The urinary excretion of pyridinoline and deoxypyridinoline during rheumatoid arthritis therapy with infliximab

Rheumatoid arthritis is a systemic disease that causes inflammation and joint destruction. As a result of pathological destruction in bone and cartilage, crosslinks in collagen are resorbed more rapidly. This causes a rise in circulating collagen crosslink levels and their urinary excretion. In RA, apart from the crosslink resorption at the site of inflamed joints, there may be increased resorption due to general bone loss associated with disease activity. The aim of this study was to evaluate the influence of therapy with infliximab on urinary excretion of pyridinoline (PYD) and deoxypyridinoline (DPYR) as a markers of collagen degradation and its correlation with clinical and biochemical parameters of disease activity. Seventeen patients with active rheumatoid arthritis treated with infliximab were recruited into the study. The therapy resulted in the reduction in the symptoms of RA and urinary excretion of PYD and DPYR. The urinary excretion of PYD correlated with a number of swollen joints, morning stiffness, CRP and ESR. The urinary excretion of DPYR correlated during infliximab therapy with the number of swollen and tender joints and morning stiffness. The measurement of urinary excretion of PYR and DPYR may give insight into bone metabolism and help us to better understand the actual changes in bone and cartilage caused by RA and its treatment.Abbreviations DPYR Deoxypyridinoline - PYR Pyridinoline - RA Rheumatoid arthritis     

Use of etanercept in a patient with rheumatoid arthritis on hemodialysis

Disease-modifying anti-rheumatic drugs (DMARDs) are typically used for the therapy of rheumatoid arthritis (RA), but most have some nephrotoxicity. In several clinical studies, etanercept had fewer adverse effects on renal function than other DMARDs. We report the case of a 64-year-old woman with RA and renal insufficiency on hemodialysis treated using etanercept therapy. This case suggests that etanercept therapy might be effective in the short term for such patients.     

Use of etanercept in a patient with rheumatoid arthritis on hemodialysis

Abstract

Disease-modifying anti-rheumatic drugs (DMARDs) are typically used for the therapy of rheumatoid arthritis (RA), but most have some nephrotoxicity. In several clinical studies, etanercept had fewer adverse effects on renal function than other DMARDs. We report the case of a 64-year-old woman with RA and renal insufficiency on hemodialysis treated using etanercept therapy. This case suggests that etanercept therapy might be effective in the short term for such patients.     

Organizing pneumonia in a patient with rheumatoid arthritis treated with etanercept

Abstract

Etanercept-induced organizing pneumonia (OP) has not been reported in Japan. We describe the case of a rheumatoid arthritis patient who developed OP during etanercept treatment and discuss the possible mechanisms underlying the development of etanercept-induced OP and the existence of factors that predispose Japanese patients to drug-induced OP.     

Etanercept reduces the serum levels of macrophage chemotactic protein-1 in patients with rheumatoid arthritis

Abstract

This study was performed to analyze the effect of etanercept, the soluble tumor necrosis factor-α (TNF-α) receptor, on the serum levels of several chemokines including monocyte chemotactic protein-1 (MCP-1), regulated upon activation normal T expressed and presumably secreted (RANTES), and granzyme B in rheumatoid arthritis (RA) patients. Twenty-eight patients with RA were administered etanercept once or twice a week for more than 6 months. Clinical and laboratory parameters were measured and serum levels of MCP-1, RANTES, and granzyme B were determined using enzyme-linked immunosorbent assay (ELISA) kits at baseline and at 3 and 6 months after the initial treatment. In addition, the levels of MCP-1, RANTES, and granzyme B produced by cultured synovial cells stimulated with TNF-α were measured. A significant decrease in serum MCP-1 levels was observed at 3 and 6 months after initial treatment with etanercept. Serum RANTES and granzyme B levels did not show significant changes. TNF-α induced MCP-1, RANTES, and granzyme B production in cultured synovial cells from RA patients. Serum MCP-1 levels were significantly correlated with the disease activity scores of 28 joints combined with CRP (DAS28-CRP), indicating the role of MCP-1 in the pathogenesis of rheumatoid inflammation. This study demonstrated that a reduction of MCP-1 production in RA patients was a newly determined effect of etanercept. Another cascade not associated with TNF-α may induce granzyme B and RANTES production in RA patients.     

