Guidelines for the proper use of etanercept in Japan

Application of biological agents targeting inflammatory cytokines such as tumor necrosis factor-α (TNF-α) dramatically caused a paradigm shift in the treatment of rheumatoid arthritis (RA). Infliximab, a chimeric anti-TNF-α monoclonal antibody, has initially been introduced to Japan in 2003 and shown to be dramatically effective in alleviating arthritis refractory to conventional treatment. However, serious adverse events such as bacterial pneumonia, tuberculosis, and Pneumocystis jiroveci pneumonia were reported to be in relatively high incidence; i.e., 2%, 0.3%, and 0.4%, respectively, in a strict postmarketing surveillance of an initial 4000 cases in Japan. Etancercept, a recombinant chimeric protein consisting of p75 TNF-α receptor and human IgG, was subsequently introduced to Japan in March of 2005. We therefore drew up treatment guidelines for the use of etanercept to avoid potential serous adverse events, since only approximately 150 cases have been included in the clinical study of etanercept in Japan. The guidelines were initially designed by the principal investigators (N.M, T.T., K.E.) of rheumatoid arthritis study groups of the Ministry of Health, Labor and Welfare (MHLW), Japan, and finally approved by the board of directors of the Japan College of Rheumatology. The MHLW assigned a duty to the pharmaceutical companies to perform a complete postmarketing surveillance of an initial 3000 cases to explore any adverse events, and this was performed according to the treatment guidelines shown in this article.     

The role of nitric oxide in arthritic joints: a therapeutic target?

Nitric oxide (NO) is produced by many cell types in the joint, and its expression is delicately regulated. Depending on its concentration and cellular origin, NO appears to have both pro- and anti-inflammatory potential in the joint. Constitutively expressed nitric oxide synthase (NOS) produces small amounts of NO, which is essential for normal physiological homeostasis. However, inflammatory stimuli such as endotoxins, cytokines, and growth factors promote inducible NOS (iNOS) expression, initially as an anti-inflammatory response, and catalyse a high output of NO. Excessive NO can amplify inflammatory pathways and contribute to the development and maintenance of arthritis. Consequently, proper regulation of NO synthesis can lead to a novel therapeutic approach for inflammatory joint diseases. Further careful study will be necessary to develop new drugs to regulate the NO pathway and to determine the dosage, timing of administration, and duration of treatment in order to avoid both undesirable immunostimulatory effects and immunosuppressive effects. Received: February 18, 2000     

Guidelines on the use of etanercept for juvenile idiopathic arthritis in Japan

Etanercept is a dimeric fusion protein consisting of the extracellular domain of human tumor necrosis factor receptor II (TNFR II, molecular weight 75 kDa) coupled to the Fc region of human immunoglobulin (IgG1). It is produced by recombinant DNA technology by first introducing the gene into Chinese hamster ovarian cells and then purifying the protein from the culture supernatant. The mechanism of action of etanercept consists of binding to serum TNF-α and lymphotoxin (LT)-α (TNF-β), which prevents TNF-α and LT-α from binding to the TNF-α receptor on the plasma membrane of the target cell. Etanercept is currently approved for treating adult rheumatoid arthritis (RA) in more than 70 countries worldwide. In Japan, it was approved for this target group in January 2005. The USA and Europe were the first to approve entanercept for use in treating juvenile idiopathic arthritis (JIA), initially for the treatment of active polyarticular JIA in patients not responding to disease-modifying antirheumatic drugs (USA in May 1999, followed by the EU in February 2000). Thereafter, the drug received approval for the treatment of JIA in many other countries. In Japan, children who have been diagnosed and treated according to Yokota et al. (Mod Rheumatol 17:353–363, 2007), but who have responded poorly to treatment must move onto the next stage of treatment. Such treatments include biological drugs, which, however, should be used with strict adhesion to the indications and exclusion criteria and should be used, for the time being, only by physicians trained on how to use them. In Japan, etanercept was approved in July 2009 for use in children. Although this drug has brought about a revolutionary advance in the treatment of JIA, it is our task to maximize its therapeutic effects and minimize its toxic effects. The guidelines presented here define the indications, exclusion criteria, usage, and evaluation criteria of etanercept for the treatment of polyarticular JIA.     

