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The Intensive Diet and Exercise for Arthritis (IDEA) trial was an 18-month randomized controlled trial that enrolled 454 overweight and obese older adults with symptomatic and radiographic knee osteoarthritis (OA). Participants were randomized to either exercise (E), intensive diet-induced weight loss (D), or intensive diet-induced weight loss plus exercise (D + E) interventions. We previously reported that the clinical benefits of D + E were significantly greater than with either intervention alone (e.g., greater pain reduction, and better function, mobility, and health-related quality of life). We now test the hypothesis that D + E has greater overall benefit on gait mechanics compared to either intervention alone. Knee joint loading was analyzed using inverse dynamics and musculoskeletal modeling. Analysis of covariance determined the interventions' effects on gait. The D + E group walked significantly faster at 18-month follow-up (1.35 m s) than E (1.29 m s, p = 0.0004) and D (1.31 m s, p = 0.0007). Tibiofemoral compressive impulse was significantly lower (p = 0.0007) in D (1069 N s) and D + E (1054 N s) compared to E (1130 N s). D had significantly lower peak hip external rotation moment (p = 0.01), hip abduction moment (p = 0.0003), and peak hip power production (p = 0.016) compared with E. Peak ankle plantar flexion moment was significantly less (p < 0.0001) in the two diet groups compared with E. There also was a significant dose-response to weight loss; participants that lost >10% of baseline body weight had significantly (p = 0.0001) lower resultant knee forces and lower muscle (quadriceps, hamstring, and gastrocnemius) forces than participants that had less weight loss. Compared to E, D produces significant load reductions at the hip, knee, and ankle; combining D with E attenuates these reductions, but most remain significantly better than with E alone.
Copyright © 2019 Elsevier Ltd. All rights reserved.
OBJECTIVES - To detail the greatest areas of unmet scientific and clinical needs in rheumatology.
METHODS - The 21st annual international Advances in Targeted Therapies meeting brought together more than 100 leading basic scientists and clinical researchers in rheumatology, immunology, epidemiology, molecular biology and other specialties. During the meeting, breakout sessions were convened, consisting of 5 disease-specific groups with 20-30 experts assigned to each group based on expertise. Specific groups included: rheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis, systemic lupus erythematosus and other systemic autoimmune rheumatic diseases. In each group, experts were asked to identify unmet clinical and translational research needs in general and then to prioritise and detail the most important specific needs within each disease area.
RESULTS - Overarching themes across all disease states included the need to innovate clinical trial design with emphasis on studying patients with refractory disease, the development of trials that take into account disease endotypes and patients with overlapping inflammatory diseases, the need to better understand the prevalence and incidence of inflammatory diseases in developing regions of the world and ultimately to develop therapies that can cure inflammatory autoimmune diseases.
CONCLUSIONS - Unmet needs for new therapies and trial designs, particularly for those with treatment refractory disease, remain a top priority in rheumatology.
© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
OBJECTIVE - Patients with rheumatoid arthritis (RA) have increased cardiovascular (CV) risk. In the general population, exercise improves several CV risk factors. In a cross-sectional study, we examined the hypothesis that more exercise is associated with protective traditional and non-traditional CV risk factor profile in patients with RA.
METHODS - Patient-reported exercise outside of daily activities was quantified by time and metabolic equivalents per week (METmin/week) and CV risk factors including blood pressure, standard lipid profiles, lipoprotein particle concentrations (NMR spectroscopy), and vascular indices were measured in 165 patients with RA. The relationship between exercise and CV risk factors was assessed according to whether patients exercised or not, and after adjustment for age, race and sex.
RESULTS - Over half (54%) of RA patients did not exercise. Among those who did exercise, median value for exercise duration was 113 min/week [IQR: 60, 210], and exercise metabolic equivalent expenditure was 484 METmin/week [IQR: 258, 990]. Disease activity (measured by DAS28 score), C-reactive protein, waist-hip ratio, and prevalence of hypertension were lower in patients who exercised compared to those who did not (all p-values < 0.05) but standard lipid profile and body mass index were not significantly different. Patients who exercised had significantly higher concentrations of HDL particles (p = 0.004) and lower vascular stiffness as measured by pulse wave velocity (p = 0.005).
CONCLUSIONS - More self-reported exercise in patients with RA was associated with a protective CV risk factor profile including lower waist-hip ratio, higher HDL particle concentration, lower vascular stiffness, and a lower prevalence of hypertension.
BACKGROUND/OBJECTIVE - Despite effective therapies, rheumatoid arthritis (RA) can result in joint destruction requiring total joint arthroplasty to maintain patient function. An estimated 16% to 70% of those undergoing total joint arthroplasty of the hip or knee will receive a blood transfusion. Few studies have described risk factors for blood transfusion following total joint arthroplasty in patients with RA. The aim of this study was to identify demographic and clinical risk factors associated with receiving a blood transfusion following total joint arthroplasty among patients with RA.
