The combination of IL-6 and its soluble receptor is associated with the response of rheumatoid arthritis patients to tocilizumab

BackgroundIL-6 contributes significantly to the chronic inflammatory process of rheumatoid arthritis (RA). Tocilizumab, a humanized anti-human IL-6 receptor antibody that blocks the signaling originated by the IL-6/IL-6R complex, is an effective treatment. However, predictors of the response to tocilizumab are still required. We aimed to combine IL-6 and soluble IL-6R (sIL-6R) levels to identify groups of responses.MethodsHeparinized blood and clinical data from 63 RA patients were collected before treatment and after 3 and 6 months. Two-step clustering (SPSS v.18) was used to establish the relationship between IL-6 and sIL-6R. Then, we compared European League Against Rheumatism (EULAR) response criteria with remission achievement in the groups of patients.ResultsThree statistical significant clusters of RA patients (i.e., g1, g2, and g3) were defined by serum concentrations of IL-6 and sIL-6R at baseline. All groups of RA patients had higher IL-6 and sIL-6R levels than healthy donors. The levels of IL-6 expressed as median (IQR) in g1 patients were 124(90–183) pg/ml, in g2 12.3(4.4–24) pg/ml, and in g3 60.1(30–146) pg/ml (p < 0.001). The levels of sIL-6R expressed as mean ± sd in g1 patients were 250.5 ± 72 ng/ml, in g2 269.1 ± 125 ng/ml, and in g3 732.7 ± 243 ng/ml (p < 0.001). Disease activity score (DAS)28, C-reactive protein, and erythrocyte sedimentation rate were comparable in the three groups at baseline. Disease duration in g3 was the longest (median(IQR) years: g1 = 11(5–15), g2 = 12(8–20), and g3 23(16–26); p = 0.006), with years of disease evolution being correlated with sIL-6R levels (R = 0.417, p < 0.001). Simple and Clinical Disease Activity Index (SDAI and CDAI) decreased significantly in the three groups. However, EULAR response criteria and remission achievement at 6 m was different in the three groups (p = 0.03 and 0.04, respectively). In all. 17 out of the 18 patients in g1 had a good or moderate response to tocilizumab. Conversely, the percentage of patients with no response to tocilizumab was higher in g3 than in g1 and g2. We also observed different changing patterns of IL-6 and sIL-6R levels among the three groups.ConclusionsRA patients could be easily stratified prior to therapeutic intervention with two molecules related to the pathway blocked by tocilizumab. G1 patients, who had the best response to tocilizumab, had the highest level of IL-6 and the lowest level of sIL-6R.     

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.     

Soluble interleukin-6 receptor in rheumatoid arthritis

Abstract

To investigate the pathophysiologic role of soluble interleukin-6 receptor (sIL-6R) in patients with rheumatoid arthritis (RA), serum sIL-6R levels were measured in 15 RA patients and 15 healthy control subjects using a sandwich enzyme-linked immunosorbent assay. Correlation analysis was performed between sIL-6R levels and clinical variables such as joint score, Lansbury’s index, C-reactive protein and platelet counts. Levels of sIL-6R and IL-6 were also measured in paired samples of serum and synovial fluid obtained at the same time from nine RA patients. Serum sIL-6R levels in RA patients (153.9±56.9 ng/ml) were significantly higher than those of control subjects (115.1±19.1 ng/ml; P<0.05). However, sIL-6R levels did not correlate with any clinical characteristic of RA. sIL-6R was detectable in synovial fluid, but was invariably lower than in serum, in contrast to IL-6 (i.e. much higher in synovial fluid). It correlated neither with total cell nor neutrophil number in synovial fluid. Serum C-reactive protein levels were significantly correlated with IL-6 in synovial fluid, but not with sIL-6R in synovial fluid. These results indicate that serum sIL-6R levels are increased in RA patients. High levels of serum sIL-6R did not seem to be derived from the site of local inflammation. The readily detectable sIL-6R in synovial fluid may co-operate with IL-6 in the pathogenesis of synovitis in RA.     

