慢性病毒性肝炎患者干扰素α治疗不良反应临床

干扰素（IFN）α广泛应用于慢性乙型肝炎（CHB）和慢性丙型肝炎（CHC）的抗病毒治疗,但存在较多不良反应,常见的不良反应有流感样症状、外周血细胞和血小板计数下降、内分泌和代谢性疾病、消化道症状和神经精神异常等［1－5］,发生率见表1。少数患者可引起严重不良反应,如间质性肺炎、自身免疫性溶血或严重精神疾病等。正确处理IFNα治疗中的不良反应可提高患者依从性,从而有效提高IFNα疗效。发生严重不良反应者常须停止治疗,以保证患者的安全。为进一步规范并优化慢性病毒性肝炎患者IFNα不良反应的管理和治疗,《中华实验和临床感染病杂志（电子版）》、《中国肝脏病杂志（电子版）》及《Infection International （Electronic Edition）》编辑部组织国内部分专家对相关资料进行整理与分析,形成《慢性病毒性肝炎患者干扰素α不良反应临床处理专家共识》（以下简称共识）。本《共识》是基于目前该领域的最新成果,遵照循证医学原则编写,可作为慢性病毒性肝炎患者IFNα不良反应临床处理的指导。随着相关临床证据的不断积累,专家委员会将对《共识》内容进行持续更新。相应证据及推荐等级见表2。     

血清BAFF预测聚乙二醇干扰素-α治疗非活动性HBsAg携带者临床治愈的效能分析*

目的 探讨血清B细胞活化因子(BAFF)预测聚乙二醇干扰素-α(Peg-IFN-α)治疗非活动性HBsAg携带者(IHCs)临床治愈的效能。方法 2018年1月～2020年8月我院诊治的IHCs 54例,给予Peg-IFN-α治疗48 w,再随访24 w。采用ELISA法检测血清BAFF,应用Logistic回归分析影响临床治愈的因素,应用受试者工作特征曲线(ROC)及其曲线下面积(AUC)评价血清BAFF预测临床治愈的效能。结果 在72 w末,24例(44.4%)患者获得临床治愈,30例未获得临床治愈;治愈组与未治愈组基线血清BAFF水平分别为(670.9±105.9)pg/mL和(612.7±183.8)pg/mL,差异无统计学意义(P>0.05);在治疗12 w和24 w时,治愈组血清BAFF水平分别为(805.8±197.6)pg/mL和(895.3±227.4)pg/mL,显著高于未治愈组【分别为(675.3±190.8)pg/mL和(724.4±218.0)pg/mL,P 均<0.05】;多因素Logistic回归分析显示基线HBsAg定量、HBV DNA<20 IU/mL、治疗12 w和24 w时血清BAFF水平是影响临床治愈的独立因素;ROC分析显示,以Peg-IFN-α治疗12 w时血清BAFF水平大于704.3 pg/mL为截断点,其预测治疗应答的AUC=0.722, 敏感度为79.2%,特异度为66.7%,以24 w时血清BAFF水平大于741.9 pg/mL为截断点,其预测治疗应答的AUC=0.725,敏感度为75.0%,特异度为70.0%。结论 应用Peg-IFN-α治疗IHCs可获得约40%的应答率,在治疗过程中监测血清BAFF水平逐渐升高的患者可能获得满意的治疗结果。     

Hyperpigmentation during interferon-alpha therapy for chronic hepatitis C virus infection

Many types of skin disorders concomitantly occur with hepatitis C virus infection. These skin lesions may be induced or worsened during antiviral therapy with interferon-alpha (IFN). To our knowledge, hyperpigmentation of the skin--and especially of the tongue--has not been reported so far. We describe two dark-skinned patients who developed hyperpigmented skin and tongue lesions during combination therapy with IFN and ribavirin. Immunohistochemical analysis of tongue biopsies confirmed the suspicion of melanin deposits in these areas of hyperpigmentation. We hypothesize that during interferon therapy, melanocytes may produce more melanin pigment in the presence of alpha-melanocyte stimulating hormone and sufficient amounts of tyrosine, leading to melanin deposits and clinical hyperpigmentation.     

The natural interferon-alpha producing cells in systemic lupus erythematosus

Prolonged exposure of the immune system to type I interferons (IFN-alpha/beta/omega) in patients receiving IFN-alpha therapy frequently results in development of autoantibodies and autoimmune disease. This is attributed to the many immunostimulatory effects of these cytokines. Patients with the autoimmune disease systemic lupus erythematosus (SLE) have an ongoing IFN-alpha production. Recent studies of SLE demonstrated the presence of endogenous IFN-alpha inducers, acting specifically on natural IFN-alpha producing cells (NIPC), often termed plasmacytoid dendritic cells (PDC). These IFN-alpha inducers were potent, present at the blood level, and characterized as immune complexes that contained DNA and IgG as essential components. They were considered a likely reason for the activated IFN-alpha production in SLE, which, in turn, might be an important etiopathogenic factor. Here, we briefly review the biology of the type I IFN system, with emphasis on inducers, producing cells (especially NIPC/PDC), IFN-alpha actions, and target immune cells, which might be relevant in SLE. Based on such information and results from studies in SLE patients, we propose a hypothesis that explains how NIPC/PDC become activated and play a pivotal etiopathogenic role in SLE and perhaps also other autoimmune diseases. This hypothesis furthermore indicates new therapeutic targets.     

