A rare giant geode of humeral head in an uncontrolled rheumatoid arthritis: a case report.

INTRODUCTION: Rheumatoid Arthritis (RA) is a chronic inflammatory disease depicted by peripheral bone erosive damage leading to joint destruction, deformity and functional impairment. Shoulder involvement is less frequent than hands, wrists and feet, and relevant joint damage may be underdiagnosed if a lower threshold for careful analysis of this joint is not settled, especially in uncontrolled disease. CASE REPORT: A 70-year-old male with a difficult-to-manage RA since 2010, presenting severe shoulder arthritis with MRI showing a striking giant geode in the left humeral head. CONCLUSION: An impressive MRI image showing a giant geode in poorly controlled RA should alert rheumatologists to raise suspicion of shoulder involvement for early investigation and treatment.

Increment of immunogenicity after third dose of a homologous inactivated SARS-CoV-2 vaccine in a large population of patients with autoimmune rheumatic diseases.

OBJECTIVE: To determine the immunogenicity of the third dose of CoronaVac vaccine in a large population of patients with autoimmune rheumatic diseases (ARD) and the factors associated with impaired response. METHODS: Adult patients with ARD and age-balanced/sex-balanced controls (control group, CG) previously vaccinated with two doses of CoronaVac received the third dose at D210 (6 months after the second dose). The presence of anti-SARS-CoV-2 S1/S2 IgG and neutralising antibodies (NAb) was evaluated previously to vaccination (D210) and 30 days later (D240). Patients with controlled disease suspended mycophenolate mofetil (MMF) for 7 days or methotrexate (MTX) for 2 weekly doses after vaccination. RESULTS: ARD (n=597) and CG (n=199) had comparable age (p=0.943). Anti-S1/S2 IgG seropositivity rates significantly increased from D210 (60%) to D240 (93%) (p<0.0001) in patients with ARD. NAb positivity also increased: 38% (D210) vs 81.4% (D240) (p<0.0001). The same pattern was observed for CG, with significantly higher frequencies for both parameters at D240 (p<0.05). Multivariate logistic regression analyses in the ARD group revealed that older age (OR=0.98, 95% CI 0.96 to 1.0, p=0.024), vasculitis diagnosis (OR=0.24, 95% CI 0.11 to 0.53, p<0.001), prednisone ≥5 mg/day (OR=0.46, 95% CI 0.27 to 0.77, p=0.003), MMF (OR=0.30, 95% CI 0.15 to 0.61, p<0.001) and biologics (OR=0.27, 95% CI 0.16 to 0.46, p<0.001) were associated with reduced anti-S1/S2 IgG positivity. Similar analyses demonstrated that prednisone ≥5 mg/day (OR=0.63, 95% CI 0.44 to 0.90, p=0.011), abatacept (OR=0.39, 95% CI 0.20 to 0.74, p=0.004), belimumab (OR=0.29, 95% CI 0.13 to 0.67, p=0.004) and rituximab (OR=0.11, 95% CI 0.04 to 0.30, p<0.001) were negatively associated with NAb positivity. Further evaluation of COVID-19 seronegative ARD at D210 demonstrated prominent increases in positivity rates at D240 for anti-S1/S2 IgG (80.5%) and NAb (59.1%) (p<0.0001). CONCLUSIONS: We provide novel data on a robust response to the third dose of CoronaVac in patients with ARD, even in those with prevaccination COVID-19 seronegative status. Drugs implicated in reducing immunogenicity after the regular two-dose regimen were associated with non-responsiveness after the third dose, except for MTX. Trial registration number NCT04754698.

