11 research outputs found
Long-term outcome in systemic lupus erythematosus; knowledge from population-based cohorts
Background: Accurate knowledge of outcomes in Systemic Lupus Erythematosus (SLE) is crucial to understanding the true burden of the disease. The main objective of this systematic review was to gather all population-based studies on mortality, end-stage renal disease (ESRD) and cancer in SLE. Method: We performed a systematic literature search in two electronic databases (MEDLINE and Embase) to identify all population-based articles on SLE and survival, mortality, ESRD and cancer. The SLE diagnosis had to be verified. We used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PRISMA). Results: We included 40/1041 articles on mortality (27), ESRD (11) and cancer (3), of which six were defined as inception studies. In the total SLE cohort, the standardized mortality ratio ranged from 1.9 to 4.6. Cardiovascular disease was the most frequent cause of death in studies with follow-up times over 15 years. SLE progressed to ESRD in 5–11% of all SLE patients. There are no data supporting increased cancer incidence from population-based inception cohorts. Conclusion: There is a need for more population-based studies on outcomes of SLE, especially inception studies, with the use of control groups and follow-up times over 15 years
Development of CT-based methods for longitudinal analyses of paranasal sinus osteitis in granulomatosis with polyangiitis
Background
Even though progressive rhinosinusitis with osteitis is a major clinical problem in granulomatosis with polyangiitis (GPA), there are no studies on how GPA-related osteitis develops over time, and no quantitative methods for longitudinal assessment.
Here, we aimed to identify simple and robust CT-based methods for capture and quantification of time-dependent changes in GPA-related paranasal sinus osteitis and compare performance of the methods under study in a largely unselected GPA cohort.
Methods
GPA patients (n = 121) with ≥3 paranasal CT scans obtained ≥12 months apart and control patients not having GPA or rhinosinusitis (n = 15) were analysed by: (i) Global osteitis scoring scale (GOSS), originally developed for chronic rhinosinusitis; (ii) Paranasal sinus volume by manual segmentation; (iii) Mean maxillary and sphenoid diameter normalised to landmark distances (i.e. diameter ratio measurement, DRM).
Results
Time-dependent changes in GPA-related osteitis were equally well measured by the simple DRM and the labour-intensive volume method while GOSS missed ongoing changes in cases with extensive osteitis. GOSS at last CT combined with DRM identified three distinct patient groups: (i) The no osteitis group, who had no osteitis and no change in DRM from baseline CT to last CT (45/121 GPA patients and 15/15 disease controls); (ii) Stable osteitis group, with presence of osteitis, but no change in DRM across time (31 GPA); (iii) Progressive osteitis, defined by declining DRM (45 GPA).
Conclusions
We suggest DRM and GOSS as complementary methods for capturing, classifying and quantifying time-dependent changes in GPA-related osteitis
Value of MRI and ultrasound for prediction of therapeutic response and erosive progression in patients with early rheumatoid arthritis managed by an aggressive treat-to-target strategy
Objectives To investigate if inflammation detected by MRI or ultrasound at rheumatoid arthritis (RA) onset is predictive of erosive progression or poor response to methotrexate monotherapy, and to investigate if subclinical inflammation in remission is predictive of future treatment escalation or erosive progression.Methods In a 2-year study, 218 patients with disease-modifying antirheumatic drug-naïve early RA were treated by a tight-control treat-to-target strategy corresponding to current recommendations. MRI and ultrasound were performed at regular intervals. Baseline imaging-based inflammation measures were analysed as predictors for early methotrexate failure and erosive progression using univariate and multivariate regression adjusted for clinical, laboratory and radiographic measures. In patients in remission after 1 year, imaging measures were analysed as predictors of treatment escalation and erosive progression during the second year. The added value of imaging in prediction models was assessed using receiver operating characteristic analyses.Results Baseline MRI inflammation was associated with MRI erosive progression and ultrasound with radiographic erosive progression. No imaging inflammation measure was associated with early methotrexate failure. Imaging inflammation was present in a majority of patients in clinical remission. Tenosynovitis was associated with treatment escalation, and synovitis and tenosynovitis with MRI/radiographic erosive progression during the second year. Imaging information did not improve prediction models for any of the outcomes.Conclusions Imaging-detected inflammation, both at diagnosis and in remission, is associated with elements of future disease development. However, the lack of a significant effect on prediction models indicates limited value of systematic MRI and ultrasound in management of early RA
Development of a feasible and responsive ultrasound inflammation score for rheumatoid arthritis through a data-driven approach
Objective: To develop and validate a responsive and
feasible ultrasound inflammation score for rheumatoid
arthritis (RA).
