| 1. |
- de Rooy, Diederik P C, et al.
(författare)
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Genetic Factors for the Severity of ACPA-negative Rheumatoid Arthritis in 2 Cohorts of Early Disease: A Genome-wide Study.
- 2015
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Ingår i: Journal of Rheumatology. - : The Journal of Rheumatology. - 0315-162X .- 1499-2752. ; 42:8, s. 1383-1391
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Tidskriftsartikel (refereegranskat)abstract
- Rheumatoid arthritis (RA) that is negative for anticitrullinated protein antibodies (ACPA) is a subentity of RA, characterized by less severe disease. At the individual level, however, considerable differences in the severity of joint destruction occur. We performed a study on genetic factors underlying the differences in joint destruction in ACPA-negative patients.
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| 2. |
- Knevel, Rachel, et al.
(författare)
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A genetic variant in osteoprotegerin is associated with progression of joint destruction in rheumatoid arthritis
- 2014
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Ingår i: Arthritis Research and Therapy. - : Springer Science and Business Media LLC. - 1478-6362 .- 1478-6354. ; 16:3
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Progression of joint destruction in rheumatoid arthritis (RA) is partly heritably; 45 to 58% of the variance in joint destruction is estimated to be explained by genetic factors. The binding of RANKL (Receptor Activator for Nuclear Factor kappa B Ligand) to RANK results in the activation of TRAF6 (tumor necrosis factor (TNF) receptor associated factor-6), and osteoclast formation ultimately leading to enhanced bone resorption. This bone resorption is inhibited by osteoprotegerin (OPG) which prevents RANKL-RANK interactions. The OPG/RANK/RANKL/TRAF6 pathway plays an important role in bone remodeling. Therefore, we investigated whether genetic variants in OPG, RANK, RANKL and TRAF6 are associated with the rate of joint destruction in RA. Methods: 1,418 patients with 4,885 X-rays of hands and feet derived from four independent data-sets were studied. In each data-set the relative increase of the progression rate per year in the presence of a genotype was assessed. First, explorative analyses were performed on 600 RA-patients from Leiden. 109 SNPs, tagging OPG, RANK, RANKL and TRAF6, were tested. Single nucleotide polymorphisms (SNPs) significantly associated in phase-1 were genotyped in data-sets from Groningen (Netherlands), Sheffield (United Kingdom) and Lund (Switzerland). Data were summarized in an inverse weighted variance meta-analysis. Bonferonni correction for multiple testing was applied. Results: We found that 33 SNPs were significantly associated with the rate of joint destruction in phase-1. In phase-2, six SNPs in OPG and four SNPs in RANK were associated with progression of joint destruction with P-value <0.05. In the meta-analyses of all four data-sets, RA-patients with the minor allele of OPG-rs1485305 expressed higher rates of joint destruction compared to patients without these risk variants (P = 2.35x10(-4)). This variant was also significant after Bonferroni correction. Conclusions: These results indicate that a genetic variant in OPG is associated with a more severe rate of joint destruction in RA.
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| 3. |
- Signorelli, Mirko, et al.
(författare)
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Longitudinal serum biomarker screening identifies malate dehydrogenase 2 as candidate prognostic biomarker for Duchenne muscular dystrophy
- 2020
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Ingår i: Journal of Cachexia, Sarcopenia and Muscle. - : Wiley. - 2190-5991 .- 2190-6009. ; 11:2, s. 505-517
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Tidskriftsartikel (refereegranskat)abstract
- AbstractBackgroundDuchenne muscular dystrophy (DMD) is a fatal disease for which no cure is available. Clinical trials have shown to be largely underpowered due to inter‐individual variability and noisy outcome measures. The availability of biomarkers able to anticipate clinical benefit is highly needed to improve clinical trial design and facilitate drug development.MethodsIn this study, we aimed to appraise the value of protein biomarkers to predict prognosis and monitor disease progression or treatment outcome in patients affected by DMD. We collected clinical data and 303 blood samples from 157 DMD patients in three clinical centres; 78 patients contributed multiple blood samples over time, with a median follow‐up time of 2 years. We employed linear mixed models to identify biomarkers that are associated with disease progression, wheelchair dependency, and treatment with corticosteroids and performed survival analysis to find biomarkers whose levels are associated with time to loss of ambulation.ResultsOur analysis led to the identification of 21 proteins whose levels significantly decrease with age and nine proteins whose levels significantly increase. Seven of these proteins are also differentially expressed in non‐ambulant patients, and three proteins are differentially expressed in patients treated with glucocorticosteroids. Treatment with corticosteroids was found to partly counteract the effect of disease progression on two biomarkers, namely, malate dehydrogenase 2 (MDH2, P = 0.0003) and ankyrin repeat domain 2 (P = 0.0005); however, patients treated with corticosteroids experienced a further reduction on collagen 1 serum levels (P = 0.0003), especially following administration of deflazacort. A time to event analysis allowed to further support the use of MDH2 as a prognostic biomarker as it was associated with an increased risk of wheelchair dependence (P = 0.0003). The obtained data support the prospective evaluation of the identified biomarkers in natural history and clinical trials as exploratory biomarkers.
