Bone impairment assessed by lumbar spine trabecular bone score (TBS) and HR-pQCT in male ankylosing spondylitis patients

Objectives. Low bone mineral density (BMD) and osteoporosis diagnosis in AS patients is based on data using dual-energy X-ray absorptiometry (DXA), which may be difficult to interpret due to the presence of syndesmophytes. The objective of this study is to evaluate bone mass and quality using areal (a) BMD, lumbar spine trabecular bone score (TBS) and HR-pQCT parameters in AS patients compared with healthy controls (HC). Methods. TBS and aBMD were evaluated using DXA. Volumetric bone mineral density (vBMD), bone microarchitecture and stiffness were analyzed at the distal tibia and radius using HR-pQCT. Seventy-three AS male patients and 52 agematched HC were evaluated. Results. Lower TBS values were observed in AS patients compared with HC (1.314 ± 0.121 vs. 1.396 ± 0.070, p<0.001); however, no difference was observed in lumbar spine aBMD between these two groups (1.080 ± 0.193 vs. 1.041 ± 0.118 g/cm2 , p=0.11). Lower trabecular vBMD (162.1 ± 39.6 vs. 186.8 ± 39.9 mg HA/cm3 , p<0.001), lower structural parameters Tb.Th (0.074 ± 0.012 vs. 0.080 ± 0.013 mm, p=0,044) and Tb.Sp (0.497 ± 0.110 vs. 0.448 ± 0.086 mm, p=0,039) and lower strength parameters stiffness (254250.8 ± 48477.7 vs. 291770.3 ± 52858.4 N/mm, p<0.001) and F.Load (12098.6 ± 2240. vs 13770.2 ± 2388.1 N, p=0,001) were observed in the trabecular compartment at the distal tibia in AS patients compared to HC. Conclusion. The lumbar spine TBS and HR-pQCT imaging measurements are superior technologies to detect impairment of bone mass and quality in AS patients compared to healthy subjects

Increased Serum Interleukin-6 and Tumor Necrosis Factor Alpha Levels in Fabry Disease: Correlation with Disease Burden

OBJECTIVES: Fabry disease (FD) is an X-linked lysosomal disease caused by variants of the GLA gene; the formation of defective alpha-galactosidase A contributes to the accumulation of substrates in several organs. Chronic inflammation is thought to contribute to organ damage in FD patients. METHODS: In total, 36 classic FD patients (15 men/21 women) and 25 healthy controls (20 men/8 women) were assessed. The Mainz Severity Score Index (MSSI) was established after conducting interviews with the patients and chart review. Serum IL-6, IL-1β, and TNF-α levels were evaluated in both groups. RESULTS: The mean age (years) for FD patients was 43.1±15.4 and that for the controls was 47.4±12.2 (p>0.05). Twenty-two patients (59.5%) were treated with enzyme replacement therapy (ERT). Serum IL-6 and TNF-α levels were significantly higher in FD patients than in the controls. Patients treated with ERT had higher serum IL-6 and TNF-α levels than those not treated with ERT. There was no difference in the serum IL-1β levels between patients treated with ERT and those who were not. The MSSI scores in the patients were correlated with serum levels of IL-6 (r=0.60, p<0.001) and TNF-α (r=0.45, p<0.001). CONCLUSION: FD was associated with elevated serum levels of IL-6 and TNF-α in this cohort. The FD patients treated with ERT, particularly, women, exhibited higher levels of serum IL-6 and TNF-α than those not treated with ERT; the serum IL-6 and TNF-α levels were correlated with the MSSI scores reflecting greater disease burden

Serum 25-hydroxyvitamin D levels in patients with Granulomatosis with Polyangiitis: association with respiratory infection

OBJECTIVES: To determine the possible association of serum 25-hydroxyvitamin D (25OHD) levels with disease activity and respiratory infection in granulomatosis with polyangiitis patients during two different periods: winter/spring and summer/autumn. METHODS: Thirty-two granulomatosis with polyangiitis patients were evaluated in the winter/spring, and the same patients (except 5) were evaluated in summer/autumn (n=27). The 25OHD levels were measured by radioimmunoassay. Disease activity was assessed by the Birmingham Vasculitis Activity Score Modified for Wegener’s Granulomatosis (BVAS/WG) and antineutrophil cytoplasmic antibody (ANCA) positivity. Respiratory infection was defined according the Centers for Disease Control and Prevention criteria. RESULTS: 25OHD levels were lower among patients in winter/spring than in summer/autumn (32.31±13.10 vs. 38.98±10.97 ng/mL, p=0.04). Seven patients met the criteria for respiratory infection: 5 in winter/spring and 2 in summer/autumn. Patients with respiratory infection presented lower 25OHD levels than those without infection (25.15±11.70 vs. 36.73±12.08 ng/mL, p=0.02). A higher frequency of low vitamin D levels (25OH

No deleterious effect of low dose methotrexate on titanium implant osseointegration in a rabbit model