Methods: We used data from cohorts of early RA
(development) and established RA starting/switching
biologic therapy (validation). 4 tendons and 36 joints
were examined by a grey scale (GSUS) and power
Doppler semiquantitative ultrasound (PDUS) scoring
system (full score). Ultrasound score components were
selected based on factor analyses of 3-month change
in the development cohort. Responsiveness was
assessed by standardised response means (SRMs). We
assessed the proportion of information retained from
the full score by linear regression.
Results: 118 patients with early and 212 patients with
established RA were included. The final ultrasound score
included 8 joints (metacarpophalangeal 1–2–3, proximal
interphalangeal 2–3, radiocarpal, metatarsophalangeal
2–3) and 1 tendon (extensor carpi ulnaris) examined
bilaterally. The 6-month SRMs for the final score were
−1.24 (95% CI −1.47 to −1.02) for GSUS, and −1.09
(−1.25 to −0.92) for PDUS in early RA, with 87% of
total information retained for GSUS and 90% for PDUS.
The new score performed somewhat better than
formerly proposed scores in the validation cohort.
Conclusions: The Ultrasound in Rheumatoid Arthritis 9
joint/tendon score (USRA9) inflammation score showed
good responsiveness, retained most of the information
from the original full score and overall performed better
than previous scores in a validation cohort
Ultrasound in management of rheumatoid arthritis: ARCTIC randomised controlled strategy trial
Objective: To determine whether a treatment strategy based on
structured ultrasound assessment would lead to
improved outcomes in rheumatoid arthritis, compared
with a conventional strategy.
Design: Multicentre, open label, two arm, parallel group,
randomised controlled strategy trial.
Setting: Ten rheumatology departments and one specialist centre
in Norway, from September 2010 to September 2015.
Participants: 238 patients were recruited between September 2010 and April 2013, of which 230 (141 (61%) female) received the allocated intervention and were analysed for the primary outcome. The main inclusion criteria were age
18-75 years, fulfilment of the 2010 American College of Rheumatology/European League Against Rheumatism classification criteria for rheumatoid arthritis, disease
modifying anti-rheumatic drug naivety with indication for disease modifying drug therapy, and time from first patient reported swollen joint less than two years.
Patients with abnormal kidney or liver function or major comorbidities were excluded.
Interventions: 122 patients were randomised to an ultrasound tight
control strategy targeting clinical and imaging remission, and 116 patients were randomised to a conventional tight control strategy targeting clinical
remission. Patients in both arms were treated according to the same disease modifying anti-rheumatic drug escalation strategy, with 13 visits over two years.
Main outcome measures: The primary endpoint was the proportion of patients
with a combination between 16 and 24 months of clinical remission, no swollen joints, and nonprogression of radiographic joint damage. Secondary
outcomes included measures of disease activity, radiographic progression, functioning, quality of life, and adverse events. All participants who attended at
least one follow-up visit were included in the full analysis set.
Results: 26 (22%) of the 118 analysed patients in the ultrasound
tight control arm and 21 (19%) of the 112 analysed patients in the clinical tight control arm reached the primary endpoint (mean difference 3.3%, 95% confidence interval −7.1% to 13.7%). Secondary endpoints (disease activity,
physical function, and joint damage) were similar between the two groups. Six (5%) patients in the ultrasound tight control arm and seven (6%) patients in
the conventional arm had serious adverse events.