The −383A>C TNFRI polymorphism is associated with soluble levels and clinical activity in rheumatoid arthritis

Tumor necrosis factor-α (TNF-α) plays a central role in inflammation, and it has been directly implicated in the pathogenesis of rheumatoid arthritis (RA). TNF-α activity is mediated through TNFRI and TNFRII cell surface receptors, which act as physiological attenuators of TNF-α activity. We recruited 190 RA patients and 190 healthy subjects (HS) in order to associate the −383A>C TNFRI polymorphism with sTNFRI levels and DAS28 score in RA. In results, sTNFRI levels were higher in RA patients than HS (P = 0.04). The −383A>C TNFRI polymorphism did not show significant differences in both studied groups. However, in the RA group the sTNFRI levels were significantly elevated (P = 0.004) in A/A genotype carriers. In addition, the A/A genotype carriers had the higher DAS28 score than A/C genotype (P = 0.02). These data suggest that −383A>C TNFRI polymorphism is not a susceptibility marker in RA, whereas the increased levels of sTNFRI could reflect the clinical activity in RA patients.     

Association of serum osteoprotegerin and osteoprotegerin gene polymorphism with subclinical carotid artery atherosclerosis and disease activity in rheumatoid arthritis patients

Aim of the workTo investigate the association of single nucleotide polymorphism (SNP) (rs2073618) of the OPG gene and of serum OPG with subclinical carotid atherosclerosis in RA patients.Patients and methodsEighty RA patients with no previous history of a cardiovascular disease were studied and forty healthy controls were enrolled in the study. Carotid atherosclerosis was evaluated by high-resolution B-mode ultrasound and the carotid intimal medial thickness (CIMT) measured. rs2073618 OPG genotyping was performed by polymerized chain reaction (PCR) and serum OPG concentrations were measured. The high sensitive C reactive protein (hs-CRP), rheumatoid factor (RF) titer and anti-cyclic citrullinated peptide (anti-CCP) were assessed. The disease activity score (DAS28) was evaluated.ResultsThe patients mean age was54.1 ± 6.2 years, disease duration of 12.5 ± 8.5 years and were 72 females and 8 males. Increased IMT was found in 38 patients, 40 age and sex matched controls were included. Patients with atherosclerosis (n = 38) had longer disease duration, higherDAS28, hs-CRP, RF titer and anti-CCP. The serum OPG levels were higher in patients with atherosclerosis (1106.4 ± 1157.1 ng/l) compared to those without (658.3 ± 151.1 ng/l)(p = 0.001). Serum OPG significantly correlated with disease duration (r = 0.42, p = 0.005), DAS28 (r = 0.53, p = 0.001), hs-CRP (r = 0.41, p = 0.007), anti-CCP (r = 0.47, p = 0.003) and mean CIMT (r = 0.37, p = 0.02). The frequencies of CC, CG and GG genotypes were comparable between those with and without atherosclerosis (39.5%, 50%, 10.4% vs 42.9%, 47.6% and 9.5% respectively).Conclusionrs2073618 OPG gene may not be associated with subclinical atherosclerosis, although the serum level could be a reliable marker for disease activity and for early detection of carotid artery atherosclerosis in RA.     

Soluble interleukin-6 receptor in rheumatoid arthritis

To investigate the pathophysiologic role of soluble interleukin-6 receptor (sIL-6R) in patients with rheumatoid arthritis (RA), serum sIL-6R levels were measured in 15 RA patients and 15 healthy control subjects using a sandwich enzyme-linked immunosorbent assay. Correlation analysis was performed between sIL-6R levels and clinical variables such as joint score, Lansbury’s index, C-reactive protein and platelet counts. Levels of sIL-6R and IL-6 were also measured in paired samples of serum and synovial fluid obtained at the same time from nine RA patients. Serum sIL-6R levels in RA patients (153.9±56.9 ng/ml) were significantly higher than those of control subjects (115.1±19.1 ng/ml;P<0.05). However, sIL-6R levels did not correlate with any clinical characteristic of RA. sIL-6R was detectable in synovial fluid, but was invariably lower than in serum, in contrast to IL-6 (i.e. much higher in synovial fluid). It correlated neither with total cell nor neutrophil number in synovial fluid. Serum C-reactive protein levels were significantly correlated with IL-6 in synovial fluid, but not with sIL-6R in synovial fluid. These results indicate that serum sIL-6R levels are increased in RA patients. High levels of serum sIL-6R did not seem to be derived from the site of local inflammation. The readily detectable sIL-6R in synovial fluid may co-operate with IL-6 in the pathogenesis of synovitis in RA.     

