Serum immunoreactive interleukin-6 and C-reactive protein levels in patients with multiple myeloma at diagnosis

Summary Serum bioactive but not immunoreactive interleukin-6 (IL-6), and serum C-reactive protein (CRP), have been reported to be of prognostic significance in multiple myeloma (MM). We measured serum immunoreactive IL-6 by a sensitive enzyme-linked immunosorbent assay in 30 MM patients at diagnosis. In 30% of the patients serum immuno-reactive IL-6 exceeded the upper reference limit. The concentrations of CRP and IL-6 showed a linear association. Logarithmically transformed IL-6, CRP and β₂-microglobulin were significant variables by univariate survival analysis: by multivariate analysis CRP was a slightly stronger prognostic factor than IL-6 and the only one of independent prognostic significance.     

Relationship between circulating serum soluble interleukin-6 receptor and the angiogenic cytokines basic fibroblast growth factor and vascular endothelial growth factor in multiple myeloma

Angiogenesis plays an important role in multiple myeloma (MM) progression. Various mitogens such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (FGF-2) have been implicated in the angiogenic process of various malignancies. Interleukin-6 (IL-6) is a growth factor of myeloma cells and its signaling is mediated via a cell surface receptor complex (IL-6r). IL-6 and tumor necrosis factor-alpha (TNF-alpha) are involved in the secretion of VEGF by IL-6r expressing myeloma cells. In this study, serum FGF-2, VEGF, IL-6r, and TNF-alpha were measured in 46 untreated MM patients and were studied in relation to disease stage (by Salmon-Durie criteria) and severity [assessed by serum beta(2)-microglobulin (beta(2)M), C-reactive protein (CRP), alpha(1)-antitrypsin (alpha(1)AT), and lactic dehydrogenase (LDH) levels]. The results showed that FGF-2, VEGF, IL-6r, and TNF-alpha were significantly elevated in MM patients in comparison to controls ( p<0.008) and were significantly higher in stage III disease in comparison to stages I and II ( p<0.03). The mean concentrations of IL-6r were 877+/-374, 1220+/-308, 1431+/-878, and 453+/-180 pg/ml for stages I, II, and III and controls, respectively. Levels of beta(2)M, alpha(1)AT, CRP, and LDH were all significantly higher in MM patients than controls and increased with advancing stage of disease. There were positive correlations of both VEGF and FGF-2 with IL-6r, TNF-alpha, beta(2)M, alpha(1)AT, CRP, and LDH. We conclude that IL-6r and TNF-alpha increase in parallel to VEGF and FGF-2 with increasing stage of MM disease. These molecules correlate with biochemical markers of disease activity and may play a role in the progression of multiple myeloma.     

C-reactive protein and beta-2 microglobulin produce a simple and powerful myeloma staging system.

Multiple myeloma (MM) staging procedures are still inadequate for detection of the optimal therapeutic procedure for an individual patient. The Durie & Salmon staging system and serum beta 2-microglobulin (beta 2M) are used worldwide because of their easy clinical application. Other prognostic parameters, such as myeloma cell proliferative activity, are of exceeding importance, but are not as simple as standard methods. Recently, interleukin-6 (IL-6) has been shown to be a major growth factor for MM. IL-6 is a pleiotropic cytokine acting on several cell lineages, and, at the hepatocyte level, stimulates the synthesis of acute phase proteins, such as the well known C-Reactive Protein (CRP). Serum CRP concentration actually reflects the IL-6 activity. A survival analysis carried out in 162 MM patients at diagnosis showed that serum CRP level is a highly significant prognostic factor. Moreover, serum CRP was independent of serum beta 2M. This feature allowed stratification of MM patients into 3 groups according to CRP and beta 2M serum levels: (1) low risk group, CRP and beta 2M less than 6 mg/L (50% of patients); (2) intermediate risk group, CRP or beta 2M greater than or equal to 6 mg/L (35% of patients); (3) high risk group, CRP and beta 2M greater than or equal to 6 mg/L (15% of patients). Survival was 54, 27, and 6 months, respectively (P less than .0001). We thus propose a new and powerful myeloma staging system based on simple and reliable laboratory evaluations.     