The effect of circulating nitric oxide level on axial bone mineral density in postmenopausal Turkish women with rheumatoid arthritis: a preliminary report

The aim is to investigate the differences in the circulating nitric oxide (NO) levels of rheumatoid arthritis (RA) patients, healthy controls and osteoporotic (OP) patients. We also examined whether the circulating NO levels may be correlated with bone mineral density (BMD) in RA patients. Forty-five patients with RA, 30 healthy women and 30 osteoporotic patients were recruited from the outpatient clinic. All the subjects were female and postmenopausal. Serum NO levels were measured (Nitrite/Nitrate, calorimetric method 1746081, Roche diagnostics, Mannheim, Germany) and BMD was measured at the spine and hip using dual energy X-Ray absorbtiometry (DEXA, Norland XR-46). Height and weight were measured and body mass index was calculated. Circulating NO levels were significantly higher in RA patients than other groups. Moreover, the RA group showed significantly higher BMD at lumbar spine and femoral neck regions compared to osteoporotic patients. However, the RA group showed significantly lower BMD at all sites than the controls. There was no correlation between circulating NO levels and BMD in all groups. We suggest that, unlike postmenopausal osteoporosis, inflammation induced osteoporosis is associated with RA is characterised by relatively preserved bone mass at the axial bone regions, and circulating NO levels as a parameter or determinant of inflammation are not correlated with axial BMD in RA patients.     

Update on the Japanese guidelines for the use of infliximab and etanercept in rheumatoid arthritis

Abstract

Application of biological agents targeting tumor necrosis factor-α (TNF-α) caused a paradigm shift in the treatment of rheumatoid arthritis (RA). The introduction of infliximab in 2003 and etanercept in 2005 in Japan had a significant impact on both Japanese rheumatologists and RA patients, although serious adverse effects such as bacterial pneumonia, tuberculosis and Pneumocystis jiroveci pneumonia are significant concerns. Based on the data from post-marketing surveillance in Japan and accumulating evidence worldwide, the Internal Medicine Rheumatology Study Group of the Ministry of Health, Labor and Welfare (MHLW), Japan, has updated the guidelines for the use of anti-TNF-α agents for RA, which were subsequently approved by the Board of Japan College of Rheumatology (JCR). In the present revised guidelines, we combined the guidelines for use of each of infliximab and etanercept together with some modifications and precautions, paying special attention to serious adverse reactions. Although it is still controversial whether the use of TNF-α blocking agents per se increases the risk of infection or not, bacterial pneumonia, regardless of the pathogens, is the most frequent complications in RA. The risk factors associated with pneumonia identified in the post-marketing surveillance of infliximab in Japan are presented in this guideline. The diagnostic algorithm is also designed for early diagnosis and treatment of pulmonary lesions seen during the treatment of biological agents. Preventive measures and precautions against tuberculosis, another frequent and significant complication in Japan, are also described. Furthermore, risk factors for developing Pneumocystis pneumonia, which uniquely occurs at 30- to 50-fold frequency under TNF-α blockade therapy in Japan, are described here and its preventive measures are discussed. It is stressed that secondary-care rheumatologists should be better familiarized with the proper use of TNF-α blocking agents and be alert to any adverse events for a better management of RA patients.     

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.     

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.     

Update on the Japanese guidelines for the use of infliximab and etanercept in rheumatoid arthritis

Application of biological agents targeting tumor necrosis factor-α (TNF-α) caused a paradigm shift in the treatment of rheumatoid arthritis (RA). The introduction of infliximab in 2003 and etanercept in 2005 in Japan had a significant impact on both Japanese rheumatologists and RA patients, although serious adverse effects such as bacterial pneumonia, tuberculosis and Pneumocystis jiroveci pneumonia are significant concerns. Based on the data from post-marketing surveillance in Japan and accumulating evidence worldwide, the Internal Medicine Rheumatology Study Group of the Ministry of Health, Labor and Welfare (MHLW), Japan, has updated the guidelines for the use of anti-TNF-α agents for RA, which were subsequently approved by the Board of Japan College of Rheumatology (JCR). In the present revised guidelines, we combined the guidelines for use of each of infliximab and etanercept together with some modifications and precautions, paying special attention to serious adverse reactions. Although it is still controversial whether the use of TNF-α blocking agents per se increases the risk of infection or not, bacterial pneumonia, regardless of the pathogens, is the most frequent complications in RA. The risk factors associated with pneumonia identified in the post-marketing surveillance of infliximab in Japan are presented in this guideline. The diagnostic algorithm is also designed for early diagnosis and treatment of pulmonary lesions seen during the treatment of biological agents. Preventive measures and precautions against tuberculosis, another frequent and significant complication in Japan, are also described. Furthermore, risk factors for developing Pneumocystis pneumonia, which uniquely occurs at 30- to 50-fold frequency under TNF-α blockade therapy in Japan, are described here and its preventive measures are discussed. It is stressed that secondary-care rheumatologists should be better familiarized with the proper use of TNF-α blocking agents and be alert to any adverse events for a better management of RA 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.     