OBJECTIVE: To evaluate the effect of low dose methotrexate alone or in combination with glucocorticoid treatment on titanium implant osseointegration. METHODS: Groups of 6-8 adult New Zealand White rabbits were treated for 18 weeks with saline (control), methotrexate, glucocorticoid, or methotrexate plus glucocorticoid. The animals received a titanium implant in the tibia at week 6. Lumbar spine and tibia bone mineral densities were analyzed before and after treatment. Histomorphometric analysis of bone cortical thickness, total bone area around the implant, and % of bone to implant contact was performed. RESULTS: After 18 weeks, the change in the bone mineral density in the lumbar spines and tibias in the methotrexate group was comparable to the control group (0.035 vs. 0.055 g/cm² and 0.021 vs. 0.041 g/cm², respectively). In contrast, both the glucocorticoid group and glucocorticoid plus methotrexate group had significant reductions at both sites. Histomorphometric analysis of the tibia in the control and methotrexate groups revealed no significant changes in cortical thickness (133 vs. 126 μm), total bone area around the implant (33 vs. 30%), or bone to implant contact (40 vs. 38%). In contrast, glucocorticoid group had significant reductions compared to controls in tibia cortical thickness (99 vs. 133 μm), total bone area around the implant (24 vs. 33%), and bone to implant contact (27 vs. 40%). Similar reductions were observed in the glucocorticoid plus methotrexate group. CONCLUSIONS: Our results demonstrate that low dose methotrexate treatment does not affect titanium implant osseointegration, suggesting that this therapy is safe for surgical procedures requiring a titanium implant

Critical illness-related bone loss is associated with osteoclastic and angiogenic abnormalities

Critically ill patients are at increased risk of fractures during rehabilitation, and can experience impaired healing of traumatic and surgical bone fractures. In addition, markers of bone resorption are markedly increased in critically ill patients, while markers of bone formation are decreased. In the current study, we have directly investigated the effect of critical illness on bone metabolism and repair. In a human in vitro model of critical illness, Fluorescence-activated cell sorting (FACS) analysis revealed an increase in circulating CD14+/CD11b+ osteoclast precursors in critically ill patient peripheral blood compared to healthy controls. In addition, the formation of osteoclasts was increased in patient peripheral blood mononuclear cell (PBMC) cultures compared to healthy controls, both in the presence and absence of osteoclastogenic factors receptor activator of NF-κB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF). Culturing PBMCs with 10% critically ill patient serum further increased osteoclast formation and activity in patient PBMCs only, and neutralization studies revealed that immunoglobulin G (IgG) antibody signaling through the immunoreceptor Fc receptor common γ chain III (FcRγIII) played an important role. When analyzing bone formation, no differences in osteogenic differentiation were observed using human periosteal-derived cells (hPDCs) treated with patient serum in vitro, but a decrease in the expression of vascular endothelial growth factor receptor 1 (VEGF-R1) suggested impaired vascularization. This was confirmed using serum-treated hPDCs implanted onto calcium phosphate scaffolds in a murine in vivo model of bone formation, where decreased vascularization and increased osteoclast activity led to a decrease in bone formation in scaffolds with patient serum-treated hPDCs. Together, these findings may help to define novel therapeutic targets to prevent bone loss and optimize fracture healing in critically ill patients

Incidence and risk factors of lower limb injury in runners: a prospective cohort study

A prática de corrida de média e longa distância tem crescido em todo o mundo. Apesar de todos os efeitos benéficos da prática de corrida, tem-se observado uma elevada incidência de lesões, sobretudo em membros inferiores. O mecanismo de lesão relacionada à corrida obedece a um padrão comum a todas as lesões nos diferentes esportes e decorre da sobreposição de dois ou mais fatores. Os objetivos desse estudo foram: 1) relatar prospectivamente a incidência de lesões osteomioarticulares em corredores amadores durante 12 meses de seguimento; e 2) detectar os principais fatores extrínsecos e intrínsecos para as lesões encontradas. Dezoito corredores (13 homens e cinco mulheres) amadores foram selecionados para participarem do estudo. Eles foram submetidos a uma avaliação clínica com exame físico completo e do aparelho locomotor, avaliação nutricional, exames laboratoriais, teste ergométrico, avaliação da densidade mineral óssea e composição corporal e radiografia dos pés no período basal e após um ano de seguimento. Aqueles que apresentaram alguma lesão foram comparados com seus pares que não lesionados, considerando-se as diversas variáveis coletadas. Metade da amostra (50%) apresentou alguma lesão osteomuscular em membros inferiores no período do estudo. Os fatores de risco significantemente associados foram graus de extensão de joelho e flexão plantar diminuídos, frequência cardíaca de repouso menor e velocidade de treino maior. A alta frequência de lesões osteomioartculates nestes corredores de longa distância esteve associada a fatores intrínsecos e extrínsecos. A avaliação clínica deve ser focada nesses parâmetros com intuito de prevenir lesões em corredores.The practice of middle- and long-distance running has become worldwide popular. Despite the number of benefits associated with this sport, increased incidence of lower limb injury has been observed. The injury mechanisms related to running are similar to those seen in different sports and can be a result of two or more factors. The aims of this study were: 1) to report prospectively the incidence of injuries in non professional runners after a 12-month follow-up; and 2) to determine the main intrinsic and extrinsic factors related to the observed injuries. Eighteen runners (13 males and five females) took part in this study. They were submitted to clinical examination, nutritional and biochemical assessments, VO2max test, bone mineral density and body composition evaluation, and foot radiography at baseline and after one year. The subjects who had injury were compared to those non-injured taken into account the several variables assessed. Fifth percent of the sample presented at least one lower limb injury. The factors significantly associated with the injuries were reduced knee extension and plantar flexion range of motion, lower resting heart rate, and high training speed. The high incidence of injuries observed in this study was associated with intrinsic and extrinsic factors. The clinical assessment should focus on these parameters in order to prevent injuries

