The balance between soluble receptors regulating IL-6 trans-signaling is predictive for the RANKL/osteoprotegerin ratio in postmenopausal women with rheumatoid arthritis

The objective of this study is to investigate the relationship between soluble components of the interleukin 6 (IL-6) system mediating and modifying IL-6 trans-signaling and the RANKL–RANK–osteoprotegerin system in postmenopausal women with rheumatoid arthritis (RA). The following parameters were investigated in 126 postmenopausal women with RA: IL-6, soluble IL-6-receptor (sIL-6R), soluble glycoprotein 130 (sgp130), sRANKL, osteoprotegerin (OPG), osteocalcin, erythrocyte sedimentation rate and C-reactive protein in sera, pyridinolin and desoxypyridinolin crosslinks in the morning urine. Bone mineral density (BMD) was measured by dual X-ray absorptiometry at the lumbar spine (BMD-LS) and at the femoral neck (BMD-FN). Predictors of RANKL/OPG ratio and BMD were evaluated by multiple linear regression analysis. The following determinants of the RANKL/OPG ratio were identified: sIL-6R/sgp130 ratio and daily glucocorticoid (GC) dose as positive determinants in the whole group (R ² = 0.56; P = 0.001), sIL-6R/sgp130 ratio as the exclusive positive determinant in patients with GC therapy (R ² = 0.48; P = 0.001) and sgp130 as negative determinant in patients without GC (R ² = 0.42; P = 0.031). Sgp130 was highly significantly positively correlated with OPG in the whole group (P < 0.001) as well as in patients with (n = 70; P < 0.05) and without GC therapy (n = 56; P < 0.01). sIL-6R was the main negative predictor of BMD-LS (R ² = 0.41; P = 0.019). High sIL-6R/sgp130 ratio and/or low sgp130 are associated with a high sRANKL/OPG ratio in sera of postmenopausal women with RA indicating the critical significance of IL-6 trans-signaling for an increase in the RANKL/OPG ratio and of bone resorption. Inhibition of IL-6 trans-signaling may be an effective bone-protecting principle in postmenopausal women with RA.     

Hypercalcemia in rheumatoid arthritis: relationship with disease activity and bone metabolism

To investigate the relationship between ionized calcium and disease activity, parameters of bone metabolism and bone mineral density (BMD) at the lumbar spine (BMD-LS) and the femoral neck (BMD-FN) measured by dual X-ray absorptiometry in rheumatoid arthritis (RA). In 146 patients with RA, the following parameters were investigated: serum levels of ionized calcium, total calcium, vitamin D metabolites 25-hydroxyvitamin D3 (25D3) and 1,25-dihydroxyvitamin D3 (1,25D3), intact parathyroid hormone (iPTH), interleukin-6, osteocalcin, erythrocyte sedimentation rate (ESR) and c-reactive protein (CRP); renal excretion of pyridinolin (PYD)- and desoxypyridinolin (DPD)-crosslinks. A total of 30.1% of the patients were hypercalcemic (ionized calcium >1.30 mmol/l). In comparison with normocalcemic patients, those with hypercalcemia had significantly higher ESR (P<0.01) and CRP values (P<0.05) and significantly lower serum levels of both iPTH (P<0.01) and 1,25D3 (P<0.05) and a significantly lower BMD-LS (P<0.05). The results indicate that a substantial part of RA patients is hypercalcemic. Hypercalcemia is associated with high disease activity and may contribute to suppression of PTH secretion and vitamin D hormone synthesis. High levels of ionized calcium may be a reflection of disease-activity-related systemic bone loss, and could be a predictor of BMD at the lumbar spine in RA.     

Soluble receptor activator of nuclear factor-κB ligand (RANKL) and osteoprotegerin in ankylosing spondylitis: OPG is associated with poor physical mobility and reflects systemic inflammation

