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34394126 Increased Expression of Extracellular Vesicles Is Associated With the Procoagulant State i 2021 This study sought to identify different subpopulations of extracellular vesicles (EVs) in plasma from female patients with established rheumatoid arthritis (RA) in relation to the activation of coagulation and fibrin formation in these patients. Forty women were included in the study, 20 patients and 20 age-matched healthy controls. The mean disease duration in patients was 13.0 (5.0-25.0) years, with medium to high disease activity despite ongoing treatment with low-dose prednisolone and methotrexate. There were no differences between the investigated groups regarding the presence of traditional cardiovascular risk factors. The concentration of phosphatidylserine-positive (PS(+)) EVs; platelet (CD42a(+)), leucocyte (CD45(+)), monocyte (CD14(+)), and endothelial (CD144(+))-derived EVs; and EVs-expressing tissue factor (CD142(+)), P-selectin (CD62P(+)), and E-selectin (CD62E(+)) were determined by flow cytometry analysis. Overall hemostasis potential (OHP) was assessed to follow the hemostatic disturbances, including the parameters for overall coagulation potential (OCP) and overall fibrinolytic potential (OFP). Fibrin clot turbidity was measured together with clot lysis time, and scanning electron microscopy was performed. Increased concentrations of PS(+), CD42a(+), CD142(+), CD45(+), CD14(+), and CD62P(+) EVs were found in plasma from patients with RA compared to healthy controls, and the concentrations of PS(+), CD42a(+), CD14(+), and CD62P(+) EVs were positively correlated with the inflammatory parameters in RA patients. Positive correlations were also found between the levels of PS(+) and CD42a(+) EVs and OCP as well as between the levels of PS(+), CD42a(+), and CD62P(+)EVs and OHP. The levels of PS(+), CD42a(+), CD14(+), CD62P(+), and CD62E(+) EVs were negatively correlated with OFP. Elevated levels of circulating EVs of different cell origins were found in patients with established RA, in relation to the inflammatory burden and coagulation activation in the disease.
32604244 Anti-Cyclic Citrullinated Peptide Antibodies Correlate to Ultrasound Synovitis in Rheumato 2021 Dec 1 OBJECTIVES: The aim of this study was to compare ultrasound (US) grading and laboratory measures in patients with rheumatoid arthritis. METHODS: Two-hundred four patients with rheumatoid arthritis who received US evaluation for synovitis were included after excluding those using tocilizumab. Ultrasound grading of synovial hypertrophy (SH) and power Doppler (PD) at the most severe site were recorded. An assessment of the correlation of laboratory measures and US grading was conducted by reviewing the electronic medical records. RESULTS: High-titer anti-cyclic citrullinated peptide (anti-CCP) antibodies positivity was associated with SH grade ≥2 (odds ratio [OR], 6.00; 95% confidence interval [CI], 1.78-20.2) and PD grade ≥2 (OR, 5.56; 95% CI, 1.82-16.9). Recent C-reactive protein (CRP) levels ≥0.3 mg/dL were associated with SH grade ≥2 (OR, 3.13; 95% CI, 1.38-7.10) and PD grade ≥2 (OR, 2.38; 95% CI, 1.31-4.31). Anti-CCP antibody levels correlated with US scores better than the levels of CRP with higher Spearman ρ correlation coefficients. Most of the patients with recent CRP levels <0.3 mg/dL had US synovitis. In logistic regression, high levels of anti-CCP antibodies and CRP were both independently associated with SH grade ≥2 and PD grade ≥2. CONCLUSIONS: Higher levels of anti-CCP antibodies and CRP may predict synovitis on US, whereas discrepancies existed between inflammatory markers and US grading. These findings suggest that US has a role in the comprehensive assessment of disease activity, especially for patients with high-titer positive anti-CCP antibodies.
