英夫利西单抗治疗风湿性疾病的安全性评价

目的:为临床安全使用英夫利西单抗提供参考。方法:收集2008年8月-2013年4月我院风湿科行英夫利西单抗治疗的患者共209例,通过门诊和病房随诊以及电话随访的方式记录患者用药过程中及停药后所发生的药品不良反应(ADR),并对国内外相关文献进行分析。结果:随访成功的166例接受英夫利西单抗治疗的患者中总的ADR发生率为19.3%(32/166),位居前3位的ADR类型为过敏反应5.4%(9/166)、皮疹4.8%(8/166)及感染3.6%(6/166),从用药到发生ADR的时间为(20.4±30.2)周(2~122周)。因重度ADR导致停药的占4.2%(7/166),分别为结核感染4例和迟发性过敏3例。结论:英夫利西单抗的疗效和安全性在临床应用中得到了认可,ADR大多温和、可耐受,但在用药时需要严格掌握适应证和患者类型。     

英夫利西单抗输液反应的临床特点及护理对策

英夫利西单抗即类克,是一种细胞因子（TNF-α）抑制剂,在自身免疫性风湿病（ARDs）发病机制中,TNF-α具有诱导致炎细胞因子生成的功能活性,在自身免疫性风湿病（ARDs）病理生理过程中起着重要作用[1]。英夫利西单抗通过抑制TNF-α生物活性、靶向性治疗自身免疫性风湿病的关节破坏,改善关节功能,取得了显著效果,近年来被批准应用于自身免疫性疾病（类风湿关节炎和强直性脊柱炎）的治疗。英夫利西单抗是一种价格昂贵的新型生物制剂,治疗风湿病的主要不良反应是输液反应[2],护士作为输液治疗的执行者,有必要对生物制剂的输液反应加以研究,以预防和减少输液反应、合理处置、提高用药安全性。本研究对2010年1月～2013年3月南京医科大学附属无锡市人民医院类风湿关节炎和强直性脊柱炎输注英夫利西单抗发生输液反应的病例进行了回顾分析。     

加拿大通报与英夫利西单抗相关的肝脾T细胞淋巴瘤病例

2006年7月24日,加拿大卫生部与Cento-cor公司、Schering Canada公司共同发布信息,通报与英夫利西单抗(Infliximab,商品名:REMI-CADE)相关的严重不良事件。英夫利西单抗是一种嵌合IgG单克隆抗体,可直接抑制肿瘤细胞坏死因子(TNFα)的生物学应答。在加拿大,该药用于治疗成人类风湿性关节炎、强直性脊柱炎、克隆病(Crohn,s病)、溃疡性结肠炎、银屑病、关节炎以及慢性斑块状银屑病,未获准用于儿科患者。加拿大卫生部称,上市后监测发现了6例罕见的肝脾T细胞淋巴瘤(HSTCL)病例,其中5例死亡。这些患者均使用英夫利西单抗治疗克隆病,暴露…     

119例英夫利西单抗不良反应的文献分析

目的探讨英夫利西单抗不良反应的特点,为临床安全用药提供参考。方法在中国期刊全文数据库和万方数据库中,检索2008~2015年之间公开发表的关于英夫利西单抗不良反应的文献,对筛选出的119例病例进行回顾性分析。结果原患疾病主要包括类风湿性关节炎、强直性脊柱炎、溃疡性结肠炎、克罗恩病、银屑病/银屑病性关节炎、幼年特发性关节炎。不良反应最易发生于第3~4次输液期间。输液反应最常见,常累及的系统-器官主要包括皮肤黏膜(29.49%)、呼吸系统(30.77%)、消化系统(14.10%)、心血管系统(10.26%)等。多数药品不良反应预后良好。结论英夫利西单抗药品不良反应累及多个系统-器官,须提高警惕,注意监测,及时处理。     