The objective of the study was to investigate the role of receptor activator of nuclear factor-κB ligand (RANKL) and osteoprotegerin (OPG) in ankylosing spondylitis (AS). Serum levels of soluble RANKL (sRANKL) and OPG were measured in 42 AS patients and 26 healthy controls. We evaluated the AS patient's disease activity, functional ability, global assessment, and physical mobility and tested markers of systemic inflammation, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) levels. Serum levels of sRANKL [mean (SD), 4.75 (1.88) vs. 3.70 (1.14) pmol/l, p = 0.015] and OPG [mean (SD), 5.18 (1.19) vs. 4.52 (0.85) pmol/l, p = 0.026] were significantly higher in the 42 AS patients than the 26 healthy controls. Interestingly, serum OPG levels correlated significantly with ESR (r = 0.417, p = 0.007), CRP (r = 0.524, p < 0.001), tragus-to-wall distance (r = 0.556, p < 0.001), fingertip-to-floor distance (r = 0.423, p = 0.007), and occiput-to-wall distance (r = 0.465, p = 0.002) and correlated inversely with modified Schober index (r = −0.525, p = 0.001), cervical rotation (r = −0.403, p = 0.022), lateral lumbar flexion (r = −0.587, p < 0.001), and chest expansion (r = −0.553, p < 0.001). Moreover, in the AS patients with higher (≥4.925 pmol/l, n = 21) serum OPG levels, there were significant increases in the tragus-to-wall distance (p = 0.007), fingertip-to-floor distance (p = 0.023), and CRP levels (p = 0.014) and decreased in the modified Schober index (p = 0.012), lateral lumbar flexion (p = 0.019), and chest expansion (p = 0.005). Serum levels of sRANKL and OPG are increased in the AS patients and may participate in the disease process of AS. Production of OPG has association with poor physical mobility and may reflect systemic inflammation in AS.     

Serum levels of tissue inhibitor of metalloproteinase-1 and periarticular bone loss in early rheumatoid arthritis

We investigated the relationship between disease activity, serum biological mediators of joint damage, and periarticular bone loss in inflammatory arthritis. Patients with early inflammatory arthritis were recruited from a dedicated early arthritis clinic. At the time of recruitment, all had clinical evidence of synovitis. Patients were assessed at baseline and at 1-year follow-up. Periarticular and axial bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry. Serum levels of matrix metalloproteinase 1 and tissue inhibitor of metalloproteinases 1 (TIMP-1) were measured by enzyme-linked immunosorbent assay. A total 38 patients were included in the study. Twenty had rheumatoid arthritis (RA) and 18 had a seronegative spondylarthropathy (SpA). At baseline, periarticular hand BMD measurements were similar in RA and SpA. At 1 year, the mean periarticular hand BMD was significantly lower in RA (p < 0.05). Significant inverse correlations between both the Ritchie articular index and C-reactive protein levels and the change in periarticular hand BMD at 1 year were observed in RA (r = −0.792, p < 0.001 and r = −0.478, p = 0.045, respectively). Baseline TIMP-1 levels correlated with the change in periarticular hand BMD at 1 year in RA (r = 0.519, p = 0.02). At 1 year, radiographic measures of joint damage were highest in RA. Inverse correlations between the change in periarticular hand BMD and the changes in erosion score (r = −0.90, p = 0.04) were observed in patients demonstrating significant periarticular bone loss. Persistent disease activity was associated with increased periarticular bone loss in the hands in patients with RA, consistent with synovitis-mediated periarticular bone loss. The correlation between baseline TIMP-1 levels and periarticular bone loss over 1 year suggests that TIMP-1 may have utility as a biomarker of periarticular bone loss in early RA.     

Synovial fluid RANKL and matrix metalloproteinase levels in enthesitis related arthritis subtype of juvenile idiopathic arthritis

In chronic arthritis cartilage and bone destruction occur as a consequence of synovial inflammation. It is mainly mediated by matrix metalloproteinases and RANKL-OPG pathways. Data on synovial fluid levels of these mediators in enthesitis related arthritis subtype (ERA) of JIA are not available. MMP-1, MMP-3, TIMP, sRANKL and OPG levels were measured in synovial fluid from patients with ERA and compared with other arthritides, polyarticular (Poly) JIA, RA and osteoarthritis (OA). sRANKL was detectable in 25/41 of ERA patients, 4/16 of Poly JIA patients. Median SF sRANKL level in patients with ERA was higher as compared to OA (p < 0.001) and poly JIA (p < 0.05) but were comparable to RA. The median OPG level in ERA was lower as compared to OA (p < 0.001), comparable to RA but was higher than poly JIA (p < 0.001). sRANKL/OPG ratio was significantly higher in ERA and Poly JIA compared to OA (p < 0.0001, p < 0.0001 respectively). The median MMP3 levels in ERA (74 ug/ml) was lower as compared to poly JIA (410 ug/ml; p < 0.0001) and RA (340 ug/ml; p < 0.0001) but was comparable to OA (107 ug/ml). The median level of ProMMP1 in ERA (0.70 ug/ml) was lower as compared to RA (2.9 ug/ml; p < 0.0001) and poly JIA but was elevated as compared to OA patients (0.1 ug/ml; p < 0.0001). TIMP1 levels in ERA were higher than poly JIA and RA patients. MMP3/TIMP1 ratio was lower in ERA compared to polyarticular JIA patients (p < 0.05). Ours is the first study reporting elevated sRANKL and reduced OPG levels and elevated sRANKL/OPG ratio in SF of children with JIA resulting in a mileu associated with bone loss. In addition, ERA patients had lower MMP level as well as MMP/TIMP ratio as compared to poly JIA which may partly explain lesser degree of joint damage seen in ERA as compared to poly JIA.     