34562416 Pancytopenia after Low-Dose Methotrexate Therapy in Two Hemodialysis Patients with Rheumat 2022 Feb Methotrexate (MTX) is an effective medication in the treatment of rheumatoid arthritis (RA), other rheumatic diseases and various solid tumors. However, its side effects, including gastrointestinal discomfort, oral ulcers, and especially bone marrow suppression, could be fatal and require special attention, particularly in patients with renal failure. We present two hemodialysis patients with RA who presented with a complication of severe pancytopenia after treatment with MTX. After receiving various supportive and blood purification treatments, both patients recovered. We reviewed twenty-four pancytopenia patients on dialysis associated with methotrexate. Among these patients, high morbidity and mortality were observed, indicating that MTX should be used cautiously in the absence of alternatives in such a population. Compared with the patients who recovered, the deceased patients showed a lower level of leukocytes. Which dialysis method might be the best choice is unclear. The mode of renal replacement therapy can be chosen according to the actual situation.
33153331 Status of fracture risk assessment and osteoporosis treatment in Japanese patients with rh 2021 Sep OBJECTIVES: This study aimed to investigate the prevalence of patients with rheumatoid arthritis (RA) at a high risk of major osteoporosis (OP)-related fractures and the status of OP-related medical treatment for these patients. METHODS: We enrolled 120 patients aged ≥40 years (average, 69.1 years) with RA. The Fracture Risk Assessment Tool (FRAX(®)) was used to evaluate the fracture risk. Of the 120 patients, the femoral neck bone mineral density (BMD) was evaluated in 102 patients, and their FRAX(®) scores were calculated alongside the BMD values. Patients observed to be at a high risk of a major OP-related fracture (10-year probability >20% or hip fracture risk >3%), according to FRAX(®), were identified as those requiring OP treatment; medication ratio for OP (percentage of patients actually receiving medication among patients requiring OP treatment) was assessed. RESULTS: OP treatment was indicated in 75 (63%) patients; the medication ratio for OP was 49%. The use of biological disease-modifying anti-rheumatic drugs and corticosteroids showed a positive effect; however, the use of methotrexate showed a negative effect on the medication ratio. CONCLUSION: The number of potential patients requiring OP treatment is underestimated. All patients with RA should be assessed to determine their eligibility for OP treatment.
32886175 Evaluations of daily teriparatide using finite-element analysis over 12 months in rheumat 2021 Mar INTRODUCTION: The objective of this study was to quantitatively evaluate the effects of daily teriparatide on rheumatoid arthritis patients using predicted bone strength (PBS) assessed by quantitative computed tomography-based finite-element analysis (QCT/FEA) and using bone mineral density (BMD) assessed by dual-energy X-ray absorptiometry (DXA), and to prospectively investigate clinical determinants associated with PBS and BMD increases. MATERIALS AND METHODS: Participants comprised 39 patients (mean age, 69 years; disease activity score assessing 28 joints with CRP, 3.0; previous vertebral fractures, 82%) enrolled in this study. BMD by DXA and PBS by QCT/FEA of lumbar spine (LS) and proximal femur were measured at baseline, and after 6 and 12 months. In the groups showing increases in these values, variables that may have affected these increases were evaluated using univariate logistic regression analysis. RESULTS: Daily teriparatide treatment significantly increased not only LS BMD, but also LS PBS in RA patients with osteoporosis after both 6 and 12 months of treatment. Increases in N-terminal type I procollagen propeptide (PINP) at 1 and 3 months were significantly associated with increased LS PBS at 12 months according to univariate logistic regression analysis. The threshold value for increased PINP at 1 month for increased PBS at 12 months was 75 µg/L. CONCLUSIONS: Increased LS PBS at 12 months was predicted by increased PINP at 1 month from baseline.
