小剂量糖皮质激素联合艾拉莫德治疗早期活动性类风湿关节炎的临床研究

目的 探讨小剂量糖皮质激素联合艾拉莫德治疗早期活动性类风湿关节炎（RA）的临床疗效及安全性。方法 将60例早期活动性RA患者随机分为观察组和对照组，每组各30例。两组患者均给予艾拉莫德25mg、每天2次口服，观察组患者在此基础上给予泼尼松5mg、每天2次口服，12周作为1个疗程，共治疗2个疗程。比较两组患者治疗12周及24周时美国风湿病学会(ACR)20、ACR50、ACR70缓解率，比较两组患者治疗前及治疗24周时RA疾病活动度评分DAS28及实验室检查指标。结果 与同组治疗12周时比较，观察组和对照组治疗24周时ACR20、ACR50、ACR70缓解率均呈上升趋势，但差异无统计学意义(P＞0.05)。观察组治疗12周、24周时ACR20缓解率均高于对照组同一时间，差异有统计学意义(P<0.05)。两组患者治疗前DAS28、红细胞沉降率(ESR)、C反应蛋白(CRP)、类风湿因子（RF）、基质金属蛋白酶(MMP)-1、MMP-3水平比较，差异均无统计学意义(P<0.05)。两组患者治疗后DAS28、ESR、CRP、RF、MMP-1、MMP-3水平均低于治疗前(P<0.05)。治疗后观察组DAS28、ESR、RF、MMP-1、MMP-3水平均低于对照组(P<0.05)。观察组和对照组患者不良反应发生率比较差异无统计学意义(30.0%比23.3%，P>0.05)。结论 小剂量糖皮质激素联合艾拉莫德可快速缓解早期活动性RA患者的关节症状，降低疾病活动度，抑制MMP-1和MMP-3的表达水平以防止骨破坏，安全性较好。     

氨基咪唑氨甲酰转移酶基因多态性在类风湿关节炎患者甲氨蝶呤治疗中的研究

目的 探讨类风湿关节炎(RA)患者氨基咪唑氨甲酰转移酶(ATIC)基因347C/G(rs2372536)单核苷酸多态性(SNP)与甲氨蝶呤(MTX)疗效和不良反应的相关性.方法 收集RA患者359例,分为单用MTX组、MTX联用其他改善病情药(DMARDs)组、非MTX的DMARDs组,于治疗前和治疗后12、24周检查患者临床及实验室指标,评价疗效(采用ACR20)及不良反应.采用实时荧光定量聚合酶链反应(PCR)法检测RA患者及340名健康对照组的ATIC基因C347G多态性,比较2组间基因型分布及等位基因频率.结果 RA与健康对照组ATIC基因347C/G基因型分布频率差异无统计学意义(P>0.05).单用MTX治疗组的有效率为72%(77/107例),有效组ATIC 347CC,CG,GG基因型与无效组间差异无统计学意义(P>0.05),不良反应发生率为32.7%,且携带ATIC G等位基因型患者的不良反应发生率(22.4%)明显高于CC基因型组(10.3%)(OR=2.67,95%可信区间为1.27～5.59),差异有统计学意义(P<0.05).MTX联用其他DMARDs(128例)组及非MTX的DMARDs组(90例),ATIC基因多态性与其疗效及不良反应无关(P>0.05).结论 ATIC基因347C/G多态性在RA患者与健康对照组间差异无统计学意义;与MTX治疗RA的疗效无明显相关性,但ATIC G等位基因与MTX的不良反应密切相关.因此ATIC基因347C/G多态性可能作为患者使用MTX的出现不良反应的预测指标.     

