甲氨蝶呤治疗类风湿关节炎的新思考

甲氨蝶呤(MTX)为目前治疗类风湿关节炎(RA)首选的改善病情抗风湿药(DMARDs)。MTX在减轻症状和体征、减少致残及延缓影像学结构破坏等方面优于其他DMARDs。在生物制剂和MTX等传统DMARDs之间进行选择时,需充分考虑成本效益因素以保障患者的依从性和病情缓解。预测MTX治疗反应性或安全性的生物或基因标记物可指导临床医生制定最佳的RA治疗方案。     

Methotrexate is a new consideration in treatment of rheumatoid arthritis

甲氨蝶呤(MTX)为目前治疗类风湿关节炎(RA)首选的改善病情抗风湿药(DMARDs).MTX在减轻症状和体征、减少致残及延缓影像学结构破坏等方面优于其他DMARDs.在生物制剂和MTX等传统DMARDs之间进行选择时,需充分考虑成本效益因素以保障患者的依从性和病情缓解.预测MTX治疗反应性或安全性的生物或基因标记物可指导临床医生制定最佳的RA治疗方案.     

CD4+CD25high调节性T细胞在类风湿性关节炎病程中的消长及其意义

目的研究类风湿性关节炎(RA)患者病情发展不同阶段外周血及滑液中CD4 CD25high调节性T细胞数量的差别,及其与类风湿性关节炎活动程度的相关性,探讨CD4 CD25highT细胞在RA发生发展中所发挥的免疫抑制和调节作用。方法分别选取未经过缓解病情抗风湿药(DMARDs)治疗的活动性RA患者11例,经DMARDs治疗病情缓解的RA患者12例,和DMARDs治疗后效果不佳的RA患者9例,以及正常对照8例,检测他们的外周血淋巴细胞,以流式细胞术检测CD4 CD25high调节性T细胞的百分率,并研究CD4 CD25highT细胞百分率与抗环瓜氨酸(CCP)抗体,C反应蛋白(CRP),血沉(ESR)及类风湿因子(RF)的相关性。对其中部分患者的血液和关节滑液同时进行分析。结果RA未经治疗组和治疗效果不佳组CD4 CD25highT细胞的百分率(分别是5.24%和6.43%)明显低于正常对照组和治疗后病情缓解组(分别是17.17%和11.79%,P<0.01)。RA患者CD4 CD25highT细胞的百分率与抗CCP抗体(58.0Ru/mL),ESR(38.8mm/h)及CRP(2.73μg/L)呈明显负相关(P<0.05),与类风湿因子(RF=14.4Iu/mL)无明显的相关性(P=0.054)。正常对照组的CD4 CD25highT细胞百分率与抗CCP抗体(均<5.0Ru/mL),ESR(4.67mm/h),CRP(0.15μg/L)及RF(1.37)无明显相关性(P>0.1)。RA患者关节滑液中CD4 CD25highT百分率明显低于强直性脊柱炎(ankilosing spondylitis,AS)关节积液患者(P<0.05)。结论试验结果表明未经缓解病情治疗和治疗后效果不佳者的外周血中,CD4 CD25high调节性T细胞相对减少,且与病情活动程度负相关,这可能是RA发生和发展的一个重要因素。     

类风湿关节炎药物治疗基因多态性研究进展

类风湿关节炎(RA)是一种系统性疾病,可致关节破坏和残疾.治疗以传统DMARDs和生物制剂为主.药物疗效与患者基因多态性密切相关.药物主要包括甲氨蝶呤、来氟米特、柳氮磺胺吡啶和生物制剂如TNF拮抗剂、妥珠单抗、力妥昔单抗等.RA患者遗传背景是影响药物疗效的重要因素,必然对个体化治疗产生深远影响,因而研究基因多态性与RA患者疗效反应的相关机制具有重要意义.     