两种生物制剂联合甲氨蝶呤治疗类风湿性关节炎的疗效

目的比较益赛普、英夫利西单抗联合甲氨蝶呤治疗类风湿性关节炎的临床效果。方法将62例类风湿患者随机分为3组,分别给予益赛普＋甲氨蝶呤、英夫利西单抗＋甲氨蝶呤、甲氨蝶呤治疗,分析临床效果及不良反应。结果益赛普和英夫利西单抗分别联合甲氨蝶呤治疗类风湿性关节炎的总有效率分别为90.9%和90.5%,两组比较,差异无统计学意义。结论益赛普、英夫利西单抗联合甲氨蝶呤治疗类风湿性关节炎均具有较好的疗效,但应根据临床特点合理选择。     

英夫利西单抗治疗难治性重症类风湿关节炎临床研究

目的:观察英夫利西单抗(infliximab)治疗难治性重症类风湿关节炎(RA)8周的临床疗效及不良反应。方法:10例难治性重症RA患者接受英夫利西单抗治疗(0周,第2周,第6周),观察治疗前、第1周、第4周及第8周各项观察指标变化,并记录不良反应发生情况。结果:10例RA患者临床指标、实验室指标及DAS28评分均有显著改善(P<0.05),未见明显不良反应。结论:英夫利西单抗能在短时间内迅速改善难治性重症RA的各项症状、体征和实验室炎性活动指标,显著改善病情。     

英夫利西单抗联合环孢素治疗快速进展型类风湿关节炎的疗效与安全性

目的观察英夫利西单抗联合环孢素治疗快速进展型类风湿关节炎（RA）的疗效及安全性。方法将18例快速进展型RA随机分为2组,各9例。英夫利西单抗组在第0、2、6、14、22周给予英夫利西单抗3mg/kg静脉输注,环孢素200mg/d口服;对照组给予泼尼松5～10mg/d口服,环孢素200mg/d口服,比较2组疗效及安全性。结果治疗第2周,英夫利西单抗组ACR20有效率与对照组比较,差异无统计学意义（P〉0.05）;治疗第6、14、22周,英夫利西单抗组ACR20有效率均高于对照组,差异有统计学意义（P〈0.05）。治疗第14、22周,英夫利西单抗组ACR50、ACR70有效率均高于对照组,差异有统计学意义（P〈0.05）。结论英夫利西单抗联合环孢素治疗快速进展型RA疗效显著,安全性较好。     

英夫利西单抗联合甲氨蝶呤治疗活动性类风湿关节炎的临床效果

目的：观察英夫利西单抗联合甲氨蝶呤治疗活动性类风湿关节炎的临床效果。方法选择本院2011年9月～2013年9月收治的活动性类风湿关节炎患者60例,随机分为对照组与观察组,各30例,对照组采用口服甲氨蝶呤及安慰剂维生素C片治疗,观察组采用英夫利西单抗联合甲氨蝶呤治疗（口服甲氨蝶呤10 mg,1次/周,静脉注射5 mg/kg的英夫利西单抗,第1次给药后的第2、6周及以后每隔8周给予同量的英夫利西单抗进行持续治疗）,观察两组的相关观察指标及治疗效果。结果观察组的总有效率高于对照组,差异有统计学意义（P〈0.05）。两组治疗后的关节肿胀发生率、关节压痛发生率、红细胞沉降率及C反应蛋白比较,差异有统计学意义（P〈0.05）。结论英夫利西单抗联合甲氨蝶呤治疗活动性类风湿关节炎的效果明显,值得临床推广应用。     

英夫利西单抗治疗溃疡性结肠炎合并强直性脊柱炎临床分析

目的探讨英夫利西单抗治疗溃疡性结肠炎合并强直性脊柱炎的临床效果。方法对我院收治的5例溃疡性结肠炎合并强直性脊柱炎患者进行英夫利西单抗治疗,6周后观察患者临床表现,分析并总结英夫利西单抗的治疗效果。结果 2例溃疡性结肠炎合并强直性脊柱炎患者经过英夫利西单抗治疗2周后,胸部、腰背部疼痛明显缓解;6周后C反应蛋白（CRP）、红细胞沉降率（ESR）较治疗前明显降低。结论英夫利西单抗能迅速减轻溃疡性结肠炎合并强直性脊柱炎患者的临床症状与体征,对显著改善患者功能与生活质量具有重要的临床作用。     

