Etanercept and adalimumab treatment in patients with rheumatoid arthritis and spondyloarthropathies in clinical practice: adverse events and other reasons leading to discontinuation of the treatment

In the present study, we determined from a single-center data the treatment continuation, discontinuation and reasons for discontinuation in the patients with active rheumatoid arthritis (RA) or spondyloarthropathies (SpA) who were treated with etanercept or adalimumab. All RA and SpA patients, who were treated with etanercept (n = 53) or adalimumab (n = 43) as their first biological treatment according to national guidelines in the Center for Rheumatic Diseases, Tampere University Hospital during the years 1999–2005, were analyzed at baseline and after 1-year treatment. The treatment was regarded ineffective if the clinical response was lower than ACR50 in RA or the reduction of BASDAI was lower than 50% or 2 cm in SpA. After 1 year, the continuation rate was 74% with etanercept and 60% with adalimumab. Mean prednisolone dose among continuers was diminished by 52% in etanercept-treated patients and by 44% in adalimumab-treated patients. During 1-year follow-up, 14 (26%) of the etanercept-treated patients and 17 (40%) of the adalimumab-treated patients discontinued the medication. Eleven patients were regarded as poor responders, seven in etanercept group and four in adalimumab group. Adverse events (mainly infections and injection reactions) caused six discontinuations in etanercept-treated group and 11 discontinuations in adalimumab-treated group. Etanercept was discontinued due to other adverse event in two patients: in one patient due to adenocarcinoma of ovary and in one patient due to drug-related leukopenia. One patient treated with adalimumab developed clinical and immunological features of systemic lupus erythematosus (SLE). In the present study, etanercept and adalimumab treatments were started in patients who had active RA or SpA despite ongoing treatment with combinations of traditional disease modifying antirheumatic drugs (DMARDs). Thirty-nine (74%) patients and twenty-six (60%) patients achieved at least 50% response when etanercept or adalimumab was added to their earlier DMARD treatment. Adverse events (mainly infections and injection reactions) were in line with previous reports. Three rare adverse events were reported: one patient with ovarial carcinoma, one with leukopenia and one with features of drug-induced SLE.     

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.     

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.     

Etanercept and infliximab induce the same serological autoimmune modifications in patients with rheumatoid arthritis

Etanercept and infliximab treatments are often associated with autoantibodies induction. Their reported prevalences vary among different studies and the conclusions are somehow conflicting, mainly regarding whether the two drugs induce the same modifications. In this small prospective study, specifically designed to identify transient phenomena, we assess the prevalence of different relevant rheumatologic autoantibodies during anti-TNF-α courses in patients with rheumatoid arthritis. We report that both etanercept and infliximab transiently induce anti-DNA antibodies in 50–78% of patients, respectively, and these antibodies seem to be different from the typical lupus associated ones. Antinuclear antibodies (ANA) increased their titres and were newly produced up to 100% of patients. No other relevant antibodies are affected. Finally, as also confirmed for the first time by the patients switched from one drug to the other, the two TNF-α blockers behave similarly.     

Etanercept response in patients with rheumatoid arthritis after secondary loss of efficacy of infliximab

Abstract

This study was carried out to determine the effectiveness of half-dose administration of etanercept in patients with rheumatoid arthritis (RA) who exhibited secondary loss of efficacy of infliximab. Seventeen patients were administered 25 mg of etanercept once weekly for at least 1 year after secondary loss of efficacy of infliximab. The mean duration of treatment with infliximab was 32.5 ± 1.3 months. The patient cohort consisted of 3 males and 14 females, with a mean age of 56.3 ± 11.4 years and mean weight of 57.2 ± 10.9 kg. The mean duration of RA was 16.2 ± 10.9 years. The mean Disease Activity Score 28 was decreased significantly, from 5.8 at the initiation of infliximab therapy to 3.6 at the end of observation. There were no withdrawals due to adverse reactions during the study period, although in 2 subjects the agent was changed to tocilizumab due to lack of effect, one after 18 months and the other after 36 months, and 1 subject withdrew after 18 months for financial reasons. A good response can be expected to a half dose of etanercept in patients with secondary loss of efficacy of infliximab. Reduction of the patient’s cost burden also makes this a superior treatment.     