Detection of bone erosion in early rheumatoid arthritis: ultrasonography and conventional radiography versus non-contrast magnetic resonance imaging

Nowadays, there is a trend toward early diagnosis and treatment of rheumatoid arthritis (RA) especially in patients with early signs of bone erosion which can be detected by magnetic resonance imaging (MRI). The aim of following study is to compare the sensitivity and specificity of ultrasonography (US) and conventional radiography (CR) compared to MRI for early detection of bone erosion in RA patients. In 12 patients with RA diagnosis, 120 first to fifth metacarpophalangeal joints and 96 second to fifth proximal interphalangeal joints were examined. Non-contrast MRI, US and CR were performed for bone erosion evaluation. For further analysis, the patients were divided in two equal groups according to disease activity score (DAS28). The overall sensitivity and specificity of US compared to MRI in detecting bone erosion were 0.63 and 0.98, respectively with a considerable agreement (kappa = 0.68, p < 0.001). Sensitivity and specificity of CR compared to MRI in detecting bone erosion were 0.13 and 1.00, respectively (kappa = 0.20, p < 0.001). In patients with more active disease, the sensitivity and specificity were 0.67 and 0.99 (kappa = 0.74, p < 0.001) compared to 0.59 and 0.97 (kappa = 0.61, p < 0.001) for the rest of patients according to DAS28. Conclusively, these findings reveal an acceptable agreement between US and MRI for detection of bone erosion in patients with early RA but not CR. US might be considered as a valuable tool for early detection of bone erosion especially when MRI is not available or affordable. Besides, it seems the US could be more reliable when the disease is more active.     

The relation of serum vascular endothelial growth factor level with disease duration and activity in patients with rheumatoid arthritis

Vascular endothelial growth factor (VEGF) is known to be involved in the pathogenesis of rheumatoid arthritis (RA). In order to elucidate the association between VEGF levels and RA disease activity, VEGF concentrations were measured in RA patients at different phases and severity levels. Thirty-eight healthy subjects and 40 patients with RA were prospectively included in the study. Subjects were further categorized into four subgroups (high, moderate, low, or remission) using the disease activity score-28 (DAS28) scoring system. VEGF levels were significantly higher in patients than controls (p < 0.001). VEGF levels differed significantly in controls, early and late-phase RA patients (p = 0.002). A significant difference was found between controls and patients with high RA disease activity scores (p < 0.0001). VEGF levels were not correlated with age (r = −0.016; p = 0.921) or sex (r = 0.209; p = 0.921). VEGF values were correlated with erythrocyte sedimentation rate (r = 0.445; p = 0.004), but was not correlated with serum rheumatoid factor levels (r = −0.130; p = 0.424) in the patient group. In conclusion, higher VEGF levels are associated with late phase and high disease activity in RA, independent of age and sex.     

Haemoglobin levels are associated with bone mineral density in the elderly: a population-based study

Hypoxemia has been associated with low bone mineral density (BMD) in animal and human models. We assessed the association of haemoglobin levels with ultrasound-derived (UD) T score, Z score and the stiffness index in all 358 subjects aged 75+ living in Tuscania (Italy). Also, we searched for the haemoglobin cutoff levels that might best identify participants with osteoporosis. In the multivariable linear regression analysis, haemoglobin levels were associated among participants with the UD T score [β = 0.13; 95% confidence interval (CI) = 0.01–0.25; p = 0.030], Z score (β = 0.11; 95% CI = 0.01–0.22; p = 0.045) and stiffness index (β = 1.87; 95% CI = 0.51–3.21; p = 0.007) after adjusting for potential confounders. Haemoglobin levels <140 g/L in men and <130 g/L in women best predicted osteoporosis in linear discriminant analysis. Haemoglobin is independently associated with all UD-BMD parameters. Haemoglobin levels <140 g/L in men and 130 g/L in women might be adopted in clinical practice to identify older subjects in whom screening for osteoporosis might yield higher effectiveness.     