Correlation between the uptake of Tc-99m-sestaMIBI and prognostic factors in patients with multiple myeloma

Technetium 99m-2-methoxyisobutil-isonitrile (Tc-99m-MIBI), also called sestaMIBI, has been used successfully to detect malignant tumours at diagnosis. Recently, it has been proposed as a safe and effective tracer in patients with multiple myeloma (MM). The purpose of this study was to demonstrate the value of the Tc-99m-MIBI uptake in disease detection and to assess the correlation between the uptake of this scintigraphy agent and prognostic factors in newly diagnosed MM patients. Thirty-five untreated patients were enrolled in the study. Tc-99m-MIBI scanning was performed in 33 patients after intravenous injection of 7.4 MBq/kg. Whole-body anterior and posterior scans were obtained after 30 min, 60 min, 2 and 4 h. The correlation between known prognostic factors of MM and the intensity of Tc-99m-MIBI uptake was assessed. Our results showed seven patients with an intensity score of I0, 12 patients with I1, eight patients with I2 and six patients with a score of I3. There was a positive correlation between Tc-99m-MIBI intensity and C-reactive protein (CRP; r=0.506, P < 0.01), erythrocyte sedimentation rate (ESR; r=0.368, P < 0.05), beta2- microglobulin (beta2M; r=0.749, P < 0.001), interleukin-6 (IL-6; r=0.823, P < 0.001), soluble Interleukin-6 receptor (sIL-6r; r=0.806, P < 0.001), serum calcium (r=0.578, P < 0.001) and bone alkaline phosphatase (BAP; r=0.472, P < 0.01). An inverse correlation was found between Tc-99m-MIBI intensity and osteocalcin (OC) and type I procollagen carboxyterminal propeptide (PICP). In conclusion, the results of this study suggest that more extensive disease activity, as determined by high levels of CRP, beta2M, IL-6 and sIL-6r correlated with a higher uptake of the radiotracer.     

The clinical and prognostic significance of erythrocyte sedimentation rate (ESR), serum interleukin-6 (IL-6) and acute phase protein levels in multiple myeloma

Interleukin-6 (IL-6) and acute phase proteins are commonly increased in patients with multiple myeloma. Several of these acute phase proteins are believed to predict prognosis and influence survival. We measured interleukin-6 (IL-6), C-reactive protein (CRP), alpha-1-antitrypsin (a1AT), acid alpha-1-glycoprotein (a1AG), haptoglobin (HAP), transferrin (TRF), hemoglobin (Hb), beta-2-microglobulin (beta2M) and erythrocyte sedimentation rate (ESR) in 42 newly diagnosed multiple myeloma patients and 25 normal controls. At the time of blood collection, nine patients were at stage I of disease, 14 at stage II, and 19 at stage III according to the Durie and Salmon myeloma staging system. Mean +/- SD values of IL-6, CRP, a1AT, a1AG, HAP, beta2M, and ESR were significantly higher and Hb significantly lower than those found in the controls. Univariate analysis, using the log-rank test, showed that among the acute phase proteins, serum CRP (P < 0.002), a1AT (P < 0.008) and ESR (P < 0.008) were significantly correlated with survival. However, when a multivariate Cox proportional hazard model was performed, ESR, CRP, a1AT, a1AG and beta2M were identified as independent prognostic factors, while the others were not. We conclude that ESR, a simple and easily performed marker, was found to be an independent prognostic factor for survival in patients with multiple myeloma.     

