Two cases of inflammatory bowel disease with multiple myeloma

A significant increase has been reported in reticuloendothelial neoplasms in patients with inflammatory bowel diseases. We present two rare cases of multiple myeloma in patients with inflammatory bowel diseases. One was in a 58-year-old woman with ulcerative colitis, and the other was in a 59-year old woman with Crohn's disease. In both patients, multiple myeloma occurred during long-term observation of inflammatory bowel disease and during the inactive stage of intestinal inflammation. The multiple myeloma appeared to have resulted from monoclonal gammopathy of undertermined significance in both patients, and was diagnosed by characteristic serum and bone marrow findings. Our findings suggested that multiple myeloma should be particularly considered in women of middle or advanced age with ulcerative colitis or Crohn's colitis and serum monoclonal gammopathy. Received: October 29, 1998 / Accepted: April 4, 1999     

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.     

单克隆丙种球蛋白血症639例临床观察分析

目的了解M蛋白的分型及临床意义,提高认识和诊断水平。方法通过对1998年1月至2005年12月上海交通大学医学院附属新华医院血液科诊治及少量外院送检标本M蛋白阳性者共639例结合临床对年龄、性别和疾病分布,以及多发性骨髓瘤(MM)与意义未明或继发性单克隆丙种球蛋白(MGUS)的特点进行分析。结果639例M蛋白血症中IgG型409例(64.0%)、IgA型80例(12.5%)、IgM型79例(12.4%)、IgD型4例(0.6%)、轻链型27例(4.2%,其中κ9例、λ18例)、双克隆型27例(4.2%)、单克隆型13例(2.0%)。该组患者病种分布,MM115例(18.0%)、华氏巨球蛋白血症(WM)13例(2.0%)、肾原发性淀粉样变性(AL)1例、非霍奇金淋巴瘤(NHL)19例(3.0%)、慢性淋巴细胞白血病(CLL)5例(0.8%)、MGUS473例(74.0%)、寡克隆13例(2.0%)。结论M蛋白血症是一种亚临床现象,主要见于MM及淋巴细胞增殖性疾病,意义未明或继发者检出率有增加趋势。     

Monoclonal gammopathy of unknown significance in a bone marrow donor

We report on a patient suffering from multiple myeloma, for whom allogeneic bone marrow transplantation was planned. Donor workup revealed monoclonal gammopathy of unknown significance. We discuss this finding and stress the importance of performing complete donor examinations.     

Serum neural cell adhesion molecule in multiple myeloma and other plasma cell disorders

Serum embryonic neural cell adhesion molecule (eNCAM) levels were measured at diagnosis in 92 patients with plasma cell disorders. Significantly elevated levels of serum eNCAM were detected in patients with multiple myeloma when compared to both normal controls and patients with monoclonal gammopathy of uncertain significance (MGUS). Very high levels of serum eNCAM were seen in patients with high tumour burdens. There was a significant correlation between serum eNCAM and β2-microglobulin (β2m) ( r  = 0.33; P  = 0.002), but not between serum eNCAM and C-reactive protein or serum albumen. There was a trend towards longer survival for patients with low serum NCAM. The median survival of the low serum eNCAM group (eNCAM < 20 U/ml) was 36 months compared to 16 months for the high serum eNCAM group (log rank test χ² = 2.42, P  = 0.1). Serum eNCAM is a new marker of tumour mass in multiple myeloma and correlates with clinical stage and β2m. Patients with low serum eNCAM levels may have a survival advantage. Serum eNCAM warrants further evaluation as a tumour marker and prognostic factor in multiple myeloma.     

Radioimmunoassay for the measurement of serum IL-6 and its correlation with tumour cell mass parameters in multiple myeloma.