Etanercept reduces the serum levels of macrophage chemotactic protein-1 in patients with rheumatoid arthritis

This study was performed to analyze the effect of etanercept, the soluble tumor necrosis factor-α (TNF-α) receptor, on the serum levels of several chemokines including monocyte chemotactic protein-1 (MCP-1), regulated upon activation normal T expressed and presumably secreted (RANTES), and granzyme B in rheumatoid arthritis (RA) patients. Twenty-eight patients with RA were administered etanercept once or twice a week for more than 6 months. Clinical and laboratory parameters were measured and serum levels of MCP-1, RANTES, and granzyme B were determined using enzyme-linked immunosorbent assay (ELISA) kits at baseline and at 3 and 6 months after the initial treatment. In addition, the levels of MCP-1, RANTES, and granzyme B produced by cultured synovial cells stimulated with TNF-α were measured. A significant decrease in serum MCP-1 levels was observed at 3 and 6 months after initial treatment with etanercept. Serum RANTES and granzyme B levels did not show significant changes. TNF-α induced MCP-1, RANTES, and granzyme B production in cultured synovial cells from RA patients. Serum MCP-1 levels were significantly correlated with the disease activity scores of 28 joints combined with CRP (DAS28-CRP), indicating the role of MCP-1 in the pathogenesis of rheumatoid inflammation. This study demonstrated that a reduction of MCP-1 production in RA patients was a newly determined effect of etanercept. Another cascade not associated with TNF-α may induce granzyme B and RANTES production in RA patients.     

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.     

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.     

Synovial fluid and serum levels of soluble interleukin-6 receptor in patients with rheumatoid arthritis

Our objective was to measure both synovial fluid (SF) and serum levels of soluble interleukin-6 receptor (sIL-6R) in patients with rheumatoid arthritis (RA) and patients with osteoarthritis (OA), and to investigate the amounts of sIL-6R protein produced by cultured synovial cells, chondrocytes and mononuclear cells (MNCs). We measured levels of sIL-6R using a sensitive and specific enzyme-linked immunosorbent assay. Synovial cells, chondrocytes and MNCs were cultured, and the supernatants were also measured for sIL-6R. SF levels of sIL-6R in RA were significantly higher than those in OA. SF levels of sIL-6R significantly correlated with SF levels of IL-6 in RA. The serum level of sIL-6R was approximately 3-fold higher than the SF level of sIL-6R. sIL-6R protein was not detected in the supernatants of synovial cells and chondrocytes. As compared to the SF levels of sIL-6R, a small amount of sIL-6R protein was produced by SF MNCs. The above findings suggest that increased amounts of sIL-6R form IL-6-sIL-6R complexes which mediate IL-6 function in RA joints and that SF sIL-6R protein might be not only produced in affected joints, but also supplied from the serum.     

Synovial fluid and serum levels of soluble interleukin-6 receptor in patients with rheumatoid arthritis

Abstract

Our objective was to measure both synovial fluid (SF) and serum levels of soluble interleukin-6 receptor (sIL-6R) in patients with rheumatoid arthritis (RA) and patients with osteoarthritis (OA), and to investigate the amounts of sIL-6R protein produced by cultured synovial cells, chondrocytes and mononuclear cells (MNCs). We measured levels of sIL-6R using a sensitive and specific enzyme-linked immunosorbent assay. Synovial cells, chondrocytes and MNCs were cultured, and the supernatants were also measured for sIL-6R. SF levels of sIL-6R in RA were significantly higher than those in OA. SF levels of sIL-6R significantly correlated with SF levels of IL-6 in RA. The serum level of sIL-6R was approximately 3-fold higher than the SF level of sIL-6R. sIL-6R protein was not detected in the supernatants of synovial cells and chondrocytes. As compared to the SF levels of sIL-6R, a small amount of sIL-6R protein was produced by SF MNCs. The above findings suggest that increased amounts of sIL-6R form IL-6-sIL-6R complexes which mediate IL-6 function in RA joints and that SF sIL-6R protein might be not only produced in affected joints, but also supplied from the serum.     

