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- Acosta-Herrera, M, et al.
(författare)
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Genome-wide meta-analysis reveals shared new loci in systemic seropositive rheumatic diseases
- 2019
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Ingår i: Annals of the rheumatic diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 78:3, s. 311-319
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Tidskriftsartikel (refereegranskat)abstract
- Immune-mediated inflammatory diseases (IMIDs) are heterogeneous and complex conditions with overlapping clinical symptoms and elevated familial aggregation, which suggests the existence of a shared genetic component. In order to identify this genetic background in a systematic fashion, we performed the first cross-disease genome-wide meta-analysis in systemic seropositive rheumatic diseases, namely, systemic sclerosis, systemic lupus erythematosus, rheumatoid arthritis and idiopathic inflammatory myopathies.MethodsWe meta-analysed ~6.5 million single nucleotide polymorphisms in 11 678 cases and 19 704 non-affected controls of European descent populations. The functional roles of the associated variants were interrogated using publicly available databases.ResultsOur analysis revealed five shared genome-wide significant independent loci that had not been previously associated with these diseases: NAB1, KPNA4-ARL14, DGQK, LIMK1 and PRR12. All of these loci are related with immune processes such as interferon and epidermal growth factor signalling, response to methotrexate, cytoskeleton dynamics and coagulation cascade. Remarkably, several of the associated loci are known key players in autoimmunity, which supports the validity of our results. All the associated variants showed significant functional enrichment in DNase hypersensitivity sites, chromatin states and histone marks in relevant immune cells, including shared expression quantitative trait loci. Additionally, our results were significantly enriched in drugs that are being tested for the treatment of the diseases under study.ConclusionsWe have identified shared new risk loci with functional value across diseases and pinpoint new potential candidate loci that could be further investigated. Our results highlight the potential of drug repositioning among related systemic seropositive rheumatic IMIDs.
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- Aggarwal, R, et al.
(författare)
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2016 American College of Rheumatology/European League Against Rheumatism criteria for minimal, moderate, and major clinical response in adult dermatomyositis and polymyositis: An International Myositis Assessment and Clinical Studies Group/Paediatric Rheumatology International Trials Organisation Collaborative Initiative
- 2017
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Ingår i: Annals of the rheumatic diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 76:5, s. 792-801
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Tidskriftsartikel (refereegranskat)abstract
- To develop response criteria for adult dermatomyositis (DM) and polymyositis (PM). Expert surveys, logistic regression, and conjoint analysis were used to develop 287 definitions using core set measures. Myositis experts rated greater improvement among multiple pairwise scenarios in conjoint analysis surveys, where different levels of improvement in 2 core set measures were presented. The PAPRIKA (Potentially All Pairwise Rankings of All Possible Alternatives) method determined the relative weights of core set measures and conjoint analysis definitions. The performance characteristics of the definitions were evaluated on patient profiles using expert consensus (gold standard) and were validated using data from a clinical trial. The nominal group technique was used to reach consensus. Consensus was reached for a conjoint analysis-based continuous model using absolute per cent change in core set measures (physician, patient, and extramuscular global activity, muscle strength, Health Assessment Questionnaire, and muscle enzyme levels). A total improvement score (range 0–100), determined by summing scores for each core set measure, was based on improvement in and relative weight of each core set measure. Thresholds for minimal, moderate, and major improvement were ≥20, ≥40, and ≥60 points in the total improvement score. The same criteria were chosen for juvenile DM, with different improvement thresholds. Sensitivity and specificity in DM/PM patient cohorts were 85% and 92%, 90% and 96%, and 92% and 98% for minimal, moderate, and major improvement, respectively. Definitions were validated in the clinical trial analysis for differentiating the physician rating of improvement (p<0.001). The response criteria for adult DM/PM consisted of the conjoint analysis model based on absolute per cent change in 6 core set measures, with thresholds for minimal, moderate, and major improvement.
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| 5. |
- Che, WI, et al.
(författare)
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Familial aggregation and heritability: a nationwide family-based study of idiopathic inflammatory myopathies
- 2021
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Ingår i: Annals of the rheumatic diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 80:11, s. 1461-1466
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Tidskriftsartikel (refereegranskat)abstract
- The magnitude of the genetic contribution to idiopathic inflammatory myopathies (IIMs) is unknown. In this project, we aimed to investigate the familial aggregation and heritability of IIM.MethodsThis is a family-based study using nationwide healthcare register data in Sweden. We matched each patient with IIM to individuals without IIM, identified their first-degree relatives and determined the IIM status among all first-degree relatives. We estimated the adjusted ORs (aORs) of familial aggregation of IIM using conditional logistic regression. In addition, we used tetrachoric correlation to estimate the heritability of IIM.ResultsWe included 7615 first-degree relatives of 1620 patients with IIM diagnosed between 1997 and 2016 and 37 309 first-degree relatives of 7797 individuals without IIM. Compared with individuals without IIM, patients with IIM were more likely to have ≥1 first-degree relative affected by IIM (aOR=4.32, 95% CI 2.00 to 9.34). Furthermore, the aOR of familial aggregation of IIM in full siblings was 2.53 (95% CI 1.62 to 3.96). The heritability of IIM was 22% (95% CI 12% to 31%) among any first-degree relatives and 24% (95% CI 12% to 37%) among full siblings.ConclusionsIIM has a familial component with a risk of aggregation among first-degree relatives and a heritability of about 20%. This information is of importance for future aetiological studies and in clinical counselling.
