Comparative evaluation of the effects of treatment with tocilizumab and TNF-α inhibitors on serum hepcidin,anemia response and disease activity in rheumatoid arthritis patients

Introduction

Anemia of inflammation (AI) is a common complication of rheumatoid arthritis (RA) and has a negative impact on RA symptoms and quality of life. Upregulation of hepcidin by inflammatory cytokines has been implicated in AI. In this study, we evaluated and compared the effects of IL-6 and TNF-α blocking therapies on anemia, disease activity, and iron-related parameters including serum hepcidin in RA patients.

Methods

Patients (n = 93) were treated with an anti-IL-6 receptor antibody (tocilizumab) or TNF-α inhibitors for 16 weeks. Major disease activity indicators and iron-related parameters including serum hepcidin-25 were monitored before and 2, 4, 8, and 16 weeks after the initiation of treatment. Effects of tocilizumab and infliximab (anti-TNF-α antibody) on cytokine-induced hepcidin expression in hepatoma cells were analyzed by quantitative real-time PCR.

Results

Anemia at base line was present in 66% of patients. Baseline serum hepcidin-25 levels were correlated positively with serum ferritin, C-reactive protein (CRP), vascular endothelial growth factor (VEGF) levels and Disease Activity Score 28 (DAS28). Significant improvements in anemia and disease activity, and reductions in serum hepcidin-25 levels were observed within 2 weeks in both groups, and these effects were more pronounced in the tocilizumab group than in the TNF-α inhibitors group. Serum hepcidin-25 reduction by the TNF-α inhibitor therapy was accompanied by a decrease in serum IL-6, suggesting that the effect of TNF-α on the induction of hepcidin-25 was indirect. In in vitro experiments, stimulation with the cytokine combination of IL-6+TNF-α induced weaker hepcidin expression than did with IL-6 alone, and this induction was completely suppressed by tocilizumab but not by infliximab.

Conclusions

Hepcidin-mediated iron metabolism may contribute to the pathogenesis of RA-related anemia. In our cohort, tocilizumab was more effective than TNF-α inhibitors for improving anemia and normalizing iron metabolism in RA patients by inhibiting hepcidin production.     

Is IL-6 an appropriate target to treat spondyloarthritis patients refractory to anti-TNF therapy? a multicentre retrospective observational study

Introduction

The aim of this study was to evaluate, under real-life conditions, the safety and efficacy of tocilizumab in patients having failed anti-TNFα therapy for spondyloarthritis.

Methods

French rheumatologists and internal-medicine practitioners registered on the Club Rhumatismes et Inflammations website were asked to report on patients given tocilizumab (4 or 8 mg/kg) to treat active disease meeting Assessment of SpondyloArthritis International Society (ASAS) criteria for axial or peripheral spondyloarthritis, after anti-TNFα treatment failure. Safety and efficacy after 3 and 6 months were assessed retrospectively using standardised questionnaires.

Results

Data were obtained for 21 patients, 13 with axial spondyloarthritis (46% men; median age, 42 years; disease duration, 11 years; HLA-B27-positive, 92.3%) and eight with peripheral spondyloarthritis (25% men; median age, 40 years; disease duration, 10 years; HLA-B27-positive, 62.5%). No patients with axial disease had at least a 20 mm decrease in the BASDAI, nor a BASDAI50 response or major ASAS-endorsed disease activity score improvements after 3 or 6 months; an ASAS-endorsed disease activity score clinically important improvement was noted at month 3 in five of 13 patients and at month 6 in one of four patients. A good DAS28 response was achieved in four patients with peripheral disease, including one in EULAR remission at month 3. Four patients were still taking tocilizumab at month 6, including one in EULAR remission and one with a good DAS28 response. Tocilizumab was well tolerated, with no serious adverse events. Initially elevated acute-phase reactants declined during tocilizumab therapy.

Conclusion

In patients having failed anti-TNFα therapy, tocilizumab decreased acute-phase reactants but failed to substantially improve axial spondyloarthritis and was inconsistently effective in peripheral spondyloarthritis.     

Exercise-Induced Changes in Iron Status and Hepcidin Response in Female Runners

Background and Aims

Exercise-induced iron deficiency is a common finding in endurance athletes. It has been suggested recently that hepcidin may be an important mediator in this process.

