Gout is a chronic disease that is caused by an innate immune response to deposited monosodium urate crystals in the setting of hyperuricemia. Here, we provide insights into the molecular mechanism of the poorly understood inflammatory component of gout from a genome-wide association study (GWAS) of 2.6 million people, including 120,295 people with prevalent gout. We detected 377 loci and 410 genetically independent signals (149 previously unreported loci in urate and gout). An additional 65 loci with signals in urate (from a GWAS of 630,117 individuals) but not gout were identified. A prioritization scheme identified candidate genes in the inflammatory process of gout, including genes involved in epigenetic remodeling, cell osmolarity and regulation of NOD-like receptor protein 3 (NLRP3) inflammasome activity. Mendelian randomization analysis provided evidence for a causal role of clonal hematopoiesis of indeterminate potential in gout. Our study identifies candidate genes and molecular processes in the inflammatory pathogenesis of gout suitable for follow-up studies.
- MeSH
- celogenomová asociační studie * MeSH
- dna (nemoc) * genetika MeSH
- genetická predispozice k nemoci * MeSH
- hyperurikemie genetika MeSH
- jednonukleotidový polymorfismus * MeSH
- kyselina močová * MeSH
- lidé MeSH
- mendelovská randomizace MeSH
- protein NLRP3 genetika MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
INTRODUCTION: Hip and knee osteoarthritis (OA) are increasingly common with a significant impact on individuals and society. Non-pharmacological treatments are considered essential to reduce pain and improve function and quality of life. EULAR recommendations for the non-pharmacological core management of hip and knee OA were published in 2013. Given the large number of subsequent studies, an update is needed. METHODS: The Standardised Operating Procedures for EULAR recommendations were followed. A multidisciplinary Task Force with 25 members representing 14 European countries was established. The Task Force agreed on an updated search strategy of 11 research questions. The systematic literature review encompassed dates from 1 January 2012 to 27 May 2022. Retrieved evidence was discussed, updated recommendations were formulated, and research and educational agendas were developed. RESULTS: The revised recommendations include two overarching principles and eight evidence-based recommendations including (1) an individualised, multicomponent management plan; (2) information, education and self-management; (3) exercise with adequate tailoring of dosage and progression; (4) mode of exercise delivery; (5) maintenance of healthy weight and weight loss; (6) footwear, walking aids and assistive devices; (7) work-related advice and (8) behaviour change techniques to improve lifestyle. The mean level of agreement on the recommendations ranged between 9.2 and 9.8 (0-10 scale, 10=total agreement). The research agenda highlighted areas related to these interventions including adherence, uptake and impact on work. CONCLUSIONS: The 2023 updated recommendations were formulated based on research evidence and expert opinion to guide the optimal management of hip and knee OA.
- MeSH
- artróza kolenních kloubů * terapie rehabilitace MeSH
- artróza kyčelních kloubů * terapie rehabilitace MeSH
- hmotnostní úbytek MeSH
- lidé MeSH
- medicína založená na důkazech MeSH
- pomůcky pro sebeobsluhu MeSH
- self-management metody MeSH
- terapie cvičením * metody MeSH
- vzdělávání pacientů jako téma metody MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- směrnice pro lékařskou praxi MeSH
- Geografické názvy
- Evropa MeSH
AIM: As part of its strategic objectives for 2023, EULAR aims to improve the work participation of people with rheumatic and musculoskeletal diseases (RMDs). One strategic initiative focused on the development of overarching points to consider (PtC) to support people with RMDs in healthy and sustainable paid work participation. METHODS: EULAR's standardised operating procedures were followed. A steering group identified six research areas on paid work participation. Three systematic literature reviews, several non-systematic reviews and two surveys were conducted. A multidisciplinary taskforce of 25 experts from 10 European countries and Canada formulated overarching principles and PtC after discussion of the results of literature reviews and surveys. Consensus was obtained through voting, with levels of agreement obtained anonymously. RESULTS: Three overarching principles and 11 PtC were formulated. The PtC recognise various stakeholders are important to improving work participation. Five PtC emphasise shared responsibilities (eg, obligation to provide active support) (PtC 1, 2, 3, 5, 6). One encourages people with RMDs to discuss work limitations when necessary at each phase of their working life (PtC 4) and two focus on the role of interventions by healthcare providers or employers (PtC 7, 8). Employers are encouraged to create inclusive and flexible workplaces (PtC 10) and policymakers to make necessary changes in social and labour policies (PtC 9, 11). A research agenda highlights the necessity for stronger evidence aimed at personalising work-related support to the diverse needs of people with RMDs. CONCLUSION: Implementation of these EULAR PtC will improve healthy and sustainable work participation of people with RMDs.