依那西普治疗中国接受甲氨蝶呤治疗的活动性类风湿关节炎患者随机双盲多中心对照研究

目的 研究依那西普每周1次皮下注射50 mg对接受甲氨蝶呤(MTX)治疗的中国活动性类风湿关节炎(RA)患者的疗效及安全性.方法 本研究由2部分组成:12周双盲治疗阶段和12周安全性开放研究阶段.双盲期间的随机通过临床操作随机化(CORE)系统完成.在双盲阶段,RA患者被随机分配到依那西普50mg治疗组或安慰剂组,每周1次皮下注射给药,同时坚持一定剂量MTX给药.完成双盲治疗的RA患者在开放治疗中均接受每周1次依那西普50 mg和MTX给药.以美国风湿病学会(ACR)疗效评价指标ACR 20为主要终点疗效指标.次要终点疗效指标包括医生和患者总体评价、晨僵持续时间、疼痛目视模拟测试表(VAS)、健康评估问卷(HAQ)、C反应蛋白(CRP)值、疼痛和肿胀关节数.并且比较2组的安全性结果.采用Fisher精确概率法对主要终点疗效指标第12周ACR 20应答情况及其他次要终点疗效指标进行分析.使用协方差方法分析连续终点相对于基线的变化.结果 双盲治疗期间修正的意向性治疗人群(Mitt)共有156例患者,其中依那西普+MTX组77例.安慰剂+MTX组79例,149例患者完成双盲阶段的治疗.治疗4周时,依那西普+MTX组ACR 20有效率为39%(30/77),安慰剂+MTX组为16%(13/79),差异有统计学意义(P<0.01);12周时,依那西普+MTX组ACR 20有效率为62%(48/77),安慰剂+MTX组为23%(18/79),差异有统计学意义(P<0.01).其他疗效指标包括医生和患者总体评价、晨僵持续时间、疼痛VAS、HAQ、CRP、触痛关节数、肿胀关节数等均从第4周开始,在依那西普+MTX组明显优于安慰剂+MTX组(P<0.01).总的不良反应发生率在2组间差异无统计学意义.结论 与安慰剂治疗活动性RA相比.依那西普治疗活动性RA起效迅速、疗效显著.依那西普50 mg+MTX每周1次给药治疗中国成年活动性RA患者24周,耐受性良好.     

人重组白细胞介素-1受体拮抗剂在类风湿关节炎治疗中的继发性失效

目的 观察人重组白细胞介素-1受体拮抗剂(IL-1Ra)联合甲氨蝶呤治疗活动期类风湿关节炎(RA)患者的疗效.方法 54例经甲氨蝶呤治疗至少12周以上的活动期RA患者,随机接受每日皮下注射IL-1Ra 80 mg或安慰剂,每4周进行随访,按照美国风湿病学会制订的疗效标准评估临床疗效,共24周.应用x2检验比较2治疗组间疗效达到ACR20、ACR50和ACR70的患者比例的差异.应用t检验(参数分析)或者秩和检验(非参数分析)比较2治疗组间基线值变量和28个关节的疾病活动指数(DAS28)的差异.结果 在治疗第24周,IL-1Ra联合甲氨蝶呤治疗组中27例(64％)的患者疗效改善达到ACR20,显著高于安慰剂组2例(17％)(P=0.004).IL-1Ra治疗组中,38％的患者疗效改善达到ACR50,17％达到ACR70;而安慰剂组中无一例达到ACR50或ACR70改善.然而,接受IL-1Ra治疗的42例患者中有9例在初始治疗时病情显著改善,但之后却出现疗效下降.结论 IL-1Ra通过阻断IL-1,可有效改善活动期RA患者的临床表现.然而,大约1/5接受IL-1Ra治疗的患者发生继发性失效.     