Objective

To determine hepcidin levels and markers of iron status during long-term exercise training in female runners with depleted and normal iron stores.

Methods

Fourteen runners were divided into two groups according to iron status. Blood samples were taken during a period of eight weeks at baseline, after training and after ten days’ recovery phase.

Results

Of 14 runners, 7 were iron deficient at baseline and 10 after training. Hepcidin was lower at recovery compared with baseline (p<0.05). The mean cell haemoglobin content, haemoglobin content per reticulocyte and total iron binding capacity all decreased, whereas soluble transferrin receptor and hypochromic red cells increased after training and recovery (p<0.05 for all).

Conclusion

The prevalence of depleted iron stores was 71% at the end of the training phase. Hepcidin and iron stores decreased during long-term running training and did not recover after ten days, regardless of baseline iron status.     

Plasma Concentrations of Hepcidin in Anemic Zimbabwean Infants

Objective

Anemia in infancy is a global public health problem. We evaluated the relative contributions of iron deficiency and inflammation to infant anemia.

Methods

We measured plasma hepcidin, ferritin, soluble transferrin receptor (sTfR), alpha-1-acid glycoprotein and C-reactive protein (CRP) by ELISA on archived plasma from 289 HIV-unexposed anemic or non-anemic Zimbabwean infants at ages 3mo, 6mo and 12mo. Among anemic infants, we determined the proportion with iron-deficiency anemia (IDA) and anemia of inflammation (AI). We undertook regression analyses of plasma hepcidin and anemia status, adjusting for sex, age and birthweight.

Results

Anemic infants at 3mo were more stunted and had higher CRP (median 0.45 vs 0.21mg/L; P = 0.037) and hepcidin (median 14.7 vs 9.7ng/mL; P = 0.022) than non-anemic infants, but similar levels of ferritin and sTfR; 11% infants had IDA and 15% had AI. Anemic infants at 6mo had higher hepcidin (median 7.9 vs 4.5ng/mL; P = 0.016) and CRP (median 2.33 vs 0.32mg/L; P<0.001), but lower ferritin (median 13.2 vs 25.1μg/L; P<0.001) than non-anemic infants; 56% infants had IDA and 12% had AI. Anemic infants at 12mo had lower ferritin (median 3.2 vs 22.2μg/L; P<0.001) and hepcidin (median 0.9 vs 1.9ng/mL; P = 0.019), but similar CRP levels; 48% infants had IDA and 8% had AI. Comparing anemic with non-anemic infants, plasma hepcidin was 568% higher, 405% higher and 64% lower at 3mo, 6mo and 12mo, respectively, after adjusting for sex and birthweight (all p<0.01). Plasma hepcidin declined significantly with age among anemic but not non-anemic infants. Girls had 61% higher hepcidin than boys, after adjusting for age, anemia and birthweight (p<0.001).

Conclusion

Anemia is driven partly by inflammation early in infancy, and by iron deficiency later in infancy, with plasma hepcidin concentrations reflecting the relative contribution of each. However, there is need to better characterize the drivers of hepcidin during infancy in developing countries.     

Inverse Relationship of Serum Hepcidin Levels with CD4 Cell Counts in HIV-Infected Patients Selected from an Indonesian Prospective Cohort Study

Background

Distortion of iron homeostasis may contribute to the pathogenesis of human immunodeficiency virus (HIV) infection and tuberculosis (TB). We studied the association of the central iron-regulatory hormone hepcidin with the severity of HIV and the association between hepcidin and other markers of iron homeostasis with development of TB.

Methods

Three groups of patients were selected from a prospective cohort of HIV-infected subjects in Bandung, Indonesia. The first group consisted of HIV-infected patients who started TB treatment more than 30 days after cohort enrollment (cases). The second group consisted of HIV-infected patients who were matched for age, gender and CD4 cell count to the cases group (matched controls). The third group consisted of HIV-infected patients with CD4 cell counts above 200 cells/mm³ (unmatched controls). Iron parameters including hepcidin were compared using samples collected at cohort enrollment, and compared with recently published reference values for serum hepcidin.

Results

A total of 127 HIV-infected patients were included, 42 cases together with 42 matched controls and 43 unmatched controls. Patients with advanced HIV infection had elevated serum hepcidin and ferritin levels. Hepcidin levels correlated inversely with CD4 cells and hemoglobin. Cases had significantly higher hepcidin and ferritin concentrations at cohort enrollment compared to matched controls, but these differences were fully accounted for by the cases who started TB treatment between day 31 and 60 after enrollment. Hepcidin levels were not different in those with or without hepatitis C infection.