Interleukin-6 (IL-6) was demonstrated to be a strong autocrine or paracrine plasmocytoma cell growth factor in humans. Using a bioassay, high serum IL-6 (S-IL-6) levels were correlated with disease severity in plasma cell dyscrasias. Since other cytokines could interfere with the bioassays, we developed a specific radioimmunoassay to study S-IL-6 levels in 102 patients with monoclonal gammopathy (MG). S-IL-6 level was studied by a double antibody radioimmunoassay using a rabbit polyclonal anti-IL-6 antibody and a human recombinant IL-6 as the standard. The lowest value of the standard significantly different from zero was found to be 78 pg/ml. Within-run and between-run precisions were characterized by a mean coefficient of variation of 3.72 and 5.5%, respectively. The mean analytical recovery was found to be 113% and the immunochemical identity of IL-6 standard and S-IL-6 was shown by dilution tests. IL-6 was detected in all tested sera. Sera from 66 healthy volunteers and 43 patients with acute leukemia or malignant lymphoma were tested as controls. In healthy subjects, S-IL-6 values were 294 +/- 86 pg/ml. MG were classified as multiple myeloma (MM), macroglobulinemia, and MG of undetermined significance (MGUS). The distribution of S-IL-6 levels in patients with MG was significantly higher than in healthy subjects but lower than in patients with acute leukemia or Hodgkin's lymphoma. Results obtained in 55 patients with MM were related to other biological parameters. S-IL-6 levels correlated with bone-marrow plasmacytosis (P less than .0005), serum-lactate dehydrogenase (S-LDH; P less than .005), serum beta 2 microglobulin (S -beta 2m; P less than .01), and serum calcium (S-Ca; P less than .025) and inversely correlated with haemoglobin (P less than .025). Our results indicate that 1) radioimmunoassay is suitable for the measurement of human IL-6 in serum; 2) high S-IL-6 levels are observed in a small number of patients with MG; and 3) S-IL-6 level correlates with tumour cell mass in patients with overt MM.     

Serum neural cell adhesion molecule in multiple myeloma and other plasma cell disorders

Serum embryonic neural cell adhesion molecule (eNCAM) levels were measured at diagnosis in 92 patients with plasma cell disorders. Significantly elevated levels of serum eNCAM were detected in patients with multiple myeloma when compared to both normal controls and patients with monoclonal gammopathy of uncertain significance (MGUS). Very high levels of serum eNCAM were seen in patients with high tumour burdens. There was a significant correlation between serum eNCAM and β2-microglobulin (β2m) (r = 0.33; P = 0.002), but not between serum eNCAM and C-reactive protein or serum albumen. There was a trend towards longer survival for patients with low serum NCAM. The median survival of the low serum eNCAM group (eNCAM < 20 U/ml) was 36 months compared to 16 months for the high serum eNCAM group (log rank test χ² = 2.42, P = 0.1). Serum eNCAM is a new marker of tumour mass in multiple myeloma and correlates with clinical stage and β2m. Patients with low serum eNCAM levels may have a survival advantage. Serum eNCAM warrants further evaluation as a tumour marker and prognostic factor in multiple myeloma.     

Expansion of CD8+ T cells that express low levels of the B cell-specific molecule CD20 in patients with multiple myeloma

An expanded cytotoxic/memory T-cell subpopulation expressing low levels of the B-cell-specific CD20 molecule was found in peripheral blood and bone marrow of patients with multiple myeloma at the time of diagnosis, but returned to normal levels following treatment. CD3+CD20dim cells were also increased in monoclonal gammopathy of unknown significance albeit at lower levels. Lower CD3+CD20dim cell numbers at baseline may be associated with lack of response to treatment and a poor outcome. Because expansion of these T cells may be related to disease status, further studies should investigate their potentially unique function in plasma cell dyscrasias.     

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.     