Serum level of interleukin-16 in multiple myeloma patients and its relationship to disease activity

Interleukin-16 (IL-16) is a chemoattractant of CD4+ lymphocytes, and it has been implicated in the pathogenesis of various inflammatory diseases. There is evidence that it may have a role in multiple myeloma (MM). In the present study, we determined the serum level of IL-16 both before and after treatment of MM and related it to inflammatory markers and survival. Forty-eight newly diagnosed MM patients were included in the study. Disease stage was defined using the Durie-Salmon classification system (10 patients were in stage I, 19 in stage II, and 19 in stage III). After standard treatment, 22 patients reached the plateau phase and were re-evaluated. The following serum parameters were measured: IL-16, IL-6, alpha-1 antitrypsin (alpha1AT), and C-reactive protein (CRP). Survival was determined as the number of months elapsed since original diagnosis. The mean +/- SD of serum IL-16 was 343 +/- 195 pg/ml in the pre-treatment MM group and 101 +/- 30 pg/ml in the control group. All measured parameters were higher in the patient group compared to healthy controls. Furthermore, IL-16, IL-6, alpha1AT, and CRP were significantly increased with increasing stage of disease, from stage I to stage III (P<0.01). All parameters decreased significantly following effective chemotherapy (P<0.002). Patients with a high level of IL-16 (>430 pg/ml) displayed an inferior survival time in comparison to those with lower levels of IL-16. In the pre-treatment group, IL-16 correlated with alpha1AT and IL-6 (r=0.374, P<0.01 and r=0.454, P<0.002, respectively). IL-16 may play a role in multiple myeloma; however, further functional studies are required.     

Fibrinolytic activity in multiple myeloma

The incidence of thromboembolic events is high as a result of disease, disease-related complications, and therapy in multiple myeloma (MM). In patients with hematologic tumors, impaired fibrinolysis may be present and may contribute to the development of thrombotic complications. Therefore, we designed a study to investigate fibrinolytic activity in MM. We compared plasma levels of interleukin (IL)-6, C-reactive protein (CRP), IL-1beta, IL-11, tissue plasminogen activator (tPA) activity, plasminogen activator inhibitor-1 (PAI-1) activity, and global fibrinolytic capacity (GFC) in patients with MM (n = 66) and in control subjects (n = 18). The prevalence of venous thromboembolism was 4.5%, with a median follow-up period of 7 months in our myeloma group. Results are given as mean (median, range). Plasma levels of IL-6 (8.27 +/- 0.74 [9.65, 0.90-13.32] pg/mL versus 2.64 +/- 0.66 [1.80, 0.10-11.86] pg/mL, P < 0.001), CRP (45.57 +/- 9.92 [21.00, 1.34-330.00] mg/L versus 1.96 +/- 0.50 [1.05, 0.19-8.03] mg/L, P < 0.001), PAI-1 (7.40 +/- 0.67 [5.57, 2.40-31.80] IU/mL versus 4.73 +/- 0.65 [3.60, 2.32-11.00] IU/mL, P < 0.01), GFC score (1.90 +/- 0.02 [2, 1-3] versus 2.50 +/- 0.14 [3, 1-3], P < 0.001) were increased compared with controls. In patients with MM, the level of IL-6 was positively correlated with CRP (r = 0.66, P < 0.001), IL-1beta (r = 0.29, P < 0.05), and PAI-1 (r = 0.35, P < 0.01) and negatively correlated with GFC (r = -0.37, P < 0.01). CRP level was positively correlated with plasma PAI-1 level (r = 0.40, P < 0.01) and negatively correlated with GFC (r = -0.44, P < 0.001). A significant negative correlation between PAI-1 level and GFC (r = -0.75, P < 0.001) was also detected. IL-1beta levels were negatively correlated with tPA level (r = -0.26, P < 0.05). These results suggest that patients with myeloma have a decreased fibrinolytic activity mainly because of increased PAI-1 activity. In MM, increased PAI-1 activity seems to be related with elevated IL-6 level. MM should be considered as a hypercoagulable state as a result of both increased procoagulant activity and decreased fibrinolytic activity. Achieving a plateau by means of conventional chemotherapies does not improve the decreased fibrinolytic activity.     

