| 1. |
- Andersson, Maria L.E., et al.
(författare)
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Autoantibodies to Disease-Related Proteins in Joints as Novel Biomarkers for the Diagnosis of Rheumatoid Arthritis
- 2023
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Ingår i: Arthritis & Rheumatology. - : Wiley. - 2326-5191 .- 2326-5205. ; 75:7, s. 1110-1119
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Tidskriftsartikel (refereegranskat)abstract
- Objective. This study was undertaken to develop and characterize a multiplex immunoassay for detection of autoantibodies against peptides derived from proteins known to play a role in development of arthritis and that are also expressed in joints.Methods. We selected peptides from the human counterpart of proteins expressed in the joints, based on mouse models that showed these to be targeted by pathogenic or regulatory antibodies in vivo. Using bead-based flow immunoassays measuring IgG antibodies, we selected triple helical or cyclic peptides, containing the epitopes, to avoid collinear reactivity. We characterized the analytical performance of the immunoassay and then validated it in 3 independent rheumatoid arthritis (RA) cohorts (n = 2,110), Swedish age- and sex-matched healthy controls, and patients with osteoarthritis (OA), patients with psoriatic arthritis (PsA), and patients with systemic lupus erythematosus (SLE).Results. Screening assays showed 5 peptide antigens that discriminated RA patients from healthy controls with 99% specificity (95% confidence interval [CI] 98-100%). In our validation studies, we reproduced the discriminatory capacity of the autoantibodies in 2 other RA cohorts, showing that the autoantibodies had high discriminatory capacity for RA versus OA, PsA, and SLE. The novel biomarkers identified 22.5% (95% CI 19-26%) of early RA patients seronegative for anti-cyclic citrullinated peptide and rheumatoid factor. The usefulness of the biomarkers in identifying seronegative RA patients was confirmed in validation studies using 2 independent cohorts of RA patients and cohorts of patients with OA, PsA, and SLE.Conclusion. A multiplex immunoassay with peptides from disease-related proteins in joints was found to be useful for detection of specific autoantibodies in RA serum. Of note, this immunoassay had high discriminatory capacity for early seronegative RA.
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| 2. |
- Aoun, M., et al.
(författare)
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Antigen-presenting autoreactive B cells activate regulatory T cells and suppress autoimmune arthritis in mice
- 2023
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Ingår i: Journal of Experimental Medicine. - Stockholm : Karolinska Institutet, Dept of Medical Biochemistry and Biophysics. - 0022-1007 .- 1540-9538. ; 220:11
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Tidskriftsartikel (refereegranskat)abstract
- B cells undergo several rounds of selection to eliminate potentially pathogenic autoreactive clones, but in contrast to T cells, evidence of positive selection of autoreactive B cells remains moot. Using unique tetramers, we traced natural autoreactive B cells (C1-B) specific for a defined triple-helical epitope on collagen type-II (COL2), constituting a sizeable fraction of the physiological B cell repertoire in mice, rats, and humans. Adoptive transfer of C1-B suppressed arthritis independently of IL10, separating them from IL10-secreting regulatory B cells. Single-cell sequencing revealed an antigen processing and presentation signature, including induced expression of CD72 and CCR7 as surface markers. C1-B presented COL2 to T cells and induced the expansion of regulatory T cells in a contact-dependent manner. CD72 blockade impeded this effect suggesting a new downstream suppressor mechanism that regulates antigen-specific T cell tolerization. Thus, our results indicate that autoreactive antigen-specific naive B cells tolerize infiltrating T cells against self-antigens to impede the development of tissue-specific autoimmune inflammation.
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| 3. |
- Bower, H., et al.
(författare)
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Effects of the COVID-19 pandemic on patients with inflammatory joint diseases in Sweden: from infection severity to impact on care provision
- 2021
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Ingår i: Rmd Open. - : BMJ. - 2056-5933. ; 7:3
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Tidskriftsartikel (refereegranskat)abstract
- Objectives To compare risks for COVID-19-related outcomes in inflammatory joint diseases (IJDs) and across disease-modifying antirheumatic drugs (DMARDs) during the first two waves of the pandemic and to assess effects of the pandemic on rheumatology care provision. Methods Through nationwide multiregister linkages and cohort study design, we defined IJD and DMARD use annually in 2015-2020. We assessed absolute and relative risks of hospitalisation or death listing COVID-19. We also assessed the incidence of IJD and among individuals with IJD, rheumatologist visits, DMARD use and incidence of selected comorbidities. Results Based on 115 317 patients with IJD in 2020, crude risks of hospitalisation and death listing COVID-19 (0.94% and 0.33% across both waves, respectively) were similar during both waves (adjusted HR versus the general population 1.33, 95% CI 1.23 to 1.43, for hospitalisation listing COVID-19; 1.23, 95% CI 1.08 to 1.40 for death listing COVID-19). Overall, biological disease-modifying antirheumatic drugs (bDMARDs)/targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs) did not increase risks of COVID-19 related hospitalisation (with the exception of a potential signal for JAK inhibitors) or death. During the pandemic, decreases were observed for IJD incidence (-7%), visits to rheumatology units (-16%), DMARD dispensations (+6.5% for bDMARD/tsDMARDs and -8.5% for conventional synthetic DMARDs compared with previous years) and for new comorbid conditions, but several of these changes were part of underlying secular trends. Conclusions Patients with IJD are at increased risk of serious COVID-19 outcomes, which may partially be explained by medical conditions other than IJD per se. The SARS-CoV-2 pandemic has exerted measurable effects on aspects of rheumatology care provision demonstrated, the future impact of which will need to be assessed.
