Etanercept (Enbrel) administration for idiopathic pneumonia syndrome after allogeneic hematopoietic stem cell transplantation.

Acute pulmonary dysfunction remains a frequent and severe complication of hematopoietic stem cell transplantation (SCT). Almost half of the pulmonary insults that occur in this seating are noninfectious in origin and are referred to as idiopathic pneumonia syndrome (IPS). In this series of 3 patients, etanercept (Enbrel; Immunex, Seattle, WA), a soluble, dimeric tumor necrosis factor alpha-binding protein, was administered to 3 consecutive pediatric allogeneic BMT recipients with IPS. The administration of etanercept, in combination with standard immunosuppressive therapy, was well tolerated and associated with significant improvements in pulmonary dysfunction within the first week of therapy. These data suggest that etanercept may represent a safe, non-cross-reactive, therapeutic option for patients with IPS and that clinical trials studying etanercept for this indication are warranted.     

Etanercept therapy in children with juvenile rheumatoid arthritis.

Etanercept is an effective inhibitor of tumor necrosis factor that has shown a beneficial effect in patients with juvenile rheumatoid arthritis (JRA) that did not respond to other disease-modifying drugs. Here we report 3 patients with JRA who were refractory to traditional therapy; 1 with systemic JRA and 2 with polyarticular JRA. They received etanercept 0.4 mg/kg (maximum 25 mg) subcutaneously, twice a week for 3 months. The symptoms of arthritis improved significantly except that the patient with systemic JRA had disease flare-up during etanercept therapy. Two patients had upper respiratory tract infection during etanercept therapy and 1 suffered from seizure attack. The 2 patients with polyarticular JRA had disease flare-up within 2 months after etanercept was discontinued. This is the first report of etanercept treatment in JRA patients in Taiwan.     

Etanercept reduces late endotoxin-induced pulmonary hypertension in the pig.

To evaluate whether etanercept, a tumor necrosis factor (TNF)-blocking agent, may counteract hemodynamic deterioration in endotoxemic shock, we designed a prospective, randomized placebo-controlled trial with parallel groups, consisting of 13 pigs aged 10-14 weeks receiving general anesthesia. Five pigs were given 25 mg of etanercept, 1 h before the start of a 4-h continuous infusion of endotoxin. Another 5 pigs were given the corresponding volume of saline, 1 h before the start of a 4-h continuous infusion of endotoxin. Three pigs were given 25 mg of etanercept, 1 hr before the start of a 4-h continuous infusion of saline. At 1 h of endotoxemia, mean pulmonary arterial pressure (MPAP) and pulmonary vascular resistance index (PVRI) increased identically in both groups of pigs receiving endotoxin. Thereafter, two distinct different patterns in hemodynamics were observed. TNF-blocked pigs showed significantly lower MPAP and PVRI compared to controls. In the etanercept-treated endotoxemic pigs, Doppler analysis of the diastolic mitral inflow demonstrated a significantly increased E/A-ratio (early mitral wave inflow was divided by the atrial wave) at 2 h. The TNFblocking agent etanercept normalized two hemodynamic features of endotoxin-induced septic shock in pigs: (1) the sustained pulmonary hypertension and (2) diastolic dysfunction.     

Etanercept for the treatment of non-radiographic axial spondyloarthritis

Presently, tumor necrosis factor α antagonist therapy is the only effective alternative treatment to nonsteroidal anti-inflammatory drugs for the entire spectrum of axial spondyloarthritis, including non-radiographic and radiographic (=ankylosing spondylitis) forms. Recently, etanercept has been approved by the European Medicines Agency for the treatment of non-radiographic axial spondyloarthritis, increasing the number of available treatment options for this indication. The latest data on etanercept concerning clinical efficacy and safety in short-term and long-term treatment of patients with non-radiographic axial spondyloarthritis who do not respond to the first-line therapy with non-steroidal anti-inflammatory drugs suggests good efficacy and safety profiles similar to that observed previously in ankylosing spondylitis. This article reviews recent data on the efficacy and safety of etanercept and is focused on the treatment of non-radiographic axial spondyloarthritis. This article will also discuss the role of etanercept in the context of current and developing treatment options.     