Prognostic values of tumor necrosis factor/cachectin, interleukin-1, interferon-alpha, and interferon-gamma in the serum of patients with septic shock. Swiss-Dutch J5 Immunoglobulin Study Group

Serum concentrations of immunoreactive tumor necrosis factor/cachectin (TNF), interleukin-1 beta (IL-1 beta), interferon-gamma (IFN gamma), and interferon-alpha (IFN alpha) were prospectively measured in 70 patients with septic shock to determine their evolution and prognostic values. In a univariate analysis, levels of TNF (P = .002) and IL-1 beta (P = .05) were associated with the patient's outcome, but not IFN alpha (P = .15) and IFN gamma (P = .26). In contrast, in a stepwise logistic regression analysis, the severity of the underlying disease (P = .01), the age of the patient (P = .02), the documentation of infection (nonbacteremic infections vs. bacteremias, P = .03), the urine output (P = .04), and the arterial pH (P = .05) contributed more significantly to prediction of patient outcome than the serum levels of TNF (P = .07). After 10 days, the median concentration of TNF was undetectable (less than 100 pg/ml) in the survivors, whereas it remained elevated (305 pg/ml, P = .002) in the nonsurvivors. Thus, in patients with septic shock due to various gram-negative bacteria, other parameters than the absolute serum concentration of immunoreactive TNF contributed significantly to the prediction of outcome.     

Elevated serum concentration of hepatocyte growth factor in patients with multiple myeloma: correlation with markers of disease activity

Hepatocyte growth factor (HGF) has been shown to be involved in angiogenesis, epithelial cell proliferation, and osteoclast activation. HGF and its receptor are expressed on myeloma cell lines and could be involved in the pathogenesis of bone destruction in multiple myeloma (MM). The aim of this study was to examine serum levels of HGF in untreated MM patients and its correlation with bone turnover indices and markers of disease activity. Forty-seven newly diagnosed MM patients and 25 controls were included: 12 patients were of stage I, 13 of stage II, and 22 of stage III (Durie-Salmon classification). Bone lesions were scored from 0 to 3, according to X-ray findings. Serum osteocalcin (OC), interleukin-6 (IL-6), TNF-alpha, beta(2)-microglobulin (beta(2)M), CRP, calcium, and 24-hr urine N-telopeptide cross-links of collagen breakdown (NTx) were determined. HGF levels were significantly higher at stage III compared to stages II and I (medians: 1,990.4 vs. 1,743.8 and 1,432.4 pg/mL, respectively, P < 0.05). Similarly, NTx, IL-6, TNF-alpha, CRP, beta(2)M, and calcium increased significantly with advancing stage (P < 0.01). OC was higher at stage I in comparison to stages II and III (P < 0.01). All parameters were significantly higher in patients than controls. HGF showed a strong correlation with IL-6 and TNF-alpha and less with beta(2)M, CRP, NTx, and OC. We conclude that serum HGF levels are increased in advanced stages of MM disease and extended bone lesions. HGF correlates with IL-6 and TNF-alpha, which are cytokines involved in osteoclast stimulation in MM. However, an independent association of HGF with bone turnover markers was not shown in this study, thus its role in MM bone disease needs to be further clarified.     