33617713 Predictors of joint damage in patients with rheumatoid arthritis: focus on short- and long 2021 Nov BACKGROUND/AIMS: To investigate the short- and long-term efficacy of intra-articular glucocorticoid injections (IAGI) in patients with rheumatoid arthritis (RA). METHODS: This was a retrospective study of RA patients who had active arthritis in the hand or wrist joints and who received IAGI (or not) as an adjunct to disease-modifying antirheumatic drugs (DMARDs). Short-term efficacy was assessed based on changes in the disease activity score in 28 joints (DAS28) after 3 months and long-term efficacy was assessed based on changes in the van der Heijde Sharp score (HSS) of hand radiographs over 2 years. Radiographic progression was defined as ΔHSS/year ≥ 2. Logistic regression analysis identified predictors of early achievement of low disease activity (LDA) and radiographic progression. RESULTS: Overall, 126 RA patients received IAGI into the hand or wrist joints and 107 were IAGI-naive. After 3 months, 67% of IAGI-treated patients and 48% of IAGI-naive patients achieved LDA (p = 0.002). Over the next 2 years, 35% of patients treated with IAGI showed radiographic progression compared with 27% of IAGI-naive patients (p = 0.2). IAGI plus biologic DMARDs was associated with achievement of LDA in 3 months. Achieving LDA in 3 months (odds ratio [OR], 0.403; 95% confidence interval [CI], 0.192 to 0.847), wrist arthritis (OR, 2.408; 95% CI, 1.184 to 4.897), and baseline HSS (OR, 1.021; 95% CI, 1.003 to 1.039) were associated with radiographic progression. CONCLUSION: IAGI was associated with early achievement of LDA. LDA was associated with slower radiographic progression. The wrist is more vulnerable to joint damage and requires more aggressive treatment.
33897713 MicroRNA Expression Differences in Blood-Derived CD19+ B Cells of Methotrexate Treated Rhe 2021 Rheumatoid arthritis (RA) is a complex disease with a wide range of underlying susceptibility factors. Recently, dysregulation of microRNAs (miRNAs) in RA have been reported in several immune cell types from blood. However, B cells have not been studied in detail yet. Given the autoimmune nature of RA with the presence of autoantibodies, CD19+ B cells are a key cell type in RA pathogenesis and alterations in CD19+ B cell subpopulations have been observed in patient blood. Therefore, we aimed to reveal the global miRNA repertoire and to analyze miRNA expression profile differences in homogenous RA patient phenotypes in blood-derived CD19+ B cells. Small RNA sequencing was performed on CD19+ B cells of newly diagnosed untreated RA patients (n=10), successfully methotrexate (MTX) treated RA patients in remission (MTX treated RA patients, n=18) and healthy controls (n=9). The majority of miRNAs was detected across all phenotypes. However, significant expression differences between MTX treated RA patients and controls were observed for 27 miRNAs, while no significant differences were seen between the newly diagnosed patients and controls. Several of the differentially expressed miRNAs were previously found to be dysregulated in RA including miR-223-3p, miR-486-3p and miR-23a-3p. MiRNA target enrichment analysis, using the differentially expressed miRNAs and miRNA-target interactions from miRTarBase as input, revealed enriched target genes known to play important roles in B cell activation, differentiation and B cell receptor signaling, such as STAT3, PRDM1 and PTEN. Interestingly, many of those genes showed a high degree of correlated expression in CD19+ B cells in contrast to other immune cell types. Our results suggest important regulatory functions of miRNAs in blood-derived CD19+ B cells of MTX treated RA patients and motivate for future studies investigating the interactive mechanisms between miRNA and gene targets, as well as the possible predictive power of miRNAs for RA treatment response.
34539648 Critical Role of Synovial Tissue-Resident Macrophage and Fibroblast Subsets in the Persist 2021 Rheumatoid arthritis (RA) is a chronic prototypic immune-mediated inflammatory disease which is characterized by persistent synovial inflammation, leading to progressive joint destruction. Whilst the introduction of targeted biological drugs has led to a step change in the management of RA, 30-40% of patients do not respond adequately to these treatments, regardless of the mechanism of action of the drug used (ceiling of therapeutic response). In addition, many patients who acheive clinical remission, quickly relapse following the withdrawal of treatment. These observations suggest the existence of additional pathways of disease persistence that remain to be identified and targeted therapeutically. A major barrier for the identification of therapeutic targets and successful clinical translation is the limited understanding of the cellular mechanisms that operate within the synovial microenvironment to sustain joint inflammation. Recent insights into the heterogeneity of tissue resident synovial cells, including macropahges and fibroblasts has revealed distinct subsets of these cells that differentially regulate specific aspects of inflammatory joint pathology, paving the way for targeted interventions to specifically modulate the behaviour of these cells. In this review, we will discuss the phenotypic and functional heterogeneity of tissue resident synovial cells and how this cellular diversity contributes to joint inflammation. We discuss how critical interactions between tissue resident cell types regulate the disease state by establishing critical cellular checkpoints within the synovium designed to suppress inflammation and restore joint homeostasis. We propose that failure of these cellular checkpoints leads to the emergence of imprinted pathogenic fibroblast cell states that drive the persistence of joint inflammation. Finally, we discuss therapeutic strategies that could be employed to specifically target pathogenic subsets of fibroblasts in RA.
