Leukoencephalopathy during administration of etanercept for refractory rheumatoid arthritis

A 74-year-old Japanese woman was diagnosed with rheumatoid arthritis due to polyarthralgia. She was prescribed various disease-modifying anti-rheumatic drugs, but most of them were discontinued because of side effects or poor effectiveness. She was referred to our hospital in 2004, and etanercept was administered from June 2005. This resulted in rapid improvement of polyarthritis; however, she developed disorientation from February 2006. She was admitted to our hospital because of convulsions and loss of consciousness. She was diagnosed with progressive multifocal leukoencephalopathy on the basis of clinical symptoms and magnetic resonance imaging of the brain. In this significant and important case, leukoencephalopathy occurred during etanercept administration, and we refer to the risk of anti-TNFα drugs.     

Plasma TNF binding capacity profiles during treatment with etanercept in rheumatoid arthritis

BACKGROUND: Etanercept (Enbrel) induces a rapid and sustained decline in disease activity in the majority of patients with refractory rheumatoid arthritis (RA). In these patients neutralization of TNFalpha and lymphotoxin (LT), previously termed TNFbeta is mediated by etanercept itself, as well as by naturally occurring soluble TNF receptors. However, the clinical response to treatment with etanercept may vary. Previously, pharmacokinetic studies have focused on the molar concentrations of etanercept, but very little is known about the kinetics of bioactive etanercept in patients treated with etanercept. The purpose of this study was to evaluate kinetics, including inter- and intraindividual variations of the total TNF binding capacity, in RA patients who were on a standard treatment schedule with etanercept. METHODS: Plasma samples were collected daily from 16 RA patients who were in the steady-state phase during treatment with etanercept 25 mg subcutaneous once (n = 2) or twice (n = 14) weekly. The inflammatory activity, including Health Assessment Questionnaire (HAQ) score, numbers of painful and swollen joints, and ESR, was assessed at inclusion; CRP was measured on a daily basis. The samples were incubated with human recombinant LT to a concentration of 1000 pg/mL and the levels of detectable LT were measured by ELISA specific for free LT. The LT binding capacity (LTBC) was expressed in arbitrary units (AU) as the percentage value of bound LT to added LT. RESULTS: The median LTBC values measured during the treatment schedule from Day 1 (before the injection) to Day 4 (before the next injection) were 47 AU. The LTBC values in each individual patient generally remained fairly stable through the treatment schedule, and there were no significant differences in LTBC levels in samples obtained on a daily basis during the treatment schedule. However, a pronounced variation between the patients was noticed with LTBC values ranging from 10-82 AU (coefficient of variation=38%). No significant association was found between LTBC levels and clinical measures of disease activity, including HAQ and numbers of swollen or painful joints. However, among patients with high LTBC levels (> or =65 AU), elevated levels of ESR and CRP were less frequent (0%) compared with patients who had lower LTBC levels, in which the frequencies of elevated ESR and CRP were 53% and 37%, respectively. Soluble TNF receptor 1 (sTNFR1) remained stable between the injections and correlated with the number of swollen joints, but did not correlate with LTBC values. CONCLUSION: LTBC levels appeared stable in each individual RA patient who was on the standard treatment schedule with weekly injections of etanercept, but the inter-individual variations were considerable.     

Successful etanercept treatment of constrictive pericarditis complicating rheumatoid arthritis

SIR, Effusive-constrictive pericarditis is a rare complicationof pericarditis. Indeed, Sagrista-Sauleda et al. [1] observedonly 15 cases in a prospective series of 1184 patients withpericarditis collected over 15 yr. After observing one caseof rheumatoid arthritis with relapsing pericarditis eventuallyleading to severe pericardial constriction, despite intensiveuse of common disease-modifying drugs, we tested etanercept,an antagonist of tumour necrosis factor alpha (TNF-), in a lastattempt to avoid surgery. A 36-yr-old woman was admitted to the cardiothoracic surgerydepartment of our hospital in September 2003 because     

Decreased flares of rheumatoid arthritis during the first year of etanercept treatment: further evidence of clinical effectiveness in the "real world"