Serum and in vitro production of IL-1 receptor antagonist correlate with C-reactive protein levels in newly diagnosed, untreated lupus patients

OBJECTIVE: To examine the correlation between C-reactive protein (CRP) and CRP-inducing cytokines (IL-1 beta, IL-6, TNF-alpha) and IL-1 receptor antagonist (IL-1ra), as well as to study their relationship with systemic lupus erythematosus disease activity (SLEDAI) in newly diagnosed, untreated lupus patients. METHODS: Sera from newly diagnosed untreated lupus and rheumatoid arthritis (RA) patients were examined for CRP and cytokines. Data were compared among patient groups and correlated individually among the lupus group. Lupus monocytes and neutrophils were cultured in vitro to produce IL-1ra and experimental results were related to CRP levels and SLEDAI. RESULTS: Within lupus, serum CRP, IL-6, IL-1 beta and TNF-alpha levels were significantly lower than those of RA (all p values were < 0.005) and generally higher than those in the controls (p = 0.002, < 0.001, > 0.2, and < 0.001, respectively). Except IL-1ra, which was correlated with CRP (p = 0.045), no substantial correlation was discovered between CRP and IL-6, IL-1 beta or TNF-alpha individually. Moreover, excluding IL-1ra (p = 0.024), there was no association between cytokines and SLEDAI. In vitro IL-1ra as secreted by monocytes correlated with serum CRP and SLEDAI. CONCLUSION: In lupus patients, serum IL-1 beta, IL-6 or TNF-alpha levels failed to correlate with low CRP levels. This indicates a complicated CRP production process, which can not be explained solely by single cytokines as reported previously. Both serum and in vitro produced IL-1ra may be applied clinically as a surrogate CRP marker in untreated lupus patients as they are both correlated with serum CRP.     

慢性肾衰竭患者高同型半胱氨酸血症、氧化应激和微炎症反应间的关系及其在动脉粥样硬化中的作用

目的　探讨同型半胱氨酸 (Hcy)血症和氧化应激、微炎症反应之间的关系 ,及其在慢性肾衰竭 (CRF)患者动脉粥样硬化 (AS)形成中的作用。方法　测 114例CRF患者 (CRF组 ,其中 6 2例行血液透析 ,非透析治疗 5 2例 )和 37例健康对照者 (健康对照组 )血浆总Hcy(tHcy)水平、循环丙二醛 (MDA)、谷胱苷肽过氧化物酶活性 (GSHPx)及血清C 反应蛋白 (CRP)、白细胞介素 (IL) 6、肿瘤坏死因子 (TNF)α水平 ,高分辨超声技术测颈动脉内膜 中层厚度 (IMT)及粥样硬化斑块。结果　非透析CRF患者血浆tHcy、MDA、CRP和TNFα水平高于健康对照组 ,且随肾功能损害程度的加重而升高 ,GSHPx则低于健康对照组 ;血液透析患者tHcy、MDA、CRP、IL 6和TNFα水平均高于非透析患者 ,GSHPx进一步降低。CRF患者IMT增厚阳性率、平均IMT及颈动脉粥样斑块检出率明显高于健康对照组。动脉病变越重 ,血浆tHcy、MDA及CRP水平越高 ,GSHPx越低。多因素逐步回归分析显示 ,tHcy、MDA、CRP、血糖和极低密度脂蛋白水平是影响颈总动脉IMT的危险因素 (R2 =0 5 72 ,P<0 0 0 1) ,影响CRF患者血浆MDA水平的因素有血浆GSHPx、tHcy、血肌酐 ,影响CRF患者血清CRP水平的因素有血清IL 6、TNFα、MDA、血浆白蛋白。结论　Hcy血症可能参与了CRF患者氧化应激的发生     

Serum interleukin-6 has no discriminatory role in paraproteinaemia nor a prognostic role in multiple myeloma.