Anti-agalactosyl IgG antibody in ankylosing spondylitis and psoriatic arthritis

Anti-agalactosyl IgG antibody (anti-Gal(0) IgG) has been regarded as a useful serological marker for rheumatoid arthritis (RA). It is unknown whether it is also elevated in serum and implicated in the pathogenesis of joint inflammation in seronegative spondyloarthropathy (SpA) such as ankylosing spondylitis (AS) and psoriatic arthritis (PsA). Sera were collected from 43 patients with AS or PsA with axial joint involvement, 22 patients with RA, and 25 healthy normal individuals for the detection of anti-Gal(0) IgG with a cup-type lectin enzyme immunoassay (Eitest CA^.RF). The disease activity of the AS/PsA was evaluated by Bath Ankylosing Spondylitis Disease Activity Score (BASDAI), the serum C-reactive protein (CRP) and IgA were measured by nephelometry, and erythrocyte sedimentation rate (ESR) was measured by Westergren’s method. The median titers of anti-Gal(0) IgG were significantly elevated in patients with RA (167.85, 15.73∼797.58 AU/mL) and AS/PsA (186.15, 34.71∼651.19 AU/mL), compared to those of the normal controls (13.04, 12.00∼202.43 AU/mL). The titers of the anti-Gal(0) IgG in patients with AS/PsA were correlated to the BASDAI scores (r ² = 0.422, SEE = 1.443, p < 0.001) and serum CRP (r ² = 0.345, SEE = 2.434, p < 0.001) but not to IgA (r ² = 0.0259, SEE = 126.30, p < 0.001) or ESR (r ² = 0.171, SEE = 31.053, p = 0.0059). Collectively, the anti-Gal(0) IgG is elevated and vaguely correlated with the disease activity of AS/PsA although its titers in these patients were erratic. The result of the present investigation has suggested that anti-Gal(0) IgG may be more ubiquitously present in inflammatory arthritides including RA or SpA.     

Latitude gradient influences the age of onset in rheumatoid arthritis patients

The mean age of rheumatoid arthritis (RA) onset is around 50 years as reported in several clinical trials involving Caucasian patients. However, clinical observations suggest that Mexican RA patients’ disease is initiated at a younger age. The objective of the study was to assess whether the age of onset of RA is different in Mexican and in Canadian RA patients. Certified rheumatologists from Canada and Mexico directly interviewed consecutive RA patients attending their clinics regarding the date patients first noticed a swollen joint. None of the participant rheumatologists were aware of the primary aim of this exploratory study at the time of the interviews. Data was gathered from 161 Mexican (91% women) and 130 Canadian (77% women) RA patients collected by three rheumatologists in each country. Duration since disease onset was not different within countries (mean 95% confidence interval [CI] for differences −10 to 16 years, p = 0.12 for Canadians, and −6 to 10 years, p = 0.26, for Mexicans). However, there was a significant difference between the two countries. Mexicans patients on average developed RA almost 12 years younger than Canadians (95% CI for difference 9 to 15 years, p < 0.001). Frequency distribution showed that 35.5% of Canadians but only 4% of Mexicans had the onset of the disease after the age of 55 (all p < 0.001). It appears that RA begins at a much younger age in Mexican than Canadian patients. If this were confirmed after controlling for different confounders and biases, it would have important societal, economic, and therapeutic implications.     