Anti-SARS-CoV-2 inactivated vaccine in patients with ANCA-associated vasculitis: Immunogenicity, safety, antibody decay and the booster dose

Objective: To evaluate inactivated CoronaVac prime vaccination, antibody decay, booster dose, and safety in ANCA-Associated Vasculitis (AAV) patients. Methods: Fifty-three AAV patients and 106 Controls (CG) received CoronaVac on days: D0 (first dose), D28(second dose), and D210 (booster dose, 32 AAV: 32 CG). The primary outcome was immunogenicity after the second vaccine dose (day 69) assessed by Seroconversion Rates (SC) of anti-SARS-CoV-2 S1/S2 IgG and Neutralizing Antibodies (NAb). Secondary outcomes were safety, immunogenicity (D28/D240), 6-months antibody decay (D210) and the booster dose response (D240). Results: At D69 SC (65.1% vs. 96.8%, p = 0.0001), GMT (21.3 UA/mL vs. 67.7 UA/mL, p < 0.001) and NAb- positivity (53.7% vs. 80.6%, p = 0.001) were moderate but lower in naïve-AAV patients than CG. Patients without SC used more often IS (93.3% vs. 53.3%, p = 0.015), mycophenolate mofetil (20% vs. 0%, p = 0.037) and prednisone (60.0% vs. 28.6%, p = 0.057) than seroconverted. NAb negativity in AAV patients was associated with prednisone treatment (57.9% vs. 18.2%, p = 0.015) and IS (84.2% vs. 55.0%, p = 0.046). Logistic regression analysis models showed that only prednisone was associated with lower seroconversion (OR = 0.2, 0,95% CI 0.05‒0.86, p = 0.030) and with lower NAb positivity (OR = 0.2, 0,95% CI 0.05‒0.88, p = 0.034). After six months (D69‒D210) a decrease in IgG positivity occurred in 32 AAV patients (15.7%, p = 0.074) and 32 CG (18.7%, p = 0.041). For the NAb positivity, the 6-month decrease was not significant (p = 0.114) whereas a major reduction occurred for CG (p < 0.001). A booster dose (D240) resulted in an increment in IgG-positivity (21.9%, p = 0.023) and NAb-positivity (34.4%, p = 0.006) in AAV patients. No moderate/severe adverse events attributable to the vaccine were observed. Conclusion: This study provides novel data on the excellent safety and moderate immunogenicity of CoronaVac in AAV patients. A six-month mild antibody waning was observed with a good response to the booster dose, although levels remained lower than CG (CoronavRheum-NCT04754698)

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

IntroductionEvidence-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.MethodsThirty-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.ResultsRNA-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.ConclusionThese 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

Transcriptomic signatures of classical monocytes reveal pro-inflammatory modules and heterogeneity in polyarticular juvenile idiopathic arthritis

IntroductionPolyarticular juvenile idiopathic arthritis (pJIA) is a childhood-onset autoimmune disease. Immune cells contribute to persistent inflammation observed in pJIA. Despite the crucial role of monocytes in arthritis, the precise involvement of classical monocytes in the pathogenesis of pJIA remains uncertain. Here, we aimed to uncover the transcriptomic patterns of classical monocytes in pJIA, focusing on their involvement in disease mechanism and heterogeneity.MethodsA total of 17 healthy subjects and 18 premenopausal women with pJIA according to ILAR criteria were included. Classical monocytes were isolated, and RNA sequencing was performed. Differential expression analysis was used to compare pJIA patients and healthy control group. Differentially expressed genes (DEGs) were identified, and gene set enrichment analysis (GSEA) was performed. Using unsupervised learning approach, patients were clustered in two groups based on their similarities at transcriptomic level. Subsequently, these clusters underwent a comparative analysis to reveal differences at the transcriptomic level.ResultsWe identified 440 DEGs in pJIA patients of which 360 were upregulated and 80 downregulated. GSEA highlighted TNF-α and IFN-γ response. Importantly, this analysis not only detected genes targeted by pJIA therapy but also identified new modulators of immuno-inflammation. PLAUR, IL1B, IL6, CDKN1A, PIM1, and ICAM1 were pointed as drivers of chronic hyperinflammation. Unsupervised learning approach revealed two clusters within pJIA, each exhibiting varying inflammation levels.ConclusionThese findings indicate the pivotal role of immuno-inflammation driven by classical monocytes in pJIA and reveals the existence of two subclusters within pJIA, regardless the positivity of rheumatoid factor and anti-CCP, paving the way to precision medicine