Serum-soluble interleukin-2 receptor (sIL-2R) is an extremely strong prognostic factor for patients with peripheral T-cell lymphoma, unspecified (PTCL-U)

Purpose  The aim of this study was to assess the prognostic factors of peripheral T-cell lymphoma, unspecified (PTCL-U). Patients and methods  We retrospectively analyzed 30 cases fulfilling the criteria of PTCL-U defined by the World Health Organization classification. The patients were treated with 6–8 cycles of a CHOP or THP (pirarubicin)-COP regimen. Results  A high serum sIL-2R level (≥2,000 U/ml) at onset was associated with a low complete remission rate. Patients with high sIL-2R had significantly lower survival rates (5 year, 15.1%) than those with low sIL-2R (<2,000 U/ml) (100%) (P < 0.005). Factors associated with worse overall survival in a univariate analysis were high sIL-2R (P < 0.005), high age (>60 years) (P < 0.05), poor performance status (P < 0.01) and poor international prognostic index (P < 0.05). No correlation was observed between sIL-2R and other markers. Multivariate analysis showed that only sIL-2R was a prognostic factor for overall survival (P < 0.01). Conclusion  The results suggest that a high serum sIL-2R level predicts a poor prognosis in PTCL-U.     

Clinical significance of elevated soluble interleukin-6 receptor levels in the sera of patients with plasma cell dyscrasias

Summary .We investigated the clinical significance of the serum soluble interleukin-6 receptor (sIL-6R) in 42 patients with plasma cell dyscrasias (27 with multiple myeloma (MM), 13 with monoclonal gammopathy of undetermined significance (MGUS), and two with plasma cell leukaemia (PCL)). Serum levels of sIL-6R in normal individuals were 77 ± 21 ng/ml (mean ± SD, n = 18); those in patients with MGUS and with MM were elevated (102 ± 33 ng/ml, mean ± SD, P < 0–05 and 126 ± 60ng/ml, mean ± SD, P < 0–01, respectively). Significant correlations were not found between the serum levels of sIL-6R and known prognostic factors (C-reactive protein, haemoglobin levels, calcium, creatinine, β₂-microglobulin, amounts of M-protein, or percentages of plasma cells in bone marrow). Elevated serum sIL-6R did not affect the survival of the patients with MM. Serial measurements of sIL-6R together with the clinical course of patients with plasma cell neoplasias revealed a good correlation between the sIL-6R level and disease activity. We conclude that sIL-6R can be used as a clinical factor correlated with the disease activity, at least in some patients with plasma cell neoplasias.     

Serum Interleukin-6, Soluble Interleukin-6 Receptor and Crohn’s Disease Activity

The relationship between plasma interleukin-6 (IL-6) concentration and its soluble receptor in Crohn’s disease (CD) is not well elucidated. Twenty healthy volunteers and 94 consecutive patients with CD (44 in relapse and 50 in remission) were studied. Plasma IL-6 concentrations in patients with active disease [80 ± 9 pg/ml; mean ± standard error of the mean (SEM)] were significantly higher than in patients with inactive disease (50 ± 4 pg/ml; P < 0.001) or controls (3 ± 1 pg/ml; P < 0.001). However, concentrations did not vary with the severity of CD attacks. Plasma concentrations of soluble interleukin-6 receptor (sIL-6R) in active-CD patients (77 ± 5 ng/ml) did not differ significantly from those with inactive disease (82 ± 5 ng/ml), while both groups had significantly raised concentrations compared with those of controls (58 ± 6 ng/ml; P < 0.03 and P < 0.01, respectively). Plasma IL-6 concentrations correlated significantly with serum C-reactive protein (CRP) (r = 0.34; P < 0.001), whereas plasma sIL-6R concentrations did not. Taken together, these data suggest that, although IL6 and sIL6-R are both involved in the inflammatory process of CD, they are poor markers of disease activity.     