α-干扰素和COX-2抑制剂对人肝癌细胞SMMC-7721细胞增殖的抑制作用研究

目的研究α-干扰素和环氧合酶(COX-2)抑制剂塞来昔布(Celecoxib)对人肝癌SMMC-7721细胞的生长抑制作用。方法采用MTT比色法观察不同浓度的塞来昔布和α-干扰素处理对肝癌细胞增殖的影响;通过荧光显微镜检测细胞凋亡。结果实验组与对照组相比,能抑制人肝癌SMMC-7721细胞的增殖,两种药物高浓度联合作用48 h后,对肝癌细胞的生长抑制率可达92.44%±0.98%。α-干扰素和塞来昔布对肝癌细胞的增殖抑制具有协同作用。荧光显微镜观察到细胞皱缩、核质浓缩、核碎裂以及凋亡小体形成等凋亡形态学改变。结论 COX-2抑制剂塞来昔布和α-干扰素对人肝细胞癌SMMC-7721细胞的增殖有协同抑制作用,同时能诱导其凋亡,并且呈剂量和时间依赖性,这提示α-干扰素和COX-2抑制剂塞来昔布对HCC的预防和治疗可能有积极意义。     

Recognizable inherited syndrome of progressive central nervous system degeneration and generalized intracranial calcification with overlapping phenotype of the syndrome of Aicardi and Goutières

Five boys and two girls from a large consanguineous British Muslim family of Pakistani origin are described. All presented from infancy to early childhood with progressive moderate to severe developmental delay, postnatal microcephaly, spastic quadriplegia, refractory seizures, and visual handicap. Cerebrospinal fluid (CSF) pleocytosis was present in three children. Neuroimaging with computerized tomography on three boys and a girl showed generalized cortical atrophy, dilatation of the lateral, third, and fourth ventricles, widening of the surface CSF spaces, hypoplasia of the posterior fossa structures, and multiple and solitary calcifications in the cerebral cortex and punctate calcifications involving basal ganglia, cerebellum, and the Sylvian fissure. Histopathological examination of the brain from three boys and one girl confirmed generalized cortical and cerebellar atrophy with widespread calcifications within the cortical grey and white matter, the basal ganglia, the cerebellum, and in some areas along the capillaries. Investigations excluded a possible nongenetic cause. Parental consanguinity favor autosomal recessive inheritance. This appears to be a recognizable syndrome overlapping the syndrome of Aicardi and Goutières (MIM 225750). Am. J. Med. Genet. 75:508–515, 1998. © 1998 Wiley-Liss, Inc.     

Clinical and cytogenetic remission induced by interferon-α in a patient with chronic eosinophilic leukemia associated with a unique t(3;9;5) translocation

A patient with chronic eosinophilic leukemia and a unique complex chromosomal translocation 46,XY,t(3;9;5)(q25;q34;q33) who had elevated blood interleukin-5 is reported. Complete cytogenetic remission was induced by interferon-α after treatment failure with corticosteroids and cytotoxic drugs. Severe cardiopulmonary symptoms due to hypereosinophilia and thromboembolic complication improved dramatically in the first 6 months of interferon therapy. Since it is known that the gene encoding for interleukin-5 resides on the long arm of chromosome 5, it may be possible that the chromosomal translocation in our patient resulted in overproduction of this cytokine, and our findings may be helpful for understanding the pathogenesis of this disorder. Am. J. Hematol. 58:137–141, 1998. © 1998 Wiley-Liss, Inc.     

IFN-α治疗慢性乙型肝炎的效果及其影响因素

目的分析干扰素-α（IFN-α）治疗慢性乙型肝炎（CHB）效果的影响因素。方法选择2006—2009年青岛市传染病医院住院的CHB病人46例,应用IFN-α治疗48周,根据IFN-α疗效将其分为应答组与无应答组,评价病人的宿主、病毒载量及生化指标等因素对疗效的影响。结果两组的性别比例、年龄和病程比较差异无显著性（P〉0.05）;应答组治疗前HBV-DNA载量显著低于无应答组,ALT水平显著高于无应答组（t=2.381、2.800,P〈0.05）;HBeAg阳性病人的应答率显著高于HBeAg阴性病人（χ2=4.193,P〈0.05）;应答组在治疗12周时HBV-DNA载量下降〉2 log的比例显著高于无应答组（χ2=4.278,P〈0.05）。结论治疗前HBV-DNA载量低、ALT水平高和HBeAg阳性以及治疗12周时HBV-DNA应答情况可以作为IFN-α治疗CHB病人48周时应答的预测因素。     

干扰素α对BEL-7402细胞生长与端粒酶活性影响的观察

目的:探讨干扰素α(IFN-α)对肝癌BEL-7402细胞的生长抑制作用及其对肝癌细胞端粒酶hTERT-mRNA表达水平和端粒酶活性的影响。方法:以不同浓度的IFN-α作用于体外培养的肝癌BEL-7402细胞,MTT法检测细胞生长抑制率,应用流式细胞仪及ho-echst33258荧光染色法观察细胞凋亡;并对细胞凋亡前后的端粒酶hTERT-mRNA表达水平及端粒酶活性进行检测。结果:IFN-α可显著抑制肝癌BEL-7402细胞的生长及诱导细胞发生凋亡,呈现出明显的量-效与时-效关系。在细胞凋亡过程中端粒酶hTERT-mRNA的表达水平及端粒酶活性均显著下降。结论:IFN-α能抑制BEL-7402细胞的生长并诱导细胞发生凋亡,降低端粒酶hTERT-mRNA的表达水平及端粒酶活性可能是其重要作用机制。