- MeSH
- konsensus MeSH
- lidé MeSH
- muskuloskeletální nemoci * terapie MeSH
- průzkumy a dotazníky MeSH
- revmatické nemoci * terapie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
OBJECTIVES: The expanded therapeutic arsenal in rheumatoid arthritis (RA) raises new clinical questions. The objective of this study is to compare the effectiveness of cycling Janus kinase inhibitors (JAKi) with switching to biologic disease-modifying antirheumatic drug (bDMARD) in patients with RA after failure to the first JAKi. METHODS: This is a nested cohort study within data pooled from an international collaboration of 17 national registries (JAK-pot collaboration). Data from patients with RA with JAKi treatment failure and who were subsequently treated with either a second JAKi or with a bDMARD were prospectively collected. Differences in drug retention rates after second treatment initiation were assessed by log-rank test and Cox regression analysis adjusting for potential confounders. Change in Clinical Disease Activity Index (CDAI) over time was estimated using a linear regression model, adjusting for confounders. RESULTS: 365 cycling and 1635 switching patients were studied. Cyclers were older and received a higher number of previous bDMARDs. Both strategies showed similar observed retention rates after 2 years of follow-up. However, adjusted analysis revealed that cycling was associated with higher retention (p=0.04). Among cyclers, when the first JAKi was discontinued due to an adverse event (AE), it was more likely that the second JAKi would also be stopped due to an AE. Improvement in CDAI over time was similar in both strategies. CONCLUSIONS: After failing the first JAKi, cycling JAKi and switching to a bDMARD appear to have similar effectiveness. Caution is advised if an AE was the reason to stop the first JAKi.
OBJECTIVE: To develop evidence-based European Alliance of Associations for Rheumatology (EULAR) points to consider (PtCs) for the management of difficult-to-treat rheumatoid arthritis (D2T RA). METHODS: An EULAR Task Force was established comprising 34 individuals: 26 rheumatologists, patient partners and rheumatology experienced health professionals. Two systematic literature reviews addressed clinical questions around diagnostic challenges, and pharmacological and non-pharmacological therapeutic strategies in D2T RA. PtCs were formulated based on the identified evidence and expert opinion. Strength of recommendations (SoR, scale A-D: A typically consistent level 1 studies and D level 5 evidence or inconsistent studies) and level of agreement (LoA, scale 0-10: 0 completely disagree and 10 completely agree) of the PtCs were determined by the Task Force members. RESULTS: Two overarching principles and 11 PtCs were defined concerning diagnostic confirmation of RA, evaluation of inflammatory disease activity, pharmacological and non-pharmacological interventions, treatment adherence, functional disability, pain, fatigue, goal setting and self-efficacy and the impact of comorbidities. The SoR varied from level C to level D. The mean LoA with the overarching principles and PtCs was generally high (8.4-9.6). CONCLUSIONS: These PtCs for D2T RA can serve as a clinical roadmap to support healthcare professionals and patients to deliver holistic management and more personalised pharmacological and non-pharmacological therapeutic strategies. High-quality evidence was scarce. A research agenda was created to guide future research.