33241926 Relationships of the stand-up time to falls and fractures in patients with rheumatoid arth 2021 Feb AIM: Patients with rheumatoid arthritis (RA) have a higher risk of falls and fractures due to muscle weakness and painful joints of the lower extremities. Evaluation of muscle functions is important to predict falls and fractures. The aim was to investigate the relationships of muscle functions with falls and fractures in RA patients. METHODS: Stand-up muscle power, speed, and stabilizing time were evaluated by a muscle function analyzer in 90 RA patients in the CHIKARA study (UMIN000023744). The relationships of the muscle functions with falls, fractures, body composition, Disease Activity Score of 28 joints - erythrocyte sedimentation rate (DAS28-ESR), modified Health Assessment Questionnaire (mHAQ) scores, Steinbrocker class, stage, sarcopenia, and frailty were investigated in a cross-sectional study. RESULTS: Each parameter of muscle function was related to age, falls, frailty, and the leg muscle score. However, only stabilizing time was related with fractures (r = .217, P = .04). When stabilizing time was ≥ 1.13 and ≥1.36 seconds, the odds ratios for falls and fractures were increased 6.2-fold compared to < 1.13 seconds (95% CI: 1.2-20.1, P = .002) and 11.4-fold compared to <1.36 seconds (95% CI: 1.7-92.5, P = .071), respectively. Sarcopenia and skeletal muscle mass were not significantly related to each muscle function. There was a negative correlation between DAS28-ESR and power. Steinbrocker class and mHAQ had negative correlations with power and speed. CONCLUSIONS: Sarcopenia and skeletal muscle mass were not adequate indicators of muscle functions in RA patients. Analyzing muscle functions is helpful to predict falls and fractures. Patients with extended stabilizing times should recognize the increased risk of falls and fractures.
33640008 Advanced machine learning for predicting individual risk of flares in rheumatoid arthritis 2021 Feb 27 BACKGROUND: Biological disease-modifying anti-rheumatic drugs (bDMARDs) can be tapered in some rheumatoid arthritis (RA) patients in sustained remission. The purpose of this study was to assess the feasibility of building a model to estimate the individual flare probability in RA patients tapering bDMARDs using machine learning methods. METHODS: Longitudinal clinical data of RA patients on bDMARDs from a randomized controlled trial of treatment withdrawal (RETRO) were used to build a predictive model to estimate the probability of a flare. Four basic machine learning models were trained, and their predictions were additionally combined to train an ensemble learning method, a stacking meta-classifier model to predict the individual flare probability within 14 weeks after each visit. Prediction performance was estimated using nested cross-validation as the area under the receiver operating curve (AUROC). Predictor importance was estimated using the permutation importance approach. RESULTS: Data of 135 visits from 41 patients were included. A model selection approach based on nested cross-validation was implemented to find the most suitable modeling formalism for the flare prediction task as well as the optimal model hyper-parameters. Moreover, an approach based on stacking different classifiers was successfully applied to create a powerful and flexible prediction model with the final measured AUROC of 0.81 (95%CI 0.73-0.89). The percent dose change of bDMARDs, clinical disease activity (DAS-28 ESR), disease duration, and inflammatory markers were the most important predictors of a flare. CONCLUSION: Machine learning methods were deemed feasible to predict flares after tapering bDMARDs in RA patients in sustained remission.