英夫利西单抗与益赛普治疗强直性脊柱炎患者的安全性观察及护理

目的通过观察英夫利西单抗及益赛普（重组人Ⅱ型肿瘤坏死因子受体-抗融合蛋白）的注射安全性,探讨两种药物在临床应用中相应的护理对策。方法分析93例强直性脊柱炎（AS）患者静脉注射英夫利西单抗（43例,类克组）与注射益赛普（50例,益赛普组）后出现的不良反应,总结在临床中应用的护理对策。结果药物变态反应、肝损害及肺结核为静脉注射英夫利西单抗的主要不良反应,而益赛普的主要反应则为注射部位局部红肿、皮疹、发热、呼吸道感染、肺结核。除肺结核患者外,经对症处理后可继续维持治疗用药。结论 AS患者在临床治疗中应用英夫利西单抗、益赛普具有较好的安全性和耐受性,早期采取护理干预,可降低不良反应发生率及其严重程度,从而提高患者配合治疗、护理的依从性,提高疗效。     

Novel approaches in the treatment of ankylosing spondylitis and other spondyloarthritides

The therapeutic options for patients suffering from severe forms of spondyloarthritis (SpA) have been rather limited in recent decades. There is now accumulating evidence that anti-TNF therapy is highly effective in SpA, especially in ankylosing spondylitis (AS) and psoriatic arthritis (PsA). Based on the data recently published on what is now several hundred AS and PsA patients, this treatment seems to be even more effective than the same therapy in rheumatoid arthritis (RA). The anti-TNF-alpha agents currently available, infliximab (Remicade); Centocor), etanercept (Enbrel); Amgen) and adalimumab (Humira; Abbott), are approved for the treatment of RA in the US; infliximab and etanercept are approved in Europe. The situation in SpA is different to RA because there is an unmet medical need, especially in AS, since no therapies with disease-controlling antirheumatic drugs are available for severely affected patients, especially with spinal disease. Thus, TNF blockers might even be considered as first-line immunosuppressive agents in patients with active AS and PsA who are not sufficiently treated by non-steroidal anti-inflammatory drugs and sulfasalazine, if peripheral arthritis is present. For infliximab, a dosage of 5 mg/kg at intervals between 6 and 12 weeks was necessary to constantly suppress disease activity; this is also a major aim of long-term treatment. No dose-finding studies have yet been performed. The standard dose of etanercept is 25 mg s.c. twice-weekly. No studies on adalimumab (standard RA dose 20 - 40 mg s.c. every 2 weeks) have yet been conducted in SpA. The efficacy of etanercept was first demonstrated in PsA and etanercept is now approved for this indication. A double-blind study has also been performed in AS, with similarly clearcut efficacy. There is preliminary evidence that both agents do also work in other SpA such as undifferentiated SpA. Infliximab has recently been approved for short-term treatment of severe uncontrolled AS; the approval for etanercept is pending. Studies should be performed to document the long-term efficacy of this treatment. There is hope that ankylosis might be preventable but it remains to be shown whether patients benefit from long-term anti-TNF therapy and whether radiological progression and ankylosis can be stopped. Severe adverse events have remained rare. Complicated infections including tuberculosis have been reported. Tuberculosis can be mostly prevented if patients are checked for previous contact with tuberculosis. Currently, the benefits of anti-TNF therapy in AS seem to outweigh these shortcomings.     

Novel approaches in the treatment of ankylosing spondylitis and other spondyloarthritides