METHODS - A retrospective study (n = 3270) was conducted using deidentified patient health claims information from a commercially insured, US data set (2007-2009). Data analysis included descriptive statistics and multivariate logistic regression.
RESULTS - Females were more likely to receive a blood transfusion (odds ratio [OR], 1.48; 95% confidence interval [CI], 1.16-1.87; p = 0.001). When compared with those in the South, patients residing the Midwest were less likely to receive a blood transfusion following total joint arthroplasty (OR, 0.56; 95% CI, 0.44-0.71). Relative to those receiving total knee arthroplasty, patients who underwent total hip arthroplasty were more likely to receive a blood transfusion (OR, 1.39; 95% CI, 1.14-1.70), and patients who underwent a total shoulder arthroplasty were less likely to receive a blood transfusion (OR, 0.14; 95% CI, 0.05-0.38; p < 0.001). Patients with a history of anemia were more likely to receive a blood transfusion compared with those who did not have this diagnosis (OR, 3.30; 95% CI, 2.62-4.14; p < 0.001).
CONCLUSIONS - Risk factors for the receipt of blood transfusions among RA patients who have undergone total joint arthroplasty were identified.
Current therapies used in the treatment of inflammatory bowel disease (IBD) are not effective in all patients. Biologic agents result in approximately 40% remission rates at 1 year in selected populations, prompting a growing interest in combining biologic therapy to improve outcomes. There are limited published data regarding the efficacy and safety of combination targeted therapy in IBD specifically, which include only 1 exploratory randomized control trial and 3 case reports or series. This review evaluates the published literature regarding this therapeutic paradigm in IBD and its extensive utilization in the treatment of other immune-mediated inflammatory disorders. The combination of biologic therapies demonstrates variable degrees of efficacy and highlights some safety concerns, depending upon the agents used and the disease state treated. A trial (Clinical Trials.gov Identifier: NCT02764762) combining vedolizumab and adalimumab is currently underway evaluating the effectiveness and safety of this approach in patients with Crohn's disease, which should provide further insight into this treatment concept. While combination biologic therapy is an attractive strategy, the lack of consistent superior efficacy as well as safety concerns militates the need for further trials prior to its general application in IBD.
Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.
OBJECTIVES - We aimed to investigate the role of serum uric acid (SUA) level in a broad spectrum of disease outcomes using data for 120 091 individuals from UK Biobank.
METHODS - We performed a phenome-wide association study (PheWAS) to identify disease outcomes associated with SUA genetic risk loci. We then implemented conventional Mendelianrandomisation (MR) analysis to investigate the causal relevance between SUA level and disease outcomes identified from PheWAS. We next applied MR Egger analysis to detect and account for potential pleiotropy, which conventional MR analysis might mistake for causality, and used the HEIDI (heterogeneity in dependent instruments) test to remove cross-phenotype associations that were likely due to genetic linkage.
RESULTS - Our PheWAS identified 25 disease groups/outcomes associated with SUA genetic risk loci after multiple testing correction (P<8.57e-05). Our conventional MR analysis implicated a causal role of SUA level in three disease groups: inflammatory polyarthropathies (OR=1.22, 95% CI 1.11 to 1.34), hypertensive disease (OR=1.08, 95% CI 1.03 to 1.14) and disorders of metabolism (OR=1.07, 95% CI 1.01 to 1.14); and four disease outcomes: gout (OR=4.88, 95% CI 3.91 to 6.09), essential hypertension (OR=1.08, 95% CI 1.03 to 1.14), myocardial infarction (OR=1.16, 95% CI 1.03 to 1.30) and coeliac disease (OR=1.41, 95% CI 1.05 to 1.89). After balancing pleiotropic effects in MR Egger analysis, only gout and its encompassing disease group of inflammatory polyarthropathies were considered to be causally associated with SUA level. Our analysis highlighted a locus () that may influence SUA level and multiple cardiovascular and autoimmune diseases via pleiotropy.
CONCLUSIONS - Elevated SUA level is convincing to cause gout and inflammatory polyarthropathies, and might act as a marker for the wider range of diseases with which it associates. Our findings support further investigation on the clinical relevance of SUA level with cardiovascular, metabolic, autoimmune and respiratory diseases.
© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.