33433365 Association of cardiovascular disease and traditional cardiovascular risk factors with the 2021 Feb OBJECTIVE: To determine the incidence of dementia in patients with rheumatoid arthritis (RA) 65 years and older, and compare the incidence of dementia in patients with RA with prevalent cardiovascular (CV) disease (CVD), CV risk factors but no prevalent CVD and neither (referent group). METHODS: We analyzed claims data from the Center for Medicare & Medicaid Services (CMS) from 2006-2014. Eligibility criteria included continuous medical and pharmacy coverage for ≥ 12 months (baseline period 2006), > 2 RA diagnoses by a rheumatologist and at least 1 medication for RA. CVD and CV risk factors were identified using codes from the Chronic Condition Data Warehouse. Incident dementia was defined by 1 inpatient or 2 outpatient claims, or one dementia specific medication. Age-adjusted incident rates were calculated within each age strata. Univariate and multivariate Cox proportional hazard models were used to calculate Hazard Ratios (HR) and 95% confidence intervals. RESULTS: Among 56,567 patients with RA, 11,789 (20.1%) incident cases of dementia were included in the main analysis. Age adjusted incident rates were high among all groups and increased with age. After adjustment for age, sex, comorbidities and baseline CV and RA medications, patients with CVD and CV risk factors between 65 and 74 years had an increased risk for incident dementia compared to those without CVD and without CV risk factors (HR 1.18 (95% CI 1.04-1.33) and HR 1.03 (95% CI 1.00-1.11), respectively). We observed a trend towards increased risk in patients between 75 and 84 years with CVD at baseline. CONCLUSION: Patients with RA with both CVD and CV risk factors alone are at an increased risk for dementia compared to those with neither CVD nor CV risk factors; however, this risk is attenuated with increasing age. The impact of RA treatment and CV primary prevention strategies in the prevention of dementia in patients with RA warrants further studies.
34770992 Pyridinone Derivatives as Interesting Formyl Peptide Receptor (FPR) Agonists for the Treat 2021 Oct 30 Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by joint inflammation, cartilage damage and bone destruction. Although the pharmacological treatment of RA has evolved over the last few years, the new drugs have serious side effects and are very expensive. Thus, the research has been directed in recent years towards new possible targets. Among these targets, N-formyl peptide receptors (FPRs) are of particular interest. Recently, the mixed FPR1/FPR2 agonist Cpd43, the FPR2 agonist AT-01-KG, and the pyridine derivative AMC3 have been shown to be effective in RA animal models. As an extension of this research, we report here a new series of pyridinone derivatives containing the (substituted)phenyl acetamide chain, which was found to be essential for activity, but with different substitutions at position 5 of the scaffold. The biological results were also supported by molecular modeling studies and additional pharmacological tests on AMC3 have been performed in a rat model of RA, by repeating the treatments of the animals with 10 mg/kg/day of compound by 1 week.
34098104 Palindromic rheumatism: Evidence of four subtypes of palindromic-like arthritis based in e 2021 Dec INTRODUCTION: MEFV mutations have been documented in patients with palindromic rheumatism (PR) who do not meet FMF criteria, and RF and ACPA positive RA may start with PR. OBJECTIVE: To analyze the clinical phenotype and disease evolution of patients with intermittent, palindromic-like (PL) arthritis seen in our Arthritis Unit according to the RF, ACPA and MEFV mutation status. METHODS: MEFV genotyping was done in 76 patients with PL arthritis as defined by predominantly short attacks (≤7days) and a relapsing course. Characteristics of arthritic episodes, RF and ACPA positivity, and the colchicine response were retrospectively collected. Patients were stratified and evaluated according to MEFV mutations and/or positive autoantibodies (ACPA and/or RF). RESULTS: Among the patients, 26.3% (20/76) had a MEFV mutation and 23 (30%) were ACPA and/or RF positive. MEFV mutations and/or autoantibody status allowed four PL arthritis patients to be distinguished: group I (MEFV+), with younger age of onset, short duration attacks (<3days), mainly located in the knee, more frequent non-articular manifestations (fever, pericarditis or abdominal pain) and good response to colchicine; group II (autoantibody+) is older than group I, with the same frequency of short attacks, but the most affected joints were the wrists and small joints of hands: 48% met RA classification criteria during follow-up and were taking DMARDs; group III (MEFV- and autoantibody-) was the most frequent (48%) and clinically heterogeneous group; 51% had attacks lasting>3days, and 15 patients developed criteria of immune-mediated inflammatory, autoinflammatory or infectious diseases. Group IV (MEFV+ associated with preexisting immune-inflammatory disease), was associated with very short attacks, like groups I and II, superimposed or coincident with definite immune-inflammatory disease, including seropositive RA, with good response to colchicine. CONCLUSIONS: Patients with PL arthritis can be classified in four groups according to the presence or not of MEFV mutations and ACPA/RF antibodies with a different clinical evolution and therapeutic response.