We determined interleukin-6 (IL-6) levels in the serum of 212 well-defined patients with newly diagnosed paraproteinaemia and evaluated its discriminatory value and prognostic role in multiple myeloma (MM). Results were compared with serum neural cell adhesion molecule and beta-2-microglobulin, both established prognostic MM markers. Paraproteinaemia-related diagnoses were: MM (60), other haematological diseases (46), solid tumours (35), autoimmune diseases (17) and monoclonal gammopathy of unknown significance (MGUS) (54). The range of IL-6 levels in all diagnostic groups overlapped widely and did not serve as a discriminatory marker in newly diagnosed paraproteinaemia even when patients with infection or fever (42) were excluded. In MM high IL-6 levels (>/= 50 pg/ml) were not associated with a shorter survival (P = 0.24). We compared our results with 20 published studies on serum IL-6 in paraproteinaemia and/or MM. IL-6 data have to be related to the assay used (bio- or immunoassay) and to the status of MM (newly diagnosed, during therapy, progressive disease). We conclude that serum IL-6 is not specific for paraproteinaemia-related diseases and will not serve as a reliable discriminatory or prognostic marker in paraproteinaemia and MM.     

Serum oncostatin M in multiple myeloma: impact on disease severity and prognosis

Since high levels of serum IL-6 predict a poor prognosis of patients with multiple myeloma (MM), we investigated if a related cytokine, oncostatin M (OSM), correlates with clinical or biochemical findings or has prognostic significance in patients with MM. Among 82 newly diagnosed MM patients, OSM was detected in the sera in 45 (55%). Serum OSM had a borderline statistical correlation with serum IL-6 (r = 0.198, p = 0.074) and C-reactive protein (r = 0.199, p = 0.074) concentrations. However, OSM did not have prognostic significance alone or in combination with other factors. The median survival of patients with detectable serum OSM concentration was 41 months (range 2-124 months) and of OSM negative patients 35 months (1-75 months). Serum OSM concentration was not associated with clinical factors or severity of bone disease at diagnosis. We conclude that serum OSM concentration is not a prognostic factor in MM patients.     

High levels of interleukin-6 are associated with low tumor burden and low growth fraction in multiple myeloma

Interleukin-6 (IL-6) is a multifunctional cytokine postulated to play a central role as a growth factor for multiple myeloma (MM). We evaluated the spontaneous secretion of IL-6 in supernatants of Ficoll-Hypaque-- enriched bone marrow (BM) cultures from 35 patients with MM. The levels of IL-6 were correlated with biological and clinical characteristics of the disease. High levels of IL-6 production defined a subgroup of patients with low tumor burden as determined by lower serum beta 2- microglobulin (B2M) (P = .02) and lower percentage of myeloma cells infiltrating the bone marrow (P = .003), higher synthetic rates of monoclonal protein (P = .006), and low proliferative compartments as measured by the percentage of Ki-67--positive myeloma cells. Patients with high proliferative fractions (Ki-67--positive myeloma cells > 20%) had significantly lower levels of IL-6 when compared with patients with low proliferative fractions (P = .005). Our findings do not support IL- 6 as a major growth factor for MM, but demonstrate an association of high levels of IL-6 secretion with low tumor cell burden and low proliferative fraction.     

Serum levels of cytokines in chronic liver diseases.

Serum levels of interleukin-1 (IL-1 beta), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-alpha), interferon gamma (IFN-gamma), and C-reactive protein (CRP) were investigated in patients with chronic liver diseases (CLD) and correlated with the type of underlying disease and various clinical and laboratory parameters. Two hundred sixty-four patients suffering from various CLD were studied; 136 cases presented with liver cirrhosis, and 128 patients were in the noncirrhotic stage of their underlying liver diseases. Serum levels of IL-1 beta, IL-6, TNF-alpha, IFN-gamma, and CRP were elevated in patients with CLD. Endogenous cytokine patterns in CLD were stage dependent and only marginally affected by the type of underlying disease. The cirrhotic group of CLD patients showed higher serum levels in IL-1 beta, IL-6, TNF-alpha, and CRP than did noncirrhotic cases, and these differences reached the level of statistical significance. IL-1 beta and TNF-alpha values were closely correlated but did not correlate with IL-6 levels. Elevated concentrations of cytokines represent a characteristic feature of CLD regardless of underlying disease. This and the apparent stage-dependency suggest that enhanced endogenous cytokine levels represent a consequence of liver dysfunction rather than of inflammatory disease.     