多药耐药相关蛋白基因多态性与类风湿性关节炎关系的研究进展

类风湿性关节炎(RA)是一种慢性多关节对称性受累,以手小关节为主,伴多系统受累的全身性免疫系统疾病,发病率与致残率高,目前临床治疗主要以缓解病情抗风湿药(DMARD)控制病情进展为主,延缓关节的破坏。长期应用DMARD过程中发现其疗效逐渐下降,即产生耐药,然而DMARD耐药机制研究甚少。药物疗效和毒副作用的个体差异主要是由遗传因素决定的。我们总结了多药耐药相关蛋白基因多态性与RA传统药物治疗的相关性,分析了不同的基因型患者对药物的疗效及毒副作用,为个体化用药提供依据,从而实现精准医疗,RA的个体化用药。     

131I治疗前不同撤药时间对分化型甲状腺癌患者甲状腺激素、血脂、心血管相关因素的影响及其临床分析

目的 研究分化型甲状腺癌(differentiated thyroid carcinoma,DTC)患者在131 I治疗前不同撤药时间对甲状腺激素、血脂、心血管相关因素的影响及其临床分析.方法 选取我科就诊的188例DTC患者,按照不同撤用左甲状腺素钠的时间分为:撤药3周组与撤药4周组.完善甲功3项[游离三碘甲腺原氨酸...     

MEKK2在类风湿关节炎患者中的表达及临床意义

研究丝裂原活化蛋白激酶(mitogen-activated protein kinase,MAPK)信号通路中有丝分裂原活化蛋白激酶激酶激酶2(mitogen-activated protein kinase kinase kinase 2,MEKK2)分子在类风湿关节炎(rheumatoid arthritis,RA)患者中的表达及临床意义。Western blotting和Real-time PCR分别检测20例RA患者经艾拉莫德治疗前后,外周血单个核细胞(peripheral blood mononuclear cell,PBMC)中MEKK2蛋白和基因的表达水平变化,并与健康对照者比较其表达情况。结果显示:与健康对照者相比,RA患者PBMC中MEKK2的蛋白及基因水平降低,经艾拉莫德治疗后临床症状明显改善,且MEKK2的表达水平有所升高。该研究提示MEKK2的表达对RA发病过程起到重要作用,缓解病情抗风湿药物艾拉莫德有可能影响到MEKK2通路而发挥其临床疗效。     

冠脉微血管功能障碍与慢性炎性风湿病

慢性炎性风湿病(chronic inflammatory rheumatoid diseases,CIRD)包括类风湿关节炎(rheumatoid arthiritis,RA)、系统性红斑狼疮(systemic lupus,SLE)、系统性硬皮病(systemicsclerosis,SSC)是导致缺血性心脏病的重要危险因素,也是导致心血管发病率和死亡率增加的重要原因之一.即使没有梗阻性心外膜冠状动脉疾病,炎症也可影响CIRD患者冠脉微血管功能,促进心肌缺血和心血管事件的发生.了解CIRD与冠脉微血管功能障碍(coronary microvascular dysfunction,CMD)的分子机制对制定治疗目标至关重要.     

血藤乌头汤治疗类风湿性关节炎的疗效观察及护理

目的 探讨血藤乌头汤对类风湿性关节炎的临床疗效.方法 将69例类风湿性关节炎患者分为两组,治疗组35例给予中药血藤乌头汤每日一刘.时照组34例给予非甾体类抗炎药(NSAIDs)(布洛芬缓稀胶囊0.3g,口服,每日2次)与和慢作用抗风湿药(DMARDs)(甲氨喋呤15 mg,口服,每周1次),治疗组、对照组分别实施全程针对性的护理.6周后观察疗效并记录相关结果.结果 治疗组、其中31例均恢复全部生活自理能力,在家康复;4例因疾病活动再次住院治疗;对照组、其中30例均恢复全部生活自理能力,在家康复;4例因疾病活动再次住院治疗.结论 早期全面的用药护理配合其他方面护理工作的开展能促进患者得到及时有效的治疗,把握住治疗的关键时机,可使患者得到良好的康复.     