Conclusion

Iron metabolism is distorted in advanced HIV infection with CD4 cell counts correlating inversely with serum hepcidin levels. High serum hepcidin levels and hyperferritinemia were found in patients starting TB treatment shortly after cohort enrollment, suggesting that these parameters have a predictive value for development of manifest TB in HIV-infected patients.     

Increase of Hemoglobin Levels by Anti-IL-6 Receptor Antibody (Tocilizumab) in Rheumatoid Arthritis

Objective

To compare the effect of tocilizumab (TCZ) with other biologic therapies in improving anemia of rheumatoid arthritis (RA) patients.

Methods

We compared the change of hemoglobin (Hb) levels in a cohort of 147 consecutive RA patients who were treated with biologics for more than 12 weeks. Twenty eight patients were treated with TCZ, and 119 patients were treated with biologics other than TCZ (87 with TNF inhibitors and 32 with abatacept). The change of Hb levels from baseline to week 12 was compared between the TCZ and the non-TCZ groups. We performed univariate and multivariate analyses with adjustment of potential confounders such as baseline characteristics, concomitant treatment, and the clinical response to treatment.

Results

Hb levels generally increased after biologic therapies both in the TCZ and the non-TCZ groups. The increase of Hb levels was greater in the TCZ group than in the non-TCZ groups (1.1 g/dL in the TCZ group vs 0.3 g/dL in the non-TCZ group, p = 0.009). Univariate analysis revealed that increase of Hb levels was also significantly associated with lower Hb, higher Low Hemoglobin Density, and higher CRP levels at baseline and greater reduction in the clinical disease activity index. TCZ therapy was significantly associated with the increase of Hb levels even after adjustment for these factors by multivariate analysis (p<0.001, effect size 0.08–0.12).

Conclusion

TCZ therapy is an independent factor associated with the increase of Hb level after biologic therapies in RA patients. It will help in selecting appropriate biologics for RA patients with anemia.     

Long-term weekly iron-folic acid and de-worming is associated with stabilised haemoglobin and increasing iron stores in non-pregnant women in Vietnam

Background

The prevalence of anaemia and iron deficiency in women remains high worldwide. WHO recommends weekly iron-folic acid supplementation where anaemia rates in non-pregnant women of reproductive age are higher than 20%. In 2006, a demonstration project consisting of weekly iron-folic acid supplementation and regular de-worming was set up in two districts in a northern province in Vietnam where anaemia and hookworm rates were 38% and 76% respectively. In 2008 the project was expanded to all districts in the province, targeting some 250,000 women. The objectives of this study were to: 1) examine changes in haemoglobin, iron stores and soil transmitted helminth infection prevalence over three years and 2) assess women''s access to and compliance with the intervention.

Methods and Findings

The study was a semi-cross-sectional, semi-longitudinal panel design with a baseline survey, three impact surveys at three-, twelve- and thirty months after commencement of the intervention, and three compliance surveys after ten weeks, eighteen and thirty six months.

Results

After thirty months, mean haemoglobin stabilised at 130.3 g/L, an increase of 8.2 g/L from baseline, and mean serum ferritin rose from 23.9 µg/L to 52 µg/L. Hookworm prevalence fell from 76% to 22% over the same period. After thirty six months, 81% of the target population were receiving supplements and 87% were taking 75% or more of the supplements they received.

Conclusions

Weekly iron-folic acid supplementation and regular de-worming was effective in significantly and sustainably reducing the prevalence of anaemia and soil transmitted helminth infections and high compliance rates were maintained over three years.     

Prevalence and Risk Factors of Anaemia among Children Aged between 6 Months and 14 Years in Kenya

Background

Anaemia is one of the significant public health problems among children in the world. Understanding risk factors of anaemia provides more insight to the nature and types of policies that can be put up to fight anaemia. We estimated the prevalence and risk factors of anaemia in a population-based, cross-sectional survey.

Methodology

Blood samples from 11,711 children aged between 6 months and 14 years were collected using a single-use, spring-loaded, sterile lancet to make a finger prick. Anaemia was measured based on haemoglobin concentration level. The generalized linear model framework was used to analyse the data, in which the response variable was either a child was anemic or not anemic.