Different monocyte reaction patterns in newly diagnosed,untreated rheumatoid arthritis and lupus patients probably confer disparate C-reactive protein levels

OBJECTIVES: To investigate the different capacities of monocytes to produce cytokines in newly diagnosed, untreated patients with rheumatoid arthritis (RA) or systemic lupus and to examine the possible correlation among serum C-reactive protein (CRP), cytokines, swollen joint counts, and erythrocyte sedimentation rates (ESR) in untreated RA patients. METHODS: Monocytes from untreated RA or lupus patients were cultured in vitro with lipopolysaccharide (LPS, as bacterial infection) or immune complexes (as endogenous immune deviation) and supernatants were collected for cytokine determination. Sera from RA patients were assayed for interleukin-6 (IL-6), IL-1 beta, IL-10, tumor necrosis factor-alpha (TNF-alpha) and IL-1 receptor antagonist (IL-1ra). These cytokines were related to serum CRP, swollen joint counts, and ESR. RESULTS: RA monocytes uniformly produced IL-6, IL-1 beta, TNF-alpha, or IL-10 in vitro. In contrast, lupus monocytes could be divided into two subsets: (i) monocytes which produce cytokines on LPS stimulation but not on challenging with immune complexes; and (ii) monocytes which, interestingly, generate cytokines on stimulation by immune complexes but not LPS. These cytokines in turn stimulate the liver to synthesize CRP differently in the SLE subsets and RA patients. Moreover, serum IL-1ra levels correlated significantly with serum IL-6, IL-1 beta, and TNF-alpha concentrations (p = 0.005, 0.008, or 0.040, respectively), but not with IL-10 (p = 0.582) in RA patients. CONCLUSIONS: Two lupus subsets exist that react either to LPS or immune complexes to produce CRP-inducing cytokines, in contrast to homogeneous RA monocytes. This is the first report that different reaction patterns of CRP-inducing cytokine production in RA and lupus monocytes probably underlie the high CRP levels in RA versus low heterogeneity in lupus. The correlation of serum IL-1ra levels with serum IL-6, IL-1 beta, or TNF-alpha concentrations, and the borderline correlation of the former with CRP levels, demonstrate that IL-1ra is an acute phase reactant in RA as well as in SLE patients.     

Serum levels of interleukin-6 in multiple myeloma and other hematological disorders: correlation with disease activity and other prognostic parameters

Summary Interleukin-6 (IL-6) is a multifunctional cytokine involved in the regulation of the terminal differentiation pathway of B lymphocytes. Recent reports revealed its potential role in the in vitro and in vivo growth of human multiple myeloma cells. The mechanism, however, by which IL-6 triggers proliferation of malignant plasma cells remains controversial. Using the very sensitive 7TD1 bioassay we quantified endogenous circulating IL-6 levels in serum samples of 104 patients suffering from monoclonal gammopathies and other hematological disorders [47 with multiple myeloma (MM), 24 with monoclonal gammopathy of unknown significance (MGUS), 8 with myeloproliferative disease, and 25 suffering from lowgrade non-Hodgkin's lymphoma (NHL)]. Elevated serum levels of IL-6 (>5 pg/ml) were detected in 42% of the patients with MM, in 13% with MGUS, in 15% with low-grade B-NHL, and in 1 patient with T-NHL. In patients suffering from chronic myeloproliferative diseases, IL-6 levels were within the normal range. In patients with myeloma, IL-6 levels were significantly higher at advanced stages (II/III) or with progressive disease than in patients with MM stage I, MGUS, or at the plateau phase (P<0.01). In patients with monoclonal gammopathies including MGUS, serum IL-6 levels correlated with neopterin, tumor necrosis factor alpha and ₂-microglobulin. An inverse correlation was found with hemoglobin levels. From these results, we propose that in myeloma patients serum IL-6 levels may reflect disease activity and tumor cell mass. The correlation with serum neopterin, a macrophage product, also suggests its origin in an activated immune system.     