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| 4. |
- Bower, Hannah, et al.
(författare)
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Impact of the COVID-19 pandemic on morbidity and mortality in patients with inflammatory joint diseases and in the general population : a nationwide Swedish cohort study
- 2021
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ Publishing Group Ltd. - 0003-4967 .- 1468-2060. ; 80:8, s. 1086-1093
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: To estimate absolute and relative risks for all-cause mortality and for severe COVID-19 in inflammatory joint diseases (IJDs) and with antirheumatic therapies.Methods: Through Swedish nationwide multiregister linkages, we selected all adult patients with rheumatoid arthritis (RA, n=53 455 in March 2020), other IJDs (here: spondyloarthropathies, psoriatic arthritis and juvenile idiopathic arthritis, n=57 112), their antirheumatic drug use, and individually matched population referents. We compared annual all-cause mortality March-September 2015 through 2020 within and across cohorts, and assessed absolute and relative risks for hospitalisation, admission to intensive care and death due to COVID-19 March-September 2020, using Cox regression.Results: During March-September 2020, the absolute all-cause mortality in RA and in other IJDs was higher than 2015-2019, but relative risks versus the general population (around 2 and 1.5) remained similar during 2020 compared with 2015-2019. Among patients with IJD, the risks of hospitalisation (0.5% vs 0.3% in their population referents), admission to intensive care (0.04% vs 0.03%) and death (0.10% vs 0.07%) due to COVID-19 were low. Antirheumatic drugs were not associated with increased risk of serious COVID-19 outcomes, although for certain drugs, precision was limited.Conclusions: Risks of severe COVID-19-related outcomes were increased among patients with IJDs, but risk increases were also seen for non-COVID-19 morbidity. Overall absolute and excess risks are low and the level of risk increases are largely proportionate to those in the general population, and explained by comorbidities. With possible exceptions, antirheumatic drugs do not have a major impact on these risks.
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| 5. |
- Di Giuseppe, D., et al.
(författare)
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Comparison of treatment retention of originator vs biosimilar products in clinical rheumatology practice in Sweden
- 2021
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Ingår i: Rheumatology. - : Oxford University Press (OUP). - 1462-0324 .- 1462-0332. ; 61:9, s. 3596-3605
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Tidskriftsartikel (refereegranskat)abstract
- Objectives To compare treatment retention between biosimilars and their originator products among first starters (etanercept, infliximab, adalimumab and rituximab), as well as after non-medical switch. Methods Patients with rheumatic diseases starting, for the first time, an originator or biosimilar etanercept, infliximab, adalimumab or rituximab were identified in the national Swedish Rheumatology Quality Register. Moreover, patients switching from an originator to its biosimilar were identified and individually matched to patients continuing on the originator. One-year treatment retention was calculated and hazard ratios (HR) for discontinuation with 95% CIs were estimated, adjusting for comorbidities and socio-economic factors. Results In total, 21 443 first treatment courses were identified. The proportion of patients still on the drug at 1 year and the HR for discontinuation revealed no differences across adalimumab (Humira, Imraldi, Amgevita and Hyrimoz) nor across rituximab products (Mabthera, Ritemvia/Truxima and Rixathon). The proportions on the drug at 1 year were similar for Benepali (77%) and Enbrel (75%) and the adjusted HR for Benepali compared with Enbrel was 0.91 (95% CI 0.83, 0.99). For infliximab, the proportion still on the drug at 1 year was 67% for Remicade and 66% for Remsima/Inflectra and the HR compared with Remicade was 1.16 (95% CI 1.02, 1.33). Among 2925 patients switching from an originator drug to one of its biosimilars, we noted no statistically significant or clinically relevant differences in drug survival compared with those who remained on originator therapy. Conclusion This large observational study supports the equivalence of biologic DMARD biosimilar products and originators when used in routine rheumatology care.