Correlation of interleukin-6 serum levels with bone density in postmenopausal women

Summary In order to identify possible correlations between interleukin-6 (IL-6) and hormonal and biochemical parameters of bone metabolism, or bone density, 24 postmenopausal women were studied. Serum IL-6, estradiol, calcium, phosphorus, osteocalcin, alkaline phosphatase, the urinary secretion of calcium, phosphoru and hydroxyproline, and bone density of the lumbar spine, femur and radius were measured. No significant correlation was found between IL-6 and the biochemical parameters. A negative correlation was found between IL-6 and serum estradiol, as well as between IL-6 and bone density in 5 out of 6 sites studied. It is possible that women with high IL-6 levels, may develop lower bone mass.     

多发性骨髓瘤患者血清白细胞介素-6含量与临床骨病关系的研究

目的:探讨血清白细胞介素(IL)-6水平与多发性骨髓瘤(MM)及其MM骨病的关系。方法:MM组37例,其中0分组10例,1分组6例,2分组8例,3分组11例,用ELISA方法检测血清IL-6的水平。结果:①MM组和实体瘤骨转移组血清IL-6水平明显高于正常对照组(P<0.05);②各骨损评分组间IL-6水平差异有统计学意义(P<0.05);③血钙正常组和异常组间的IL-6水平存在显著不同(P<0.05)。结论:MM患者血清IL-6水平升高,且IL-6的水平与MM骨损程度密切相关。     

Circulating levels of interleukin-6, its soluble receptor and interleukin-6/interleukin-6 receptor complexes in patients with type 2 diabetes mellitus

We evaluated the relationship between plasma fibrinogen concentration and the serum levels of interleukin-6 (IL-6), its soluble receptor, and their complex in patients with type 2 diabetes mellitus. The study comprised 57 patients with type 2 diabetes and 15 normal healthy controls. Serum levels of IL-6, soluble IL-6 receptor (IL-6R), and circulating IL-6/IL-6R complex were determined by enzyme-linked immunosorbent assays. Correlations between the different study parameters and serum IL-6, IL-6R, or IL-6/IL-6R complex levels were determined by multiple linear regression analysis. Any association between the different study parameters and the serum levels of IL-6, IL-6R, or IL-6/IL-6R complex were determined by stepwise linear regression analysis. The serum IL-6 level in diabetic subjects was significantly higher than in normal healthy controls (3.48 ± 3.29 pg/ml vs 0.784 ± 0.90 pg/ml, mean ± SD, respectively, P = 0.0001). The specific optical density of the serum IL-6/IL-6R complex in diabetic patients was also significantly higher than in normal healthy controls, although there was no significant difference in the serum IL-6R level between diabetic patients and controls. The serum IL-6 concentration was correlated significantly with the HbA_1C level (β = 0.58, P = 0.04) by multiple regression analysis. Stepwise regression analysis revealed that the levels of serum IL-6 (F = 8.251), HbA_1C (F = 1.08), and serum urea nitrogen (F = 5.603) were associated with the plasma fibrino gen concentration. These results suggest that hyperglycaemia and increased levels of serum IL-6 can increase the plasma fibrinogen concentration, one of the known risk factors for atherosclerosis in patients with type 2 diabetes mellitus. Received: 24 August 1998 / Accepted in revised form: 2 February 1999     