Cytokine and acute-phase reactant levels in serum of children with cancer admitted for fever and neutropenia.

Serum concentrations of tumor necrosis factor-alpha (TNF alpha), interleukin (IL)-1 beta, IL-6, and the acute-phase reactants C-reactive protein (CRP) and serum amyloid A (SAA) were measured on admission in 46 neutropenic children with cancer in 81 episodes of fever. The aim was to find out whether any of these variables would differentiate true bacteremia from fever due to other causes. In most episodes serum concentrations of TNF alpha and IL-1 beta were elevated. IL-6 was detectable in 68%, but the serum concentration was elevated in only 15%. SAA proved to be more sensitive than CRP for the early detection of bacteremia. However, not even SAA was sufficiently accurate at the individual level. We conclude that the cytokine and acute-phase protein levels found were related to the febrile response but did not correlate with documented bacterial etiology.     

Malignancy: Identification of Predictors of Disease Status and Progression in Patients with Myeloma (MM)

Multiple studies have attempted to recognize the best markers of disease activity and outcome in myeloma (MM). Our objective was to identify the best variables that can reflect MM disease status. Design and methods: The data obtained from all the following tests were included in the analysis: serum levels of the 2 growth factors known to be crucial for MM growth (i.e. IL-6, and sIL-6R), routine peripheral blood data (Hb%, serum calcium, albumin, CRP, B2m, LDH) and bone marrow plasma cell (BMPC)%, as well as the age and sex of patients. The study was conducted on 21 cases of MM under chemotherapy (aged 48-74 years; M/F = 13/8) and 12 matched normal individuals. The patients were categorized into 2 groups according to their clinical status: Group#1 (n = 16; cases in plateau/stable phase), and Group#2 (n = 5; advanced/refractory cases). Results: Student t-test confirms that serum IL-6 and sIL-6R are the most statistically different variables upon comparing cases in plateau phase (Group#1) with those of advanced disease (Group#2). Stepwise discriminant analysis of data has resulted in a function that is composed of the 2 most salient variables (i.e. serum IL-6, sIL-6R). The proposed function was highly significant (p = 0.0000) with Wilk's Lambda = 0.02538. The diagnostic capability of the proposed function was very high (percent of grouped cases that were classified correctly= 100%). Conclusion: measurement of serum IL-6 and sIL-6R gives the best prediction of disease activity in patients with MM.     

Soluble interleukin-6 receptor as a prognostic factor in multiple myeloma

Interleukin-6 (IL-6) is a major growth factor for the clonal malignant plasma cells in multiple myeloma (MM). The effect of IL-6 may be enhanced by soluble IL-6 receptor (sIL-6R). As there is a clinical need for improved stratification of MM patients at diagnosis, we have studied the role of sIL-6R as a prognostic marker in 207 newly diagnosed MM patients. Serum sIL-6R concentration was above the upper reference limit in 47% of the patients at diagnosis. The concentrations of sIL-6R and two other prognostic factors, IL-6 and β-2 microglobulin (β2M), were all significantly higher in the patients who died within 3 years compared with those who survived. However, serum sIL-6R did not show linear correlation with IL-6 or β2M levels. In univariate logistic regression analysis sIL-6R was a significant predictor of 3-year mortality. Kaplan-Meier analysis showed that raised levels of sIL-6R were associated with shorter survival. When the patients were stratified into four groups according to their serum IL-6 and sIL-6R levels, the patients with normal serum levels of both parameters had clear survival benefit. As β2M was the most powerful prognostic factor in the multivariate analysis, the patients were also stratified according to their serum β2M and sIL-6R levels. The patients with raised levels of both β2M and sIL-6R had shorter survival than the patients in the other three groups. Thus, measurement of these parameters at diagnosis would help to stratify MM patients.