- MeSH
- adherence k farmakoterapii MeSH
- antirevmatika aplikace a dávkování terapeutické užití MeSH
- cvičení MeSH
- hepatitida B komplikace farmakoterapie MeSH
- hepatitida C komplikace farmakoterapie MeSH
- kognitivně behaviorální terapie MeSH
- komorbidita MeSH
- lidé MeSH
- revmatoidní artritida komplikace diagnóza farmakoterapie terapie MeSH
- určení symptomu MeSH
- vzdělávání pacientů jako téma MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- směrnice pro lékařskou praxi MeSH
BACKGROUND: There is no international consensus on an optimal ultrasound score for monitoring of rheumatoid arthritis (RA) on patient-level yet. Our aim was to reassess the US7 score for the identification of the most frequently pathologic and responsive joint/tendon regions, to optimize it and contribute to an international consensus. Furthermore, we aimed to evaluate the impact of disease duration on the performance of the score. METHODS: RA patients were assessed at baseline and after 3 and 6 months of starting/changing DMARD therapy by the US7 score in greyscale (GS) and power Doppler (PD). The frequency of pathologic joint/tendon regions and their responsiveness to therapy were analyzed by Friedman test and Cochrane-Q test respectively, including the comparison of palmar vs. dorsal regions (chi-square test). The responsiveness of different reduced scores and the amount of information retained from the original US7 score were assessed by standardized response means (SRM)/linear regression. Analyses were also performed separately for early and established RA. RESULTS: A total of 435 patients (N = 138 early RA) were included (56.5 (SD 13.1) years old, 8.2 (9.1) years disease duration, 80% female). The dorsal wrist, palmar MCP2, extensor digitorum communis (EDC) and carpi ulnaris (ECU) tendons were most frequently affected by GS/PD synovitis/tenosynovitis (wrist: 45%/43%; MCP2: 35%/28%; EDC: 30%/11% and ECU: 25%/11%) and significantly changed within 6 months of therapy (all p ≤0.003 by GS/PD). The dorsal vs. palmar side of the wrist by GS/PD (p < 0.001) and the palmar side of the finger joints by PD (p < 0.001) were more frequently pathologic. The reduced US7 score (GS/PD: palmar MCP2, dorsal wrist, EDC and ECU, only PD: dorsal MCP2) showed therapy response (SRM 0.433) after 6 months and retained 76% of the full US7 score's information. No major differences between the groups of early and established RA could be detected. CONCLUSIONS: The wrist, MCP2, EDC, and ECU tendons were most frequently pathologic and responsive to therapy in both early and established RA and should therefore be included in a comprehensive score for monitoring RA patients on patient-level.
- MeSH
- lidé MeSH
- mladiství MeSH
- revmatoidní artritida * diagnostické zobrazování farmakoterapie patologie MeSH
- šlachy diagnostické zobrazování MeSH
- stupeň závažnosti nemoci MeSH
- synovitida * patologie MeSH
- ultrasonografie MeSH
- zápěstí MeSH
- zápěstní kloub diagnostické zobrazování patologie MeSH
- Check Tag
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- pozorovací studie MeSH
BACKGROUND: Despite treatment according to the current management recommendations, a significant proportion of patients with rheumatoid arthritis (RA) remain symptomatic. These patients can be considered to have 'difficult-to-treat RA'. However, uniform terminology and an appropriate definition are lacking. OBJECTIVE: The Task Force in charge of the "Development of EULAR recommendations for the comprehensive management of difficult-to-treat rheumatoid arthritis" aims to create recommendations for this underserved patient group. Herein, we present the definition of difficult-to-treat RA, as the first step. METHODS: The Steering Committee drafted a definition with suggested terminology based on an international survey among rheumatologists. This was discussed and amended by the Task Force, including rheumatologists, nurses, health professionals and patients, at a face-to-face meeting until sufficient agreement was reached (assessed through voting). RESULTS: The following three criteria were agreed by all Task Force members as mandatory elements of the definition of difficult-to-treat RA: (1) Treatment according to European League Against Rheumatism (EULAR) recommendation and failure of ≥2 biological disease-modifying antirheumatic drugs (DMARDs)/targeted synthetic DMARDs (with different mechanisms of action) after failing conventional synthetic DMARD therapy (unless contraindicated); (2) presence of at least one of the following: at least moderate disease activity; signs and/or symptoms suggestive of active disease; inability to taper glucocorticoid treatment; rapid radiographic progression; RA symptoms that are causing a reduction in quality of life; and (3) the management of signs and/or symptoms is perceived as problematic by the rheumatologist and/or the patient. CONCLUSIONS: The proposed EULAR definition for difficult-to-treat RA can be used in clinical practice, clinical trials and can form a basis for future research.