The therapeutic options for patients suffering from severe forms of spondyloarthritis (SpA) have been rather limited in recent decades. There is now accumulating evidence that anti-TNF therapy is highly effective in SpA, especially in ankylosing spondylitis (AS) and psoriatic arthritis (PsA). Based on the data recently published on what is now several hundred AS and PsA patients, this treatment seems to be even more effective than the same therapy in rheumatoid arthritis (RA). The anti-TNF-α agents currently available, infliximab (Remicade^®; Centocor), etanercept (Enbrel^®; Amgen) and adalimumab (Humira?; Abbott), are approved for the treatment of RA in the US; infliximab and etanercept are approved in Europe. The situation in SpA is different to RA because there is an unmet medical need, especially in AS, since no therapies with disease-controlling antirheumatic drugs are available for severely affected patients, especially with spinal disease. Thus, TNF blockers might even be considered as first-line immunosuppressive agents in patients with active AS and PsA who are not sufficiently treated by non-steroidal anti-inflammatory drugs and sulfasalazine, if peripheral arthritis is present. For infliximab, a dosage of 5 mg/kg at intervals between 6 and 12 weeks was necessary to constantly suppress disease activity; this is also a major aim of long-term treatment. No dose-finding studies have yet been performed. The standard dose of etanercept is 25 mg s.c. twice-weekly. No studies on adalimumab (standard RA dose 20 – 40 mg s.c. every 2 weeks) have yet been conducted in SpA. The efficacy of etanercept was first demonstrated in PsA and etanercept is now approved for this indication. A double-blind study has also been performed in AS, with similarly clearcut efficacy. There is preliminary evidence that both agents do also work in other SpA such as undifferentiated SpA. Infliximab has recently been approved for short-term treatment of severe uncontrolled AS; the approval for etanercept is pending. Studies should be performed to document the long-term efficacy of this treatment. There is hope that ankylosis might be preventable but it remains to be shown whether patients benefit from long-term anti-TNF therapy and whether radiological progression and ankylosis can be stopped. Severe adverse events have remained rare. Complicated infections including tuberculosis have been reported. Tuberculosis can be mostly prevented if patients are checked for previous contact with tuberculosis. Currently, the benefits of anti-TNF therapy in AS seem to outweigh these shortcomings.     

Assessment of effectiveness and safety of biosimilar infliximab (CT-P13) in a real-life setting for treatment of patients with active rheumatoid arthritis or ankylosing spondylitis

Objective: To assess the effectiveness and safety of infliximab biosimilar, CT-P13, administered in a real-life setting to adult patients with active rheumatoid arthritis (RA) or ankylosing spondylitis (AS).

Methods: This multi-center, non-interventional, observational study was conducted in Bulgaria, the Czech Republic, and Romania. A total of 151 patients with severe active RA (n?=?81) or AS (n?=?70) were enrolled and treated with CT-P13 for 24 weeks, according to current medical recommendations. Effectiveness was assessed using the 4-item Disease Activity Score 28 with C-reactive protein (DAS28-CRP) for RA patients, and the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) for AS patients. Safety was assessed by withdrawals and adverse events (AEs).

Results: A total of 129 patients (RA: 67; AS: 62) were included in the effectiveness analysis. CT-P13 treatment significantly improved DAS28-CRP scores at 12 and 24 weeks (p?=?.0001 vs baseline for both timepoints) in patients with RA and BASDAI scores at 12 and 24 weeks (p?=?.0001 vs baseline for both timepoints) in patients with AS. CRP levels were significantly reduced at 12 and 24 weeks (p?=?.0001 vs baseline for both timepoints). Among 713 infusions, 34 AEs were reported (4.8% of infusions), of which 11 were considered related to CT-P13 treatment. Two of seven serious AEs were considered possibly (hepatocellular injury) or definitely (dyspnoea due to allergic infusion reaction) treatment-related. Eight patients discontinued CT-P13 due to AEs and four patients were withdrawn due to therapeutic failure.

Conclusions: CT-P13 was effective and safe in a real-life setting in patients with active RA or AS.     

Risk: benefit profile of etanercept in elderly patients with rheumatoid arthritis, ankylosing spondylitis or psoriatic arthritis

Rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA) are commonly thought of as inflammatory diseases that affect younger individuals. Although the initial presentation of these diseases is commonly in a patient's twenties or thirties, they usually persist for the duration of the patient's life. In addition, up to one-third of patients with RA have disease onset after 60 years of age. Older patients with any of these three diseases are more likely to have more severe disease with significant functional decline. They are also more likely to have co-morbid diseases and use concomitant medications than patients who are younger. In patients with RA, AS or PsA, the introduction of anti-tumour necrosis factor (TNF)-alpha therapies such as etanercept, infliximab and adalimumab has had a significant impact in ameliorating the signs and symptoms of disease, improving patient function and inhibiting radiographic progression. Anti-TNFalpha therapies now have well recognised safety profiles that have been demonstrated in the usual clinical trial populations for these diseases, but such populations under-represent patients > or =65 years of age. This review explores the information currently available regarding patients aged > or =65 years treated with anti-TNFalpha therapies for RA, AS or PsA, focusing on etanercept in RA because of a lack of data for other therapies and conditions. The analyses conducted show that there is similar efficacy in the treatment of RA in patients <65 years old and those > or =65 years of age. Although there are some differences in the adverse events noted in these two age groups, it appears as though treatment of patients > or =65 years of age, compared with age-matched controls, is not dissimilar to treatment of patients <65 years of age compared with their age-matched controls. Only by understanding the risks and benefits of therapy in the older age group can a true risk : benefit profile for etanercept, and ultimately other anti-TNFalpha therapies, be determined by the practising physician and the patient.     

Safety and tolerability of infliximab therapy: suggestions and criticisms based on wide clinical experience

Infliximab, an IgG1 monoclonal chimeric antibody against tumor necrosis factor (TNF)-alpha, represents the main biological drug employed for the treatment of several immuno-mediated inflammatory disorders. Infliximab infusion can be complicated by clinically heterogeneous adverse reactions, potentially interfering with the course of treatment. We analysed the adverse events recorded in 49 patients affected by different chronic inflammatory disorders (rheumatoid arthritis, seronegative spondyloarthritis, Beh?et's disease, Wegener's granulomatosis, Churg-Strauss syndrome, Cogan's disease) who were receiving a total of 709 infliximab infusions, in order to correlate the development of infliximab reactions and their features to some potential risk factors. We displayed a lower frequency of infusion reactions (1.5 percent; 11 out of 709 infusions) than those previously reported. However, patients suffering from rheumatoid arthritis and/or patients who underwent re-treatment after a long period, showed a higher prevalence of infliximab-related reactions. In conclusion, in our experience infliximab treatment is rarely complicated by adverse reactions which are, more importantly, almost always mild. Some good clinical practices, such as the low rate of infusion, pre-treatment with anti-histamine and prednisone in all patients, chronic immunosuppressive therapy and avoidance of long intervals between infusions may represent a combined useful strategy to reduce the frequency of infliximab reactions and to increase safety.     

Etanercept: efficacy and safety for approved indications

INTRODUCTION: Etanercept is a tumor necrosis factor alpha (TNF-α) inhibitor, which is approved for the treatment of immune-mediated inflammatory conditions including rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), psoriatic arthritis (PsA), ankylosing spondylitis (AS) and psoriasis (PsO). AREAS COVERED: Clinical efficacy and safety data of etanercept for the approved indications are reviewed in this paper. Data were obtained from published clinical trials, registries, post-marketing data as well as information provided by Amgen. EXPERT OPINION: Etanercept is a generally well-tolerated treatment for the approved inflammatory diseases. The most common adverse effect of etanercept treatment is injection site reaction, which is generally self-limiting and often does not require treatment. Etanercept may be associated with an increased risk for infection, the development of malignancy, demyelinating disease and congestive heart failure. Fewer patients withdraw from etanercept due to adverse events than with other biologics. For pediatric patients, there are more data for etanercept than other biologics, and etanercept may have lower rates for the development of malignancy.     

Persistent clinical response of infliximab therapy in patients with refractory rheumatoid arthritis, over a 3-year period