Clinical impact of switching from infliximab to etanercept in patients with rheumatoid arthritis

We assessed the disease activity in patients with rheumatoid arthritis (RA) after switching from infliximab to etanercept according to the reason of infliximab discontinuation. At Helsinki University Central Hospital during the period 1999 to 2003, 49 patients with RA were switched from infliximab to etanercept. The reasons for infliximab discontinuation were: 42% for failure to respond by >American College of Rheumatology 50% criteria; 12% for adverse events; 46% responded to infliximab and were switched for non-medical reasons. Clinical outcome after the switch was compared between the groups according to the reason of infliximab discontinuation. Disease activity was measured with the 28-joint count Disease Activity Score (DAS28). In patients in the non-medical reasons group, the disease activity was suppressed effectively both during infliximab and etanercept. Furthermore, the one-year drug survival of etanercept in this group was the highest of 77% (95% confidence interval (CI), 62 to 97) among the three groups. In patients in the infliximab failure and adverse event groups, DAS28 values improved significantly during etanercept therapy. The 1-year drug survival of etanercept was 43% (95% CI, 26 to 70) and 50% (95% CI, 33 to 100), respectively. For RA patients who discontinued taking infliximab because of non-medical reasons experienced similar treatment efficacy during both biological agents. The treatment with etanercept provided sufficient disease control also for patients with infliximab failure or adverse event. Therefore, etanercept can be suggested when infliximab has failed or discontinued for other reasons.     

益赛普联合甲氨蝶呤治疗对类风湿关节炎临床及炎性细胞因子的影响

目的 研究类风湿关节炎（RA）患者益赛普（ETA）联合甲氨蝶呤（MTX）治疗后,临床表现及血清肿瘤坏死因子α（TNF-α）、白细胞介素-6（IL-6）、干扰素-γ（IFN-γ）浓度的变化.方法 选取活动性RA患者25例和正常人18例作为研究对象,研究期间患者均给予甲氨蝶呤10 mg每周1次口服,以及益赛普25 mg每周2次,皮下注射.治疗前及治疗后第6周收集患者血清,检测其TNF-α,IFN-γ、IL-6浓度,并记录肿胀关节数、压痛关节数、疾病活动性评分（DAS）、健康评估问卷评分（HAQ）、血沉（ESR）、C反应蛋白（CRP）和类风湿因子（RF）等,同时收集正常人血清检测上述指标.结果 RA组患者血清IL-6、TNF-α和IFN-γ浓度明显高于正常对照组（P分别＜0.01、0.05、0.05）.治疗后患者DAS28评分降低（P＜0.01）,HAQ、ESR、CRP、肿胀及压痛关节数也明显好转（P＜0.01）,血清RF、IL-6和TNF-α浓度也明显下降（P分别＜0.05,0.01,0.05）,治疗后血清IFN-γ浓度较前下降,但无显著性差异.结论 血清IL-6、TNF-α和IFN-γ浓度增高以及ESR、CRP、RF增加可作为RA病情活动指标.益赛普和甲氨蝶呤联合治疗能快速缓解患者关节炎症,并改善关节功能.     

A case of rheumatoid arthritis complicated by demyelination in both cerebral cortex and spinal cord during etanercept therapy

Abstract

Tumor necrosis factor (TNF) antagonists, including etanercept, have been approved for the treatment of rheumatoid arthritis (RA). These agents are not free of adverse events like other antirheumatic agents. Several important adverse events in CNS lesions have been reported. In this paper, we report on one patient with RA that had complications from a demyelinating disorder during TNF-blockade therapy using etanercept at 24 months after initial administration. A 66-year-old Japanese woman was diagnosed with RA in 1959. She received various disease-modifying antirheumatic drugs (DMARDs), but all of these agents were ineffective. She was administered etanercept in June 2005, and stayed well. Twenty-four months after the initial administration of etanercept, she developed palsy of bilateral upper extremities and gait disturbance subacutely, and was then admitted to our institute in August 2007. MRI of her spinal cord revealed a high-intensity lesion from the third through to the seventh cervical (C3–C7) levels. Additionally, T2-weighted MRI images showed disseminated high-intensity lesions in the white matter of brain. She was suspected of having a demyelinating disorder based on these MRI findings. There was no significant finding that pointed to another neurological disorder. High-dose corticosteroid therapy was conducted and was effective for her.     

