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ID PMID Title PublicationDate abstract
26000112 Serum levels of anti-CCP antibodies, anti-MCV antibodies and RF IgA in the follow-up of pa 2010 Nov Rheumatoid arthritis (RA) is characterized by the presence of circulating rheumatoid factor (RF) and anticitrullinated peptide antibodies (ACPA), which are positive in about 70-80% of patients. APCA have a higher specificity and therefore a higher diagnostic power than RF, but are less informative than RF in monitoring the course of the disease in patients under treatment. Recently, it has been reported that the anticitrullinated vimentin (a-MCV) antibody test can identify a particular subgroup of APCA that may be negative for anticyclic citrullinated peptide (a-CCP) antibodies. Concerning RF, the RF IgA isotype has been described as a more specific marker of erosive joint damage than total RF. The aim of our study was to monitor the levels of a-CCP, a-MCV, total RF and RF IgA in the follow-up of patients with RA treated with B-lymphocytedepletive rituximab (RTX), to detect any differences or peculiarities in patterns of these autoantibodies, especially in relation to their potential use as predictive markers of therapeutic response. We studied 30 patients with RA treated with RTX. All patients were previously unresponsive to at least 6 months of therapy with disease-modifying antirheumatic drugs (DMARDs; methotrexate, leflunomide, cyclosporine, chloroquine) and/or at least 6 months of therapy with anti-TNF biologics. The evaluation of response to RTX was made at month +6 using the EULAR criteria (DAS28). a-CCP, a-MCV, total RF and RF IgA were determined at baseline (before the first infusion of RTX) and after 1, 3 and 6 months. In serum samples obtained before treatment two cytokines essential for Blymphocyte proliferation, interleukin 6 (IL-6) and B-lymphocyte stimulator (BLyS) were also determined. In all patients a significant and consistent reduction in all the tested antibodies was found during follow-up, with no differences in respect of the degree of response to RTX. Of note, at baseline, generally a higher titre of all autoantibodies was seen in patients who then showed a better response to RTX. Finally, there were no differences in serum concentrations of IL-6 and BLyS in patients in relation to the presence or absence of the autoantibodies investigated, nor was there any significant correlation between the serum concentrations of the cytokines and the titres of the autoantibodies. Thus, neither a-MCV compared to a- CCP, nor RF IgA compared to routine total RF, provided any additional predictive information in the follow-up of patients with RA treated with RTX.
25197521 Methotrexate hepatotoxicity in patients with rheumatoid arthritis. 2010 Sep BACKGROUND Increases in aminotransferases (transaminitis) are potential major adverse reactions seen with long-term use of methotrexate (MTX). The aim of this study, therefore was to evaluate the incidence of MTX induced hepatotoxicity and its risk factors among rheumatoid arthritis (RA) patients. METHODS This retrospective study described 286 patients with RA who received ≥ 7.5 mg MTX weekly in an academic rheumatology clinic over a 15 year period. The results of serial liver function tests, concurrent MTX dose, cumulative dose and use of hepatotoxic drugs were collected and statistically analyzed according to a consecutive elevation in aminotransferases which occurred over at least a two week interval. RESULTS During the study period, 286 patients (84.4% female) with mean age of 46.6±12.7 years (18-84 years) were enrolled. Transaminitis occurred among 23.7% of patients (incidence: 6.9 per 100 person-years) during 40.5±34.6 month's exposure to MTX (989.6 person-years). The time difference between onset of therapy and occurrence of transaminitis was 22.1±22.0 months. The only significant factor related to the occurrence of transaminitis was the duration of MTX therapy. The average duration of treatment among patients with transaminitis (59.6±42.3 months) was greater than those with no transaminitis (p<0.001). The cumulative dose of MTX was significantly related to the occurrence of transaminitis (p<0.001). CONCLUSION MTX hepatotoxicity is a common complication of long-term treatment with MTX. It is associated with mild liver enzyme elevation and related to the duration of therapy.