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| 6. |
- Di Giuseppe, D., et al.
(författare)
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Uptake of rheumatology biosimilars in the absence of forced switching
- 2018
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Ingår i: Expert Opinion on Biological Therapy. - : Informa UK Limited. - 1471-2598 .- 1744-7682. ; 18:5, s. 499-504
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Tidskriftsartikel (refereegranskat)abstract
- Background: To describe the uptake and system-level effects of the introduction of biosimilars in a setting without forced switching.Research design and methods: We used data from the Swedish Rheumatology Quality register from start of marketing of infliximab (Remsima (R) and Inflectra (R)) and etanercept (Benepali (R)) biosimilars until 31 December 2016. We compared users of each originator-product and its biosimilar(s) by line of treatment: bDMARD-naive patients, non-medical switchers (vs. matched patients remaining on originator), and patients switching from a previous bDMARD of another type.Results: From the start of marketing 1343 patients started an infliximab biosimilar (22 months) and 2691 started etanercept (9months). Overall, the introduction of these biosimilars resulted in an increase of the total number of ongoing infliximab and etanercept treatments (originator + biosimilar) . At the end of the study period, biosimilars accounted for 31% of all infliximab treatments and 31% of all etanercept-treated patients. For each line of therapy, we noted only small differences in patient characteristics between those starting the originator product vs. its biosimilar(s).Conclusions: Introduction of biosimilars have effects beyond replacement of the originator product, in terms of an increased rate of bDMARD initiation. Selection to non-medical switching displayed no particular disease- or patient-characteristics.
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| 7. |
- Eriksson, Per, et al.
(författare)
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Successful Treatment of AA Amyloidosis in Ankylosing Spondylitis Using Tocilizumab: Report of Two Cases and Review of the Literature
- 2021
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Ingår i: Frontiers in Medicine. - : Frontiers Media SA. - 2296-858X. ; 8
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Forskningsöversikt (refereegranskat)abstract
- Historically, secondary amyloidosis has been a feared complication of chronic inflammatory conditions. The fibril protein AA derives from the acute phase reactant serum amyloid A (SAA). Long-term elevation of SAA levels remains a major risk factor for the development of AA amyloidosis in rheumatic diseases, and the prognosis may be unpredictable. Nowadays, with increased availability of effective biological agents, the incidence of AA amyloidosis seems to be declining. Still, genetically predisposed subjects with slowly progressive disease and mild symptoms combined with ongoing systemic inflammation may be at risk. Interleukin-6 (IL-6) is one of the drivers of SAA release and effectiveness of the humanized anti-IL-6 receptor antibody tocilizumab (TCZ) for the treatment of AA amyloidosis has been observed in some rheumatic conditions. Herein, we report two male subjects with longstanding ankylosing spondylitis (AS) complicated by renal amyloidosis who received TCZ with rapid and beneficial effects regarding inflammation and proteinuria. To the best of our knowledge, the use of TCZ in AS patients with this extra-articular manifestation has not previously been described. The paper includes histopathology, clinical follow-up, and longitudinal data of the two cases along with a comprehensive review of relevant literature. Mechanisms behind amyloid-mediated tissue damage and organ dysfunction are discussed. Altogether, our data highlight that blocking IL-6 signaling may represent a promising therapeutic option in patients with renal AA amyloidosis.
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| 8. |
- Hedenstedt, Anna, et al.
(författare)
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B cell polygenic risk scores associate with anti-dsDNA antibodies and nephritis in systemic lupus erythematosus.
- 2023
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Ingår i: Lupus science & medicine. - : BMJ Publishing Group Ltd. - 2053-8790. ; 10:2
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Tidskriftsartikel (refereegranskat)abstract
- B cell function and autoantibodies are important in SLE pathogenesis. In this work, we aimed to investigate the impact of cumulative SLE B cell genetics on SLE subphenotype and autoantibody profile.Female patients with SLE (n=1248) and healthy controls (n=400) were genotyped using Illumina's Global Screening Array. Two polygenic risk scores (PRSs), one representing B cell genes and the other B cell activation genes, were calculated for each individual using risk loci for SLE in genes assigned to B cell-related pathways according to the Kyoto Encyclopedia of Genes and Genomes, Gene Ontology and Reactome Databases.Double-stranded DNA (dsDNA) antibodies were more prevalent among patients with a high compared with a low SLE B cell PRS (OR 1.47 (1.07 to 2.01), p=0.018), and effect sizes were augmented in patients with human leucocyte antigen (HLA) risk haplotypes HLA-DRB1*03:01 and HLA-DRB1*15:01 (DRB1*03/15 -/- (OR 0.99 (0.56 to 1.77), p=0.98; DRB1*03/15 +/- or -/+ (OR 1.64 (1.06 to 2.54), p=0.028; and DRB1*03/15 +/+ (OR 4.47 (1.21 to 16.47), p=0.024). Further, a high compared with a low B cell PRS was associated with low complement levels in DRB1*03/15 +/+ patients (OR 3.92 (1.22 to 12.64), p=0.022). The prevalence of lupus nephritis (LN) was higher in patients with a B cell activation PRS above the third quartile compared with patients below (OR 1.32 (1.00 to 1.74), p=0.048).High genetic burden related to B cell function is associated with dsDNA antibody development and LN. Assessing B cell PRSs may be important in order to determine immunological pathways influencing SLE and to predict clinical phenotype.