Sleep disruption frequency in rheumatoid arthritis: perceived stress predicts poor outcome over one year

Background: Sleep is an important daily process that can be disrupted by chronic illnesses including rheumatoid arthritis (RA). Aims: We tested whether demographic, medical and psychological factors act as predictors of change in frequency of sleep disruption associated with RA. Methods: A cohort of 129 White British people with RA (mean duration of RA 7.19 years; mean age 55.40 years; 75% women) was followed for one year. Self‐report questionnaires were employed to record demographic information and assess participants' sleep disruption (on a 4‐point frequency scale), morning stiffness (duration), pain and fatigue (visual analogue scales), impact of disability, anxiety, depression, stress, coping, illness perceptions and self‐efficacy. Hospital notes were reviewed for duration of RA, antidepressant use and comorbidity. Results: Participants were split into those with sleep disruption that was consistently infrequent or decreasing in frequency (n = 56; 43%) and those with sleep disruption that was consistently frequent or increasing in frequency (n = 73; 57%). Results of a logistic regression demonstrated that greater perceived stress at baseline predicted sleep disruption that was consistently frequent or increasing in frequency over the year. Change in sleep disruption frequency was not predicted by any other assessed variable. Perceived stress at the end of the year was not predicted by change in frequency of sleep disruption. Conclusions: Self‐reported frequency of sleep disruption among people with RA relates to perceived stress. Psychoeducational programmes that help people with RA manage their stress may be a non‐pharmacological method of improving sleep quality and therefore merits testing in specific interventional studies. Copyright: © 2007 John Wiley & Sons, Ltd.     

Musculoskeletal ultrasonography delineates ankle symptoms in rheumatoid arthritis

Objectives: To clarify the use of musculoskeletal ultrasonography (US) of ankle joints in rheumatoid arthritis (RA).

Methods: Consecutive RA patients with or without ankle symptoms participated in the study. The US, clinical examination (CE), and patients’ visual analog scale for pain (pVAS) for ankles were assessed. Prevalence of tibiotalar joint synovitis and tenosynovitis were assessed by grayscale (GS) and power Doppler (PD) US using a semi-quantitative grading (0–3). The positive US and CE findings were defined as GS score ≥2 and/or PD score ≥1, and joint swelling and/or tenderness, respectively. Multivariate analysis with the generalized linear mixed model was performed by assigning ankle pVAS as a dependent variable.

Results: Among a total of 120 ankles from 60 RA patients, positive ankle US findings were found in 21 (35.0%) patients. The concordance rate of CE and US was moderate (kappa 0.57). Of the 88 CE negative ankles, US detected positive findings in 9 (10.2%) joints. Multivariate analysis revealed that ankle US, clinical disease activity index, and foot Health Assessment Questionnaire, but not CE, was independently associated with ankle pVAS.

Conclusion: US examination is useful to illustrate RA ankle involvement, especially for patients who complain ankle pain but lack CE findings.     

An 8-year follow-up study of pulmonary function in patients with rheumatoid arthritis

To evaluate longitudinal alterations in pulmonary function, 63 patients suffering from rheumatoid arthritis (RA) with previously reported reduced pulmonary diffusing capacity were re-examined in an 8-year follow-up study. Cross-sectional examination revealed normal values for vital capacity (VC), forced expiratory volume in 1 s (FEV1) and diffusing capacity per litre alveolar volume (KCO). Total diffusing capacity (D_LCO; P>0.0001), maximal expiratory flow at 75% of expired VC (MEF 75; P>0.0001) and MEF 50 (P>0.01) were decreased. Longitudinal evaluation revealed unchanged MEF50, MEF75 and FEV1, whereas increases in D_LCO (P>0.0001) and KCO (P>0.0001) and a decrease in VC (P>0.05) were found. The longitudinal changes in diffusing capacity were unrelated to patient age, disease duration, disease activity in the study period or pulmonary function at the first examination. Thus, in patients suffering from RA, the most prominent functional pulmonary abnormality, decreased diffusing capacity, appeared to improve in the course of time, despite a slight decrease in VC and continued articular disease activity.     

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.     

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.     

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.     

Etanercept reduces the serum levels of interleukin-23 and macrophage inflammatory protein-3 alpha in patients with rheumatoid arthritis