Pilot trial on the use of etanercept and methylprednisolone as primary treatment for acute graft-versus-host disease.

Clinical and preclinical data indicate that tumor necrosis factor (TNF)-alpha is an important mediator of acute graft-versus-host disease (aGVHD) after allogeneic bone marrow transplantation. We completed a study using etanercept, a fusion protein capable of neutralizing TNF-alpha, for the initial treatment of aGVHD. Etanercept (25 mg subcutaneously) was administered twice weekly for 16 doses, along with methylprednisolone (2 mg/kg) and tacrolimus for biopsy-proven aGVHD. Twenty patients with a median age of 47 years (range, 8-63 years) were enrolled. Fourteen patients with grade II aGVHD (11 family donors and 3 unrelated donors) and 6 patients with grade III aGVHD (3 family donors and 3 unrelated donors) were treated. Twelve patients completed 16 doses of therapy, and 8 received 5 to 15 doses. Reasons for not completing all doses of etanercept included progression of aGVHD (n = 4), relapsed leukemia (n = 2), progression of pulmonary and central nervous system lesions (n = 1), and perforated duodenal ulcer (n = 1). Fifteen (75%) of 20 patients had complete resolution of aGVHD within 4 weeks of therapy. Increasing levels of soluble TNF receptor 1 plasma concentration during the first 4 weeks of therapy indicated progression of aGVHD in 5 patients. In contrast, for 15 responding patients, soluble TNF receptor 1 plasma concentration levels returned to baseline. These data demonstrate the feasibility of using cytokine blockade in the early treatment of aGVHD.     

Etanercept (SB4): A Review in Autoimmune Inflammatory Diseases

Etanercept (SB4) [Benepali^®], a tumour necrosis factor inhibitor that is a biosimilar of reference etanercept (Enbrel^®), is approved in the EU for use in all adult indications for which reference etanercept is approved, namely rheumatoid arthritis, axial spondyloarthritis (ankylosing spondylitis and non-radiographic axial spondyloarthritis), psoriatic arthritis, and plaque psoriasis. The approval of etanercept (SB4) was based on the results of stringent comparability exercises designed to demonstrate similarity to reference etanercept in terms of quality, biological activity, efficacy, safety, and immunogenicity. In two well-designed clinical trials, etanercept (SB4) was equivalent to reference etanercept with regard to pharmacokinetic properties in healthy volunteers and in terms of efficacy in patients with moderate to severe rheumatoid arthritis despite methotrexate therapy. Longer-term efficacy (up to 52 weeks) was also similar in both treatment groups. Etanercept (SB4) was generally well tolerated, with a similar safety profile to that of reference etanercept. Preliminary results of the open-label extension period (100 weeks) suggest that transitioning from reference etanercept to etanercept (SB4) was associated with sustained efficacy and no change in the adverse event profile or immunogenicity. In conclusion, etanercept (SB4) provides therapeutically equivalent alternative in adult patients with autoimmune inflammatory diseases requiring treatment with etanercept.     

Spotlight on Etanercept in Plaque Psoriasis and Psoriatic Arthritis

Etanercept (Enbrel), a tumor necrosis factor (TNF)-alpha antagonist produced by recombinant technology, is approved for use in the US as subcutaneous monotherapy in adults with moderate-to-severe psoriasis who are candidates for systemic therapy or phototherapy. The drug is also indicated in patients with psoriatic arthritis, in whom it may be used in combination with methotrexate.In well designed trials in patients with moderate-to-severe psoriasis, short-term etanercept therapy (typically 25 or 50mg twice weekly) significantly increased the proportion of patients achieving a 75% reduction in the Psoriasis Area and Severity Index score compared with placebo. Similarly, in well designed trials in patients with psoriatic arthritis, treatment with short-term etanercept 25mg twice weekly, alone or in combination with methotrexate, improved clinical features of the disease, while radiographic progression of joint damage appeared to be significantly slowed in a nonblind 1-year extension. Short-term etanercept therapy was well tolerated in patients with psoriasis or psoriatic arthritis. Etanercept is thus a valuable new option for the treatment of patients with chronic moderate-to-severe plaque psoriasis (who are candidates for systemic therapy or phototherapy or have failed other systemic therapies) or with psoriatic arthritis.     