Bone erosion in the 2nd metacarpophalangeal head: association with its bone mineral density by HR-pQCT in rheumatoid arthritis patients.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic autoimmune disease depicted by synovial inflammation leading to local and systemic bone loss. The aim of this study was to evaluate by a HR-pQCT (High Resolution Peripheral Quantitative Computed Tomography) study which parameters are associated with volume of bone erosions including bone mineral density (BMD) around erosions (VOI 1 to 4 = volume of interest), BMD of metacarpophalangeal (MCP) head, BMD of radius, presence of osteophytes and joint space width (JSW). METHODS: Fifty female RA patients (18-50 years) were enrolled in this study. Demographic and disease-specific data, laboratory inflammatory parameters and handgrip test were performed. All patients underwent HR-pQCT of 2nd and 3rd MCP joints and distal radius, according to established protocols. The volume of bone erosions was evaluated by MIAF (Medical Image Analysis Framework) software. Osteophytes were analyzed by manual method. RESULTS: The mean of age and disease duration were 40.0 ± 6.0 yrs. and 10.8 ± 4.8 yrs., respectively. According to DAS-28 (Disease Activity Score), 54% (27) of the sample were in remission. However, when SDAI (Simplified Disease Activity Index) was used, only 18% (9) were under remission. The mean of HAQ (Health Assessment Questionnaire), ESR (Erythrocyte sedimentation rate) and CRP (C reactive protein) were 0.9 ± 0.7, 13.9 ± 12.2 mm and 5.6 ± 7.5 mg/mL, respectively. Forty-six bone erosions (0.9 ± 1.2 erosion/patient) and 14 osteophytes (0.3 ± 0.7 osteophyte/patient) were found in 2nd MCP head. The median (IQR-Interquartile range) of volume of erosion and volume of osteophytes were 14.9 (5.7;35.9)mm3 and 3.1 (2.1, 4.3)mm3, respectively. The mean of JSW was 80.5 ± 34.2 mm3. The volume of bone erosions was negatively correlated with BMD of 2nd MCP head, VOI-4 and JSW; and it was positively correlated with osteophytes number. Regarding absence or presence of erosion in 2nd MCP head, a significant difference was found between BMD of MCP head, osteophyte number and JSW. Multiple linear regression analysis showed that only BMD of 2nd MCP head was independently associated with volume of bone erosions. CONCLUSION: BMD of MCP head was independently associated with volume of bone erosion, suggesting that this parameter should be used to analyze and monitoring bone destruction, as well as to evaluate treatment response in RA patients.

HR-pQCT in vivo imaging of periarticular bone changes in chronic inflammatory diseases: Data from acquisition to impact on treatment indications.

Imaging is essential for the assessment of bone and inflammatory joint diseases. There are several imaging techniques available that differ regarding resolution, radiation exposure, time expending, precision, cost, availability or ability to predict disease progression. High-resolution peripheral quantitative computed tomography (HR-pQCT) that was introduced in 2004 allows the in vivo evaluation of peripheral bone microarchitecture and demonstrated high precision in assessing bone changes in inflammatory musculoskeletal diseases. This review summarizes the use of HR-pQCT for the evaluation of the hand skeleton in inflammatory joint diseases. We conducted a review of the literature regarding the protocols that involve hand joints assessment and evaluation of bone changes as erosions and osteophytes in chronic inflammatory diseases. Apart from measuring bone density and structure of the radius and the tibia, HR-pQCT has contributed to assessment of bone erosions and osteophytes, considered the hallmark of diseases as rheumatoid arthritis and psoriatic arthritis, respectively. In this way, there are some conventions recently established by rheumatic study groups that we just summarized here in order to standardize HR-pQCT measurements.

Insulin does not stimulate ß-alanine transport into human skeletal muscle.

To test whether high circulating insulin concentrations influence the transport of ß-alanine into skeletal muscle at either saturating or subsaturating ß-alanine concentrations, we conducted two experiments whereby ß-alanine and insulin concentrations were controlled. In experiment 1, 12 men received supraphysiological amounts of ß-alanine intravenously (0.11 g·kg-1·min-1 for 150 min), with or without insulin infusion. ß-Alanine and carnosine were measured in muscle before and 30 min after infusion. Blood samples were taken throughout the infusion protocol for plasma insulin and ß-alanine analyses. ß-Alanine content in 24-h urine was assessed. In experiment 2, six men ingested typical doses of ß-alanine (10 mg/kg) before insulin infusion or no infusion. ß-Alanine was assessed in muscle before and 120 min following ingestion. In experiment 1, no differences between conditions were shown for plasma ß-alanine, muscle ß-alanine, muscle carnosine and urinary ß-alanine concentrations (all P > 0.05). In experiment 2, no differences between conditions were shown for plasma ß-alanine or muscle ß-alanine concentrations (all P > 0.05). Hyperinsulinemia did not increase ß-alanine uptake by skeletal muscle cells, neither when substrate concentrations exceed the Vmax of ß-alanine transporter TauT nor when it was below saturation. These results suggest that increasing insulin concentration is not necessary to maximize ß-alanine transport into muscle following ß-alanine intake.

Transcriptomic characterization of classical monocytes highlights the involvement of immuno-inflammation in bone erosion in Rheumatoid Arthritis.