Osteoprotegerin and the receptor activator of NF-kappa B ligand in the serum and synovial fluid. A comparison of patients with longstanding rheumatoid arthritis and osteoarthritis

We examined OPG and soluble RANKL in the serum (sOPG, sRANKL) and synovial fluid (synOPG, synRANKL) in patients with rheumatoid arthritis (RA) and osteoarthritis (OA). OPG and RANKL were measured in 85 patients (44 with RA, 41 patients with OA) in serum and synovial fluid as well. For measuring of OPG and RANKL ELISA tests were used. The results of OPG and RANKL were compared with clinical and radiological scores. We found a negative correlation for OPG and RANKL in synovial fluids: not only for the whole group of patients (P< 0.003, r=–0.32), but also for the subgroups (RA: P<0.04, r=–0.28, OA: P<0.002, r=–0.54). SRANKL and synRANKL were positively correlated in the whole group (P<0.01, r=0.25) and in the OA group (P<0.02, r=0.35); the RA group was showing a trend (P<0.063, r=0.24), however. Serum OPG was lower in RA, synOPG higher in OA. The difference between the two patient groups was only significant for synOPG (P<0.03, r=0.056), but not for sOPG (P<0.09, r=0.19), sRANKL (P<0.43, r=0.85) or synRANKL (P<0.11, r=0.22). The synOPG:synRANKL ratio was significantly correlated with the Larsen score (P<0.004, r=0.38). Synovial OPG is significantly decreased in rheumatoid joints, whereby synovial RANKL is increased. Lower synOPG could reflect a lower protective effect on bone, thus leading to an earlier and more pronounced bone destruction in RA. However, the effect of different mediators for joint destruction in RA and OA seems not to be important to the pathophysiological changes in the joints. The upregulation of serum OPG might be the result of the inflammation; in contrast, an upregulation of RANKL could not be found in the serum of patients with RA and OA.     

Increased osteoclastic activity in acute Charcot’s osteoarthopathy: the role of receptor activator of nuclear factor-kappaB ligand

Aims/hypothesis Our aims were to compare osteoclastic activity between patients with acute Charcot’s osteoarthropathy and diabetic and healthy controls, and to determine the effect of the receptor activator of nuclear factor-kappaB ligand (RANKL) and its decoy receptor osteoprotegerin (OPG). Methods Peripheral blood monocytes isolated from nine diabetic Charcot patients, eight diabetic control and eight healthy control participants were cultured in the presence of macrophage-colony stimulating factor (M-CSF) alone, M-CSF and RANKL, and also M-CSF and RANKL with excess concentrations of OPG. Osteoclast formation was assessed by expression of tartrate-resistant acid phosphatase on glass coverslips and resorption on dentine slices. Results In cultures with M-CSF, there was a significant increase in osteoclast formation in Charcot patients compared with healthy and diabetic control participants (p = 0.008). A significant increase in bone resorption was also seen in the former, compared with healthy and diabetic control participants (p < 0.0001). The addition of RANKL to the cultures with M-CSF led to marked increase in osteoclastic resorption in Charcot (from 0.264 ± 0.06% to 41.6 ± 8.1%, p < 0.0001) and diabetic control (0.000 ± 0.00% to 14.2 ± 16.5%, p < 0.0001) patients, and also in healthy control participants (0.004 ± 0.01% to 10.5 ± 1.9%, p < 0.0001). Although the addition of OPG to cultures with M-CSF and RANKL led to a marked reduction of resorption in Charcot patients (41.6 ± 8.1% to 5.9 ± 2.4%, p = 0.001), this suppression was not as complete as in diabetic control patients (14.2 ± 16.5% to 0.45 ± 0.31%, p = 0.001) and in healthy control participants (from 10.5 ± 1.9% to 0.00 ± 0.00%, p < 0.0001). Conclusions/interpretation These results indicate that RANKL-mediated osteoclastic resorption occurs in acute Charcot’s osteoarthropathy. However, the incomplete inhibition of RANKL after addition of OPG also suggests the existence of a RANKL-independent pathway.     

Differences between the United States and the United Kingdom in the treatment of rheumatoid arthritis: analyses from a hand arthroplasty trial

Previous studies have found differences in rheumatoid hand surgical practice around the world. The specific aim of this study is to compare baseline characteristics of rheumatoid arthritis (RA) patients in the United States (US) and the United Kingdom (UK) that may be influenced by the two different health-care systems. Patients were recruited from three sites (two in the US and one in England) as part of a National Institutes of Health funded study to examine outcomes of silicone metacarpophalangeal joint (MCPJ) arthroplasty in RA patients. Outcomes measurements included biomechanical assessments (grip strength, pinch strength, and mean ulnar drift and extensor lag at the MCPJs of all four fingers), a health-related quality of life questionnaire (the Michigan Hand Outcomes Questionnaire), and a medication assessment. American patients have a significantly higher income level (p < 0.001) and have completed higher levels of education (p < 0.001) than British patients. There were no significant differences in terms of self-reported disease severity or deformity at the MCPJs. RA patients in the US are more likely to take biologic medications (p < 0.001), steroids (p = 0.02), and Cox-2 inhibitors (p = 0.02). Patients in the UK are significantly more likely (p < 0.001) to take nonsteroidal anti-inflammatory drugs. There are differences in the demographic characteristics and medication use of RA patients with hand deformities in the US and UK. These differences may be influenced by the private versus socialized health-care systems. However, the perception of hand disease severity in participants in this study appears to be comparable between these countries.     