Results

The overall prevalence of anaemia among the children in Kenya was estimated to be 28.8%. The risk of anaemia was found to decrease with age progressively with increase in each year of age; children below 1 year were at highest risk of anaemia. The risk of anaemia was significantly higher in male than female children. Mothers with secondary and above education had a protective effect on the risk of anaemia on their children. Malaria diagnosis status of a child was positively associated with risk anaemia.

Conclusion

Controlling co-morbidity of malaria and improving maternal knowledge are potential options for reducing the burden of anaemia.     

Rituximab and abatacept but not tocilizumab impair antibody response to pneumococcal conjugate vaccine in patients with rheumatoid arthritis

Introduction

The objective of the study was to investigate the impact of newer biologic treatments including rituximab, abatacept and tocilizumab on antibody response following pneumococcal vaccination using a 7-valent conjugate vaccine in patients with established rheumatoid arthritis (RA).

Methods

Patients with RA receiving rituximab, abatacept or tocilizumab as monotherapy or combined with methotrexate (MTX) participated in the study. Specific IgG antibodies against 23F and 6B serotypes were measured at vaccination and 4 to 6 weeks after vaccination using standardised ELISA. Geometric mean antibody levels (GML) were calculated. Antibody response (AR) was defined as the ratio between post- and pre-vaccination antibody levels and a positive antibody response (posAR) was AR ≥2.

Results

In total, 88 patients were enrolled in the study. Of 55 patients treated with rituximab, 26 (46%) were on concomitant MTX. Of patients receiving abatacept (n = 17) and tocilizumab (n = 16) biologic treatment was given in combination with MTX in 13 (76%) and 9 (56%) patients, respectively. Patients treated with rituximab had significantly lower AR compared to those on tocilizumab, as well as compared to previously reported RA patients on MTX and controls (spondylarthropathy patients treated with NSAIDs and/or analgesics). In total, 10.3% of patients on rituximab monotherapy and no patient on rituximab + MTX had posAR for both serotypes. For abatacept and tocilizumab the corresponding figures were 17.6% and 50%.

Conclusion

In this cohort of patients with established RA, treatment with rituximab and abatacept was associated with diminished antibody response but this was most pronounced for rituximab. Pneumococcal conjugate vaccine administrated during ongoing tocilizumab treatment seems to be associated with sufficient antibody response. Pneumococcal vaccination should preferably be encouraged before initiation of rituximab or abatacept treatment.

Trial registration

NCT00828997 and EudraCT EU 2007-006539-29.     

Serum Copeptin and Cortisol Do Not Accurately Predict Sickle Cell Anaemia Vaso-Occlusive Crisis as C-Reactive Protein

Objective

This study assessed the diagnostic performance and prognostic properties of C-reactive protein (CRP), copeptin and cortisol in individuals with sickle cell anaemia (SCA).

Design

Prospective case-control study

Methods

Sixty consecutive SCA subjects (18–40 years) comprising 30 subjects in the steady state and 30 subjects in vaso-occlusive crisis (VOC) were recruited into this study. Thirty (30) apparently healthy individuals with HbAA genotype served as controls. ELISA was used for the determination of serum levels of copeptin, CRP and cortisol. Data obtained were statistically analyzed using the Student’s t-test and Mann Whitney U as appropriate and P<0.05 was considered significant.

Results

SCA subjects in VOC had significantly lower copeptin level and significantly higher CRP level compared with controls. However, serum levels of copeptin, cortisol and CRP were significantly higher in SCA subjects in VOC compared with SCA subjects in steady state. Furthermore, CRP had the widest Area under the ROC curve (AUROC) than copeptin and cortisol. No significant difference was observed in the levels of copeptin, CRP and cortisol when SCA subjects in VOC who were hospitalized for less ≤5 days were compared with subjects who had longer stays.

Conclusion

It could be concluded that C-reactive protein has a superior diagnostic performance for vaso-occlusive crisis in individuals with sickle cell anaemia and that C-reactive protein, cortisol and copeptin are not good prognostic markers in SCA subjects in vaso-occlusive crisis.     