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| 4. |
- Spitali, Pietro, et al.
(författare)
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Tracking disease progression non-invasively in Duchenne and Becker muscular dystrophies
- 2018
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Ingår i: Journal of Cachexia, Sarcopenia and Muscle. - : Wiley-VCH Verlagsgesellschaft. - 2190-5991 .- 2190-6009. ; 9:4, s. 715-726
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Tidskriftsartikel (refereegranskat)abstract
- Background Analysis of muscle biopsies allowed to characterize the pathophysiological changes of Duchenne and Becker muscular dystrophies (D/BMD) leading to the clinical phenotype. Muscle tissue is often investigated during interventional dose finding studies to show in situ proof of concept and pharmacodynamics effect of the tested drug. Less invasive readouts are needed to objectively monitor patients' health status, muscle quality, and response to treatment. The identification of serum biomarkers correlating with clinical function and able to anticipate functional scales is particularly needed for personalized patient management and to support drug development programs. Methods A large-scale proteomic approach was used to identify serum biomarkers describing pathophysiological changes (e.g. loss of muscle mass), association with clinical function, prediction of disease milestones, association with in vivo(31)P magnetic resonance spectroscopy data and dystrophin levels in muscles. Cross-sectional comparisons were performed to compare DMD patients, BMD patients, and healthy controls. A group of DMD patients was followed up for a median of 4.4years to allow monitoring of individual disease trajectories based on yearly visits. Results Cross-sectional comparison enabled to identify 10 proteins discriminating between healthy controls, DMD and BMD patients. Several proteins (285) were able to separate DMD from healthy, while 121 proteins differentiated between BMD and DMD; only 13 proteins separated BMD and healthy individuals. The concentration of specific proteins in serum was significantly associated with patients' performance (e.g. BMP6 serum levels and elbow flexion) or dystrophin levels (e.g. TIMP2) in BMD patients. Analysis of longitudinal trajectories allowed to identify 427 proteins affected over time indicating loss of muscle mass, replacement of muscle by adipose tissue, and cardiac involvement. Over-representation analysis of longitudinal data allowed to highlight proteins that could be used as pharmacodynamic biomarkers for drugs currently in clinical development. Conclusions Serum proteomic analysis allowed to not only discriminate among DMD, BMD, and healthy subjects, but it enabled to detect significant associations with clinical function, dystrophin levels, and disease progression.
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| 5. |
- van Hamersveld, Koen T., et al.
(författare)
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Risk Factors for Tibial Component Loosening : A Meta-Analysis of Long-Term Follow-up Radiostereometric Analysis Data
- 2021
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Ingår i: Journal of Bone and Joint Surgery. American volume. - : NLM. - 0021-9355 .- 1535-1386. ; 103:12, s. 1115-1124
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Radiostereometric analysis (RSA) is a highly accurate tool to detect implant migration and predict loosening following total knee arthroplasty (TKA). However, little is known about the predisposing risk factors for implant migration, nor which migration profile should be considered physiological (i.e., merely part of an implant-settling phase) and which should be considered pathological (i.e., having a high probability for implant loosening). By pooling individual participant data from long-term follow-up RSA studies, we aimed to identify predisposing risk factors for tibial component loosening.METHODS: Individual data were collected for 630 patients from 11 RSA studies. The repeated measurements were analyzed with use of a linear mixed-effects model, determining the effect of age, sex, body mass index, diagnosis, preoperative and postoperative limb alignment, and prosthesis characteristics on tibial component migration over time, taking into account the clustering of patients within studies.RESULTS: High initial migration was found to result in early mechanical loosening in 18 cases (2.9%) and septic loosening in 2 cases (0.3%), whereas stabilization of high initial migration occurred in 17 cases (2.7%). Late loosening occurred in 13 cases (2.1%). All other 580 cases (92.1%) showed early stabilization and remained stable over time. Mixed-effects model analyses showed that for cemented prostheses, sex, diagnosis, and posterior cruciate ligament type had an effect on migration, but these differences were nonsignificant when analyzing migration from 3 months onwards. Uncemented prostheses aligned in varus showed more migration than neutrally and valgus-aligned TKAs (p = 0.031), and this difference increased over time (p < 0.001). Significantly higher migration was observed following uncemented TKA without an osseointegration-promoting surface (p < 0.001).CONCLUSIONS: For cemented prostheses, increased migration during the first 3 postoperative months was observed for female patients, patients with rheumatoid arthritis, and patients who underwent a posterior-stabilized TKA. For uncemented prostheses, both postoperative varus alignment of the lower limb and the absence of an osseointegration-promoting surface significantly increased postoperative tibial component migration.LEVEL OF EVIDENCE: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence.
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