重组人细胞毒T淋巴细胞相关抗原-4抗体融合蛋白治疗类风湿关节炎的疗效及其对血清肿瘤坏死因子-α和CX3CL1水平的影响

目的 探讨重组人细胞毒T淋巴细胞相关抗原(CTLA)-4抗体融合蛋白(rhCTLA-4Ig)治疗类风湿关节炎(RA)患者的临床疗效和安全性,及其对血清肿瘤坏死因子(TNF)-α和趋化因子CX3CL1水平的影响.方法 44例中重度RA患者随机分为rhCTLA-4Ig治疗组和安慰剂组,应用美国风湿病学会( ACR )20/50/70疗效标准和28个关节的疾病活动度评分(DAS28)评估临床疗效,并观察用药前后血清TNF-α和趋化因子CX3CL1水平.采用t检验和x2检验进行统计分析.结果 治疗12周后,rhCTLA-4Ig治疗组RA患者达到ACR20、ACR50、ACR70的比率分别为95％(20/21)、76％( 16/21)和19％(4/21),而安慰剂组无一例达到ACR20、ACR50、ACR70标准,2组ACR20及ACR50缓解率比较差异有统计学意义(x2=39.17,26.69,P均＜0.01).rhCTLA-4Ig治疗组DAS28由基线的6.2±1.1降至3.1±1.3 (P＜0.01),健康状况问卷(HAQ)评分由基线的1.4±0.5降至0.4±0.5 (P＜0.01);而安慰剂组DAS28评分治疗前后差异无统计学意义(分别为6.0±0.7,5.8±1.2,P＞0.05),HAQ评分治疗前后差异无统计学意义(分别为1.6±0.4,1.6±0.6,P＞0.05).RA患者TNF-α和CX3CL1水平明显高于健康对照组(P＜0.01),经rhCTLA-4Ig治疗12周后,rhCTLA-4Ig组血清TNF-α和CX3CL1水平明显下降(P＜0.01),而安慰剂组治疗前后差异无统计学意义(P＞0.05).结论 rhCTLA4-Ig治疗RA能够显著减低疾病活动度、改善关节功能,且耐受性良好,可明显减低血清TNF-α和趋化因子CX3CL1水平.     

类风湿关节炎亚甲基四氢叶酸还原酶基因多态性与甲氨蝶呤疗效和不良反应的关系

目的 探讨类风湿关节炎(RA)患者亚甲基四氢叶酸还原酶(MTHFR)基因677CDT[rs1801133)、1298A/C(rs1801131)单核苷酸多态性(SNP)及其与甲氨蝶呤(MTX)治疗的疗效和不良反应相关性.方法 收集RA患者184例.分为单用MTX组、MTX联用其他改善病情抗风湿药(DMARD)组、非MTX的DMARD组,于治疗前及治疗后24周检查临床及实验室指标,评价疗效及不良反应.采用实时荧光定量聚合酶链反应(FQ-PCR)方法检测RA患者及100名健康对照组的MTHFR基因677C/T及1298A/C多态性,比较两组间基因型分布及等位基因频率.结果 677CC/CT/TT基因型分布在RA组(19%、67%、14%)与健康对照组(27%、56%、17%)基因型分布频率差异无统计学意义(P>0.05);1298AA/AC/CC基因型分布在RA组(66%、31%、3%)健康对照组(70%、30%、0%)基因型分布频率差异无统计学意义(P>0.05).677CC/CT/TT基因型分布在RA有心血管并发症组(6%、75%、19%)与正常对照组(27%、56%、17%)差异有统计学意义(P<0.05).在单用MTX治疗者巾,1298AA/AC/CC在MTX治疗有效组(54%、44%、2%)和无效组(90%、10%、O%)中差异有统计学意义(P<0.05),677CC/CT/TT在MTX有不良反应组(13%、71%、16%)和无不良反应组(48%、48%、4%)中差异有统计学意义(P<0.05).在MTX联用其他DMARD组,677CC/CT/TT在有不良反应组(9%、78%、13%)和无不良反应组(35%、50%、15%)中差异有统计学意义(P<0.05).结论 MTHFR基因677C/T及1298A/C多态性与RA发病无关;677 C/T多态性与RA心血管并发症的出现有关、与MTX治疗后的不良反应相关,1298 A/C多态性与MTX的疗效相关.     

~(99)锝-亚甲基二磷酸盐联合甲氨蝶呤治疗对老年类风湿关节炎患者CRP、IL-4、IL-10水平的影响

目的探讨~(99)锝-亚甲基二磷酸盐联合甲氨蝶呤治疗对老年类风湿关节炎患者C反应蛋白(CRP)、白细胞介素(IL)-4、IL-10水平的影响。方法老年类风湿关节炎患者84例根据随机数字表法分成观察组和对照组各42例。对照组予以甲氨蝶呤治疗,观察组在对照组的基础上加用~(99)锝-亚甲基二磷酸盐治疗。对比两组临床疗效、临床症状改善情况及治疗前后血清CRP、IL-4、IL-10水平及不良反应发生情况。结果观察组治疗总有效率明显高于对照组(P<0.05)。观察组关节肿胀、关节压痛、晨僵时间均显著低于对照组(均P<0.05)。治疗后观察组血清CRP水平显著低于对照组,而IL-4、IL-10水平均显著高于对照组(均P<0.05)。两组白细胞减少、胃肠道反应、肝功能异常的发生率差异均无统计学意义(均P>0.05)。结论~(99)锝-亚甲基二磷酸盐联合甲氨蝶呤治疗老年类风湿关节炎的临床疗效显著,安全性较好。     