Protein biochip array technology for cytokine profiling predicts etanercept responsiveness in rheumatoid arthritis

In rheumatoid arthritis (RA) there are currently no useful indicators to predict a clinical response to tumour necrosis factor-alpha (TNF-alpha) blockade. The purpose of this study was to determine the role of peripheral blood cytokine profiling in differentiating between a good versus poor response to etanercept in RA. Peripheral blood samples were collected at baseline and at 3 months from 33 patients with active disease who were treated twice weekly by etanercept therapy. Responders are defined by the presence of three of four American College of Rheumatology criteria: > or =20% decrease in C-reactive protein (CRP), visual analogue score of disease activity, erythrocyte sedimentation rate and improvement of the disease activity score (28; four values) by > or =1.2 obtained at 3 months. Twelve cytokines were measured from serum collected on days 0 and 90 by proteomic array (protein biochip array, Investigator Evidence, Randox France), including interleukin (IL)-6, TNF-alpha, IL-1a, IL-1b, IL-2, IL-8, interferon-gamma, IL-4, IL-10, monocyte chemoattractant protein (MCP)-1, epidermal growth factor (EGF) and vascular endothelium growth factor. Our results showed that high serum levels of MCP-1 and EGF were associated with a response to etanercept. In addition, the increase of two combined parameters CRP and EGF was predictive of a response to etanercept treatment at 3 months (sensitivity: 87.5% and specificity: 75%, accuracy: 84.4%). These findings suggest that cytokine profiling by proteomic analysis before treatment initiation may help to identify a responder patient to TNF-alpha blocking agents in RA.     

Safety and clinical responses in ankylosing spondylitis after three months of etanercept therapy

We aimed to evaluate the safety and clinical responses in Korean ankylosing spondylitis (AS) patients after three months of etanercept therapy. AS patients satisfying the Modified New York Criteria were enrolled. They were assessed for safety and clinical responses at enrollment and after three months of etanercept therapy. A total of 124 patients completed the study. After three months, the rate of ASsessment in AS International Working Group 20% improvement (ASAS 20) response was 79.8%. The rates of ASAS 40 and ASAS 5/6 responses were 58.5 and 62.8%, respectively. Significant improvement of Korean version of Bath AS Disease Activity Index (KBASDAI) (p<0.0001), Bath AS Functional Activity Index (BASFI) (p<0.0001), and Bath AS Metrology Index (BASMI) (p=0.0009) were achieved after three months. Quality of life was also significantly improved after three months, as demonstrated by scores for SF-36 (p<0.0001) and EQ-5D (p<0.0001). Erythrocyte sedimentation rate and C-reactive protein were significantly decreased (p<0.0001, p<0.0001, respectively). None of the patients developed tuberculosis and there were no serious adverse event. AS patients with inadequate response to conventional therapy showed significant clinical improvement without serious adverse events after three months of etanercept therapy.     

Treatment with etanercept for patients with juvenile rheumatoid arthritis in Taiwan--a preliminary report.

Tumor necrosis factor (TNF) is a major inflammatory cytokine involved in the pathogenesis of juvenile rheumatoid arthritis (JRA). Etanercept, approved in the United States and in Europe for use in patients with rheumatoid arthritis (RA) and JRA, is an effective inhibitor of TNF that has been shown to provide rapid and sustained improvement in both diseases. Here we report the preliminary results of etanercept use in 3 cases of JRA with poor response to traditional therapy including non-steroidal anti-inflammatory drugs and disease-modifying antirheumatic drugs. Two of the patients had polyarticular JRA and 1 had systemic JRA. Etanercept was administered at a dosage of 0.4 mg/kg (maximum 25 mg) subcutaneously twice a week. Clinical as well as inflammatory parameter improvement was noted after use of etanercept in all cases. The preliminary results of etanercept use in these 3 cases showed significant clinical benefit without obvious adverse effects.     