A case of rheumatoid arthritis complicated by demyelination in both cerebral cortex and spinal cord during etanercept therapy

Tumor necrosis factor (TNF) antagonists, including etanercept, have been approved for the treatment of rheumatoid arthritis (RA). These agents are not free of adverse events like other antirheumatic agents. Several important adverse events in CNS lesions have been reported. In this paper, we report on one patient with RA that had complications from a demyelinating disorder during TNF-blockade therapy using etanercept at 24 months after initial administration. A 66-year-old Japanese woman was diagnosed with RA in 1959. She received various disease-modifying antirheumatic drugs (DMARDs), but all of these agents were ineffective. She was administered etanercept in June 2005, and stayed well. Twenty-four months after the initial administration of etanercept, she developed palsy of bilateral upper extremities and gait disturbance subacutely, and was then admitted to our institute in August 2007. MRI of her spinal cord revealed a high-intensity lesion from the third through to the seventh cervical (C3–C7) levels. Additionally, T2-weighted MRI images showed disseminated high-intensity lesions in the white matter of brain. She was suspected of having a demyelinating disorder based on these MRI findings. There was no significant finding that pointed to another neurological disorder. High-dose corticosteroid therapy was conducted and was effective for her.     

Toxic hepatitis induced by infliximab in a patient with rheumatoid arthritis with no relapse after switching to etanercept

We present a case of toxic hepatitis related to infliximab treatment in a 38-year-old woman with rheumatoid arthritis (RA). The patient had previously been treated with different disease-modifying drugs (DMARDs) alone or in combination but had never revealed signs of liver dysfunction. Due to high disease activity, treatment with infliximab (3 mg/kg i.v.) was initiated in combination with methotrexate (MTX) (25 mg/week) and folic acid (5 mg/week). The patient stopped MTX and folic acid on her own initiative after 3 weeks due to improvement of joint symptoms. After seven infusions, progressive elevations of the transaminases up to five times the upper normal limit were noted and treatment with infliximab was terminated. Serological tests for viral and autoimmune hepatitis and for ANA and anti-dsDNA were all negative. Specific infliximab antibodies could not be detected. Ultrasound of the liver was normal. Liver biopsy showed late signs of acute toxic hepatitis without MTX-related fibrosis. This is one the first cases that convincingly demonstrates that infliximab treatment may cause toxic hepatitis. Moreover, the case suggests a lack of hepatic cross-toxicity between infliximab and etanercept as the patient continued with etanercept without new episodes of liver dysfunction.     

Whole genome analysis on the genetic backgrounds associated with the secondary failure to etanercept in patients with rheumatoid arthritis

Objectives: Etanercept is effective for the treatment of rheumatoid arthritis (RA). However, some of the patients eventually lose efficacy (secondary failure) despite the absence of neutralizing antibodies. We aimed to explore single nucleotide polymorphisms (SNPs) associated with secondary failure.

Methods: We recruited RA patients given etanercept at 50?mg/week for ≥6 months from the Matsubara Mayflower Hospital RA registry. They were assigned to responders, secondary failure patients, and non-responders according to Disease Activity Score. Genome-wide association study (GWAS) was performed using Illumina HumanHAP300k BeadChips and the results were analyzed with Plink software. Clinical backgrounds were compared by ANOVA and contingency table analysis. The protocol was approved by IRB and written informed consent was obtained.

Results: Ninety, 27 and 17 patients were assigned to responders, secondary failure patients, and non-responders, respectively. No significant differences were observed regarding clinical backgrounds among the groups. GWAS revealed that six and 37 SNPs may be associated with secondary failure to etanercept with p?6 and <10^?5, respectively.

Conclusion: While our preliminary results with borderline significance should be validated by studies with a greater population size, some of the SNPs detected by our GWAS may be involved in the development of secondary failure to etanercept.     