21794593 [Inhibition of interleukin 6, a new therapeutic option in rheumatoid arthritis]. 2009 May Tocilizumab (TCZ) is a humanized monoclonal antibody which targets the receptor for IL-6, developed by the Japanese pharmaceutical company Chugai and the swiss company Roche. In Japan it is already under use for Castleman's disease, rheumatoid arthritis (RA) and Juvenile Idiopathic Arthritis. The clinical development outside Japan is very extensive and has shown efficacy in possible RA scenarios; early RA (part of the AMBITION study), established, MTX-resistant RA (OPTION) and RA resistant to other DMARD (TOWARD), and anti-TNF-α resistant RA (RADIATE). Both monotherapy with TCZ (AMBITION) and associated to other background drugs. Radiological efficacy has also been proven (LITHE). So TCZ is probably the biologic therapy with the most extensive clinical development before marketing in the western hemisphere. In this review we will specifically deal with clinical and radiological efficacy, as wel as its safety profile.
20461222 Tolerability and patient/physician satisfaction with subcutaneously administered methotrex 2010 Mar 18 OBJECTIVES: To determine preference, satisfaction, usability and local tolerability by patients, physicians and study nurses of two subcutaneously administered methotrexate (MTX) formulations of different concentrations. METHODS: This was an open-label, comparative, within-patient controlled, multicentre study of 132 patients with rheumatoid arthritis (RA). MTX treatment consisted of 20 mg/week administered as a medium-concentration formulation (MC) (2.0 ml of 10 mg/ml solution in prefilled syringe; separate needle) compared to a novel high-concentration formulation (HC) (0.4 ml of 50 mg/ml in prefilled syringe; pre-attached needle). Each treatment was given for three weeks. Questionnaires and visual analogue scales were used to measure outcomes. RESULTS: At the end of the study, 93% of the patients preferred HC over MC as further treatment. Overall assessment of HC was "good" or "very good" in 90.6% vs 34.4% in MC-treated patients. Physician's and patients global assessment of syringe usability showed highly statistically significant differences (P < 0.0001) in favour of HC. Overall assessment by study nurses' and investigators' was "good" (18.8%) or "very good" (81.2%) for HC and "good" in 31.3% or "very good" in 12.5% for MC, and no preference in 50%. Local tolerability improved slightly also with HC. CONCLUSIONS: The total smaller volume of administered drug and the improved usability of a pre-attached needle in combination with a smaller prefilled syringe resulted in preference of the patients of HC over MC. The slightly improved local tolerability may also have added to this preference. This assessment was confirmed by similar assessments made by healthcare professionals. Eudra-CT number: 2007-003591-19.
20029652 Changes in plasma IL-6, plasma VEGF and serum YKL-40 during Treatment with Etanercept and 2009 Sep 23 Changes in plasma IL-6, plasma VEGF and serum YKL-40 were determined in rheumatoid arthritis (RA) patients during treatment with etanercept alone or in combination with methotrexate. Twenty-five patients with active RA (DAS28 >/= 3.2) were randomized to receive etanercept (25 mg sc. biweekly) plus methotrexate (n = 12) or etanercept alone (n = 13). Plasma IL-6, plasma VEGF and serum YKL-40 were determined by ELISA. The 3 biomarkers and DAS28 scores were evaluated at baseline and after 4, 8, 12 and 16 weeks of treatment. At inclusion all patients had significantly (p < 0.001) elevated plasma IL-6, plasma VEGF and serum YKL-40 compared to healthy subjects. Eighteen patients responded to treatment (pooled data from both treatment groups), and they had significant (p < 0.05 to p < 0.001) decreases in plasma IL-6, plasma VEGF, serum YKL-40, ESR and DAS28 after 4 weeks of treatment and throughout the study (except serum YKL-40 at week 16). Plasma IL-6 showed the largest reductions. Non-responders had unchanged biomarkers. At week 16 the patients with DAS28 < 3.2 had lower levels compared to baseline values in plasma IL-6 (p = 0.005), plasma VEGF (p = 0.014), and ESR (p = 0.024).Plasma IL-6, plasma VEGF and serum YKL-40, which reflect different aspects of the inflammatory process, may provide useful information regarding early differentiation of responders from non-responders.