Serum leptin in rheumatoid arthritis

Leptin is a peptide hormone that has an essential role in the regulation of body weight by inhibiting food intake and stimulating energy expenditure. The role of leptin in the modulation of the immune response and inflammation has been regarded as important. In rheumatoid arthritis (RA) patients it was reported that fasting leads to an improvement of clinical and biological measures of disease activity, which was associated with a marked decrease in serum leptin. These features suggest that leptin may also influence the inflammatory mechanisms of arthritis in humans. In this study we assessed serum leptin levels in RA and osteoarthritis (OA) patients and found a correlation between serum leptin level and other markers as well as bone mass density changes, activity of disease, disease duration and the age of the patients. The blood was collected from 30 RA and 30 OA patients who constituted the control group. Serum leptin level was determined using the DRG Leptin ELISA Kit—a solid phase enzyme—linked immunosorbent assay based on the sandwich principle. The serum level of leptin in RA patients ranged from 1.8 to 81.1 ng/ml and median value was 11.2. There was a positive correlation between body mass index (BMI) of RA patients and serum level of leptin (correlation coefficients Spearman’s r = 0.81). According to correlation coefficients, serum leptin level is independent of age of RA patients, stage of disease, number of painful and swollen joints, duration of morning stiffness, disease duration as well as value of titre of the Waaler–Rose, disease activity score (DAS 28) value and presence of rheumatoid nodules. There was a negative correlation between serum leptin level and glomerular filtration rate (GFR). No correlation between the serum leptin level and T-score was found. An influence of steroid treatment on the serum leptin level was not shown. The median serum leptin level in OA patients was 9.2 ng/ml. There was a positive correlation between body mass index of OA patients and serum level of leptin (correlation coefficients Spearman’s r = 0.57). No correlation was found between serum leptin level and patient’s age, duration of disease and value of laboratory data. There were no correlations between serum leptin level and visual analogue pain scale (VAS) for the lower-limb afflicted patients as well as stage of disease according to Kellgren and Lawrence’s score in OA patients. There was a negative correlation between serum leptin level and T-score value in OA patients (r = −0.58, P < 0.05). No statistically significant differences were found between serum leptin levels for RA and OA 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.     

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.     

Endothelial nitric oxide synthase T-786C polymorphism in rheumatoid arthritis: association with extraarticular manifestations

Several genetic factors were implicated in the pathogenesis of rheumatoid arthritis (RA). A case–control study was carried out to verify the associations of T-786C polymorphism in the promoter region of the endothelial nitric oxide synthase (eNOS) gene with RA. One hundred and five consecutive RA patients and 100 healthy controls were genotyped. The distribution of the T-786C genotype and alleles did not differ significantly between RA patients and controls. Nevertheless, the frequency of extraarticular manifestations was significantly greater among the carriers of the C/C genotype than among carriers of the T/C and T/T genotypes (P = 0.022). The C/C genotype was significantly associated with extraarticular manifestations compared with the T/T and T/C genotypes taken together (OR = 4.9, 95% CI = 1.3–18.9). The C allele was significantly associated with extraarticular manifestations of RA (P _corr = 0.032). The results suggested the existence of an association between the T-786C polymorphism of the eNOS gene and extraarticular manifestations of RA.     

Expression of decay-accelerating factor on synovial lining cells in inflammatory and degenerative arthritides

Summary The decay-accelerating factor (DAF) is a complement regulatory cell surface protein that protects cells from complement-mediated lysis. We analysed synovial tissue biopsies from patients with chronic arthritides for the presence of DAF using immunohistochemistry. DAF was expressed in the synovial lining cell layer both in rheumatoid arthritis (RA) and in osteoarthritis (OA). DAF was also on vascular endothelial cells of synovial tissue. A significant correlation was found between the expression of DAF and of HLA-DR in the lining layer, suggesting that DAF may be induced during a local inflammatory response. In addition, C5b-9 terminal complement complexes were found in several DAF-positive cases, suggesting that complement activation might, in itself, induce DAF expression. We propose that the occurrence of DAF may represent a physiological mechanism for local complement regulation in synovial tissue.     