肿瘤坏死因子受体-Fc融合蛋白治疗类风湿关节炎与强直性脊柱炎短期疗效及不良反应的差异

目的 观察重组人Ⅱ型肿瘤坏死因子受体-抗体Fc融合蛋白[rhTNFR:Fc,益赛普(etanercept)]治疗类风湿关节炎(RA)及强直性脊柱炎(AS)的疗效及不良反应,评估其在不同关节病中的作用.方法 对18例难治性RA和22例难治性AS患者,使用ATNFR:Fc 25 mg/次,每周2次皮下注射,持续3个月.在治疗前和治疗后2、4、12周进行疗效及不良反应评估.RA组和AS组疗效评价分别采用美国风湿病学会(ACR20)H和ASAS20疗效评价标准.结果 ①rhTNFR:Fc治疗后As组达到ASAS20的总体有效率为95.5%,而RA组达到ACR20为50%,组间比较差异有统计学意义(P＜0.01);②AS组在rhTNFR:Fc治疗第2、4、12周时达到ASAS20疗效的患者分别为12例、21例和21例,而RA组达到ACR20疗效的为3例、5例和9例,各时段组间比较差异有统计学意义(P＜0.01);③RA组发生不良反应的患者占50%,显著高于AS组的9%(P＜0.01).RA组因无效及不良反应停药的患者5例,而AS组仅1例,脱漏率差异有统计学意义(P＜0.05),AS组的依从性好于RA组;④两组治疗前与治疗后12周X线比较均无明显改变.结论 相对RA患者总体反应而言,AS组患者对rhTNFR:Fc治疗起效快,有效率高,不良反应少,依从性好:但两组治疗前后关节X线均无明显改变.     

雷公藤多苷联合依那西普治疗老年类风湿关节炎及其对血清炎性因子和骨代谢因子的影响

目的探讨雷公藤多苷联合依那西普治疗老年类风湿关节炎(RA)的疗效及其对血清炎性因子和骨代谢因子的影响。方法选取老年RA患者120例,根据随机数表法分为研究组和对照组,每组各60例。对照组给予依那西普联合甲氨蝶呤进行治疗,研究组给予雷公藤多苷联合依那西普进行治疗。比较两组临床疗效、不良反应及血清白细胞介素(IL)-1β、IL-6及肿瘤坏死因子(TNF)-α、总Ⅰ型胶原氨基端延长肽(TPⅠNP)、β-胶原降解产物(CTX)、骨钙素(BGP)水平。结果两组总有效率比较差异无统计学意义(P0.05)。两组治疗后血清IL-1β、IL-6、TNF-α水平均较治疗前明显下降,且研究组血清IL-1β、IL-6、TNF-α水平均明显低于对照组,差异均有统计学意义(均P0.05)。两组治疗后TPⅠNP、BGP水平均较治疗前明显上升,β-CTX水平较治疗前明显下降,差异均有统计学意义(P0.05),治疗后两组TPⅠNP、β-CTX、BGP水平比较差异无统计学意义(P0.05)。两组不良反应总发生率比较差异无统计学意义(P0.05)。结论雷公藤多苷联合依那西普可有效治疗老年RA,并可降低血清炎性因子水平,改善骨代谢异常情况,且不良反应少而轻微。     

亚甲基四氢叶酸还原酶基因多态性对小剂量甲氨喋呤治疗类风湿关节炎不良反应的影响

目的探讨亚甲基四氢叶酸还原酶（MTHFR）基因C677T多态性对小剂量甲氨喋呤（MTX）治疗类风湿关节炎的影响。方法收集类风湿关节炎患者治疗前及治疗后0,12,24及48 w的临床表现及实验室指标和不良反应信息,评估疗效。采用实时荧光定量聚合酶链反应（FQ-PCR）方法测定类风湿关节炎患者183例（RA组）及健康对照组100例的MTHFR基因C677T多态性,比较两组间基因型分布及等位基因频率。结果 C677T基因型分布在RA组与健康对照组间差异无统计学意义（P〉0.05）;C677T各基因型在MTX治疗有效率差异无统计学意义（P〉0.05）。TT基因型组肝毒性及血液系统不良反应的发生率明显高于CC基因型组,差异均有统计学意义（P〈0.05）。结论 MTHFR基因C677T多态性与RA发病和MTX疗效无关,但与MTX治疗后血液系统不良反应、肝毒性有关联。     