- MeSH
- antirevmatika terapeutické užití MeSH
- biologické přípravky terapeutické užití MeSH
- glukokortikoidy terapeutické užití MeSH
- kombinovaná farmakoterapie MeSH
- léková rezistence MeSH
- lidé MeSH
- poradní výbory MeSH
- progrese nemoci MeSH
- revmatoidní artritida diagnostické zobrazování farmakoterapie patofyziologie MeSH
- revmatologie MeSH
- směrnice pro lékařskou praxi jako téma MeSH
- terapie neúspěšná MeSH
- terminologie jako téma MeSH
- účast zainteresovaných stran MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Geografické názvy
- Evropa MeSH
BACKGROUND: Biopharmaceutical products (BPs) are widely used to treat autoimmune diseases, but immunogenicity limits their efficacy for an important proportion of patients. Our knowledge of patient-related factors influencing the occurrence of antidrug antibodies (ADAs) is still limited. METHODS AND FINDINGS: The European consortium ABIRISK (Anti-Biopharmaceutical Immunization: prediction and analysis of clinical relevance to minimize the RISK) conducted a clinical and genomic multicohort prospective study of 560 patients with multiple sclerosis (MS, n = 147), rheumatoid arthritis (RA, n = 229), Crohn's disease (n = 148), or ulcerative colitis (n = 36) treated with 8 different biopharmaceuticals (etanercept, n = 84; infliximab, n = 101; adalimumab, n = 153; interferon [IFN]-beta-1a intramuscularly [IM], n = 38; IFN-beta-1a subcutaneously [SC], n = 68; IFN-beta-1b SC, n = 41; rituximab, n = 31; tocilizumab, n = 44) and followed during the first 12 months of therapy for time to ADA development. From the bioclinical data collected, we explored the relationships between patient-related factors and the occurrence of ADAs. Both baseline and time-dependent factors such as concomitant medications were analyzed using Cox proportional hazard regression models. Mean age and disease duration were 35.1 and 0.85 years, respectively, for MS; 54.2 and 3.17 years for RA; and 36.9 and 3.69 years for inflammatory bowel diseases (IBDs). In a multivariate Cox regression model including each of the clinical and genetic factors mentioned hereafter, among the clinical factors, immunosuppressants (adjusted hazard ratio [aHR] = 0.408 [95% confidence interval (CI) 0.253-0.657], p < 0.001) and antibiotics (aHR = 0.121 [0.0437-0.333], p < 0.0001) were independently negatively associated with time to ADA development, whereas infections during the study (aHR = 2.757 [1.616-4.704], p < 0.001) and tobacco smoking (aHR = 2.150 [1.319-3.503], p < 0.01) were positively associated. 351,824 Single-Nucleotide Polymorphisms (SNPs) and 38 imputed Human Leukocyte Antigen (HLA) alleles were analyzed through a genome-wide association study. We found that the HLA-DQA1*05 allele significantly increased the rate of immunogenicity (aHR = 3.9 [1.923-5.976], p < 0.0001 for the homozygotes). Among the 6 genetic variants selected at a 20% false discovery rate (FDR) threshold, the minor allele of rs10508884, which is situated in an intron of the CXCL12 gene, increased the rate of immunogenicity (aHR = 3.804 [2.139-6.764], p < 1 × 10-5 for patients homozygous for the minor allele) and was chosen for validation through a CXCL12 protein enzyme-linked immunosorbent assay (ELISA) on patient serum at baseline before therapy start. CXCL12 protein levels were higher for patients homozygous for the minor allele carrying higher ADA risk (mean: 2,693 pg/ml) than for the other genotypes (mean: 2,317 pg/ml; p = 0.014), and patients with CXCL12 levels above the median in serum were more prone to develop ADAs (aHR = 2.329 [1.106-4.90], p = 0.026). A limitation of the study is the lack of replication; therefore, other studies are required to confirm our findings. CONCLUSION: In our study, we found that immunosuppressants and antibiotics were associated with decreased risk of ADA development, whereas tobacco smoking and infections during the study were associated with increased risk. We found that the HLA-DQA1*05 allele was associated with an increased rate of immunogenicity. Moreover, our results suggest a relationship between CXCL12 production and ADA development independent of the disease, which is consistent with its known function in affinity maturation of antibodies and plasma cell survival. Our findings may help physicians in the management of patients receiving biotherapies.