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| 9. |
- Leu Agelii, Monica, 1977, et al.
(författare)
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Autoantibodies to joint-related peptides as predictive markers in early rheumatoid arthritis
- 2024
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Ingår i: RHEUMATOLOGY. - : OXFORD UNIV PRESS. - 1462-0324 .- 1462-0332.
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Tidskriftsartikel (refereegranskat)abstract
- Objective For better management of RA, new biomarkers are needed to predict the development of different disease courses. This study aims to identify autoantibodies against epitopes on proteins in the joints and to predict disease outcome in patients with new onset RA.Methods Sera from new-onset RA patients from the Swedish BARFOT (Better Anti Rheumatic PharmacOTherapy) and TIRA-2 (Swedish acronym for 'tidiga insatser vid reumatoid artrit') cohorts (n = 1986) were screened for autoantibodies to selected peptides (JointIDs) in a bead-based multiplex flow immunoassay. Disease outcomes included Boolean remission 1.0, swollen joint count and radiographic destruction. Multivariate logistic regression and zero-inflated negative binomial models that accounted for clinical factors were used to identify JointIDs with the strongest potential to predict prognosis.Results Boolean remission was predicted with 42% sensitivity and 75% specificity in male patients positive for antibodies to a non-modified collagen type II (COL2) peptide at 12 months. When antibodies to a specific citrullinated cartilage oligomeric protein (COMP) peptide were absent and the patient was in Boolean remission at 6 months, the sensitivity was 13% and the specificity 99%. Positivity for the non-modified COL2 peptide also reduced the frequency of swollen joints by 41% and 33% at 6 and 12 months, respectively. Antibodies to CCP predicted joint destruction with low specificity (58%). Positivity for a COL2 and a glucose-6-phosphate dehydrogenase peptide in citrullinated forms increased specificity (86%) at the expense of sensitivity (39%).Conclusion Autoantibodies against joint-related proteins at RA diagnosis predict remission with high specificity and, in combination with clinical factors, may guide future treatment decisions.
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| 10. |
- Leu Agelii, Monica, 1977, et al.
(författare)
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Disease activity trajectories in rheumatoid arthritis: a tool for prediction of outcome
- 2021
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Ingår i: Scandinavian Journal of Rheumatology. - : Informa UK Limited. - 0300-9742 .- 1502-7732. ; 501:1, s. 1-10
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Tidskriftsartikel (refereegranskat)abstract
- Objective Predicting treatment response and disease progression in rheumatoid arthritis (RA) remains an elusive endeavour. Identifying subgroups of patients with similar progression is essential for understanding what hinders improvement. However, this cannot be achieved with response criteria based on current versus previous Disease Activity Scores, as they lack the time component. We propose a longitudinal approach that identifies subgroups of patients while capturing their evolution across several clinical outcomes simultaneously (multi-trajectories). Method For exploration, the RA cohort BARFOT (n = 2829) was used to identify 24 month post-diagnosis simultaneous trajectories of 28-joint Disease Activity Score and its components. Measurements were available at inclusion (0), 3, 6, 12, 24, and 60 months. Multi-trajectories were found with latent class growth modelling. For validation, the TIRA-2 cohort (n = 504) was used. Radiographic changes, assessed by the modified Sharp van der Heijde score, were correlated with trajectory membership. Results Three multi-trajectories were identified, with 39.6% of the patients in the lowest and 18.9% in the highest (worst) trajectory. Patients in the worst trajectory had on average eight tender and six swollen joints after 24 months. Radiographic changes at 24 and 60 months were significantly increased from the lowest to the highest trajectory. Conclusion Multi-trajectories constitute a powerful tool for identifying subgroups of RA patients and could be used in future studies searching for predictive biomarkers for disease progression. The evolution and shape of the trajectories in TIRA-2 were very similar to those in BARFOT, even though TIRA-2 is a newer cohort.
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