33094465 Comparison of the effectiveness of pilates exercises, aerobic exercises, and pilates with 2021 Aug BACKGROUND: Rheumatoid arthritis (RA) is a rheumatic disease characterized by erosive synovitis and polyarthritis. Exercise is known to improve many symptoms in RA patients. AIM: This study was designed to compare the effects of pilates exercises, aerobic exercises, and combined training including pilates with aerobic exercises on fatigue, depression, aerobic capacity, pain, sleep quality, and quality of life. METHODS: Thirty voluntary RA patients were included in this study. Patients were divided into three groups equally, and treatment was applied to each group for 8 weeks. Pilates exercises were practiced to the first group, aerobic exercises were practiced to the second group, and combined training was performed to the third group. Fatigue, depression, aerobic capacity, pain, sleep quality, and quality of life were evaluated using Fatigue Severity Scale (FSS), Beck Depression Inventory (BDI), 6-minute walk test (6MWT), McGill Pain Questionnaire- Short Form (MPQ-SF), Pittsburg Sleep Quality Index (PSQI), and Rheumatoid Arthritis Quality of Life (RAQoL), respectively. RESULTS: The results of the present study showed significant improvements for the first group on fatigue, depression, aerobic capacity, and quality of life (p < 0.05). Improvements in all parameters except for pain were obtained for the second and third groups (p < 0.05). In addition, there was no statistically significant difference among the treatment groups in assessments (p > 0.05). CONCLUSION: Pilates exercises may have similar effects to aerobic exercises in patients with RA. Addition of clinical pilates exercises to the routine treatment of RA may enhance the success of rehabilitation. Trial registration NCT03836820.
34845417 IL-38 and IL-36 Target Autophagy for Regulating Synoviocyte Proliferation, Migration, and 2021 Rheumatoid arthritis (RA) is an autoimmune disease leading to severe joint damage and disability. Fibroblast-like synoviocytes (FLSs) mostly contribute to the joint inflammation and destruction in RA through distinct mechanisms. However, little is known about newly discovered interleukin- (IL-) 36 and IL-38 involving in the pathology of RA. Here, we assessed the effect of IL-36 and IL-38 on RA-FLS function using IL-36 and IL-38 overexpression plasmids. We found that IL-36 inhibited synoviocytes proliferation while IL-38 showed an opposite influence. Furthermore, IL-36 and IL-38 significantly sequestered or accelerated RA-FLS migration and invasion capacity, respectively. Mechanically, IL-36 and IL-38 targeted autophagy for RA-FLS modulation. Using autophagy inhibitor 3-MA and inducer compound rapamycin, we found that autophagy negatively regulated the survival, migration, and invasion of synovial cells. Based on these results, IL-38 in combination with autophagy inhibitor 3-MA treatment demonstrated the strongest blockage of the above three activities of RA-FLS, and IL-38 overexpression reversed rapamycin-inhibited cell proliferation, migration, and invasion. Moreover, injection of IL-36 can improve the symptoms of RA in a rat model of RA. Taken together, we conclude that IL-38 and IL-36 target autophagy for regulating synoviocyte proliferation, migration, and invasion in RA.