Conclusions: The systematic use of ultrasound in the follow-up of
patients with early rheumatoid arthritis treated according to current recommendations is not justified on the basis of the ARCTIC results. The findings
highlight the need for randomised trials assessing the clinical application of medical technology
The HLA region in ANCA-associated vasculitis : characterisation of genetic associations in a Scandinavian patient population
Objective: The antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are inflammatory disorders with ANCA autoantibodies recognising either proteinase 3 (PR3-AAV) or myeloperoxidase (MPO-AAV). PR3-AAV and MPO-AAV have been associated with distinct loci in the human leucocyte antigen (HLA) region. While the association between MPO-AAV and HLA has been well characterised in East Asian populations where MPO-AAV is more common, studies in populations of European descent are limited. The aim of this study was to thoroughly characterise associations to the HLA region in Scandinavian patients with PR3-AAV as well as MPO-AAV. Methods: Genotypes of single-nucleotide polymorphisms (SNPs) located in the HLA region were extracted from a targeted exome-sequencing dataset comprising Scandinavian AAV cases and controls. Classical HLA alleles were called using xHLA. After quality control, association analyses were performed of a joint SNP/classical HLA allele dataset for cases with PR3-AAV (n=411) and MPO-AAV (n=162) versus controls (n=1595). Disease-associated genetic variants were analysed for association with organ involvement, age at diagnosis and relapse, respectively. Results: PR3-AAV was significantly associated with both HLA-DPB1*04:01 and rs1042335 at the HLA-DPB1 locus, also after stepwise conditional analysis. MPO-AAV was significantly associated with HLA-DRB1*04:04. Neither carriage of HLA-DPB1*04:01 alleles in PR3-AAV nor of HLA-DRB1*04:04 alleles in MPO-AAV were associated with organ involvement, age at diagnosis or relapse. Conclusions: The association to the HLA region was distinct in Scandinavian cases with MPO-AAV compared with cases of East Asian descent. In PR3-AAV, the two separate signals of association to the HLD-DPB1 region mediate potentially different functional effects
The HLA region in ANCA-associated vasculitis : characterisation of genetic associations in a Scandinavian patient population
Objective: The antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are inflammatory disorders with ANCA autoantibodies recognising either proteinase 3 (PR3-AAV) or myeloperoxidase (MPO-AAV). PR3-AAV and MPO-AAV have been associated with distinct loci in the human leucocyte antigen (HLA) region. While the association between MPO-AAV and HLA has been well characterised in East Asian populations where MPO-AAV is more common, studies in populations of European descent are limited. The aim of this study was to thoroughly characterise associations to the HLA region in Scandinavian patients with PR3-AAV as well as MPO-AAV. Methods: Genotypes of single-nucleotide polymorphisms (SNPs) located in the HLA region were extracted from a targeted exome-sequencing dataset comprising Scandinavian AAV cases and controls. Classical HLA alleles were called using xHLA. After quality control, association analyses were performed of a joint SNP/classical HLA allele dataset for cases with PR3-AAV (n=411) and MPO-AAV (n=162) versus controls (n=1595). Disease-associated genetic variants were analysed for association with organ involvement, age at diagnosis and relapse, respectively. Results: PR3-AAV was significantly associated with both HLA-DPB1*04:01 and rs1042335 at the HLADPB1 locus, also after stepwise conditional analysis. MPO-AAV was significantly associated with HLADRB1*04:04. Neither carriage of HLA-DPB1*04:01 alleles in PR3-AAV nor of HLA-DRB1*04:04 alleles in MPO-AAV were associated with organ involvement, age at diagnosis or relapse. Conclusions: The association to the HLA region was distinct in Scandinavian cases with MPO-AAV compared with cases of East Asian descent. In PR3-AAV, the two separate signals of association to the HLD-DPB1 region mediate potentially different functional effects
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The HLA region in ANCA-associated vasculitis: characterisation of genetic associations in a Scandinavian patient population.
Peer reviewed: TrueAcknowledgements: Sequencing and MASSarray genotyping were performed by the SNP&SEQ Technology Platform in Uppsala. The facility is part of the National Genomics Infrastructure (NGI) Sweden and Science for Life Laboratory, Sweden. The SNP&SEQ Platform is supported by the Swedish Research Council and the Knut and Alice Wallenberg Foundation. The computations were enabled by resources provided by the Swedish National Infrastructure for Computing (SNIC) at Uppsala Multidisciplinary Center for Advanced Computational Science (UPPMAX) partially funded by the Swedish Research Council through grant agreement no. 2018-05973. Data were analysed with support from the National Bioinformatics Infrastructure Sweden (NBIS; Science for Life Laboratory). We thank the Biobank Research Unit at Umeå University, Västerbotten Intervention Programme, the Northern Sweden MONICA study and the County Council of Västerbotten for providing data and samples and acknowledge the contribution from Biobank Sweden, supported by the Swedish Research Council (no. 2017-00650).Funder: Stiftelsen Konung Gustaf V:s 80-årsfond; FundRef: http://dx.doi.org/10.13039/501100007857; Grant(s): NAOBJECTIVE: The antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are inflammatory disorders with ANCA autoantibodies recognising either proteinase 3 (PR3-AAV) or myeloperoxidase (MPO-AAV). PR3-AAV and MPO-AAV have been associated with distinct loci in the human leucocyte antigen (HLA) region. While the association between MPO-AAV and HLA has been well characterised in East Asian populations where MPO-AAV is more common, studies in populations of European descent are limited. The aim of this study was to thoroughly characterise associations to the HLA region in Scandinavian patients with PR3-AAV as well as MPO-AAV. METHODS: Genotypes of single-nucleotide polymorphisms (SNPs) located in the HLA region were extracted from a targeted exome-sequencing dataset comprising Scandinavian AAV cases and controls. Classical HLA alleles were called using xHLA. After quality control, association analyses were performed of a joint SNP/classical HLA allele dataset for cases with PR3-AAV (n=411) and MPO-AAV (n=162) versus controls (n=1595). Disease-associated genetic variants were analysed for association with organ involvement, age at diagnosis and relapse, respectively. RESULTS: PR3-AAV was significantly associated with both HLA-DPB1*04:01 and rs1042335 at the HLA-DPB1 locus, also after stepwise conditional analysis. MPO-AAV was significantly associated with HLA-DRB1*04:04. Neither carriage of HLA-DPB1*04:01 alleles in PR3-AAV nor of HLA-DRB1*04:04 alleles in MPO-AAV were associated with organ involvement, age at diagnosis or relapse. CONCLUSIONS: The association to the HLA region was distinct in Scandinavian cases with MPO-AAV compared with cases of East Asian descent. In PR3-AAV, the two separate signals of association to the HLD-DPB1 region mediate potentially different functional effects
Stratified Genetic Analysis Reveals Sex Differences In MPO-ANCA-associated Vasculitis
OBJECTIVE: To identify and genetically characterize subgroups of patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) based on sex and ANCA subtype.METHODS: A previously established SNP dataset derived from DNA sequencing of 1853 genes and genotyping of 1088 Scandinavian cases with AAV and 1589 controls was stratified for sex and ANCA subtype and analysed for association with five top AAV SNPs. rs9274619, a lead variant at the HLA-DQB1/HLA-DQA2 locus previously associated with AAV positive for myeloperoxidase (MPO)-ANCA, was analysed for association with the cumulative disease involvement of ten different organ systems.RESULTS: rs9274619 showed a significantly stronger association to MPO-ANCA positive females than males (P = 2.0 x 1 0 -4, OR = 2.3 (95%CI 1.5-3.5), whereas proteinase 3 (PR3)-ANCA-associated variants rs1042335, rs9277341 (HLA-DPB1/A1) and rs28929474 (SERPINA1) were equally associated with females and males with PR3-ANCA. In MPO-ANCA positive cases, carriers of the rs9274619 risk allele were more prone to disease engagement of eyes (P = 0.021, OR = 11 (95%CI 2.2-205)) but less prone to pulmonary involvement (P = 0.026, OR = 0.52 (95%CI 0.30-0.92)). Moreover, AAV with both MPO-ANCA and PR3-ANCA was associated with the PR3-ANCA lead SNP rs1042335 (P = 0.0015, OR = 0.091 (95%CI 0.0022-0.55)) but not with rs9274619.CONCLUSIONS: Females and males with MPO-ANCA positive AAV differ in genetic predisposition to disease, suggesting at least partially distinct disease mechanisms between the sexes. Double ANCA-positive AAV cases are genetically similar to PR3-ANCA positive cases, providing clues to the clinical follow-up and treatment of these patients
Identification and functional characterization of a novel susceptibility locus for small vessel vasculitis with MPO-ANCA
Objective To identify and characterize genetic loci associated with the risk of developing ANCA-associated vasculitides (AAV). Methods Genetic association analyses were performed after Illumina sequencing of 1853 genes and subsequent replication with genotyping of selected single nucleotide polymorphisms in a total cohort of 1110 Scandinavian cases with granulomatosis with polyangiitis or microscopic polyangiitis, and 1589 controls. A novel AAV-associated single nucleotide polymorphism was analysed for allele-specific effects on gene expression using luciferase reporter assay. Results PR3-ANCA+ AAV was significantly associated with two independent loci in the HLA-DPB1/HLA-DPA1 region [rs1042335, P = 6.3 x 10-61, odds ratio (OR) 0.10; rs9277341, P = 1.5 x 10-44, OR 0.22] and with rs28929474 in the SERPINA1 gene (P = 2.7 x 10-10, OR 2.9). MPO-ANCA+ AAV was significantly associated with the HLA-DQB1/HLA-DQA2 locus (rs9274619, P = 5.4 x 10-25, OR 3.7) and with a rare variant in the BACH2 gene (rs78275221, P = 7.9 x 10-7, OR 3.0), the latter a novel susceptibility locus for MPO-ANCA+ granulomatosis with polyangiitis/microscopic polyangiitis. The rs78275221-A risk allele reduced luciferase gene expression in endothelial cells, specifically, as compared with the non-risk allele. Conclusion We identified a novel susceptibility locus for MPO-ANCA+ AAV and propose that the associated variant is of mechanistic importance, exerting a regulatory function on gene expression in specific cell types.Funding Agencies: Swedish Society for Medical Research; Swedish Research Council; Swedish Society of Medicine; Swedish Rheumatism Association; Knut and Alice Wallenberg Foundation; AstraZeneca-Science for Life Laboratory (SciLifeLab) Research Collaboration Grant</p