20018029 Genome-wide association studies of rheumatoid arthritis data via multiple hypothesis testi 2009 Dec 15 Genome-wide association studies often involve testing hundreds of thousands of single-nucleotide polymorphisms (SNPs). These tests may be highly correlated because of linkage disequilibrium among SNPs. Multiple testing correction ignoring the correlation among markers, as is done in the Bonferroni procedure, can cause loss of power. Several multiple testing adjustment methods accounting for correlations among tests have been developed and have shown improved power compared to the Bonferroni procedure. These methods include a Monte Carlo (MC) method and a method of computing p-values adjusted for correlated tests. The objective of this study is to apply these two multiple testing methods to genome-wide association study of the Genetic Analysis Workshop 16 rheumatoid arthritis data from the North American Rheumatoid Arthritis Consortium, to compare the performance of these two methods to the Bonferroni procedure in identifying susceptibility loci underlying rheumatoid arthritis, and to discuss the strengths and weaknesses of these methods. The results show that both the MC method and p-values adjusted for correlated tests method identified more significant SNPs, thus potentially have higher power than the corresponding Bonferroni methods using the same test statistics as in the MC method and p-values adjusted for correlated tests, respectively. Simulation studies demonstrate that the MC method may have slightly higher power than the p-values adjusted for correlated tests method.
21069419 Osteoclastogenesis and arthritis. 2011 Sep There is emerging interest for osteoclasts as key players in the erosive and inflammatory events leading to joint destruction in chronic arthritis. In fact, chronic inflammatory joint diseases such as psoriatic arthritis and rheumatoid arthritis are often characterized by destruction of juxta-articular bone and erosions due to the elevated activity of osteoclasts, which are involved in bone resorption. The main step in inflammatory bone erosion is an imbalance between bone resorption and bone formation: osteoclast formation is enhanced by proinflammatory cytokines such as TNF-α, IL-1β, and IL-17 and is not balanced by increased activity of bone-forming osteoblasts. T-cells, stromal cells, and synoviocytes enhance osteoclast formation via expression of RANKL and, under pathologic conditions, of proinflammatory cytokines. In rheumatoid arthritis, accumulation of osteoclasts in synovial tissues and their activation associated with osteoclastogenic cytokines and chemokines at cartilage erosion sites suggest that they could be usefully selected as therapeutic target. In particular, in consideration of the primary role of RANKL and TNF-α in osteoclastogenesis, the control of the production of RANKL and the inhibition of TNF-α represent important strategies for reducing bone damage in this disease.
20360897 Intima-media thickness evolution after treatment with infliximab in patients with rheumato 2009 Jul 30 BACKGROUND: Atherosclerosis is a well known progressive disease that recognizes risk factors such as diabetes, hypertension, smoking, dyslipidemia, and inflammation. Mechanisms underlying atherosclerotic processes during inflammation are not completely understood, but cytokines are also involved, in particular tumor necrosis factor-alpha (TNF-alpha). Chronic inflammatory diseases such as rheumatoid arthritis (RA) are commonly associated with atherosclerotic complication. Little is known about the role of treatment of chronic inflammatory disease on the evolution of atherosclerosis in this kind of disease. Usually, evolution of atherosclerosis is monitored by intima-media thickness and the presence of plaques on several arteries such as common carotid. AIM: The aim of the study was to monitor atherosclerosis evolution in seven RA patients on common treatment with infliximab (an anti-TNF-alpha drug) compared with seven RA patients during common treatment but not treated with infliximab. PATIENTS AND METHODS: We selected 14 patients with RA according to the American College of Rheumatology classification criteria. Seven patients were selected before and after common treatment for RA based on nonsteroidal anti-inflammatory drugs (NSAIDs), methotrexate, and steroids (12 months), and seven patients before and after treatment based on infliximab associated with NSAIDs, methotrexate, and steroids (12 months). Ultrasound vascular imaging was performed to screen intima-media thickness and the presence of atherosclerotic plaques on common carotid artery and identify evolution of atherosclerosis. RESULTS: After 12 months, patients that were treated with infliximab showed significant worsening of atherosclerosis with an increase of intima-media thickness and the presence of further atherosclerotic plaques compared to patients that were treated traditionally and showed a nonsignificant increase of the same parameters. DISCUSSION: Treatment based on anti-TNF-alpha such as infliximab shows a worsening evolution of atherosclerosis based on our data. If these data are associated with a poor clinical outcome such as atherothrombosis of cerebral vessels and/or coronary vessels, this should be evaluated by further studies.