Pentoxifylline for Anemia in Chronic Kidney Disease: A Systematic Review and Meta-Analysis

Background

Pentoxifylline (PTX) is a promising therapeutic approach for reducing inflammation and improving anemia associated to various systemic disorders. However, whether this agent may be helpful for anemia management also in CKD patients is still object of debate.

Study Design

Systematic review and meta-analysis.

Population

Adults with CKD (any KDOQI stage, including ESKD patients on regular dialysis) and anemia (Hb<13 g/dL in men or < 12 g/dL in women).

Search Strategy and Sources

Cochrane CENTRAL, EMBASE, Ovid-MEDLINE and PubMed were searched for studies providing data on the effects of PTX on anemia parameters in CKD patients without design or follow-up restriction.

Intervention

PTX derivatives at any dose regimen.

Outcomes

Hemoglobin, hematocrit, ESAs dosage and resistance (ERI), iron indexes (ferritin, serum iron, TIBC, transferrin and serum hepcidin) and adverse events.

Results

We retrieved 11 studies (377 patients) including seven randomized controlled trials (all comparing PTX to placebo or standard therapy) one retrospective case-control study and three prospective uncontrolled studies. Overall, PTX increased hemoglobin in three uncontrolled studies but such improvement was not confirmed in a meta-analysis of seven studies (299 patients) (MD 0.12 g/dL, 95% CI -0.22 to 0.47). Similarly, there were no conclusive effects of PTX on hematocrit, ESAs dose, ferritin and TSAT in pooled analyses. Data on serum iron, ERI, TIBC and hepcidin were based on single studies. No evidence of increased rate of adverse events was also noticed.

Limitations

Small sample size and limited number of studies. High heterogeneity among studies with respect to CKD and anemia severity, duration of intervention and responsiveness/current therapy with iron or ESAs.

Conclusions

There is currently no conclusive evidence supporting the utility of pentoxifylline for improving anemia control in CKD patients. Future trials designed on hard, patient-centered outcomes with larger sample size and longer follow-up are advocated.     

Paradoxical Association of C-Reactive Protein with Endothelial Function in Rheumatoid Arthritis

Background

Within the general population, levels of C-reactive protein (CRP) are positively associated with atherosclerotic cardiovascular disease (CVD). Whether CRP is causally implicated in atherogenesis or is the results of atherosclerosis is disputed. A role of CRP to protect endothelium-derived nitric oxide (EDNO) has been suggested. We examined the association of CRP with EDNO-dependent vasomotor function and subclinical measures of atherosclerosis and arteriosclerosis in patients with raised CRP resulting from rheumatoid arthritis (RA).

Methodology/Principal Findings

Patients with RA (n = 59) and healthy control subjects (n = 123), underwent measures of high sensitivity CRP, flow-mediated dilation (FMD, dependent on EDNO), intima-media thickness (IMT, a measure of subclinical atherosclerosis) and aortic pulse wave velocity (PWV, a measure of arteriosclerosis). IMT and PWV were elevated in patients with RA compared to controls but FMD was similar in the two groups. In patients with RA, IMT and PWV were not correlated with CRP but FMD was positively independently correlated with CRP (P<0.01).

Conclusions/Significance

These findings argue against a causal role of CRP in atherogenesis and are consistent with a protective effect of CRP on EDNO bioavailability.     

Decreased Serum Hepcidin Concentration Correlates with Brain Iron Deposition in Patients with HBV-Related Cirrhosis

Purpose

Excessive brain iron accumulation contributes to cognitive impairments in hepatitis B virus (HBV)-related cirrhotic patients. The underlying mechanism remains unclear. Hepcidin, a liver-produced, 25-aminoacid peptide, is the major regulator of systemic iron metabolism. Abnormal hepcidin level is a key factor in some body iron accumulation or deficiency disorders, especially in those associated with liver diseases. Our study was aimed to explore the relationship between brain iron content in patients with HBV-related cirrhosis and serum hepcidin level.

Methods

Seventy HBV-related cirrhotic patients and forty age- sex-matched healthy controls were enrolled. Brain iron content was quantified by susceptibility weighted phase imaging technique. Serum hepcidin as well as serum iron, serum transferrin, ferritin, soluble transferrin receptor, total iron binding capacity, and transferrin saturation were tested in thirty cirrhotic patients and nineteen healthy controls. Pearson correlation analysis was performed to investigate correlation between brain iron concentrations and serum hepcidin, or other iron parameters.