No erosive progression revealed by MRI in rheumatoid arthritis patients treated with etanercept,even in patients with persistent MRI and clinical signs of joint inflammation

The aim of this study is to investigate the course of magnetic resonance imaging (MRI) signs of inflammatory and destructive changes in rheumatoid arthritis (RA) wrist and metacarpophalangeal (MCP) joints during etanercept treatment. MRI of the non-dominant wrist and second to fifth MCP joints was performed in five clinical active RA patients before and 4 and 16 weeks after initiation of etanercept treatment. MRI was evaluated according to the EULAR–OMERACT RA MRI reference image atlas. The median 28-joint count disease activity score (DAS28; erythrocyte sedimentation rate based) was 5.6 (range 5.0–6.8) at baseline and 3.5 (1.5–4.1) at week 16 (decreased in all patients compared to baseline, Wilcoxon–Pratt, p < 0.05). The median MRI synovitis score was 18 (14–21), 18 (10–20) and 16 (10–20) at baseline, week 4 and 16, respectively (decreased in all patients compared to baseline, Wilcoxon–Pratt, p < 0.05), while corresponding MRI bone oedema scores were 4 (0–13), 3 (0–9) and 1 (0–3; NS). The median MRI bone erosion score was 27 (11–111; NS) at all time points. Four patients had identical total bone erosion scores at baseline and week 16, whereas one patient showed a reduced score. In conclusion, one patient showed erosive regression, while no patient showed erosive progression on MRI during 16 weeks of etanercept therapy; even though clinical and MRI signs of joint inflammation remained. This small study supports that erosive progression judged by MRI is minimal in RA patients treated with etanercept, even in joints with persistent inflammation.     

Pharmacokinetics,efficacy and safety profiles of etanercept monotherapy in Japanese patients with rheumatoid arthritis: review of seven clinical trials

Abstract

Conventional synthetic disease-modifying anti-rheumatic drugs, including methotrexate, may not be tolerated by all patients with rheumatoid arthritis (RA), and limited international data for etanercept (ETN) monotherapy are available. The aim of this review was to summarize the clinical program for ETN monotherapy in Japanese patients with RA, which has included a pharmacokinetic study, clinical trials for registration, long-term studies, and once-weekly dosing studies. Pharmacokinetic results showed that serum concentrations of ETN were linear with dose levels and were similar to other international studies. Across interventional studies, 652 Japanese patients with active RA were treated with ETN. In the registration studies, ETN treatment led to consistent improvement in American College of Rheumatology 20/50/70 scores, European League Against Rheumatism Good Response, Disease Activity Score 28 erythrocyte sedimentation rate remission, and Health Assessment Questionnaire disability index. In the long-term studies, efficacy was maintained for up to 180 weeks. Similar results were seen in the once-weekly studies. Across the studies, more than 870 patient-years of exposure to ETN were recorded. Discontinuations owing to lack of efficacy or adverse events were modest and no new safety signals were recorded. These studies demonstrated that ETN monotherapy is efficacious and well-tolerated in Japanese patients with RA.     

Visceral leishmaniasis infection in a patient with rheumatoid arthritis treated with etanercept

Visceral leishmaniasis (VL) is a severe disease that can develop in immunocompromised patients. Antitumor necrosis factor-α (TNF-α) treatment of rheumatoid arthritis can result in clinical benefits, but with an increased risk of opportunistic infections. Leishmania infection in patients treated with TNF-α antagonists is extremely rare; for this reason, we report a patient with VL after etanercept treatment who had an unfavorable outcome.     

Etanercept reduces the oxidative stress marker levels in patients with rheumatoid arthritis

This study was performed to evaluate the effects of the TNF-α inhibitor etanercept on oxidation stress markers representing DNA damage, lipid peroxidation, and protein glycosylation. Twenty-two rheumatoid arthritis (RA) patients underwent etanercept treatment. The levels of serum total, urinary total, and urinary free pentosidine, which is an advanced glycation end-product (AGE), of urinary N^ε-hexanoyl lysine (N^ε-HEL), and of 8-hydroxy-deoxy guanosine (8-OHdG) were measured at baseline and at 3 and 6 months after the initial treatment with etanercept. Serum total and urinary total pentosidine levels were reduced at 6 months after the initial treatment with etanercept, and urinary free pentosidine levels were reduced at 3 and 6 months. Urinary N^ε-HEL levels were also reduced at 3 and 6 months, and urinary 8-OHdG levels were reduced at 6 months. Serum total and urinary total pentosidine levels in RA patients correlated with the number of swelling joints and tender joints, and urinary total pentosidine levels correlated with the Disease Activity Score using 28 joints (DAS28). This study demonstrated that etanercept acts as a regulator against pentosidine formation, oxidative DNA damage, and lipid peroxidation in RA patients.