OBJECTIVE: To determine the incidence of disease flare during the first year of etanercept treatment for 88 patients with rheumatoid arthritis (RA) and compare it with the incidence of flare in those same patients in the year before etanercept use. METHODS: The outpatient clinic charts of all patients with RA who were prescribed etanercept in or before September 1999, who also had at least one year's follow up in the same outpatient clinic, were surveyed. The primary outcome measure was the number of disease flares in one year before and after etanercept use. The secondary outcome measures included the number of patients who did and did not flare, how flares were treated, and the drug alterations that were necessary during the same two time intervals. RESULTS: The total number of flares for all patients in the year before etanercept treatment was 214 (mean (SD) 2.43 (1.75)). The number of flares in the first year of etanercept treatment decreased to 83 (mean 0.94 (1.07)) (p<0.0001). The total number of patients who had at least one flare in the year before etanercept use was 80; eight had no flares. In their first year of etanercept treatment, 50 patients had at least one flare; 38 had no flares (p<0.0001). Twenty one patients (24%) stopped using etanercept before completing one year's treatment. CONCLUSION: This study of patients with RA in the "real world" shows that etanercept is effective in reducing the number of RA flares.     

Treatment of rheumatoid arthritis with etanercept

Etanercept is effective in the treatment of rheumatoid arthritis (RA)when used as monotherapy and in combination with methotrexate(MTX). Radiographic progression of disease was slowed significantly when the drug was used for a 24-month period and was statistically significantly better than MTX. In addition to its use in RA,etanercept is approved by the U.S. Food and Drug Administration for other rheumatologic conditions, including psoriatic arthritis,ankylosing spondylitis, and juvenile chronic arthritis.     

Successful childbearing in two women with rheumatoid arthritis and a history of miscarriage after etanercept treatment

Two women with rheumatoid arthritis who had experienced miscarriages became pregnant while they were under etanercept treatment. One stopped etanercept after 3 weeks with increased doses of prednisolone, and the other restarted etanercept at a half doses 3 months later. They delivered a healthy baby at full term, and no problems in both expecting mothers and babies were observed. The use of etanercept in patients with rheumatoid arthritis seemed safe for pregnant mothers and their fetuses.     

TNFalpha inhibitors for the treatment of rheumatoid arthritis

Reasons for using TNFalpha inhibitors in rheumatoid arthritis Available agents modulating TNFalpha Adverse effects to TNFalpha inhibitors Which patients should be treated with TNFalpha inhibitors? Monitoring treatment with TNFalpha inhibitors Patient follow-up Open questions Conclusions     

Histological analysis of synovium by treatment of etanercept for rheumatoid arthritis

Aims: In order to investigate the histological change in effect attenuation cases of etanercept compared with methotrexate (MTX), we performed immunohistochemical examination by seven different molecules. Methods: We histologically assessed synovial tissue from five MTX‐treated rheumatoid arthritis (RA) patients as control and six etanercept and MTX‐treated RA patients after synovectomy by arthroscopy. The synovium of both groups were assessed by hematoxylin and eosin (HE) and we also analysed the expression of tumour necrosis factor‐α (TNF‐α), interleukin‐6 (IL‐6), matrix metalloproteinase‐3 (MMP‐3), B‐cell precursors and mature B‐cell transmembrane protein, CD20, macrophage marker, CD68, bromodeoxyuridine (BrdU) and vascular endothelial growth factor (VEGF) by immunohistochemistry. Results: HE staining showed vascular and cell proliferations of the synovium of the RA patients who received etanercept compared with the control MTX group. TNF‐α and IL‐6 were expressed in both groups.MMP‐3 and CD68 expressed less significantly in the etanercept group compared with the control (P < 0.05). CD20 strongly expressed in the etanercept group significantly (P < 0.05). BrdU expressed in the synovium in the etanercept group significantly (P < 0.05). VEGF was not found overall in both group. Conclusion: Based on the histological change of synovium, treatment by etanercept may be involved in vascular and cell proliferations with inhibition of the expression of CD68 and MMP‐3 in synovium of RA patients. These findings indicate immunohistochemical change of synovium with etanercept is one of the mechanism of efficacy of etanercept.     