类风湿关节炎的诊断及内科治疗

类风湿关节炎（RA）是一种常见的全身性自身免疫病,目前尚无特异性诊断及治疗方法,尤其是不典型和特殊类型RA易于误诊误治。近年来,AKA、APF、抗RA33、抗CCP、抗Sa及抗BiP抗体等新型自身抗体的发现提高了RA诊断的敏感性和特异性;核磁共振、CT及超声检查等影像学检查提高了RA关节损害的检出率,这些新的血清学检测指标及影像学检查的应用有助于RA的早期诊断。与此同时,新的DMARDs和生物制剂不断问世,RA的治疗手段不断丰富。已经证实,绝大多数RA患者经过早期、联合、个体化的规范治疗,预后良好。     

Biological agents in rheumatoid arthritis

Rheumatoid arthritis (RA) is the commonest inflammatory joint disease with considerable morbidity and mortality. Conventional disease-modifying antirheumatic drugs like methotrexate form the cornerstone of therapy. However, they have several limitations in terms of slow onset of action, adverse effects and modest remission and retention rates. Several cytokines are involved in the pathogenesis of RA. Biological agents that specifically inhibit the effects of tumour necrosis factor-a (TNF-a) or Interleukin-1 (IL-1) represent a major advancement in the treatment of RA. By targeting molecules that are directly involved in the pathogenesis of RA, these therapies are proving to be efficacious, highly specific and better tolerated than standard therapies. The use of these agents needs to be monitored carefully for possible side-effects, including the development of infections. Additional anti-cytokine agents for the treatment of RA are under further development.     

Scientific Basis of Botanical Medicine as Alternative Remedies for Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a chronic, systemic autoimmune inflammatory disorder that causes permanent disability and mortality to approximately 1 to 100 people in the world. Patients with RA not only suffer from pain, stiffness, swelling, and loss of function in their joints, but also have a higher risk of cardiovascular disease and lymphoma. Typically prescribed medications, including pain-relieving drugs, nonsteroidal anti-inflammatory drugs (NSAID), and disease-modifying antirheumatic drugs, can help to relieve pain, reduce inflammation and slow the course of disease progression in RA patients. However, the general effectiveness of the drugs has been far from satisfactory. Other therapeutic modalities like TNF-alpha (TNF-α) inhibitors and interleukin-1 receptor antagonists targeting precise pathways within the immune system are expensive and may be associated with serious side effects. Recently, botanical medicines have become popular as alternative remedies as they are believed to be efficacious, safe and have over a thousand years experience in treating patients. In this review, we will summarize recent evidence for pharmacological effects of herbs including Black cohosh, Angelica sinensis, Licorice, Tripterygium wilfordii, Centella asiatica, and Urtica dioica. Scientific research has demonstrated that these herbs have strong anti-inflammatory and anti-arthritic effects. A wide range of phytochemicals including phenolic acids, phenylpropanoid ester, triterpene glycosides, phthalide, flavonoids, triterpenoid saponin, diterpene and triterpene have been isolated and demonstrated to be responsible for the biological effects of the herbs. Understanding the mechanisms of action of the herbs may provide new treatment opportunities for RA patients.     

Tolicizumab在类风湿性关节炎中的应用

类风湿关节炎是以滑膜炎、慢性系统性炎症反应及自身抗体分泌为特点的自身免疫性疾病.已有研究结果表明,过量表达的IL-6在类风湿关节炎起病与进展过程中发挥着重要作用.Tolicizumab是第1个人源性的IL-6受体抗体,通过特异性识别结合IL-6受体而阻断IL-6生物学活性,发挥抑制类风湿关节炎炎症反应的作用.大量临床试...     