慢性心力衰竭合并肾损害患者血清白细胞介素1、白细胞介素6水平的变化及临床意义

目的探讨慢性心力衰竭合并肾损害患者血清白细胞介素1(IL-1)和白细胞介素6(IL-6)水平的变化及其临床意义。方法选取纽约心脏病学会(NYHA)心功能分级在Ⅱ~Ⅳ级的慢性心力衰竭患者220例,测定其血清尿素氮(BUN)、血肌酐(SCr)、N末端B型利钠肽原(NT-pro BNP)及IL-1、IL-6水平,计算肾小球滤过率(e GFR),随机尿检测尿微量白蛋白(MAU),心脏超声测定左室射血分数(LVEF),比较不同心功能患者的IL-1、IL-6、NT-pro BNP、e GFR和MAU,不同肾功能患者的IL-1、IL-6,分析IL-1、IL-6与NYHA心功能分级、NT-pro BNP、LVEF、e GFR及MAU的关系。结果与NYHAⅡ级心功能患者相比,NYHAⅢ~Ⅳ级心功能患者血清IL-1、IL-6、NT-pro BNP水平及MAU升高,e GFR降低(P0.05),NYHAⅣ级心功能患者IL-1、IL-6、NT-pro BNP水平及MAU高于NYHAⅢ级(P0.05)。NYHAⅢ~Ⅳ级心功能患者中,30%≤EF≤50%患者血清IL-1、IL-6、NT-pro BNP水平及MAU高于EF50%患者(P0.05),e GFR低于EF50%患者(P0.05),EF30%患者IL-1、IL-6、NT-pro BNP水平及MAU高于30%≤EF≤50%患者(P0.05)。NYHAⅢ~Ⅳ级心功能患者中,肾功能不全组[e GFR60 m L/(min·1.73 m2)]血清IL-1、IL-6水平高于肾功能正常组[e GFR≥60 m L/(min·1.73 m2)](P0.05)。不同基础疾病的心力衰竭患者之间IL-1、IL-6水平及e GFR比较,差异无统计学意义(P0.05)。血清IL-1、IL-6水平与NYHA心功能分级、NT-pro BNP及MAU呈正相关(P0.05),与e GFR、LVEF呈负相关(P0.05)。结论慢性心力衰竭患者血清炎症因子IL-1、IL-6水平升高,与心力衰竭的严重程度和肾功能受损相关,测定血清IL-1、IL-6水平可能有助于临床心衰病情的评估。     

Serum interleukin-6 levels in response to biologic treatment in patients with psoriasis

Objectives: Psoriasis is a chronic autoimmune disease involving a complex network of cytokines such as interleukin (IL)-6. We tested the hypothesis that serum IL-6 level is a useful indicator of disease activity and predicts the treatment response to biologics in patients with psoriasis.

Methods: We analyzed 113 psoriasis patients treated with biologics (73 with infliximab [IFX], 24 with adalimumab [ADA], and 16 with ustekinumab [UST]) in our hospital. Disease severity was assessed using the Psoriasis Area and Severity Index (PASI) score, and Disease Activity Score 28 based on C-reactive protein (DAS28-CRP).

Results: Before treatment, serum IL-6 levels significantly correlated with PASI scores in patients with psoriasis vulgaris (r?=?0.432, p?=?0.001) and with DAS28-CRP in patients with psoriatic arthritis (r?=?0.469, p?=?0.010). Serum IL-6 levels were significantly decreased by IFX (from 4.8 to 1.5) and ADA (from 2.5 to 1.4) therapy. In psoriatic arthritis, serum IL-6 levels at the endpoint tended to be lower in patients who achieved DAS28-CRP <2.3 (European League Against Rheumatism remission criteria) than in patients who did not.

Conclusion: Serum IL-6 level may be a useful biomarker for assessing disease activity in patients with psoriasis and for predicting responsiveness of joint symptoms to biologic treatment.     

Differences in the distribution of cytogenetic subtypes between multiple myeloma patients with and without a family history of monoclonal gammopathy and multiple myeloma

We previously reported an increased risk of monoclonal gammopathy of undetermined significance (MGUS) in first‐degree relatives of MGUS and multiple myeloma patients. Here, we examine whether primary cytogenetic categories of myeloma differ between patients with and without a family history of MGUS or myeloma. We studied 201 myeloma patients with available data on family history and molecular cytogenetic classification. Myeloma with trisomies was more common in probands who had an affected first‐degree relative with MGUS or myeloma compared with those without a family history (46.9% vs. 33.5%, P = 0.125); however, the difference was not statistically significant. Additional studies on the cytogenetic types of myeloma associated with familial tendency are needed.     