Results

Cirrhotic patients had increased brain iron accumulation compared to controls in the left red nuclear, the bilateral substantia nigra, the bilateral thalamus, the right caudate, and the right putamen. Cirrhotic patients had significantly decreased serum hepcidin concentration, as well as lower serum transferring level, lower total iron binding capacity and higher transferrin saturation, compared to controls. Serum hepcidin level negatively correlated with the iron content in the right caudate, while serum ferritin level positively correlated with the iron content in the bilateral putamen in cirrhotic patients.

Conclusions

Decreased serum hepcidin level correlated with excessive iron accumulation in the basal ganglia in HBV-related cirrhotic patients. Our results indicated that systemic iron overload underlined regional brain iron repletion. Serum hepcidin may be a clinical biomarker for brain iron deposition in cirrhotic patients, which may have therapeutic potential.     

A Novel Immunological Assay for Hepcidin Quantification in Human Serum

Background

Hepcidin is a 25-aminoacid cysteine-rich iron regulating peptide. Increased hepcidin concentrations lead to iron sequestration in macrophages, contributing to the pathogenesis of anaemia of chronic disease whereas decreased hepcidin is observed in iron deficiency and primary iron overload diseases such as hereditary hemochromatosis. Hepcidin quantification in human blood or urine may provide further insights for the pathogenesis of disorders of iron homeostasis and might prove a valuable tool for clinicians for the differential diagnosis of anaemia. This study describes a specific and non-operator demanding immunoassay for hepcidin quantification in human sera.

Methods and Findings

An ELISA assay was developed for measuring hepcidin serum concentration using a recombinant hepcidin25-His peptide and a polyclonal antibody against this peptide, which was able to identify native hepcidin. The ELISA assay had a detection range of 10–1500 µg/L and a detection limit of 5.4 µg/L. The intra- and interassay coefficients of variance ranged from 8–15% and 5–16%, respectively. Mean linearity and recovery were 101% and 107%, respectively. Mean hepcidin levels were significantly lower in 7 patients with juvenile hemochromatosis (12.8 µg/L) and 10 patients with iron deficiency anemia (15.7 µg/L) and higher in 7 patients with Hodgkin lymphoma (116.7 µg/L) compared to 32 age-matched healthy controls (42.7 µg/L).

Conclusions

We describe a new simple ELISA assay for measuring hepcidin in human serum with sufficient accuracy and reproducibility.     

Anaemia in acute HIV-1 subtype C infection

Background

The high prevalence of anaemia and the increased morbidity and mortality associated with anaemia during AIDS has been well described yet there has been little information about anaemia and changes in haemoglobin levels during acute and early HIV-1 infection.

Methods

HIV-negative women (n = 245) were enrolled into an observational cohort as part of the Centre for the AIDS Programme of Research in South Africa (CAPRISA) Acute Infection Study. Acute infection was diagnosed following a positive HIV RNA PCR in the absence of antibodies, or detection of HIV-1 antibodies within 3 months of a previously negative antibody test. Haemotologic parameters were assessed before infection and at regular intervals in the first twelve months of HIV infection.

Results

Fifty-seven participants with acute HIV infection were identified at a median of 14.5 days post-infection (range 10–81) and were enrolled in the CAPRISA Acute Infection cohort at a median of 41 days post-infection (range 15–104). Mean haemoglobin prior to HIV-1 infection was 12.7 g/dL, with a mean decline of 0.46 g/dL following infection. The prevalence of anaemia increased from 25.0% prior to HIV-1 infection to 52.6% at 3 months post-infection, 61.1% at 6 months post-infection, and 51.4% at 12 months post-infection.

Conclusions

Haematologic derangements and anaemia with a trend towards iron deficiency are common with acute HIV-1 subtype C infection in this small cohort. The negative impact of anaemia concurrent with established HIV infection upon morbidity and mortality has been well documented but the prognostic potential and long-term effects of anaemia during acute HIV-1 infection remain unknown.     

Iron,Hepcidin and Inflammatory Status of Young Healthy Overweight and Obese Women in Australia

Background and Aims

Evidence suggests obesity-related inflammation alters iron metabolism potentially increasing the risk of iron deficiency. This cross-sectional study aimed to investigate iron, hepcidin and inflammatory status in young, healthy overweight and obese women.