- MeSH
- adalimumab terapeutické užití MeSH
- autoimunitní nemoci farmakoterapie genetika MeSH
- biologická terapie metody MeSH
- biologické přípravky imunologie terapeutické užití MeSH
- celogenomová asociační studie metody MeSH
- Crohnova nemoc farmakoterapie genetika MeSH
- dospělí MeSH
- HLA-DQ alfa řetězec genetika MeSH
- humanizované monoklonální protilátky terapeutické užití MeSH
- imunosupresiva terapeutické užití MeSH
- infliximab terapeutické užití MeSH
- interferon beta 1a terapeutické užití MeSH
- kohortové studie MeSH
- lidé středního věku MeSH
- lidé MeSH
- prospektivní studie MeSH
- revmatoidní artritida farmakoterapie genetika MeSH
- rituximab terapeutické užití MeSH
- roztroušená skleróza farmakoterapie genetika MeSH
- ulcerózní kolitida farmakoterapie genetika MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
BACKGROUND AND OBJECTIVES: The histopathologic classification for ANCA-associated GN distinguishes four classes on the basis of patterns of injury. In the original validation study, these classes were ordered by severity of kidney function loss as follows: focal, crescentic, mixed, and sclerotic. Subsequent validation studies disagreed on outcomes in the crescentic and mixed classes. This study, driven by the original investigators, provides several analyses in order to determine the current position of the histopathologic classification of ANCA-associated GN. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A validation study was performed with newly collected data from 145 patients from ten centers worldwide, including an analysis of interobserver agreement on the histopathologic evaluation of the kidney biopsies. This study also included a meta-analysis on previous validation studies and a validation of the recently proposed ANCA kidney risk score. RESULTS: The validation study showed that kidney failure at 10-year follow-up was significantly different between the histopathologic classes (P<0.001). Kidney failure at 10-year follow-up was 14% in the crescentic class versus 20% in the mixed class (P=0.98). In the meta-analysis, no significant difference in kidney failure was also observed when crescentic class was compared with mixed class (relative risk, 1.15; 95% confidence interval, 0.94 to 1.41). When we applied the ANCA kidney risk score to our cohort, kidney survival at 3 years was 100%, 96%, and 77% in the low-, medium-, and high-risk groups, respectively (P<0.001). These survival percentages are higher compared with the percentages in the original study. CONCLUSIONS: The crescentic and mixed classes seem to have a similar prognosis, also after adjusting for differences in patient populations, treatment, and interobserver agreement. However, at this stage, we are not inclined to merge the crescentic and mixed classes because the reported confidence intervals do not exclude important differences in prognosis and because an important histopathologic distinction would be lost.
- MeSH
- biopsie MeSH
- časové faktory MeSH
- glomerulonefritida klasifikace komplikace imunologie patologie MeSH
- ledviny imunologie patologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- prediktivní hodnota testů MeSH
- prognóza MeSH
- progrese nemoci MeSH
- protilátky proti cytoplazmě neutrofilů imunologie MeSH
- renální insuficience diagnóza etiologie MeSH
- reprodukovatelnost výsledků MeSH
- retrospektivní studie MeSH
- rizikové faktory MeSH
- senioři MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- metaanalýza MeSH
- multicentrická studie MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
- validační studie MeSH