Interleukin-6 is expressed by plasma cells from patients with multiple myeloma and monoclonal gammopathy of undetermined significance

Interleukin-6 (IL-6) is an important growth factor for human myeloma cells in vitro and in vivo . However, the identity of the cells producing IL-6 in vivo in patients with multiple myeloma (MM) remains the subject of debate. We have developed a sensitive dual-colour fluorescence in situ hybridization (FISH) technique to investigate the expression of IL-6 mRNA by individual bone marrow plasma cells from patients with multiple myeloma, monoclonal gammopathy of undetermined significance (MGUS) and healthy subjects. IL-6 mRNA could be identified in all immunoglobulin light chain (IgLC) expressing cells from all patients with MM and MGUS. The IL-6 protein could also be detected by direct immunofluorescence in all plasma cells (cytoplasmic light chain positive) from all patients with MM and MGUS. Furthermore, it was also possible to demonstrate cytoplasmic IL-6 staining of plasma cells from patients with MM by flow cytometric analysis. In contrast, neither the IL-6 mRNA or protein could be detected in normal plasma cells from healthy bone marrow donors. These data demonstrate that plasma cells from patients with MM and MGUS express the IL-6 mRNA and synthesize the IL-6 protein and support the hypothesis that autocrine synthesis of IL-6 is of importance in patients with MM.     

多发性骨髓瘤血管内皮生长因子和白细胞介素-6相互作用的研究

目的　研究人类多发性骨髓瘤(MM)细胞系和MM患者骨髓基质细胞(BMSCs)之间相互作用对血管内皮生长因子(VEGF)和IL6分泌的调控作用,分析VEGF和IL6的相互作用在MM发病机制中的意义。方法　建立MMBMSCs和正常人BMSCs(NBMSCs)的培养体系,用IL6、抗IL6抗体、VEGF、抗VEGF抗体作用于BMSCs和(或)MM细胞系U266后,ELISA方法检测其VEGF和IL6的分泌量。结果　U266分泌VEGF,但不分泌IL6,而MMBMSCs和NBMSCs既分泌VEGF又分泌IL6。重组人VEGF刺激BMSCs后,以时间和剂量依赖性的方式诱导IL6的分泌,此效应可被抗VEGF抗体抑制。外源性IL6促进BMSCs分泌VEGF。当U266与BMSCs黏附后,VEGF分泌增加25~50倍,IL6增加55~90倍,两者差异有统计学意义(P<005);分别加入抗VEGF或抗IL6抗体,IL6或VEGF的分泌受抑。重组人IL6作用于U266,可诱导剂量依赖性的VEGF分泌的增加,此反应可被抗IL6抗体抑制。结论　在MM中,MM细胞和BMSCs之间的相互作用调节VEGF和IL6的分泌,促进MM细胞的生长和血管新生,在MM的发病机制中发挥重要作用,为针对骨髓微环境的靶位治疗提供了理论依据。     

先天性心脏病患者体外循环术后血IL-6及ICAM-1的变化

目的：探讨先天性心脏病（CHD）患体外循环（CPB）术后血浆白细胞介素6（IL－6）及细胞间粘附分子－1（ICAM－1）的变化及其在CPB术后全身炎性反应综合症（SIRS）中的作用。方法：以25例非紫绀型CHD患CPB下手术为研究对象（试验组），10例未作CPB的心血管手术作对照（对照组），酶免法测定手术前、后多时间点外周动脉血中IL－6及ICAM－1水平，同时测定血中性粒细胞数，记录体温。结果：（1）两组术后IL－6水平较术前均明显增高（P＜0．01），但术后各时点的IL－6水平，试验组的比对照组升高更明显（P＜0．01）；（2）术后两组ICMA－1与术前相比无显差异（P＞0．05）；（3）术后两组中性粒细胞水平和体温均升高（P＜0．05），但试验组升高更明显（P＜0．05）。结论：（1）除手术应激外，CBP本身可导致IL－6翻放增加；（2）作为炎性介质，IL－6可能参与CPB后SIRS的发生；（3）单一ICAM－1在CPB心脏手术后SIRS中可能不占重要地位。