Introduction: Evidence-based data suggest that under inflammatory conditions, classical monocytes are the main source of osteoclasts and might be involved in bone erosion pathophysiology. Here, we analyze the transcriptomic profile of classical monocytes in erosive and non-erosive rheumatoid arthritis patients in order to better understand their contribution to bone erosion. Methods: Thirty-nine premenopausal RA patients were consecutively enrolled and divided into two groups based on the presence of bone erosions on hand joints. Classical monocytes were isolated from peripheral blood through negative selection, and RNA-seq was performed using a poly-A enrichment kit and Illumina® platform. Classical monocytes transcriptome from healthy age-matched women were also included to identify differentially expressed genes (DEGs). Therefore, gene sets analysis was performed to identify the enriched biological pathways. Results: RNA-seq analysis resulted in the identification of 1,140 DEGs of which 89 were up-regulated and 1,051 down-regulated in RA patients with bone erosion compared to those without bone erosions. Among up-regulated genes, there was a highlighted expression of IL18RAP and KLF14 related to the production of pro-inflammatory cytokines, innate and adaptive immune response. Genes related to collagen metabolism (LARP6) and bone formation process (PAPPA) were down-regulated in RA patients with erosions. Enriched pathways in patients with erosions were associated with greater activation of immune activation, and inflammation. Interestingly, pathways associated with osteoblast differentiation and regulation of Wnt signaling were less activated in RA patients with erosions. Conclusion: These findings suggest that alterations in expression of monocyte genes related to the inflammatory process and impairment of bone formation might have an important role in the pathophysiology of bone erosions in RA patients.

Lower hand grip in rheumatoid arthritis patients is associated with low finite element analysis using high resolution peripheral quantitative computed tomography scan of the 2nd metacarpophalangeal joint.

AIM: To evaluate hand function by hand grip test in rheumatoid arthritis (RA) patients, and its association with bone erosions and the estimated bone strength (finite element - FE analysis) through the analysis of the 2nd metacarpal head of the dominant hand using high resolution peripheral quantitative computed tomography (HR-pQCT). METHOD: Eighty-two female RA patients between 18-50 years old were selected. Demographic data, Health Questionnaire Assessment Disability Index (HAQ), Disease Activity Score of 28 joints (DAS)-28, simplified disease activity index (SDAI) and the hand grip test were set. The HR-pQCT scans of 2nd metacarpophalangeal joints of the dominant hand of all patients were performed according to SPECTRA group protocols. The images were used to assess bone erosions and FE analysis. The hand grip test was categorized in 2 groups and separately compared (< 18 vs ≥18 kgf). A logistic regression was performed using hand grip test <18 kgf as a dependent variable. RESULTS: A significant difference was found between the 2 groups regarding HAQ, inflammatory markers (erythrocyte sedimentation rate, C-reactive protein), DAS-28, SDAI, total volume of erosion and bone strength parameter (FE analysis - Failure Load [F.Load]). The logistic regression analysis showed that the risk factors associated with hand grip test <18 kgf were higher SDAI (odds ratio [OR] 0.912; 95% CI 0.837-0.993) and lower values of bone strength parameter (F.Load) (OR 1.007; 95% CI 1.002-1.012). CONCLUSION: Lower values of hand grip test were associated with higher disease activity score-SDAI and lower bone strength of 2nd metacarpal bone head of the dominant hand evaluated here through a FE analysis using HR-pQCT scan.

Evaluation of bone erosion in rheumatoid arthritis patients by high-resolution peripheral quantitative computed tomography scans: Comparison between two semi-automated programs in a three-dimensional setting.

AIM: The aim of this study was to compare OsiriX software with the previous published Medical Image Analysis Framework (MIAF) method to assess the volume of erosion in patients with rheumatoid arthritis (RA). METHODS: Forty RA patients underwent high-resolution peripheral quantitative computed tomography scans of the second and third metacarpophalangeal joints, and thirty-four patients with any bone erosion were enrolled. Two techniques were applied to erosion evaluation: (a) semi-automated MIAF software, and (b) semi-automated segmentation by free open-source Digital Imaging and Communications in Medicine viewer, OsiriX software. MIAF has been published before, but this is the first time that OsiriX has been used in this way in rheumatology. Bland & Altman plots described agreement between methods. RESULTS: Forty-eight erosions from 34 patients were analyzed. Mean age was 40.74 ± 5.32 years and mean disease duration was 10.68 ± 4.96 years. Both methods demonstrated a strong correlation regarding erosion volume (r = 0.96, P < 0.001). Median (interquartile range) of erosion volume was 12.14 (4.5-36.07) when MIAF was considered, and 11.80 (3.45-29.42) when the OsiriX tool was used (P = 0.139). MIAF and OsiriX showed good agreement when the Bland & Altman plot was performed. Evaluation by MIAF took 22.69 ± 6.71 minutes, whereas OsiriX took only 2.62 ± 1.09 minutes (P < 0.001). CONCLUSION: The three-dimensional segmentation of bone erosions can be done by both MIAF and OsiriX software with good agreement. However, because OsiriX is a widespread tool and faster, its method seems to be more feasible for evaluating peripheral bone damage, especially bone erosions.