Metabolic syndrome and the decreased levels of uric acid by leflunomide favor redox imbalance in patients with rheumatoid arthritis

Oxidative stress plays a role in the pathophysiology of rheumatoid arthritis (RA). The aim of the present study was to verify the influence of metabolic syndrome (MetS) and disease-modifying antirheumatic drugs on nitrosative and oxidative biomarkers in patients with RA. A total of 177 patients with RA and 150 healthy volunteers participated in this study, which measured lipid hydroperoxides, advanced oxidation protein products (AOPP), nitric oxide metabolites (NOx), carbonyl protein, total radical-trapping antioxidant parameter (TRAP), uric acid (UA), and C-reactive protein (CRP). NOx and the NOx/TRAP ratio were significantly increased in RA, while no significant differences in lipid hydroperoxides, AOPP, UA, and TRAP levels were found between both groups. Treatment with leflunomide was associated with increased levels of carbonyl protein, and lowered levels in TRAP and UA, while the NOx/TRAP ratio further increased. NOx and the NOx/TRAP ratio were significantly higher in women than in men, while TRAP and UA were significantly lower in women. MetS was accompanied by increased AOPP and UA levels. RA was best predicted by increased NOx/TRAP ratio, CRP, and BMI. In conclusion, our data demonstrated that NOx and NOx/TRAP are strongly associated with RA physiopathology. Our findings suggest that inhibition of iNOS may become an interesting therapeutic approach for the treatment of RA. In addition, the presence of MetS and a decrease in levels of UA by leflunomide favor redox imbalance in RA patients. More studies are needed to evaluate the impact of antioxidant capacity reduction on RA progression.     

Lung involvement and drug-induced lung disease in patients with rheumatoid arthritis

Interstitial lung disease (ILD) is a common extra-articular manifestation of rheumatoid arthritis (RA) and a significant cause of morbidity and mortality. Usual interstitial pneumonia and nonspecific interstitial pneumonia seem to be the most frequent patterns in RA patients with ILD, although the proportion of patients with usual interstitial pneumonia is higher than among patients with other systemic rheumatic autoimmune diseases. RA patients with ILD most frequently present with chronic symptoms of cough and dyspnea when climbing stairs or walking uphill. A physical examination may reveal inhalatory crackles and a pulmonary function test demonstrates restrictive physiology, often with reduced diffusing capacity. High-resolution computed tomography is generally sufficient to confirm a diagnosis of ILD, although a minority of cases may require a surgical lung biopsy. Conventional disease-modifying antirheumatic drugs such as methotrexate (MTX) or leflunomide (LEF) and biological agents such as TNF-blocking agents or rituximab may trigger or aggravate ILD in RA patients, and infections may contribute to increased mortality in such patients. LEF should not be used in patients with a history of MTX pneumonitis. The prevalence of interstitial pneumonia among RA patients treated with anti-TNF agents ranges from 0.5 to 3%; however, as the evidence that anti-TNF increases or decreases the risk of ILD is controversial, it is not clear whether this indicates more severe RA requiring biological therapy or the effect of exposure to potentially toxic drugs such as MTX or LEF. The development of treatment-related ILD is a paradoxical adverse event, and patients should be warned about this rare but serious complication of biological or disease-modifying antirheumatic drug therapy.     

Tofacitinib for the treatment of rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic inflammatory disease that affects approximately 1% of the worldwide population. It primarily targets the synovial membrane of joints, leading to a synovial proliferation, joint cartilage lesion and erosions in the adjacent bone tissue. The disease is usually progressive and if the inflammatory process is not adequately suppressed, joint deformity takes place, leading to a significant functional disability and work incapacity. Over the last decade, biological therapy was established as a major step towards disease control in those patients who experienced failure after treatment with disease-modifying antirheumatic drugs. Despite the growing number of biological agents with different immunological targets, a significant number of patients do not receive appropriate disease control, or have the use of these agents limited because of adverse events. As such, the search for new molecules with a higher efficacy and better safety profile is ongoing. This article focuses on a new drug, tofacitinib, which is a synthetic disease-modifying antirheumatic drug for treatment of RA. Preclinical studies in arthritis and transplantation animal models are reviewed as a background for the possible use of tofacitinib treatment in humans. Four Phase II (one A and three B dose-ranging) trials lasting from 6 to 24 weeks in RA patients showed significant American College of Rheumatology 20 improvements as early as week 2 and sustained at week 24 in two studies. Tofacitinib Phase III studies in RA are included in a clinical program called 'ORAL Trials'. Long-term follow-up from ongoing studies will contribute to a more accurate tofacitinib efficacy and safety profile. Trials in other illness such as psoriasis, psoriatic arthritis, renal transplant rejection prevention, inflammatory bowel diseases and dry eye are underway.     