Distressed personality is associated with lower psychological well-being and life satisfaction,but not disability or disease activity in rheumatoid arthritis patients

The distressed personality type (“type D personality”) has been shown to be associated with low quality of life and higher morbidity and mortality in various patient groups. Because the role of type D personality is unknown in patients with rheumatoid arthritis (RA), the aim of the present study was to investigate the association of type D personality with aspects of quality of life and disease activity in RA patients. In addition, a potential buffering effect by accepting mindfulness was examined. Participants were 147 patients between 22 and 87 years of age. Patients completed relevant questionnaires at home and the disease activity score was determined. After controlling for potentially confounding variables, multivariate analyses of covariance showed an association of type D personality with a lower satisfaction with life (p < 0.001) and a lower psychological well-being (p < 0.001), but not disease activity in RA patients. Although mindfulness was associated with a higher satisfaction with life (p = 0.02) and positive mood (p = 0.01), it did not diminish the unfavourable associations between type D and well-being. In conclusion, although type D personality is related with lower well-being, it does not seem to be associated with disability or disease activity in RA patients.     

Lipid profile in Tunisian patients with rheumatoid arthritis

This study aims to assess the prevalence of dyslipidaemia in Tunisian patients with active RA and to investigate the clinical and biological associated factors. A cross-sectional study was conducted on 92 unselected patients with active RA (77 females and 15 males, aged 49.1 ± 12.5 years) and 82 healthy subjects (68 females and 14 males, aged 50.8 ± 13.3 years). We recorded the patients' characteristics and the results of a lipid profile test (total cholesterol, TC; high-density lipoprotein cholesterol, HDL-c; low-density lipoprotein cholesterol, LDL-c; triglyceride, TG; lipoprotein (a), Lp (a); apolipoprotein A-1, apo A-1 and apolipoprotein B, apo B). In comparison to the control group, RA patients showed a higher prevalence of associated dyslipidaemia (95.7% versus 65.9% of cases, p < 0.001). Sera of patients showed higher TC (4.86 ± 1.07 versus 3.98 ± 0.73 mmol/L, p < 0.001), LDL-c (3.49 ± 0.98 versus 1.99 ± 0.62 mmol/L, p < 0.001), Lp (a) (288.04 ± 254.59 versus 187.94 ± 181.37 mmol/L, p = 0.004) and lower HDL-c (0.66 ± 0.24 versus 1.12 ± 0.3 mmol/L, p < 0.001). TC/HDL-c, LDL-c/HDL-c and non-HDL-c/HDL-c were also higher in RA patients; they were 8.24 ± 3.20 versus 3.76 ± 1.26 (p < 0.001), 5.91 ± 2.48 versus 1.92 ± 0.99 (p < 0.001) and 7.24 ± 3.20 versus 2.76 ± 1.26 (p < 0.001), respectively. Apo A-1 was correlated to Lp (a) (r = 0.291, p = 0.005). Corticoid dose was not associated to dyslipidaemia, but in multiple regression models, corticoid dose may be negatively related to some atherogenic markers, in particular non-HDL-c. Tunisian patients with markedly active RA experience substantially reduced serum HDL-c and increased TC, LDL-c and Lp (a) concentrations as well as increased TC/HDL-c, LDL-c/HDL-c and non-HDL-c/HDL-c ratios.     