Tumour necrosis factor receptor-associated periodic syndrome (TRAPS): State of the art and future perspectives

Tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) is an autosomal dominant autoinflammatory disorder characterized by periodic fever episodes, arthralgia, myalgia, abdominal pain, serositis, and skin rash. TRAPS is caused by mutations in the gene encoding the TNF Receptor Super Family 1A (TNFRSF1A) on chromosome 12p13. The identification of TNFRSF1A mutations as the genetic cause of TRAPS coincided with the wider use of biological agents in medicine and raised the possibility that blocking TNF could potentially represent the primary therapeutic goal in TRAPS, thus disclosing new treatment choices for this complex disease. Anti-TNF therapy in TRAPS has been based on etanercept, a recombinant human TNFR (p75)-Fc fusion protein comprising two receptors linked by an IgG₁ Fc fragment. However a decrease in responsiveness to etanercept over time has been described, and it may be due to a non-specific action of etanercept in TRAPS; its efficacy may reflect ‘generic’ anti-inflammatory properties. Long-term adherence to etanercept is poor and a significant number of patients need to switch to anti-interleukin (IL)-1β therapy. In fact, the IL-1 receptor antagonist anakinra has recently been shown to prevent disease relapses both in the short- and in the long-term, and to induce a prompt and stable disease remission.     

Etanercept: in ankylosing spondylitis

Etanercept is a dimeric fusion protein based on the p75 tumor necrosis factor (TNF) receptor. It binds to TNFalpha and blocks its biological activity. Subcutaneous etanercept is effective in the treatment of rheumatoid arthritis, psoriatic arthritis, and polyarticular-course juvenile rheumatoid arthritis. More recently, etanercept has shown efficacy in the treatment of adults with ankylosing spondylitis. In randomized, double-blind, placebo-controlled trials, subcutaneous etanercept 25mg twice weekly for 6-24 weeks significantly reduced disease activity in patients with active ankylosing spondylitis. In the largest trial, etanercept produced a response rate of 57% compared with 22% for placebo after 24 weeks (response was determined via the validated ASAS 20 response criteria developed by the Assessments in Ankylosing Spondylitis [ASAS] Working Group). Etanercept therapy significantly improved health-related quality of life in patients with ankylosing spondylitis compared with placebo. The greatest improvements in a 16-week study were seen in the domains of physical functioning, physical role, bodily pain, vitality, and social functioning. Etanercept was generally well tolerated, with few serious adverse events or treatment withdrawals. The most common adverse events were injection-site reactions and minor upper respiratory tract infections.     

Etanercept

? Etanercept is a dimeric fusion protein based on the p75 tumor necrosis factor (TNF) receptor. It binds to TNFα and blocks its biological activity. ? Subcutaneous etanercept is effective in the treatment of rheumatoid arthritis, psoriatic arthritis, and polyarticular-course juvenile rheumatoid arthritis. More recently, etanercept has shown efficacy in the treatment of adults with ankylosing spondylitis. ? In randomized, double-blind, placebo-controlled trials, subcutaneous etanercept 25mg twice weekly for 6–24 weeks significantly reduced disease activity in patients with active ankylosing spondylitis. In the largest trial, etanercept produced a response rate of 57% compared with 22% for placebo after 24 weeks (response was determined via the validated ASAS 20 response criteria developed by the Assessments in Ankylosing Spondylitis [ASAS] Working Group). ? Etanercept therapy significantly improved health-related quality of life in patients with ankylosing spondylitis compared with placebo. The greatest improvements in a 16-week study were seen in the domains of physical functioning, physical role, bodily pain, vitality, and social functioning. ? Etanercept was generally well tolerated, with few serious adverse events or treatment withdrawals. The most common adverse events were injection-site reactions and minor upper respiratory tract infections.     