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| 9. |
- Demirdal, D, et al.
(författare)
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CHARACTERISATION OF SWEDISH MYOSITIS PATIENTS WITH ANTI-MDA5 AUTOANTIBODIES AND CORRELATION OF CLINICAL FEATURES WITH AUTOANTIBODY LEVELS
- 2022
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Ingår i: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 81, s. 751-752
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- The association between anti-melanoma differentiation association protein 5 autoantibodies (aMDA5) and rapidly progressive interstitial lung disease (RP-ILD) in clinically amyopathic dermatomyositis is well established in Asian population cohorts. In western cohorts, ILD has been strongly associated with aMDA5 but data regarding RP-ILD have been more conflicting. It is also suggested that western cohorts have more pronounced myopathic features than Asian.ObjectivesTo characterise the disease manifestations of a Swedish aMDA5 positive idiopathic inflammatory myositis (IIM) cohort and to explore antigen reactivity of the MDA5 protein.MethodsFirst available serum samples collected from 28 consecutive patients with IIM and positive aMDA5 ever tested by ELISA, Line Blot (LB) or Immunoprecipitation, attending Karolinska University Hospital between 1999 and 2021, were included. Clinical data including presence of anti-SSA autoantibodies by ELISA or LB was retrieved retrospectively. An in-house ELISA was used to screen serum samples for reactivity against a recombinant MDA5 protein (rMDA5, aa A110-D1025, UniProt ID Q9BYX4) and seven MDA5-derived constructs containing different domains. Correlations between aMDA5 reactivity levels and clinical data were explored.ResultsNine patients showed no reactivity to any of the rMDA5 constructs by ELISA and were excluded from further analysis.Reactivity against rMDA5 was confirmed by ELISA in 19 patients (median 184.7 µg/mL (interquartile range (IQR) 277.07). The cohort included 13 male and 6 female patients, 94% Caucasian, with mean age at diagnosis of 41.05 years (standard deviation (SD) 10.5). Median disease duration at time of sampling was 0 months (IQR 1). All patients except one had signs of muscle involvement (muscle weakness, elevated muscle enzymes, muscle oedema or muscle biopsy consistent with myositis). At diagnosis 63.2% of patients reported muscle weakness (21.1 % had a manual muscle test 8 score <75). Dermatological findings were observed in 17/19 (89.7 %). During disease course nine patients (47.4%) had confirmed arthritis.ILD was diagnosed in 16/19 patients (84.2%), four of these (25%) developed a RP-ILD. One patient passed away due to RP-ILD and one required a lung transplant. Patients with ILD had a statistically significant higher mean age at diagnosis than those without (42.8.5 (SD 10.3) vs 31.3 (SD 4.7) years, p=0.02). Patients developing RP-ILD were not significantly older than patients with chronic ILD. Respiratory symptoms were reported by 75% of patients with ILD at time of diagnosis. The mean total lung capacity (TLC) of the ILD cohort was 68% (SD 17), mean diffusion capacity of carbon monoxide (DLCO) was 59% (SD 15) and mean forced vital capacity (FVC) was 62% (SD 19). There was a higher proportion of patients with CRP ≥ 3 times the reference range at diagnosis amongst patients with FVC <70 % than patients with FVC >70 % (88.9 % vs 16.7 %, p= 0.01).Ten patients (52.6%) had anti-SSA autoantibodies, all had ILD. Anti-SSA positive patients had a statistically significant lower TLC than those without (62% vs 79% respectively, p=0.04) and a lower FVC (57% vs 76% respectively, p=0.05).We found a weak non-statistically significant negative correlation between titres of aMDA5 and TLC, DLCO and FVC (Pearson coefficients -0.187, -0.289, -0.130 respectively). Frequency of ILD was higher in patients with aMDA5 titres >100 µg/mL than those with titers <100, but not statistically significant (81.3% vs 18.8%, respectively).ConclusionIn this Caucasian cohort of aMDA5 positive IIM patients, ILD was present in over 80% of patients, of these, one quarter had RP-ILD. Older patients were more likely to present with ILD. Anti-SSA positivity and higher CRP levels were associated with worse lung function. We found a weak negative correlation between aMDA5 titres and lung function tests, as well as a trend of higher frequency of ILD in patients with higher aMDA5 titres. Muscle and skin involvement were found in a high proportion of patients.AcknowledgementsD. Demirdal & E. Van Gompel contributed equally to this abstract.Disclosure of InterestsDeniz Demirdal: None declared, Eveline Van Gompel: None declared, Edvard Wigren: None declared, Maryam Dastmalchi: None declared, Begum Horuluoglu: None declared, Angeles Shunashy Galindo-Feria: None declared, Susanne Gräslund: None declared, Karine Chemin: None declared, Ingrid E. Lundberg Shareholder of: Roche and Novartis., Consultant of: Consulting fees from Corbus Pharmaceuticals Inc, Astra Zeneca, Bristol Myer´s Squibb, Corbus Pharmaceutical, EMD Serono Research & Development Institute, Argenx, Octapharma, Kezaar, Orphazyme, and Janssen, Grant/research support from: Research grants from Astra Zeneca, Antonella Notarnicola Speakers bureau: compensation for lecture at conference sponsored by Boehringer Ingelheim.
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