32991777 Differences in depression, anxiety and stress disorders between fibromyalgia associated wi 2021 Apr Fibromyalgia (FM) was frequently observed in patients with rheumatoid arthritis (RA). We aimed to evaluate the differences in psychiatric comorbidities and life adversities between patients with Rheumatoid arthritis + FM (secondary fibromyalgia [SFM]) and people with primary FM (PFM). In a cross-sectional, observational study, patients with PFM and SFM underwent a structured interview for the lifetime diagnosis of major depression (MDD), panic disorder (PD) and post-traumatic stress disorder (PTSD) and were assessed for childhood/adulthood adversities and FM-related symptoms severity. Thirty patients with PFM and 40 with SFM were recruited. The univariate analysis showed that the lifetime rates of MDD were significantly higher in PFM versus SFM (76.7 % and 40%, respectively, p < 0.003), as well as the rates of PD (50 % and 15%, respectively, p < 0.003), whereas there was no difference in PTSD rates. The rates of sexual abuse and physical neglect were significantly higher in PFM patients versus SFM patients (p < 0.005 and p < 0.023). Life events occurring before FM onset were different in PFM and SFM groups. In the logistic regression model, lifetime PD and physical neglect remain independent risk factors for PFM. PFM and SFM differ in psychiatric comorbidities and environmental adversities, suggesting that common pathogenesis may develop through different pathways.
33726782 Gamma heavy chain disease associated with rheumatoid arthritis: a case report. 2021 Mar 17 BACKGROUND: Gamma heavy chain disease (γ-HCD) is a monoclonal gammopathy defined by an abnormal clonal and isolated production of incomplete heavy chain gamma (γ), unable to bind with light chains kappa or lambda. This disease is rare and remains poorly described. Its association to lymphoid neoplasm is well established, but exceptional forms of γ-HCD may also accompany auto-immune diseases. We report here a new case of γ-HCD characterized by an indolent course with a 4-year follow-up, and its association with quiescent rheumatoid arthritis (RA). CASE PRESENTATION: We report the case of a 85-year old French white man followed for quiescent anti-CCP+ rheumatoid arthritis treated by prednisolone 4 mg/day and hydroxychloroquine 200 mg/day since 10 years, and a monoclonal gammopathy of undetermined significance for 6 years, who was hospitalized for costal fractures after a fall. Serum protein electrophoresis showed a stable small monoclonal peak, and capillary electrophoresis/immunosubtraction technique identified an isolated clonal γ-heavy chain (HC). Bone marrow aspiration was normal and he had no other lymphoproliferation. The monoclonal peak remained stable after 4 years of follow-up. CONCLUSIONS: In case of monoclonal peak without complete monoclonal Ig on serum protein electrophoresis, the diagnosis of γ-HCD should be discussed and capillary electrophoresis/immune-subtraction is a mean to detect isolated monoclonal heavy chain (HC). Gamma-HC disease is rare, may be associated to RA, and may have an indolent course.
33749319 Influence of RFC1 c.80A>G Polymorphism on Methotrexate-Mediated Toxicity and Therapeutic E 2021 Dec BACKGROUND: Methotrexate (MTX) is an antirheumatic drug, transported by reduced folate carrier-1 (RFC1). The most common RFC1 gene variant, c.80 A>G (rs1051266) is ambiguously linked to adverse effects of MTX therapy in some rheumatoid arthritis (RA) patients. OBJECTIVE: The purpose of meta-analysis was to summarize all major published studies on c.80 A>G SNP to clarify this ambiguity in MTX therapy. METHODS: A total of 18 studies representing 3592 RA patients comprising 699 men and 2893 women were included. Both fixed and random effect models were applied to study the data. RESULTS: The RFC1 80A-allele showed null association with MTX-mediated toxicity in both fixed (odds ratio [OR] = 0.91; 95% CI = 0.80-1.03) and random effects (OR = 0.89; 95% CI: 0.71-1.11) models. Because heterogeneity was observed in this association (P = 0.0006), data were segregated based on use of folate therapy. In 7 studies (n = 1191) where folate was used along with MTX, RFC1 AA patients showed reduced risk for MTX-mediated toxicity (OR = 0.67; 95% CI: 0.50-0.89; P = 0.0006). The RFC1 80A-allele was found to increase the efficacy of MTX therapy by 1.53-fold (95% CI: 1.24-1.88), whereas the 80AA-genotype increased the efficacy by 1.85-fold (95% CI: 1.41-2.42). No publication bias was observed in these associations. CONCLUSION AND RELEVANCE: RFC1 c.80 A>G is an important pharmacogenetic determinant of MTX therapy in RA. The RFC1 80A-allele robustly increased therapeutic efficacy and safety when folate was used along with MTX. Findings are relevant to decision-making in the clinical use of MTX as a treatment for RA patients harboring the RFC1 gene variant.