Methods

114 young (18–25 years), healthy comorbidity-free women with a body mass index (BMI) ≥27.5 kg/m² were recruited. Biochemical data were analysed using mean ± standard deviation or median (interquartile range) and multivariate modelling. Biochemical markers were also stratified according to varying degrees of overweight and obesity.

Results

Anaemia (haemoglobin <120 g/l) and iron deficiency (serum ferritin <15.0 µg/l) were prevalent in 10% and 17% of participants respectively. Mean/median soluble transferrin receptor was 1.61±0.44 mg/l; hepcidin 6.40 (7.85) ng/ml and C-reactive protein (CRP) 3.58 (5.81) mg/l. Multivariate modelling showed that BMI was a significant predictor of serum iron (coefficient = -0.379; standard error = 0.139; p = 0.008), transferrin saturation (coefficient = -0.588; standard error = 0.222; p = 0.009) and CRP (coefficient = 0.127; standard error = 0.024; p<0.001). Stratification of participants according to BMI showed those with ≥35.0 kg/m² had significantly higher CRP (p<0.001) than those in lower BMI categories.

Conclusions

Increasing obesity was associated with minor disturbances in iron metabolism. However, overall outcomes indicated simple iron deficiency (hypoferritinaemia) was the primary iron-related abnormality with no apparent contribution of inflammation or hepcidin, even in those with BMI >35.0 kg/m². This indicates that obesity alone may not be sufficient to induce clinically significant disturbances to iron metabolism as previously described. This may be attributed to the lack of comorbidity in this cohort.     

Clinical disease activity and acute phase reactant levels are discordant among patients with active rheumatoid arthritis: acute phase reactant levels contribute separately to predicting outcome at one year

Introduction

Clinical trials of new treatments for rheumatoid arthritis (RA) typically require subjects to have an elevated acute phase reactant (APR), in addition to tender and swollen joints. However, despite the elevation of individual components of the Clinical Disease Activity Index (CDAI) (tender and swollen joint counts and patient and physician global assessment), some patients with active RA may have normal erythrocyte sedimentation rate (ESR) and/or C-reactive protein (CRP) levels and thus fail to meet entry criteria for clinical trials. We assessed the relationship between CDAI and APRs in the Consortium of Rheumatology Researchers of North America (CORRONA) registry by comparing baseline characteristics and one-year clinical outcomes of patients with active RA, grouped by baseline APR levels.

Methods

This was an observational study of 9,135 RA patients who had both ESR and CRP drawn and a visit at which CDAI was >2.8 (not in remission).

Results

Of 9,135 patients with active RA, 58% had neither elevated ESR nor CRP; only 16% had both elevated ESR and CRP and 26% had either ESR or CRP elevated. Among the 4,228 patients who had a one-year follow-up visit, both baseline and one-year follow-up modified Health Assessment Questionnaire (mHAQ) and CDAI scores were lowest for patients with active RA but with neither APR elevated; both mHAQ and CDAI scores increased sequentially with the increase in number of elevated APR levels at baseline. Each individual component of the CDAI followed the same trend, both at baseline and at one-year follow-up. The magnitude of improvement in both CDAI and mHAQ scores at one year was associated positively with the number of APRs elevated at baseline.

Conclusions

In a large United States registry of RA patients, APR levels often do not correlate with disease activity as measured by joint counts and global assessments. These data strongly suggest that it is appropriate to obtain both ESR and CRP from RA patients at the initial visit. Requiring an elevation in APR levels as a criterion for inclusion of RA patients in studies of experimental agents may exclude some patients with active disease.     

Association between Farming and Chronic Energy Deficiency in Rural South India

Objective

To examine factors associated with chronic energy deficiency (CED) and anaemia in disadvantaged Indian adults who are mostly involved in subsistence farming.

Design

A cross-sectional study in which we collected information on socio-demographic factors, physical activity, anthropometry, blood haemoglobin concentration, and daily household food intake. These data were used to calculate body mass index (BMI), basal metabolic rate (BMR), daily energy expenditure, and energy and nutrient intake. Multivariable backward stepwise logistic regression was used to assess socioeconomic and lifestyle factors associated with CED (defined as BMI<18 kg/m²) and anaemia.

Setting

The study was conducted in 12 villages, in the Rishi Valley, Andhra Pradesh, India.

