Tumor necrosis factor-alpha blockade for the treatment of acute GVHD

Despite posttransplantation immunosuppressive therapy, acute graft-versus-host disease (GVHD) remains a major cause of sickness and death. Tumor necrosis factor-alpha (TNF-alpha) is implicated in the pathophysiology of GVHD at several steps in the process. Infliximab is a genetically constructed immunoglobulin G1 (IgG1) murine-human chimeric monoclonal antibody that binds the soluble subunit and the membrane-bound precursor of TNF-alpha, blocking its interaction with receptors and causing lysis of cells that produce TNF-alpha. In this study we retrospectively evaluated 134 patients who had steroid-refractory acute GVHD. Of these, 21 who received infliximab as a single agent were analyzed. The overall response rate was 67% (n = 14), and 13 patients (62%) experienced complete response (CR). Five patients (24%) did not respond, and 2 (10%) had progressive GVHD. None had a toxic reaction to infliximab. Ten patients (48%) had 18 fungal infections, including Aspergillus species in 7 and Candida species in 10. Seventeen patients (81%) had bacterial infections, including 32 gram-positive and 8 gram-negative infections. Viral infections, primarily cytomegalovirus reactivation, occurred in 14 patients (67%). The Kaplan-Meier estimate of overall survival was 38%. In conclusion, infliximab was well tolerated and active for the treatment of steroid-resistant acute GVHD, particularly with gastrointestinal tract involvement. Survival after steroid-resistant acute GVHD continues to be problematic. The possibility of excessive fungal and other infections must be explored further.     

Tumor necrosis factor-alpha blockade in the treatment of rheumatoid arthritis

The use of TNF alpha antagonists in RA has been extremely instructive. They have taught us that selective targeting of a pathogenic element can provide substantial clinical benefit. They have reinforced the concept of TNF alpha as a pivotal cytokine in the pathogenesis of RA. Pharmacodynamic studies of TNF alpha antagonists have further clarified the pathogenic processes involved in the disease. TNF alpha antagonists have set a new therapeutic standard for RA. Indeed, they are one of the most important advances in the history of the treatment of the disorder. If clinical efficacy is sustained and the safety profile remains benign over the long term, TNF alpha antagonists may replace MTX as the gold standard and become the agent of choice for combination therapy in RA. Further studies are needed to clarify their ultimate position in the therapeutic algorithm.     

肿瘤坏死因子拮抗剂治疗风湿性疾病安全性的短期临床观察

目的 描述肿瘤坏死因子(TNF)-α拮抗剂治疗风湿性疾病发生的不良反应,评价临床应用的安全性和耐受性.方法 对2007年1月至2008年10月使用TNF-α拮抗剂的患者从临床症状、体征及实验室检查方面记录使用过程中发生的不良反应及程度和最终结局.结果 78例患者中35%(27/78)为类风湿关节炎(RA),41%(32/78)为强直性脊柱炎(AS),17%(13/78)为银屑病关节炎(PsA),6%(5/78)为未分化脊柱关节病(uSpA).59例患者使用依那西普,7例(12%)发生注射局部反应、上呼吸道感染及结核病等不良反应.19例患者使用英夫利西单抗,3例(16%)发生不良反应,1例(AS)为上呼吸道感染,1例(AS)前两次均在输注完24 h内出现伞身红色丘疹及心悸,1例(RA)输注4次后出现不明原因发热.部分不良反应可自行消失,其余经适当处理后痊愈.结论 证实依那西普和英夫利西单抗治疗风湿性疾病具有较好的安全性和耐受性,发生的不良反应是温和的,经适当处理可痊愈.     

Infections associated with tumor necrosis factor-alpha antagonists

Tumor necrosis factor (TNF)-alpha antagonists are promising therapeutic agents for patients with severe autoimmune and rheumatologic conditions. Unfortunately, their use has been associated with an increased rate of tuberculosis, endemic mycoses, and intracellular bacterial infections. Infliximab, 1 of 3 available drugs in this novel class, appears to be associated with the greatest risk of infection, likely because of its long half-life and induction of monocyte apoptosis. Prospective trials are necessary to determine the exact risk associated with these agents, particularly the newer TNF-alpha antagonists. More specific TNF-alpha blockers, which reduce inflammation while maintaining adequate immunity, are needed. In the meantime, a thorough work-up is mandatory for all febrile illness occurring in TNF-alpha blocker recipients. We present 4 patients who developed severe infections during TNF-alpha antagonist therapy, review the literature, and discuss current guidelines for surveillance and prophylaxis.     