Anti-agalactosyl IgG antibodies in Thai patients with rheumatoid arthritis, systemic lupus erythematosus, and systemic sclerosis

This study was performed to determine the prevalence of anti-agalactosyl IgG antibodies in Thai patients with RA, systemic lupus erythematosus (SLE) and systemic sclerosis (SSc), and determine the sensitivity and specificity of anti-agalactosyl IgG antibodies in the diagnosis of RA in comparison with IgM-rheumatoid factor (IgM-RF) and anti-cyclic citrullinated peptide (anti-CCP) antibodies. Serum samples were obtained from 100 patients with RA, 50 cases of SLE, 50 cases of SSc, and 100 healthy controls and analyzed for the presence of anti-agalactosyl IgG antibodies, IgM-RF and anti-CCP antibodies. A serum value greater than mean + 2 standard deviation of normal value of anti-agalactosyl IgG antibodies and anti-CCP antibodies was considered positive. The prevalence of anti-agalactosyl IgG antibodies in RA, SLE, and SSc patients was 88.0%, 14.0%, and 12.0%, respectively. The serum level of anti-agalactosyl IgG antibodies in patients with RA (227.10 ± 353.64 AU/mL) was significantly higher than those in SLE (11.84 ± 52.04 AU/mL), SSc (18.85 ± 99.60 AU/mL), and healthy controls (2.14 ± 1.97 AU/mL), (p < 0.001). There was a good correlation between the log serum level of anti-agalactosyl IgG antibodies and IgM-RF (r = 0.92, p < 0.001), anti-CCP antibodies and IgM-RF (r = 0.49, p < 0.001), and anti-agalactosyl IgG antibodies and anti-CCP antibodies (r = 0.55, p < 0.001). The sensitivity and specificity in the diagnosis of RA was 88.00% and 96.00% for anti-agalactosyl IgG antibodies, 90.00% and 99.00% for anti-CCP antibodies, and 91.00% and 95.00% for IgM-RF, respectively. The serum level of anti-agalactosyl IgG antibodies was significantly higher in RA than in SLE, SSc, and healthy controls. There was a good correlation between serum levels of anti-agalactosyl IgG antibodies, anti-CCP antibodies, and IgM-RF. These three tests had comparable sensitivity and specificity.     

Effect of zoledronic acid on markers of bone turnover and mineral density in osteoporotic patients with beta-thalassaemia

Osteoporosis has emerged as an important cause of morbidity in patients with thalassemia major. Studies regarding the efficacy of bisphosphonates in thalassemia-induced osteoporosis have yielded conflicting results. We performed this prospective study to evaluate the efficacy of zoledronic acid in osteoporotic patients with thalassemia major. Patients, 29, were given 1 mg zoledronic acid intravenously every 3 months for a total of four doses. Twenty age- and sex-matched healthy blood donors served as controls. Before each infusion and 3 months after the last infusion, we determined serum levels of osteoprotegerin (OPG), N-terminal cross-linking telopeptide of type I collagen (NTX), osteocalcin (OC) and insulin-like growth factor 1 (IGF-1). Bone mineral density (BMD) of the lumbar spine was measured at baseline and after the treatment’s completion. At baseline, OPG did not differ significantly between patients and controls (p=0.2), NTX were higher in patients although not significantly (p=0.139), whereas, OC levels were significantly higher and IGF-1 levels significantly lower in patients than in controls (p<0.001 and p<0.006, respectively). Zoledronic acid administration resulted in a significant decrease in NTX, OC and IGF-1 (p<0.05, p<0.001 and p<0.05, respectively) and in a significant increase in OPG and BMD (p<0.05 for both comparisons). The change in NTX, osteocalcin and IGF-1 became significant as early as 3 months after the first administration of zoledronic acid, while the change in OPG reached significance only after three infusions. Our study supports the effectiveness of bisphosphonates in the treatment of thalassemia-induced osteoporosis.     

Osteoprotegrin interacts with biomarkers and cytokines that have roles in osteoporosis,skin fibrosis,and vasculopathy in systemic sclerosis: A potential multifaceted relationship between OPG/RANKL/TRAIL and Wnt inhibitors

Abstract

Objectives: We explored the interactions of osteoprotegerin (OPG) with biomarkers of bone turnover and cytokines, including soluble receptor activator for nuclear factor kappa beta ligand (sRANKL), tumor necrosis factor-related apoptosis-induced ligand (TRAIL), and Wnt inhibitors in osteoporosis, vasculopathy and fibrosis related to systemic sclerosis (SSc).

Methods: The study included 46 SSc patients and 30 healthy controls. Skin thickness, pulmonary fibrosis and/or hypertension, digital ulcers, and calcinosis cutis of SSc patients were assessed. We determined bone mineral density (BMD), and OPG, sRANKL, TRAIL, secreted frizzled-related protein 1 (sFRP-1), Dickkopf-related protein 1 (DKK-1), sclerostin in the serum of both patients and controls.