Histidine dipeptides are key regulators of excitation-contraction coupling in cardiac muscle: Evidence from a novel CARNS1 knockout rat model.

Histidine-containing dipeptides (HCDs) are abundantly expressed in striated muscles. Although important properties have been ascribed to HCDs, including H+ buffering, regulation of Ca2+ transients and protection against oxidative stress, it remains unknown whether they play relevant functions in vivo. To investigate the in vivo roles of HCDs, we developed the first carnosine synthase knockout (CARNS1-/-) rat strain to investigate the impact of an absence of HCDs on skeletal and cardiac muscle function. Male wild-type (WT) and knockout rats (4 months-old) were used. Skeletal muscle function was assessed by an exercise tolerance test, contractile function in situ and muscle buffering capacity in vitro. Cardiac function was assessed in vivo by echocardiography and cardiac electrical activity by electrocardiography. Cardiomyocyte contractile function was assessed in isolated cardiomyocytes by measuring sarcomere contractility, along with the determination of Ca2+ transient. Markers of oxidative stress, mitochondrial function and expression of proteins were also evaluated in cardiac muscle. Animals were supplemented with carnosine (1.8% in drinking water for 12 weeks) in an attempt to rescue tissue HCDs levels and function. CARNS1-/- resulted in the complete absence of carnosine and anserine, but it did not affect exercise capacity, skeletal muscle force production, fatigability or buffering capacity in vitro, indicating that these are not essential for pH regulation and function in skeletal muscle. In cardiac muscle, however, CARNS1-/- resulted in a significant impairment of contractile function, which was confirmed both in vivo and ex vivo in isolated sarcomeres. Impaired systolic and diastolic dysfunction were accompanied by reduced intracellular Ca2+ peaks and slowed Ca2+ removal, but not by increased markers of oxidative stress or impaired mitochondrial respiration. No relevant increases in muscle carnosine content were observed after carnosine supplementation. Results show that a primary function of HCDs in cardiac muscle is the regulation of Ca2+ handling and excitation-contraction coupling.

Creatine Supplementation (3 g/d) and Bone Health in Older Women: A 2-Year, Randomized, Placebo-Controlled Trial.

BACKGROUND: Creatine supplementation could be a nonexpensive, safe, and effective dietary intervention to counteract bone loss. The aim of this study was to investigate whether long-term creatine supplementation can improve bone health in older, postmenopausal women. METHODS: A double-blind, placebo-controlled, parallel-group, randomized trial was conducted between November 2011 and December 2017 in Sao Paulo, Brazil. Two hundred postmenopausal women with osteopenia were randomly allocated to receive either creatine monohydrate (3 g/d) or placebo for 2 years. At baseline and after 12 and 24 months, we assessed areal bone mineral density (aBMD; primary outcome), lean and fat mass (through dual X-ray absorptiometry), volumetric BMD and bone microarchitecture parameters, biochemical bone markers, physical function and strength, and the number of falls and fractures. Possible adverse effects were self-reported. RESULTS: Lumbar spine (p < .001), femoral neck (p < .001), and total femur aBMD (p = .032) decreased across time; however, no interaction effect was observed (all p > .050). Bone markers, microarchitecture parameters, and the number of falls/fractures were not changed with creatine (all p > .050). Lean mass and appendicular skeletal muscle mass increased throughout the intervention (p < .001), with no additive effect of creatine (p = .731 and p = .397, respectively). Creatine did not affect health-related laboratory parameters. CONCLUSION: Creatine supplementation more than 2 years did not improve bone health in older, postmenopausal women with osteopenia, nor did it affect lean mass or muscle function in this population. This refutes the long-lasting notion that this dietary supplement alone has osteogenic or anabolic properties in the long run. CLINICAL TRIAL REGISTRY: Clinicaltrials.gov: NCT: 01472393.