.70 (0.48-1.01)SolariumcNever9912083634336refrefRefOnce per year or more153290107461.07 (0.85-1.35)1.08 (0.83-1.40)1.11 (0.77-1.59)OR = adjusted odds ratio, CI = confidence interval, N = number of participants, RA = rheumatoid arthritis, ref = reference, RF= rheumatoid factor. a Frequency of sunbathing if the weather invites to it? b Frequency of travels to a country sunnier than Sweden in the last 5 years? c Frequency of solarium use in the last 5 years? *Adjusting for age, sex, region, index year, BMI, smoking, alcohol consumption, education level and income. <4 % of data was missing for all variables.Conclusion:Proxy markers for UV-B exposure (sunbathing frequency and solarium use within the past five years) do not seem to be strong risk factors for RA. Frequency of travels abroad was inversely associated to RA risk. The nature behind this association remains unclear.Disclosure of Interests:Johanna Hagman: None declared, Bénédicte Delcoigne: None declared, Lars Klareskog: None declared, Lars Alfredsson: None declared, Johan Askling Grant/research support from: JA acts or has acted as PI for agreements between Karolinska Institutet and the following entities, mainly in the context of the ARTIS national safety monitoring programme of immunomodulators in rheumatology: Abbvie, BMS, Eli Lilly, Merck, MSD, Pfizer, Roche, Samsung Bioepis, Sanofi, and UCB Pharma
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