Results: OPG, sclerostin, and sFRP-1 levels were similar between patients and controls (P?>?0.05). Femoral neck and lumbar spine BMD and vitamin D levels were lower, and the OC, NTX, sRANKL, DKK1 and TRAIL levels were significantly higher, in patients than in controls (p?<?0.05). In subgroup analysis, patients with higher modified Rodnan skin score (mRodnan) had higher DKK-1, sclerostin, and TRAIL levels (p?<?0.05); those with diffuse SSc subtype had lower BMD values than those with limited SSc (p?<?0.05). Skin and pulmonary fibrosis linked negatively with BMD measures.

Conclusion: we showed that sRANKL levels were higher and correlated with bone turnover markers. It may be related to osteoporosis in SSc. The OPG level was unaltered in SSc patients. Higher TRAIL levels associated with skin thickness may indicate vascular dysfunction or injury. Higher DKK-1 and sclerostin levels may be related to a reactive increase in cells and be prominently linked to fibrosis in SSc.     

Fucosylation of serum α<Subscript>1</Subscript>-acid glycoprotein in rheumatoid arthritis patients treated with infliximab

To analyze fucosylation of α₁-acid glycoprotein (AGP) and to identify relations between AGP fucosylation and clinical and biochemical indices of disease activity in patients with rheumatoid arthritis (RA) treated with monoclonal antitumor necrosis factor (TNF) antibody infliximab, we examined 22 patients with RA who underwent a 54-week treatment with infliximab according to ATTRACT protocol. Blood samples were collected at baseline and before every infusion of infliximab. AGP fucosylation was measured using lectin-binding enzyme-linked immunosorbent assay utilizing fucose-specific lectin Aleuria aurantia (AAL). Moreover, the clinical status/activity, erythrocyte sedimentation rate, serum C-reactive protein (CRP), antitrypsin, α₁-antichymotrypsin, AGP reactivity with concanavalin A, serum C3 and C4 complement components, and serum concentrations of TNF and soluble TNF type 1 and type 2 receptors were determined. In most patients, the fucosylation of AGP decreased rapidly after first infusion of infliximab and remained low during the 54-week therapy (p < 0.001). The decrease in AGP affinity to AAL closely followed changes in clinical and laboratory activity of RA and correlated with pretreatment concentrations of CRP (r = 0.4986, p < 0.05) and TNF (r = 0.5181, p < 0.05). The fucosylation of AGP can be a part of a negative feedback loop regulating migration of inflammatory cells and collagenase-3 activity in RA. The decrease in AGP fucosylation accompanied by improvement in clinical and biochemical parameters of RA could possibly reflect reduced migration of inflammatory cells to inflamed joints and AGP-mediated inhibition of collagenase-3 as a response to infliximab treatment.     

sRANKL and OPG in serum and synovial fluid of patients with rheumatoid arthritis in comparison to non-destructive chronic arthritis

The aim of this study was to investigate sRANKL and OPG levels in serum and synovial fluid (SF) and to evaluate their relations in patients with RA in comparison to those with non-erosive arthritis (NEA). The study included 45 unselected RA patients with knee joint effusions and 27 patients with knee joint effusions because of NEA. Serum and SF samples were investigated isochronously. OPG and sRANKL were measured by ELISA assays. In RA, sRANKL levels were higher in serum than in SF (P = 0.007). In contrast, the NEA revealed higher sRANKL in SF compared to the serum (P = 0.001). Though in RA the average levels of sRANKL_ser were 5.6 times and of sRANKL_syn 1.5 times higher than in NEA, the differences were not significant. The free (unbound) OPG in SF was not significantly different in RA compared to NEA. Also in serum, the measured free OPG was only slightly higher in RA. There were no significant differences between RA and NEA concerning ESR and CRP. Significant correlations could be found between sRANKL_syn and CRP (r = 0.453; P = 0.005) as well as ESR (r = 0.362; P = 0.033) in RA. Nearly a positive correlation was evident also between sRANKL_syn and CRP in NEA (r = 0.520; P = 0.08). RA and NEA differ in particular concerning their power and intensity to destruct the juxtaarticular bone. This is the most remarkable finding of this study, that in RA a high part of sRANKL seems to be OPG bound and cleared by the blood stream, but the sRANKL neutralizing capacity of produced OPG in opposite to NEA is not sufficient to prevent osteoclast activation and bone destruction in the RA joint.