Successful etanercept therapy for refractory sacroiliitis in a patient with ankylosing spondylitis and mixed connective tissue disease

The concurrence of ankylosing spondylitis (AS) in a patient with mixed connective tissue disease (MCTD) is rarely described in the literature. Significant and sustained efficacy with tumor necrosis factor (TNF)-alpha blockers has been demonstrated in AS patients. However, evidence to date has revealed associated side effects, including antinuclear antibody induction and development of a lupus-like syndrome. Several authors have reported lupus-like manifestations in MCTD patients treated with TNF-alpha blockers used to control peripheral polyarthritis. In our case report, we demonstrate a good response to etanercept therapy for refractory sacroiliitis in a patient with coexisting AS and MCTD, without development of a lupus-like syndrome. This demonstrates that etanercept therapy may be an appropriate therapeutic agent for sacroiliitis in MCTD patients, as it is in AS alone.     

停用依那西普后强直性脊柱炎病情复发相关因素分析及骨灵汤对其病情复发的影响

目的探讨停用依那西普后强直性脊柱炎（AS）病情复发情况及其相关因素,评价骨灵汤对病情复发的影响。方法 60例活动性AS随机分为两组,治疗1组（骨灵汤合依那西普组）30例,治疗2组（依那西普组）30例,基线均合用一种非甾体类抗炎药。治疗12周后达到ASAS20改善的患者,停用依那西普,基线药物继续使用,每2～4周定期随访,直至病情复发或至9个月。采用Cox比例风险模型评价与复发有关的因素,Log-rank检验比较两组之间的复发情况。结果 12周后共53例患者达到了ASAS20改善标准并进入随访研究。其中治疗1组28例,治疗2组25例,两组人口统计学资料、基线及12周时病情特征比较差异无统计学意义（P〉0.05）。至研究结束时,有81.1%的患者病情复发。治疗1组复发率为71.4%,复发时间中位数为20周;治疗2组复发率为92.0%,复发时间中位数为14周,两组差异有统计学意义（P〈0.05）。Cox回归模型分析显示,基线BASDAI和CRP高及髋关节受累是病情复发的危险因素（P〈0.05）,治疗方法为保护因素（P〈0.05）。结论 AS停用依那西普后维持原药物治疗多数患者病情会复发,基线高BASDAI、CRP和髋关节受累是疾病复发的不利因素。早期联合使用骨灵汤能够有效维持疗效,延缓复发。     

Soluble tumor necrosis factor receptor: enbrel (etanercept) for subacute pulmonary dysfunction following allogeneic stem cell transplantation

Subacute lung disease, manifested as either obstructive (OLD) or restrictive (RLD) lung dysfunction, is a common complication following allogeneic stem cell transplantation. In each case, therapeutic options are limited, morbidity remains high, and long-term survival is poor. Between 2001 and 2008, 34 patients with noninfectious, obstructive (25) or RLD restrictive lung dysfunction (nine) received etanercept (Enbrel?, Amgen Inc.) 0.4 mg/kg/dose, subcutaneously, twice weekly, for 4 (group A) or 12 weeks (group B). Corticosteroids (if present at study entry) were kept constant for the initial 4 weeks of therapy and then tapered as tolerated. Thirty-one of 34 (91%) subjects were evaluable for response, and 10 (32%) met primary response criteria. There was no difference in response based on the duration of treatment (29% group A versus 35% group B; P = .99), the presence of RLD or OLD (33% versus 32%; P = .73), or the severity of pulmonary disease at study onset. Estimated 5-year overall survival rates following therapy were 61% (95% confidence interval, 46%-80%) for all subjects and 90% (95% confidence level, 73%-100%) for the 10 who met the primary response criteria. Five-year survival estimates for subjects treated with RLD was 44%, compared with 67% for those treated for OLD (P = .19). Etanercept was well tolerated, with no bacteremia or viremia observed. Pathogens were noted on posttherapy bronchoalveolar lavage in two cases. These data support the development of expanded clinical trials to study etanercept as a therapeutic agent for subacute lung injury after allogeneic stem cell transplantation.     