The process of collecting and evaluating evidences for the development of Guidelines for the management of rheumatoid arthritis,Japan College of Rheumatology 2014: Utilization of GRADE approach

Objectives. To describe the process of collecting and evaluating evidence for treating rheumatoid arthritis (RA) for developing clinical practice guidelines (CPGs) for rheumatologists in Japan.

Methods. The task force comprised rheumatologists, epidemiologists, health economists, and patients. First, the critical outcomes were determined according to a three-round Delphi method, and eight topics with 88 clinical questions (CQs) were formulated. A systematic review of CQs was conducted using the Cochran Database of Systematic Reviews, MEDLINE, and Japana Centra Revvo Medicina (2003–2012). A questionnaire survey and focus group interview were performed to capture the patients’ values and preferences. Data from the National Health Insurance drug price list and product information provided by pharmaceutical companies were collected to evaluate drug cost and safety. The GRADE approach was used to describe the evidence quality and determine the strength of recommendations. Recommendations were developed using a modified Delphi method by a multidisciplinary panel including patients.

Results. Eight meetings and frequent e-mail communications were conducted to draft a quality assessment of evidence and recommendations. For 88 CQs, recommendation statements were determined.

Conclusions. Using the GRADE approach, new CPGs successfully addressed important clinical issues for treating RA patients. Timely updating of recommendations should be routinely considered.     

Survey on attitudes regarding EULAR recommendations for the role of nurses involved in medical care of patients with chronic inflammatory arthritis in Japan

Objective: We seek to evaluate the opinions of nurses and doctors in Japan regarding EULAR recommendations for nurses’ roles in the management of chronic inflammatory arthritis.

Methods: This is a cross-sectional survey within Japan. We randomly selected nurses and doctors engaged in consultation of patients with rheumatoid arthritis (RA) and assessed their agreement and opinions on the feasibility of implementing EULAR recommendations, including potential barriers.

Results: 431 nurses and 128 doctors completed the questionnaire. For both nurses and doctors, levels of feasibility showed statistically significant lower results compared with those of agreement for all items. When compared between nurses and doctors, agreement showed no statistically significant differences, while nurses’ answers were statistically significant lower for feasibility. Insufficient time, staff and knowledge, lack of established procedures and facilities, and lack of an education system for nurses were cited as barriers to the feasibility of implementing EULAR recommendations.

Conclusions: This is the first survey within Japan evaluating opinions regarding EULAR recommendations for nurses’ roles. We found that while agreement was high, feasibility was generally believed to be low. We recommend further research and collaboration between medical professionals in order to implement these recommendations in Japan.     

Guidelines for the use of cyclosporine in rheumatoid arthritis

Cyclosporine has now been tested in over 10 clinical trials in Rheumatoid Arthritis. These show that it provides clinically important benefit in 30–50% of patients with severe rheumatoid arthritis with an acceptable side-effect profile. It should be offered to patients who fail to (or only partially respond to Methotrexate. The use of Cyclosporine in combination with other slow acting agents shows promise and should be tested at different points in the natural history of the disease.     

Obstacles to the implementation of the treat-to-target strategy for rheumatoid arthritis in clinical practice in Japan

Abstract

Objective. To clarify the obstacles preventing the implementation of the treat-to-target (T2T) strategy for rheumatoid arthritis (RA) in clinical practice.

Methods. A total of 301 rheumatologists in Japan completed a questionnaire. In the first section, participants were indirectly questioned on the implementation of basic components of T2T, and in the second section, participants were directly questioned on their level of agreement and application.

Results. Although nearly all participants set treatment targets for the majority of RA patients with moderate to high disease activity, the proportion who set clinical remission as their target was 59%, with only 45% of these using composite measures. The proportion of participants who monitored X-rays and Health Assessment Questionnaires for all their patients was 44% and 14%, respectively. The proportion of participants who did not discuss treatment strategies was 44%, with approximately half of these reasoning that this was due to a proportion of patients having a lack of understanding of the treatment strategy or inability to make decisions. When participants were directly questioned, there was a high level of agreement with the T2T recommendations.

Conclusion. Although there was a high level of agreement with the T2T recommendations, major obstacles preventing its full implementation still remain.