Soluble interleukin-6 receptor (sIL-6R), a new prognostic factor in multiple myeloma

sIL-6R is a 55 kD soluble molecule mediating the interleukin-6 (IL-6) signal through the IL-6 receptor-associated transmembrane signal transducer, gp130. It has recently been suggested that sIL-6R serum levels may reflect disease severity in multiple myeloma (MM). We determined sIL-6R serum levels in 25 normal controls (NC) and in 80 MM patients at diagnosis and during the course of the disease. Measurements were done by ELISA. In NC, sIL-6R levels ranged from 14 to 40 ng/ml (median 28 ng/ml) whereas in MM patients the range was 10–200 ng/ml (median 38 ng/ml) ( P  < 0.01). 61 patients entered remission and 19 were resistant. Median sIL-6R value at diagnosis was 36 ng/ml (10–120) in responding patients, and 82 ng/ml (20–200) in non-responding patients ( P  < 0.001). During a follow-up from 12 to 89 months, sIL-6R values remained more or less stable in most patients. High sIL-6R levels correlated with poor survival.     

Increased plasma myeloperoxidase levels in systemic lupus erythematosus

The objective of the study was to quantify plasma myeloperoxidase (MPO) levels in systemic lupus erythematosus (SLE) patients and to evaluate a correlation between MPO levels and disease activity. 71 female SLE patients and 70 controls were studied. Patients were divided into two groups: Group I (n = 48) with SLEDAI-2K score 0–5 and Group II (n = 23) with SLEDAI-2K score ≥6. Mann–Whitney test and Spearman rank correlation were used. Two-sided P values <0.05 were considered significant and P values ≥0.05 and <0.08 were considered as a tendency. The median age of patients and controls were comparable and the mean disease duration was 99.2 ± 61.7 months. MPO levels were higher in patients than controls [5.99 (4.38–8.64) vs. 5.00 (3.33–7.08) ng/ml, P = 0.02]. We did not find correlation between MPO levels and SLEDAI-2k (r = 0.07, P = 0.58). MPO levels were not affected by treatment with prednisone, cyclophosphamide or azathioprine, however, a tendency of lower levels was observed among patients under antimalarial drugs. There was no significant difference in MPO plasma levels between Group I and Group II (5.83 vs. 6.02 ng/ml, P = 0.99). MPO levels were higher in patients with arthritis than in those without arthritis (8.15 vs. 5.56 ng/ml, P = 0.010). No difference was observed among patients with and without other organs/systems involvement. SLE patients presented increased MPO plasma levels than healthy controls. Despite the lack of correlation between MPO plasma levels and disease activity, the higher MPO levels in patients with articular involvement suggests MPO may play a different role in the inflammatory process of some SLE manifestations.     

Circulating N‐cadherin levels are a negative prognostic indicator in patients with multiple myeloma

N‐cadherin (cadherin 2, type 1, N‐cadherin (neuronal); CDN2) is a homotypic adhesion molecule that is upregulated in breast, prostate and bladder cancer. Here we investigated the prognostic significance of upregulated N‐cadherin expression in multiple myeloma (MM). Our results indicate that N‐cadherin protein and gene expression is abnormally increased in trephine biopsies and CD38⁺⁺/CD138⁺ plasma cells from MM patients, when compared with those of normal donors. In addition, levels of circulating N‐cadherin were elevated in a subset of patients with MM (n = 81; mean: 14·50 ng/ml, range: 0–146·78 ng/ml), relative to age‐matched controls (n = 27; mean: 2·66 ng/ml, range: 0–5·96 ng/ml), although this did not reach statistical significance. Notably, patients with abnormally high levels of N‐cadherin (>6 ng/ml) had decreased progression‐free survival (P = 0·036; hazard ratio: 1·94) and overall survival (P = 0·002; hazard ratio: 3·15), when compared with patients with normal N‐cadherin levels (≤6 ng/ml). Furthermore, multivariate analyses revealed that the combination of N‐cadherin levels and International Staging System (ISS) was a more powerful prognostic indicator than using ISS alone. Collectively, our studies demonstrate that circulating N‐cadherin levels are a viable prognostic marker for high‐risk MM patients.     