The purpose of this study was to analyze the effect of the soluble TNF-α receptor etanercept on the serum levels of IL-16, IL-17, IL-23, and macrophage inflammatory protein-3α (MIP-3α) in rheumatoid arthritis (RA) patients. Twenty-two patients with RA were administered etanercept once or twice a week for more than 6 months, and we evaluated clinical and laboratory parameters and serum levels of IL-16, IL-17, IL-23, and MIP-3α at the baseline and at 3 and 6 months. Additionally, the production of IL-23 and MIP-3α of cultured synovial cells stimulated with TNF-α from RA patients was determined by ELISA. We also used ELISA kits to determine synovial fluid (SF) levels of IL-17, IL-23, and MIP-3α in patients with RA, osteoarthritis (OA), pseudogouty arthritis (PGA), and gouty arthritis (GA). A significant decrease in serum levels of IL-23 and MIP-3α was observed at 3 and 6 months after initial treatment of etanercept. TNF-α induced MIP-3α but not IL-23 production in cultured synovial cells from RA patients. SF levels of IL-17, IL-23, and MIP-3α in RA patients showed significantly higher levels than those of OA, PGA, and GA patients. This study demonstrated that the reduction of IL-23 and MIP-3α production in RA patients was a newly determined function of etanercept     

Anti-tumour necrosis factor-alpha therapy over conventional therapy improves endothelial function in adults with rheumatoid arthritis

Rheumatoid arthritis (RA) is associated with cardiovascular morbidity and mortality and inflammation contributes to related endothelial dysfunction. We aimed to investigate the effect of anti-TNFα therapy on endothelial function in subjects with rheumatoid arthritis. We measured flow-mediated (FMD) and GTN-mediated dilation of the brachial artery before and following 36 weeks of anti-TNFα therapy in nine RA patients and in a group of RA patients on conventional therapy. Thirty-six weeks of anti-TNFα therapy improved FMD relative to those on conventional therapy (8.65 ± 1.50 vs. 1.70 ± 1.36%, P = 0.02). No significant changes in GTN responses were evident. Significant improvements in tender (P = 0.03) and swollen (P = 0.02) joint counts, patients’ global self-assessment (P = 0.01) and DAS-28 scores (P = 0.04) were observed in the anti-TNFα treated group. The addition of anti-TNFα treatment to conventional therapy, in those with severe RA, reduces inflammatory symptoms and improves endothelial function, potentially lowering future atherosclerotic risk     

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.     

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.     

Development of sarcoidosis in etanercept-treated rheumatoid arthritis patients

We report two rheumatoid arthritis patients developing sarcoidosis possibly induced by etanercept. Both women, aged 46 and 53, had erosive, rheumatoid-factor-positive rheumatoid arthritis (RA) for 7 and 6 years, respectively. The eldest had received infliximab for over a year with good response, which was stopped because of a perfusion reaction. She developed a cough and dyspnea after 6 months of etanercept treatment. The other developed erythema nodosum and a plaque lesion on the right arm after 1 year of etanercept. Imaging showed, in both cases, mediastinal adenopathies. Biopsies were compatible with sarcoidosis. Etanercept withdrawal led to a complete remission. Recently, there have been reports of noninfectious granulomatous syndromes in patients receiving etanercept for a variety of diseases. In our cases, the temporal association with etanercept therapy and the complete remission after suspension of etanercept suggest a triggering role of this agent. Possible mechanisms of action and supporting evidence are discussed.     

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.     

Etanercept in refractory lupus arthritis: An observational study

ObjectiveTo investigate the long-term safety and preliminary efficacy of etanercept in patients with refractory lupus arthritis.MethodsWe evaluated 43 patients in this observational cohort study. All received etanercept (50 mg/week) in addition to concomitant immunosuppressive agents. Patient and disease characteristics were collected. Incidence of adverse events and the effect on autoantibody levels were evaluated. Clinical efficacy was measured by the 28-joint count and the SLEDAI-2K scores. Remission of lupus arthritis was defined by a 28-joint score = 0. Clinically inactive systemic disease was defined by a SLEDAI-2K score <4.ResultsThe total follow-up time was 93 patient-years (median: 2.3 years per patient; range: 0.4–6.8 years). Most side effects were minor and related to local reactions. Only 2 significant adverse events occurred (8%), both were of infectious nature. The rate of autoantibody production was low (18%). A mild increase in titres of ANA (2), IgG anti-dsDNA (3) and IgM anticardiolipin (aCL) (2) antibodies was observed. All anti-dsDNA antibody increments were transient and coincided with systemic flares. No vascular events occurred. In general, disease activity declined during therapy. Most patients (83%) with lupus arthritis achieved clinical remission by week 12. All patients with simultaneous serositis experienced clinical and radiological resolution of this condition. Relapses were frequent (23%), mostly mild and related to etanercept reduction. A total of 24 patients discontinued treatment, 12 of them due to clinical remission.ConclusionsLong-term therapy with etanercept was relatively safe and had remarkable long-term efficacy for refractory lupus arthritis. In view of these results, further controlled trials are warranted.     

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.