Experience with the treatment of patients with hypertrophic cardiomyopathy with obsidan and isoptin

Forty-five patients with hypertrophic cardiomyopathy were examined clinically and echocardiographically. The results of their treatment with obsidan and isoptin in relation to various types of central hemodynamic disorders are presented. The data have been obtained making it possible to treat patients differentially with regard to the form of the disease. The treatment of this category of patients requires the echocardiographic monitoring of the parameters of the central hemodynamics and myocardial contractility.     

Risk of thrombosis with lenalidomide and its prevention with aspirin

Lenalidomide, an analog of thalidomide, is an effective new treatment for multiple myeloma. Both compounds are associated with an increased risk of venous thromboembolism, particularly when used in combination with high-dose dexamethasone. As new trials with lenalidomide are being planned and performed, investigators are placing high importance on reducing the risk of thrombosis by incorporating an antithrombotic agent into the therapeutic regimen. Low-molecular-weight heparin, warfarin, and aspirin have all been suggested as candidate drugs for thromboprophylaxis, but none of these agents have been evaluated in randomized clinical trials. A body of opinion has evolved that aspirin is very effective in preventing venous thrombosis in myeloma patients treated with lenalidomide. If correct, this view has important implications, because aspirin is inexpensive and is safer and more convenient than anticoagulants. On the other hand, aspirin is less effective than anticoagulants for preventing venous thrombosis in other high-risk groups, and therefore might not be the most appropriate choice for preventing of venous thrombosis in myeloma patients. This commentary examines the strength of the evidence supporting the effectiveness of aspirin in preventing venous thrombosis in multiple myeloma patients treated with lenalidomide. It is concluded that the evidence that aspirin is efficacious in preventing venous thrombosis in myeloma patients is based on "before/after" and retrospective studies, with potential for bias and confounders. There is, therefore, a critical need to incorporate a randomized comparison of aspirin with an anticoagulant in future trials evaluating lenalidomide in multiple myeloma.     

十二指肠乳头旁憩室与胆胰疾病的关系及对内镜诊疗的影响

目的 探讨十二指肠乳头旁憩室（JPDD）与胆胰疾病发生的关联性及JPDD对ERCP诊疗的影响。方法 2012年1月至2017年1月,中国医科大学附属盛京医院普通外科1 230例行ERCP诊疗病例纳入回顾性分析,首先按是否存在JPDD分成JPDD组（n=360）和非JPDD组（n=870）,然后再将JPDD组病例按是否为憩室内乳头分成憩室内乳头组（n=41）和非憩室内乳头组（n=319）,JPDD组与非JPDD组间、憩室内乳头组与非憩室内乳头组间胆胰疾病发生率、ERCP插管成功率、取石成功率、术后并发症发生率等数据比较采用χ2检验或Fisher确切概率法,P＜0.05为差异具有统计学意义。结果 胆总管结石、原发性胆总管结石、复发性胆总管结石发生率JPDD组分别为87.78%（316/360）、31.11%（112/360）、6.67%（24/360）,非JPDD组分别为75.52%（657/870）、19.08%（166/870）、4.02%（35/870）,2组间比较差异均有统计学意义（χ2=23.158,P＜0.001;χ2=21.068,P＜0.001;χ2=3.897,P=0.048）;ERCP插管、一次性取石成功率,术后出血、胰腺炎、高淀粉酶血症发生率,2组间比较差异均无统计学意义（P均＞0.05）。复发性胆总管结石发生率憩室内乳头组为14.63%（6/41）,非憩室内乳头组为5.64%（18/319）,2组间比较差异有统计学意义（χ2=4.721,P=0.030）;胆总管结石、原发性胆总管结石发生率,ERCP插管、一次性取石成功率,术后出血、胰腺炎、高淀粉酶血症发生率,2组间比较差异均无统计学意义（P均＞0.05）。结论 JPDD与原发性胆总管结石的发生相关,JPDD患者ERCP治疗后更易复发胆总管结石,且憩室内乳头患者更为明显。     