Subjects

Individuals aged 18 years and above, residing in the 12 villages, were eligible to participate.

Results

Data were available for 1178 individuals (45% male, median age 36 years (inter quartile range (IQR 27–50)). The prevalence of CED (38%) and anaemia (25%) was high. Farming was associated with CED in women (2.20, 95% CI: 1.39–3.49) and men (1.71, 95% CI: (1.06–2.74). Low income was also significantly associated with CED, while not completing high school was positively associated with anaemia. Median iron intake was high: 35.7 mg/day (IQR 26–46) in women and 43.4 mg/day (IQR 34–55) in men.

Conclusions

Farming is an important risk factor associated with CED in this rural Indian population and low dietary iron is not the main cause of anaemia. Better farming practice may help to reduce CED in this population.     

Classical cardiovascular disease risk factors associate with vascular function and morphology in rheumatoid arthritis: a six-year prospective study

Introduction

Patients with rheumatoid arthritis (RA) are at an increased risk for cardiovascular disease (CVD). An early manifestation of CVD is endothelial dysfunction which can lead to functional and morphological vascular abnormalities. Classical CVD risk factors and inflammation are both implicated in causing endothelial dysfunction in RA. The objective of the present study was to examine the effect of baseline inflammation, cumulative inflammation, and classical CVD risk factors on the vasculature following a six-year follow-up period.

Methods

A total of 201 RA patients (155 females, median age (25th to 75th percentile): 61 years (53 to 67)) were examined at baseline (2006) for presence of classical CVD risk factors and determination of inflammation using C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). At follow-up (2012) patients underwent assessments of microvascular and macrovascular endothelium-dependent and endothelium-independent function, along with assessment of carotid atherosclerosis. The CRP and ESR were recorded from the baseline study visit to the follow-up visit for each patient to calculate cumulative inflammatory burden.

Results

Classical CVD risk factors, but not RA disease-related inflammation, predicted microvascular endothelium-dependent and endothelium-independent function, macrovascular endothelium-independent function and carotid atherosclerosis. These findings were similar in a sub-group of patients free from CVD, and not receiving non-steroidal anti-inflammatory drugs, cyclooxygenase 2 inhibitors or biologics. Cumulative inflammation was not associated with microvascular and macrovascular endothelial function, but a weak association was apparent between area under the curve for CRP and carotid atherosclerosis.

Conclusions

Classical CVD risk factors may be better long-term predictors of vascular function and morphology than systemic disease-related inflammation in patients with RA. Further studies are needed to confirm if assessments of vascular function and morphology are predictive of long-term CV outcomes in RA.     

Associations among Erythroferrone and Biomarkers of Erythropoiesis and Iron Metabolism,and Treatment with Long-Term Erythropoiesis-Stimulating Agents in Patients on Hemodialysis

Background

We aimed to identify associations between erythroferrone (ERFE), a regulator of hepcidin 25, and biomarkers of erythropoiesis and iron metabolism. We also aimed to determine the effects of erythropoiesis-stimulating agents (ESA), continuous erythropoietin receptor activator (CERA) and darbepoetin-α (DA) on ERFE production in patients on hemodialysis (HD).

Methods

Blood samples were obtained from 59 patients before HD sessions on day 0 (baseline). Twenty patients who were injected with either CERA (N = 10) or DA (N = 10) at the end of the dialysis week (day 0), who had ferritin ≥ 100 ng/mL and/or transferrin saturation ≥ 20%, and hemoglobin > 9 g/dL were selected from among the 59 patients. Blood was sampled serially before HD sessions on days 3, 5, 7 from patients on DA and on the same days plus day 14 from those on CERA.

Results

Levels of ERFE correlated inversely with those of hepcidin 25 and ferritin, and positively with those of soluble transferrin receptor. The hepcidin 25: ERFE ratio and hepcidin 25 levels positively correlated with ferritin levels. Levels of ERFE significantly increased from day 3 of treatment with DA and CERA and decreased by days 7 and 14, respectively. Erythropoiesis-stimulating agents concomitantly decreased levels of hepcidin 25 as those of ERFE increased.

Conclusion

We identified a novel association between ESA and ERFE in patients on HD. Both DA and CERA increased levels of ERFE that regulated hepcidin 25 and led to iron mobilization from body stores during erythropoiesis.