33349216 Relation of the Serum Levels of DKK-1 and Osteoprotegerin with Bone Mass in Tightly Contro 2021 OBJECTIVE: To analyze the association between serum levels of osteoprotegerin (OPG) and Dickkopf-related protein 1 (DKK-1) and the annual percent change (Δ%) in bone mineral density (BMD) in patients with tightly controlled rheumatoid arthritis (RA). METHODS: Observational mixed-study. RA patients followed-up with a tight-control strategy were included. Bone densitometries were performed at baseline (T0) and follow-up (T1) and serum levels of OPG and DKK-1 were measured by ELISA also in T0 and T1; additional clinical variables included disease activity measures, and treatment for RA and osteoporosis. Descriptive bivariate and multivariate analyses, stratified by gender, were performed. RESULTS: We included 97 RA patients (70% female, with a mean age of 53 years, and 76% with low activity by DAS28); 95% were treated with DMARDs and 37% with anti-osteoporotic drugs. Mean time between T0 and T1 was 2.7 years. Most patients had their BMD improved. The mean Δ%BMD was +0.42% for lumbar spine, +0.15% for femoral neck and +0.91% for total femur. In men, baseline OPG was significantly associated with higher BMD loss (β coefficient -0.64) at the femoral neck. In women, DKK-1 was associated with higher BMD loss at the femoral neck (β coefficient -0.09), and total femur (β coefficient -0.11); however, DKK-1 was associated with lower BMD loss at the lumbar spine (β coefficient 0.06). CONCLUSION: In tightly controlled RA patients, we have found no evidence of bone loss. The role of DKK1 and OPG seems small and might be related to sex and location.
34916678 [Agreement between ultrasound-detected inflammation and clinical signs in ankles and feet 2021 Dec 18 OBJECTIVE: To investigate the agreement between clinical signs (tenderness and/or swelling) in ankles and feet joints and ultrasound findings in patients with rheumatoid arthritis (RA). METHODS: RA patients with at least 1 tender and/or swollen joint in bilateral ankles and metatarsophalangeal (MTP) joints detected by physical examination were enrolled and underwent ultrasound examination by greyscale (GS) and power Doppler (PD) mode. The agreement between clinical signs and ultrasound-detected inflammation (joint effusion, synovitis, or tenosynovitis) was analyzed. RESULTS: In the study, 113 consecutive RA patients were included, with mean age of (52.5±12.6) years, median duration of 60 (13, 129) months, mean disease activity score in 28 joints based on erythrocyte sedimentation rate [DAS28 (ESR)] of 5.1±1.7, mean disease activity score in 28 joints based on C reactive protein[DAS28 (CRP)]of 4.6±1.5. The tenderness and swelling was most commonly detected in ankles (52.7% and 31.9%, respectively), while GS (+) synovitis was most frequently detectable in MTP2 (34.1%), followed by ankles (32.7%) and MTP1 (27.9%), and PD (+) synovitis was most frequently detectable in MTP1 (14.2%), followed by ankles (12.4%) and MTP2 (10.6%). The prevalence of tenosynovitis was 41.1%, which mostly located in tibialis posterior tendon (22.1% of GS positive and 17.6% of PD positive). The highest prevalence of joint effusion was detected in ankles (9.7%), while that of bone erosion in MTP5 (19%). The overall concordance rate between positive clinical signs and ultrasound-determined joint inflammation was poor in the above joints (κ < 0.2, P < 0.05), in which swelling had the highest κ coefficient with ultrasound-determined joint inflammation in ankles (κ=0.225, P < 0.05). Moreover, swelling had the highest κ coefficient with synovitis in ankles (κ=0.231, P < 0.05).The concordance between tenosynovitis and signs in ankles was also poor (κ < 0.20, P < 0.05). There was no significant agreement between joint effusion and clinical signs (P > 0.05). CONCLUSION: The overall concordance between clinical signs and inflammation on ultrasound was poor in ankles and feet joints. Tenderness and swelling was more common in ankles, while more lesions were detected by ultrasound at MTP joints. Ultrasound is useful in assessing the lesions besides physical examination in patients with RA.