Treatment of strongyloidiasis with mebendazole and its combination with thiabendazole

Although Strongyloides stercoralis (S. stercoralis) infection rate in Okinawa Prefecture was less than 2% by the traditional method, it has been proven to be 6.2% by the new technique--agar plate method. Thiabendazole has strong activity to eradicate the organism, but it is well known that the rate of severe side effects is extremely high. Therefore, we attempted to evaluate the new treatment for the infection by mebendazole and its combination with thiabendazole. The reason for use of the drug is based on the reports of successful treatment of S. stercoralis infection in humans with the mild and infrequent side effects produced by the drug. Thirty three patients were orally given mebendazole 100 mg twice daily for 28 days. Twenty six patients were given thiabendazole 500 mg thrice daily for 5 days and after that, mebendazole 100 mg twice daily for 9 days. This combination therapy was repeated twice. The following results were obtained: 1) Out of a total of 59 patients, the cure rate was 83.3% (20/24) in single use of mebendazole and 100.0% (22/22) in the combination therapy. 2) Constipation (9.1%) and headache (9.1%) were of relatively high incidence in the mebendazole group, but they were mild. Nausea (19.2%) and headache (15.4%) were observed in the combination therapy group and the drug was discontinued in 2 patients. 3) The incidence of the elevation of S-GOT, S-GPT was noted in 71.4% (20/28) for the mebendazole group and 52.2% (12/23) for combination therapy group. All 13 patients of the mebendazole group were negative in lymphocyte stimulation test for mebendazole.(ABSTRACT TRUNCATED AT 250 WORDS)     

Treatment of metastatic renal cancer with ifosfamide and mesnum with and without irradiation

Ifosfamide (50-60 mg/kg of body weight, Days 1-5) and mesnum (10-12 mg/kg of body weight, Days 1-5) were given to 15 patients with measurable metastatic renal cancer. This treatment was repeated on Day 29. In addition, six of these 15 patients received irradiation to some of the metastatic areas. There was one partial remission among 11 evaluable patients after two ifosfamide courses. The partial remission was seen in a metastatic area treated with low-dose irradiation prior to the first ifosfamide course. Two cases of early death and two cases of toxic death (urotoxicity) were observed. The main hematologic complication was moderate to severe leukopenia. Previously reported high response rates to ifosfamide treatment of renal cancer could not be confirmed.     

Women with gout: efficacy and safety of urate-lowering with febuxostat and allopurinol

Objective

To compare the characteristics of female versus male gout patients and assess urate‐lowering efficacy and safety of febuxostat or allopurinol treatment in women with gout.

Methods

This was a retrospective analysis of 4,101 hyperuricemic (serum urate [sUA] level ≥8.0 mg/dl) gout subjects enrolled in 3 phase III comparative trials and randomized to receive placebo, febuxostat (40 mg, 80 mg, 120 mg, or 240 mg daily), or allopurinol (100 mg, 200 mg, or 300 mg daily, based on renal function). Baseline demographics and characteristics were summarized and compared between female and male subjects. Urate‐lowering efficacy, which was defined as the proportion of subjects with sUA levels <6.0 mg/dl at final visit, was assessed for all subjects and, among women, according to baseline renal function.

Results

Female gout subjects (n = 226) were older with significantly higher rates of obesity and metabolic and cardiovascular comorbidities than their male counterparts. The percentage of female subjects with sUA levels <6.0 mg/dl at final visit was 0% in the placebo group, 54.3%, 85.1%, 81.0%, and 100.0% in the febuxostat 40 mg, 80 mg, 120 mg, and 240 mg groups, respectively, and 45.9% in the allopurinol group. Similar patterns of urate‐lowering efficacy rates were observed when stratified by renal function. Among all the female subjects, febuxostat 80 mg was significantly more efficacious than allopurinol (P < 0.001). Rates of adverse events (AEs) were low. The most frequently reported AEs were upper respiratory tract infections, musculoskeletal/connective tissue disorders, and diarrhea.

Conclusion

These data suggest that febuxostat 80 mg may be more efficacious than commonly prescribed doses of allopurinol in female gout subjects with high rates of comorbidities.