Infliximab, a chimeric monoclonal anti-tumor necrosis factor alpha antibody is approved for the treatment of patients with rheumatoid arthritis (RA) who had an inadequate response to methotrexate (MTX) therapy. This report provides analyses by using infliximab in combination with various disease modifying anti-rheumatic drugs, infliximab "survival" over a period of three years, and its effectiveness on synovial tissue damage using magnetic resonance (MR) imaging. The study was started in 1999 as an open label study using infliximab in combination with cyclosporin A (CsA) in refractory RA patients who were unable to tolerate MTX. A total of 18 RA patients were investigated. After a year of treatment, 80% of patients achieved the 20% American College of Rheumatology Response criteria. Two patients dropped out; one because of an immediate hypersensitivity reaction and the other because of the development of pulmonary tuberculosis. In a subsequent study we investigated infliximab "survival" over a period of 3 years. A total of 84 RA patients were included in the study. After 3 years of therapy, 59% of patients still continued receiving infliximab. The factor that was associated with infliximab "survival" was the concomitant use of MTX. A total of 28 (33%) patients discontinued this study. More specifically, 16 (19%) presented adverse drug reactions, 9 (11%) had drug failure, and 3 (3%) were lost from follow-up. Finally, to evaluate by MR imaging the inflammatory tissue changes in refractory RA patients treated with infliximab, 16 patients were examined with MR imaging of the dominant affected wrist and hand before and one year after therapy. The volume of the enhancing inflammatory tissue (VEIT) was evaluated. A significant decrease of VEIT was observed in 88% of patients after therapy. We conclude that in refractory RA patients infliximab was proved to be efficacious and well tolerated in combination with CsA. The clinical response of infliximab was persistent over a 3-year period and was associated with the concomitant use of MTX. This clinical improvement was also associated with the reduction of inflammatory disease tissue damage.     

Managing immunogenic responses to infliximab: treatment implications for patients with Crohn's disease

Infliximab is a tumour necrosis factor (TNF)-alpha antagonist that has revolutionised the treatment of Crohn's disease and rheumatoid arthritis. However, infliximab therapy can be complicated by a variety of adverse reactions. Acute infusion reactions occur during or shortly after infusion and typically consist of fever, chills, nausea, dyspnoea and headaches. Delayed reactions, characterised by myalgias, arthralgias, fever, rash, pruritus, facial, hand or lip oedema, dysphagia, urticaria, sore throat and headache may occur 3-12 days after infusion. Although the mechanisms of these reactions are not yet clearly defined, emerging evidence indicates that these reactions may be associated with the immune response against infliximab and the development of antibodies to infliximab.A number of studies have identified protective factors that may minimise adverse reactions, presumably related to the immune response against infliximab. Factors that may be protective by helping to establish immune tolerance for the foreign infliximab protein include concomitant administration of immunomodulators or corticosteroids, starting infliximab therapy with a 0, 2, 6-week induction regimen, maintenance dose administration with infusions every 8 weeks or less, and avoiding long periods between infusions.Infliximab therapy also may have other immunological consequences. There is evidence that infliximab may impede the appropriate immune response to a number of pathogens, prohibiting its use in patients with active infections. In addition, patients should be screened and appropriately treated for tuberculosis before initiating infliximab therapy. The development of autoantibodies, such as antinuclear antibody or anti-ds-DNA, has also been described with infliximab therapy, although the development of clinical lupus-like syndrome is rare. While there is a theoretical risk of increased rate of malignancies due to antagonism of TNFalpha, to date there is no clear evidence of such an effect. In addition, cardiac and neurological adverse events associated with infliximab therapy have been described. The mechanism for these adverse events is unclear.In summary, infliximab therapy can be an effective treatment for Crohn's disease; however, a number of immunological consequences and adverse events may complicate the infusion of this agent. Appropriate prophylaxis and therapy of these adverse reactions will allow infliximab to be used safely in the vast majority of patients.     

Long-term treatment with infliximab in inflammatory bowel disease: safety and tolerability issues

Crohn's disease and ulcerative colitis represent the most common forms of inflammatory bowel disease (IBD), clinical conditions affecting the small and/or large bowel. It is well known that IBD is an immune-mediated condition and that TNF-alpha plays a pivotal role in the pathogenesis of the disease. TNF-alpha has been scrupulously studied as a target for therapeutic intervention in this setting. A number of biologic compounds have been developed, including the European Medicine Agency (EMEA)-approved agents, infliximab and adalimumab. Although their efficacy in induction and maintenance of remission has been established by several clinical trials, many issues regarding safety remain to be elucidated. In fact, anti-TNF treatment may be associated with a number of rare, but serious, adverse events, including infusion reactions, infections, lymphomas and other malignancies. A black-box warning has to be taken into consideration when looking at potential serious infections such as tuberculosis. Active infections, demyelinating disorders and severe heart failure are contraindications for anti-TNF treatment. This review focuses on drug toxicity and adverse events related to infliximab treatment in IBD.