Itraconazole: Its possible role in inhibiting angiogenesis in Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a chronic, inflammatory, autoimmune disorder involving mainly synovial joints. It can progress to a severely debilitating form with pulmonary, renal and cardiovascular involvement. Currently, disease-modifying antirheumatic drugs (DMARDs) remain the gold standard pharmacological therapy for RA (along with nonsteroidal anti-inflammatory drugs and corticosteroids). However, DMARDs are more or less ineffective in the late phase of the disease and adverse effects often limit their use. Studies show that serum levels of vascular endothelial growth factor (VEGF) remain elevated throughout the course of RA. In experimental models, the administration of pro-angiogenic cytokines, such as VEGF or FGF, has been shown to increase the severity of the disease. Therefore, anti-angiogenic drugs such as bevacizumab (which is already being used as an anti-tumor agent) may play a significant role in longstanding RA. However, adverse effects such as hypertension, gastro-intestinal perforation and the high cost of bevacizumab are major concerns. A recent study suggests that itraconazole, an antifungal drug, has a role in selectively inhibiting angiogenesis and growth of tumor in non-small cell lung cancer. Hence, this drug may be beneficial in the treatment of RA, especially in the later phase when other modalities have failed, or as an adjuvant. To test our hypothesis, we propose a randomized, double-blinded trial in patients with longstanding RA. The control group receives the standard DMARD therapy plus placebo, while the case group receives itraconazole in addition to DMARD therapy. Serum and synovial VEGF levels, in both the control group and the case group, are compared and their correlation with the symptoms is judged. If the VEGF levels are lower and/or the symptoms are less severe in the case group, our hypothesis will be confirmed. Multi-institutional efforts are needed to confirm this hypothesis, as it is relatively new and trial data is limited.     

Active arthritis due to cryoglobulinemia based on HCV infection in a patient with RA improvement of arthritis with IFN-alpha]

A 49-year-old Japanese woman was diagnosed with rheumatoid arthritis (RA) based on ACR criteria in May 1999. She developed liver injury after initiation of disease-modifying antirheumatic drugs (DMARDs) and was found to have contracted HCV infection. RA disease activity worsened following restriction of medication due to liver dysfunction. However, 3 mg/day of prednisolone (PSL) resulted in a temporary but marked improvement of RA in December 2001; but arthritis recurred along with Raynaud's phenomenon and palpable purpura. Differential diagnosis between arthritis caused by cryoglobulinemia and exacerbation of RA was important for the selection of appropriate treatment. She manifested non-erosive arthritis on medium and large joints with proteinuria, hematuria and hypocomplementemia. In addition, type III cryoglobulin was detected and chronic active hepatitis was observed on liver biopsy in March 2002. We considered that the main cause for the arthritis was HCV-related mixed cryoglobulinemia. Administration of IFN-alpha resulted in the disappearance of HCV-RNA and cryoglobulin followed by amelioration of arthritis without exacerbation of RA.     

Anakinra

Anakinra (Kineret) is the first biologic drug that has been developed specifically as an interleukin (IL)-1 receptor antagonist (Ra) and is derived from an endogenous IL-1Ra. The drug blocks the activity of IL-1 in synovial joints, reducing the inflammatory and joint destructive processes associated with rheumatoid arthritis (RA). In randomized, placebo-controlled trials of up to 52 weeks' duration, anakinra has shown efficacy both as monotherapy and in combination with other disease-modifying antirheumatic drugs (DMARDs) in adults with RA. It is subcutaneously administered and is generally well tolerated. Anakinra offers a useful addition to the range of drugs available for the treatment of RA.