Tumor necrosis factor-alpha inhibitor associated ulcerative colitis

BACKGROUND: Flares or onset of inflammatory bowel disease in association with immunosuppression has been reported in the literature. METHODS: We studied 4 cases of patients with rheumatic disease who developed or had a flare of ulcerative colitis either after initiation of or while taking a tumor necrosis factor-alpha inhibitor. RESULTS: We identified 4 patients, three male and one female. Two of the male patients had a seronegative spondyloarthropathy and one had rheumatoid arthritis. The female patient had amyopathic dermatomyositis. Two of the 4 patients had ulcerative colitis prior to tumor necrosis factor-alpha treatment. Both of these patients had quiescent ulcerative colitis that flared after they began taking etanercept. Two patients developed de novo ulcerative colitis while taking a tumor necrosis factor-alpha inhibitor. CONCLUSIONS: The data presented in these 4 cases supports a temporal relationship between initiating a tumor necrosis factor-alpha inhibitor and onset or flare of ulcerative colitis. These observations raise the possibility that tumor necrosis factor-alpha inhibitor therapy, which has been used as treatment for inflammatory bowel disease, may rarely be a factor in the development of disease.     

肿瘤坏死因子-α与糖尿病肾病

肿瘤坏死因子（TNF）-α是重要的炎症因子,近来越来越多的证据显示其在糖尿病肾病（DKD）的发生发展中起重要作用。实验与临床研究均已经证实,TNF-α在DKD中通过多种机制产生。肾脏损伤,而且其活性调节的潜在益处已作为目前临床治疗的一个策略。     

Tumor necrosis factor-alpha in patients with malaria

Serum concentration of Tumor Necrosis Factor-alpha (TNF-alpha) was observed in 54 parasitologically confirmed cases of malaria. Of them, 15 cases were Plasmodium falciparum with cerebral involvement, three cases with mixed infections of P. falciparum and P. vivax, 32 cases of P. vivax, three cases of P. malariae and one case of P. ovale. Five out of 15 patients of P. falciparum (33.3 per cent), one out of 54 patients with mixed infection of P. falciparum and P. malariae (1.8 per cent) and the sole case of P. ovale (1.8 per cent) had fatal outcome. The serum TNF-alpha measured by avidin-biotin sandwich ELISA, was found to be significantly raised in P. falciparum and more so in fatal infections. The degree of parasitaemia, due to single or double infection, had positive effect on cytokine production. The mean TNF-alpha concentration was statistically significantly higher (p < 0.001) in P. falciparum than in P. vivax parasites infection. The mean TNF-alpha values in P. falciparum and P. vivax were 915 and 280.6 against the values in normal healthy controls of 12.9 pcg/ml respectively (p < 0.001). The study thus showed that the serum concentration of TNF-alpha correlated well with severity of malaria and these values could be used as an important prognostic marker of the disease.     

Tumor necrosis factor-alpha and anorexia--cause or effect?

Tumor necrosis factor-alpha (TNF-alpha) is a principal cytokine that may induce weight loss in malignancies and certain chronic infections. Short-term caloric deprivation has been found to facilitate in vitro TNF-alpha production, while increased spontaneous production of TNF-alpha has been found in patients with anorexia nervosa (AN). In the present work, we studied in vitro TNF-alpha production in other types of chronic undernutrition and the changes in TNF-alpha production during the refeeding of patients with AN. Undernutrition was evaluated by calculating fat body mass (FBM) from skinfold measurements and lean body mass (LBM) by total body potassium (TBK) counting. Spontaneous and induced TNF-alpha production by peripheral blood mononuclear cells (PBMC) was studied in six chronically malnourished patients with no intercurrent infections, seven patients with AN, and 16 age-matched normal healthy subjects. Spontaneous TNF-alpha production was in the normal range in the chronically undernourished subjects (4.3 +/- 1.5 v 5.0 +/- 1.9 U/mL), but significantly increased in the seven patients with AN (221 +/- 327 v 5.0 +/- 1.9 U/mL, P less than .0006). During refeeding of patients with AN, TNF-alpha production decreased to the normal range concomitantly with weight gain. We concluded that chronic undernutrition, in general, is not always associated with increased TNF-alpha production and that it still remains to be determined whether TNF-alpha plays a primary role in the pathogenesis of AN.