<Emphasis Type="Italic">STAT4</Emphasis> rs7574865 G/T polymorphism is associated with rheumatoid arthritis and disease activity,but not with anti-CCP antibody levels in a Mexican population

Rheumatoid arthritis (RA) is a systemic autoimmune disease in whose etiology genetic factors are known to play an important role. Among the genes associated with RA, STAT4 could be an important factor in conducting helper T cells toward the pro-inflammatory Th1 and Th17 lineages. The aim of this study is to determine the association of the STAT4 polymorphism rs7574865 with RA, disease activity, and anti-cyclic citrullinated peptide (CCP) antibody levels in a Mexican population. Genotyping was carried out using the Taqman® system from Applied Biosystems in 140 patients with RA and 150 healthy subjects. Disease activity was evaluated by a rheumatologist using the DAS28 and Spanish-HAQ-DI instruments. Anti-CCP levels were determined by ELISA. Associations of the genotypes of rs7574865 with DAS28, HAQ, and anti-CCP antibody levels with RA were determined. Findings showed that the GT and TT genotypes and the T allele from rs7574865 were all associated as risk factors for RA, independently of their anti-CCP status. An association with moderate-to-high disease activity (DAS28?≥?3.2) was also found. Additionally, patients with the GT or TT genotypes showed lower HAQ values than those who carried the GG genotype. No differences in anti-CCP antibody levels or DAS28 and genotypes were found. This work supports the association of the STAT4 rs7574865 polymorphism with RA and disease activity, but not with anti-CCP antibody levels in a Mexican population.     

The relationship between D-dimer level and the development of atrial fibrillation in patients with systolic heart failure

Heart failure (HF) is one of the most common and leading cause of death worldwide. Clinical trials provide evidence that the development of atrial fibrillation (AF) is a marker of poor prognosis in patients with HF. Furthermore, elevated D-dimer level is associated with increased cardiovascular mortality independent of AF in HF patients. We investigated whether plasma D-dimer levels in patients with hospitalized systolic HF could predict development of AF. A total of 150 consecutive patients with sinus rhythm who admitted to the emergency department with hospitalized systolic HF were evaluated. All hospitalized patients were obtained D-dimer levels within the first 24 h following admission. Atrial fibrillation developed in 31 (20.7%) patients during follow-up period of 6.3 ± 5 months. Patients who developed atrial fibrillation had significantly increased levels of D-dimer [608 (339–1,022) ng/ml versus 1,100 (608–2,599) ng/ml, P = 0.001]. Optimal cut-off level of D-dimer to predict development of AF was found to be >792 ng/ml. D-dimer >792 ng/ml, right ventricular dilatation, age, systolic pulmonary pressure, left atrium size, moderate to severe tricuspid regurgitation, and beta blocker usage were found to have prognostic significance in univariate analysis. In multivariate Cox proportional-hazards model, D-dimer levels >792 ng/ml (HR = 3.019, P = 0.006), and right ventricular dilatation (HR = 8.676, P = 0.003) were associated with an increased risk of new-onset AF. In conclusion, D-dimer could predict development of AF in patients with hospitalized systolic HF.     

A genetic variant of G6PC2 is associated with type 2 diabetes and fasting plasma glucose level in the Chinese population

Aims/hypothesis  Single nucleotide polymorphisms (SNPs) in G6PC2 have been reported to be associated with fasting plasma glucose level in several populations of European descent. However, whether G6PC2 variants have a similar effect in other ethnic groups is unknown. The aim of this study was to investigate the effect of common variants of G6PC2 on type 2 diabetes and related clinical features in a Chinese population. Methods  We selected four SNPs, rs13387347, rs2232316, rs492594 and rs16856187, tagging all the common variants spanning the G6PC2 gene (r ² ≥ 0.8) based on HapMap Chinese data, and genotyped them in a group of 3,676 Shanghai Chinese individuals, comprising 1,876 cases and 1,800 controls. Results  Three SNPs were nominally associated with type 2 diabetes, with rs16856187 showing the strongest evidence for association (p = 0.0009, empirical p = 0.0047). Further conditional analysis revealed that the association signal arose from an individual SNP, rs16856187. This SNP was also associated with fasting plasma glucose level in participants with normal glucose regulation (p = 0.0002), with the fasting plasma glucose level observed to increase by 0.067 mmol/l with each copy of the rare C allele. Conclusions/interpretation  In this study we identified a novel risk-conferring G6PC2 SNP for type 2 diabetes in a Chinese population and confirmed the previous finding that G6PC2 variants are associated with fasting plasma glucose concentration. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorised users. An erratum to this article can be found at     

Interleukin-18 promoter polymorphisms in Japanese patients with rheumatoid arthritis: protective effect of the T allele and T/T genotype at rs360722