Monoarticular septic arthritis in a patient with juvenile rheumatoid arthritis under etanercept treatment

A 7-year-old girl with polyarticular type juvenile rheumatoid arthritis (JRA) presented with acute onset of right hip pain with limited range of motion and fever within the past two days. She had received etanercept for more than one year. Percutaneous arthrocentesis was performed and showed a white blood cell count of 84150/μL in the synovial fluid, although the culture showed negative results. The fever and right hip pain completely resolved after antibiotic treatment. Herein, we report the first case of septic monoarthritis of JRA under etanercept treatment.     

Acute exacerbation of preexisting interstitial lung disease after administration of etanercept for rheumatoid arthritis

A 70-year-old woman with a 6-year history of seropositive rheumatoid arthritis (RA) and asymptomatic interstitial lung disease (ILD) began taking etanercept for ongoing arthritis despite treatment with methotrexate (MTX) and bucillamine. MTX was discontinued before introduction of etanercept. She developed lung injury 8 weeks after starting etanercept. Etanercept was discontinued and oral prednisolone 40 mg/day was begun, and her clinical findings gradually improved. Lung injury, although rare, is a recently noticed, potentially fatal adverse effect of all 3 licensed biological anti-tumor necrosis factor (TNF) agents. We recommend caution in the use of anti-TNF agents in elderly RA patients with preexisting ILD.     

Safety and efficacy of etanercept treatment in elderly subjects with rheumatoid arthritis

OBJECTIVE: To evaluate safety and efficacy of etanercept treatment in elderly (age > or = 65 yrs) and younger adult subjects (age < 65 yrs) with rheumatoid arthritis (RA). METHODS: Subset analyses were used to describe the safety and efficacy of etanercept in elderly and younger subjects treated for early and disease modifying antirheumatic drug-resistant or late-stage RA (ERA and LRA) in one of 4 randomized controlled clinical studies (N = 1353) or 2 longterm extensions (N = 1049). RESULTS: Rates of serious adverse events tended to be higher in elderly than younger subjects; however, rates of safety events observed in elderly etanercept-treated subjects did not exceed rates in elderly placebo or methotrexate (MTX)-treated subjects. With regard to efficacy measures [American College of Rheumatology 20% response (ACR20), ACR50, and ACR70], elderly subjects tended to have somewhat less robust responses to treatment than younger subjects. However, for both age groups, treatment with etanercept resulted in improved efficacy and function compared with control treatment, and combination therapy with etanercept plus MTX resulted in greater efficacy than either etanercept or MTX used alone. Efficacy responses of elderly subjects were sustained for up to 6 years. Radiographic progression (measured using modified Sharp Score) after one year of treatment was lower in subjects treated with both etanercept and MTX compared with subjects treated with either agent used alone, and this pattern was similar in both age groups. CONCLUSION: Consistent with responses in younger subjects, elderly subjects with RA treated with etanercept experienced significant improvement in disease activity and function without incurring additional safety concerns.     

A case of autoimmune hepatitis exacerbated by the administration of etanercept in the patient with rheumatoid arthritis

A 50-year-old woman was admitted for active rheumatoid arthritis (RA). She was found to have RA 1 year prior to this admission. Past history was unremarkable and she had no family history for rheumatic diseases. As nonsteroidal anti-inflammatory drug (NSAID) and methotrexate were not effective, etanercept was started (25 mg, twice a week). Mild elevation of alanine transaminase (ALT) and aspartate transaminase (AST) was found as an outpatient, and it was considered to be NSAID-induced liver injury. Two weeks after the first dose of etanercept, she developed progressive elevation of AST and ALT with right upper quadrant tenderness and hepatomegaly. Etanercept was discontinued and liver biopsy was performed, which demonstrated portal-area-dominant lymphoplasmacytic inflammatory cell infiltration. She was diagnosed as autoimmune hepatitis (AIH). Glucocorticoid was started with normalized liver function and stable joint symptoms. AIH was thought to be acutely aggravated by the administration of etanercept.