Association of the tumour necrosis factor-308 variant with differential response to anti-TNF agents in the treatment of rheumatoid arthritis

Anti-tumour necrosis factor (TNF) agents have revolutionized the treatment of patients with rheumatoid arthritis (RA). These therapies are, however, expensive and 30% of patients fail to respond. In a large cohort of Caucasian RA patients treated with anti-TNF medications (total n = 1050, etanercept n = 455, infliximab n = 450), we investigated whether genotypes of eight single nucleotide polymorphisms in the region containing the TNF gene were associated with response to anti-TNF therapy. Linear regression analyses adjusted for baseline 28 joint disease activity score (DAS28), baseline health assessment questionnaire score, gender and concurrent disease modifying anti-rheumatic drug treatment were used to assess association of these polymorphisms with treatment response, defined by change in DAS28 after 6 months. Analyses were performed in the entire cohort, and also stratified by anti-TNF agent. Association between DAS28 response and TNF-308 (rs1800629) genotype (P = 0.001) was detected across the whole cohort. After stratification by anti-TNF agent, the rare TNF-308AA genotype was associated with a significantly poorer response compared with TNF-308GG in etanercept (P = 0.001, n = 7) but not infliximab (P = 0.8, n = 17) treated patients. Conversely, the GA genotype at TNF-238 (rs361525) was associated with a poorer response to infliximab (P = 0.028, n = 40), but not etanercept (P = 0.6, n = 33). Owing to the small numbers of patients in some of the genotype groups examined, our data must be regarded as preliminary and will require replication in further large cohorts of anti-TNF-treated patients. If confirmed, our findings suggest the potential for genotype at these markers to aid selection of anti-TNF agent in patients with RA.     

Immune function in patients with rheumatoid arthritis treated with etanercept

Etanercept, a recombinant human tumor necrosis factor (TNF) inhibitor that binds both soluble and cell-bound TNF, has been shown to reduce disease activity and inhibit joint destruction when administered to patients with rheumatoid arthritis (RA). Because TNF receptors are found on many types of cells that modulate the immune response, we evaluated the general immune function of a subset of RA patients in a blinded clinical study. No significant differences were seen between patients treated with etanercept or placebo in the surface antigen phenotypes of peripheral blood leukocytes, T cell proliferative responses, neutrophil function, delayed-type hypersensitivity (DTH) reactions, serum immunoglobulin levels, or incidence of infections. Although this observational study was relatively small and could detect only major changes in immunological status, the stability of immune function over time in patients receiving etanercept corroborates the findings in clinical studies, which suggest that etanercept does not alter overall global immune function.     

依那西普抑制博来霉素诱导的小鼠肺纤维化

 目的：观察肿瘤坏死因子 α(TNF-α)拮抗剂依那西普对博来霉素诱导的肺纤维化小鼠的抑制纤维化作用,并探讨依那西普治疗肺纤维化的可能机制。方法：将45只SPF级雌性昆明小鼠随机分为3组：对照组（气管内雾化生理盐水）、纤维化组（气管内博来霉素3 mg/kg溶于100 μL生理盐水内雾化）和依那西普干预组（气管内雾化博来霉素后,4 mg/kg依那西普溶于100 μL生理盐水内腹腔注射,每3 d注射1次）。处理后第28 d收集样本,小鼠左肺置于10%中性甲醛固定,石蜡包埋切片后行HE与Masson染色;右肺碱水解法检测组织羟脯氨酸(HYP)的含量;酶联免疫法检测血清TNF-α和转化生长因子 β（TGF-β）的含量;提取肺组织总蛋白,Western blotting 检测磷酸化ERK1/2、JNK和p38的表达。结果：依那西普干预组肺组织病理损伤及气道上皮下胶原沉积较纤维化组减轻,肺叶炎症损伤评分和纤维化评分明显下降（均P<0.01）,肺组织HYP含量显著降低（P<0.05）,血清TNF-α 和TGF-β的浓度明显减少（均P<0.01）,肺组织ERK1/2、JNK和p38蛋白的磷酸化水平也显著下降（P<0.01,P<0.05,P<0.01）。结论：依那西普能显著下调TNF-α 和TGF-β的水平,从而抑制ERK1/2、JNK和p38的活化,缓解博来霉素诱导的小鼠肺纤维化病变。