Rheumatoid arthritis (RA) is a chronic inflammatory disease with a strong genetic contribution to its pathogenesis. Among numerous candidate genes, cytokine gene polymorphisms have been implicated. Interleukin-18 (IL-18) induces production of tumor necrosis factor-α and promotes T helper (Th)1-type immune responses. This study investigates the association between IL-18 promoter polymorphisms and RA susceptibility. A total of 2471 Japanese case–control samples (1493 RA patients and 978 healthy controls) were examined. Three haplotype tag single-nucleotide polymorphisms, rs1946518A/C, rs360718T/G, and rs360722T/C, spanning from the 5′UTR to intron 1 were genotyped using allelic discrimination with the use of specific TaqMan probes, and three haplotypes (A–T–T, C–T–C, and A–G–C) were determined. Among these polymorphisms, the frequency of the T allele at rs360722, which tags the A–T–T haplotype, was significantly lower in the RA patient group compared with the normal subjects [0.46 versus 0.49, P = 0.0061, Fisher’s exact probability test, odds ratio (OR) = 0.85, 95% confidence interval (CI) = 0.75–0.95]. Having the T/T genotype further increased the significance (0.20 versus 0.27, P = 0.0006, OR = 0.72, 95% CI = 0.58–0.86). Therefore, presence of the T allele and T/T genotype at rs360722 reduces the susceptibility of Japanese people to RA.     

Interleukin-6 in synovial fluid is closely associated with chronic synovitis in rheumatoid arthritis

Summary Interleukin-6 (IL-6) was detected at low levels in plasma [0.014±0.006 ng/ml (mean ± SEM] and in high amounts in synovial fluid [SF; 2.6±2.2 ng/ml (mean ± SEM)] of patients with rheumatoid arthritis. No correlation of IL-6 levels in plasma or SF with the ESR (n=15) or with histological parameters of acute local synovitis (n=10) was observed. In contrast, SF IL-6 was positively correlated with histological characteristics of chronic synovitis (n=10; P0.01) and elevated plasma IgG concentrations (n=15; P0.05). In vitro concentrations of IL-6 comparable to those detected in SF increased the production of both IgG and IgM by synovial membrane mononuclear cells. The present results contribute to the view that high local IL-6 concentrations in SF promote chronic synovitis in RA.     

Regulated plasma levels of colony-stimulating factors,interleukin-6 and interleukin-10 in patients with acute leukaemia and non-Hodgkin's lymphoma undergoing cytoreductive chemotherapy

Endogenous plasma levels of granulocyte colony stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-6 and IL-10 were measured in a total of 70 patients undergoing cytoreductive chemotherapy for treatment of acute leukaemia or non-Hodgkin’s lymphomas. The diagnoses were acute myeloid leukaemia (AML; n = 30), acute lymphoblastic leukaemia (ALL; n = 6), non-Hodgkin’s lymphomas (NHL; n = 11) and other malignant haematological disorders including myelodysplastic syndromes (n = 23). After chemotherapy, plasma G-CSF was elevated (mean 5.6 ng/ml; range 1.2–10 ng/ml), and was inversely correlated with white blood cell counts (WBC) (r = ?0.7, P < 0.001). Occurrence of fever (T>38.0°C) during severe myelosuppression (WBC<1 × 10⁹/l) was associated with an additional increase of G-CSF levels (P < 0.001). Plasma IL-6 correlated significantly with fever (range <1 to 1100 pg/ml, mean 130 pg/ml; r = 0.5, P < 0.001) but revealed only a weak association with WBC or platelet counts. In patients treated with recombinant G-CSF (n = 9), an association between IL-6 and fever was still observed after chemotherapy. During the nonfebrile status (total n = 242; AML n = 124), IL-6 levels remained <9 pg/ml in 90% of cases, whereas G-CSF increased with leucopenia (r = ?0.72; P < 0.001). In contrast, endogenous GM-CSF remained normal and IL-10 showed only a slight increase (21% of samples; maximum 22 pg/ml) in severe leucopenia. In particular, IL-10 levels did not correlate with G-CSF or IL-6 levels. We conclude that systemic release of G-CSF and IL-6 is obviously not abrogated by cytoreductive chemotherapy in acute leukaemia and NHL and may add to the therapeutic efficacy of recombinant cytokines. Also, plasma levels of G-, GM-CSF or IL-6 appear to be regulated by separate mechanisms.