The goals of this study were to determine if secretory sphingomyelinase (S-SMase) activity is elevated in patients with rheumatoid arthritis (RA) compared to control subjects and to examine the relationships of S-SMase activity with functional status, quality of life, and RA disease activity measurements. We collected data on 33 patients who were diagnosed with RA and 17 non-RA controls who were comparable in terms of age, sex, and race. Demographic, clinical data and self-reported measures of fatigue, pain, and physical function were obtained directly from patients and controls. RA patients also completed quantitative joint assessment using a 28-joint count and functional status and quality of life assessment using the Modified Health Assessment Questionnaire (MHAQ). Archived serum samples were used to analyze retrospectively serum S-SMase activity in patients and controls. The mean serum S-SMase activity was 1.4-fold higher in patients with RA (RA 2.8 ± 1.0 nmol/ml/h vs. controls 2.0 ± 0.8 nmol/ml/h; p = 0.014). Spearman's rho correlations between S-SMase activity and oxidant activity, markers of inflammation and endothelial activation with the exception of P-selectin (rho = 0.40, p = 0.034), measures of disease activity, functional status, and quality of life were not statistically significant in patients with RA. We confirmed that S-SMase activity is higher among RA patients compared to controls, as in other acute and chronic inflammatory diseases. Future studies can build on the present findings to understand more fully the biologic role(s) of S-SMase activity in RA.
It has been proposed that CD6, an important regulator of T cells, functions by interacting with its currently identified ligand, CD166, but studies performed during the treatment of autoimmune conditions suggest that the CD6-CD166 interaction might not account for important functions of CD6 in autoimmune diseases. The antigen recognized by mAb 3A11 has been proposed as a new CD6 ligand distinct from CD166, yet the identity of it is hitherto unknown. We have identified this CD6 ligand as CD318, a cell surface protein previously found to be present on various epithelial cells and many tumor cells. We found that, like CD6 knockout (KO) mice, CD318 KO mice are also protected in experimental autoimmune encephalomyelitis. In humans, we found that CD318 is highly expressed in synovial tissues and participates in CD6-dependent adhesion of T cells to synovial fibroblasts. In addition, soluble CD318 is chemoattractive to T cells and levels of soluble CD318 are selectively and significantly elevated in the synovial fluid from patients with rheumatoid arthritis and juvenile inflammatory arthritis. These results establish CD318 as a ligand of CD6 and a potential target for the diagnosis and treatment of autoimmune diseases such as multiple sclerosis and inflammatory arthritis.
OBJECTIVE - Regulated in development and DNA damage response 1 (REDD1) is an endogenous inhibitor of mechanistic target of rapamycin (mTOR) that regulates cellular stress responses. REDD1 expression is decreased in aged and osteoarthritic (OA) cartilage, and it regulates mTOR signaling and autophagy in articular chondrocytes in vitro. This study was undertaken to investigate the effects of REDD1 deletion in vivo using a mouse model of experimental OA.
METHODS - OA severity was histologically assessed in 4-month-old wild-type and REDD1 mice subjected to surgical destabilization of the medial meniscus (DMM). Chondrocyte autophagy, apoptosis, mitochondrial content, and expression of mitochondrial biogenesis markers were determined in cartilage and cultured chondrocytes from wild-type and REDD1 mice.
RESULTS - REDD1 deficiency increased the severity of changes in cartilage, menisci, subchondral bone, and synovium in the DMM model of OA. Chondrocyte death was increased in the cartilage of REDD1 mice and in cultured REDD1 mouse chondrocytes under oxidative stress conditions. Expression of key autophagy markers (microtubule-associated protein 1A/1B light chain 3 and autophagy protein 5) was markedly reduced in cartilage from REDD1 mice and in cultured human and mouse chondrocytes with REDD1 depletion. Mitochondrial content, ATP levels, and expression of the mitochondrial biogenesis markers peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) and transcription factor A, mitochondrial (TFAM) were also decreased in REDD1-deficient chondrocytes. REDD1 was required for AMP-activated protein kinase-induced PGC-1α in chondrocytes.
CONCLUSION - Our findings suggest that REDD1 is a key mediator of cartilage homeostasis through regulation of autophagy and mitochondrial biogenesis and that REDD1 deficiency exacerbates the severity of injury-induced OA.
© 2017, American College of Rheumatology.
In 2013, chikungunya virus (CHIKV) transmission was documented in the Western Hemisphere, and the virus has since spread throughout the Americas with more than 1.8 million people infected in more than 40 countries. CHIKV targets the joints, resulting in symmetric polyarthritis that clinically mimics rheumatoid arthritis and can endure for months to years. At present, no approved treatment is effective in preventing or controlling CHIKV infection or disease. We treated mice with eight different disease-modifying antirheumatic drugs and identified CLTA4-Ig (abatacept) and tofacitinib as candidate therapies based on their ability to decrease acute joint swelling. CTLA4-Ig reduced T cell accumulation in the joints of infected animals without affecting viral infection. Whereas monotherapy with CTLA4-Ig or a neutralizing anti-CHIKV human monoclonal antibody provided partial clinical improvement, therapy with both abolished swelling and markedly reduced levels of chemokines, proinflammatory cytokines, and infiltrating leukocytes. Thus, combination CTLA4-Ig and antiviral antibody therapy controls acute CHIKV infection and arthritis and may be a candidate for testing in humans.
Copyright © 2017, American Association for the Advancement of Science.