27789990 Rheumatoid arthritis: Disease or syndrome? 2009 Rheumatoid arthritis (RA) has been described in the medical literature for over two hundred years, but its etiology remains unknown. RA displays phenotypic heterogeneity, and it is a relatively prevalent clinical entity: it affects approximately 1% of the population, resulting in enormous pathologic sequelae. Earlier studies targeting the cause(s) of RA suggested potential infectious involvement, whereas more recent reports have focused on a genetic origin of the disease. However, neither infection nor genetics, nor any other single factor is currently accepted as causative of RA. In this article we review studies relating to the etiology of RA, and those of several related matters, and we conclude that the literature indeed does provide insight into the causes underlying the initiation of RA pathogenesis. Briefly, given the remarkable phenotypic variation of RA, especially in its early stages, as well as a number of other characteristics of the condition, we contend that RA is not a discrete clinical entity with a single etiological source. Rather, we argue that it represents a common clinical endpoint for various starting points, each of which is largely guided by as yet poorly understood aspects of the genetic background of the affected individual. Adoption of this alternative view of the origin of RA will have significant consequences for future research and for development of new therapeutic interventions for this burdensome condition.
20618927 The rheumatoid foot: a systematic literature review of patient-reported outcome measures. 2010 Jul 9 BACKGROUND: The foot is often the first area of the body to be systematically affected by rheumatoid arthritis. The multidimensional consequences of foot problems for patients can be subjectively evaluated using patient-reported outcome measures (PROMs). However, there is currently no systematic review which has focused specifically upon the PROMs available for the foot with rheumatoid arthritis. The aim of this systematic review was to appraise the foot-specific PROMs available for the assessment and/or evaluation of the foot affected with rheumatoid arthritis. METHODS: A systematic search of databases was conducted according to pre-defined inclusion/exclusion criteria. PROMs identified were reviewed in terms of: conceptual bases, quality of construction, measurement aims and evidence to support their measurement properties. RESULTS: A total of 11 PROMs were identified and 5 papers that provided evidence for the measurement properties of some of the PROMs. Only one of the PROMs was found to be RA disease-specific. The quality of construction, pretesting and presence of evidence for their measurement properties was found to be highly variable. Conceptual bases of many of the PROMs was either restricted or based on reductionist biomedical models. All of the PROMs were found to consist of fixed scales. CONCLUSIONS: There is a need to develop an RA-disease and foot-specific PROM with a greater emphasis on a biopsychosocial conceptual basis, cognitive pre-testing methods, patient preference-based qualities and evidence to support the full complement of measurement properties.
19252373 [The role of TNFalpha-induced adipose-related protein (TIARP) in TNFalpha dependent arthri 2009 Feb Rheumatoid arthritis (RA) is a chronic inflammatory disease with a variable disease outcome, and is characterized with synovitis, erosive changes of the joints, pain and functional deficit. Etiology is unknown. In the pathogenesis of rheumatoid arthritis the key role have proinflammatory cytokines, particularly, tumour necrosis factor (TNFalpha). The prognosis of RA patients has improved significantly during recent years, after the introduction of TNFalpha-based therapy. Despite the wide use of these biologics, their precise mechanisms of action in RA remain unclear. In the K/BxN mice, glucose-6-phosphate isomerase (GPI) is an autoantigen recognized by T and B cells. Recombinant GPI immunization to DBA/1 mice also induced acute severe arthritis. This arthritis was clearly controlled by anti-TNFalpha Abs, suggesting similar etiology to RA. In this study, to understand the mechanisms of arthritis that was regulated by TNFalpha, we focused on TNFalpha-induced adipose-related protein (TIARP) in the generation of GPI-induced arthritis.
19393605 The preventive effect of adjuvant-free administration of TNF-PADRE autovaccine on collagen 2009 Adjuvants are necessary to elicit high titers of antibodies in vaccine-immunization procedures. We previously developed a mouse tumor necrosis factor-alpha (TNF-alpha) autovaccine (mTNF-PADRE) capable of inducing anti-TNF-alpha antibodies. In this study, we investigated the therapeutic effect of adjuvant-free administration of the autovaccine on collagen-type-II-induced rheumatoid arthritis (CIA) in mice. Our results showed that the vaccine could ameliorate the symptoms of CIA in mice. In addition, this study suggests that it is possible to control the antibody levels in mice immunized with mTNF-PADRE without adjuvant.
20018027 Conditional analysis of the major histocompatibility complex in rheumatoid arthritis. 2009 Dec 15 We performed a whole-genome association study of rheumatoid arthritis susceptibility using Illumina 550k single-nucleotide polymorphism (SNP) genotypes of 868 cases and 1194 controls from the North American Rheumatoid Arthritis Consortium (NARAC). Structured association analysis with adjustment for potential population stratification yielded 200 SNPs with p < 1 x 10-8 for association with RA, all of which were on chromosome 6 in a 2.7-Mb region of the major histocompatibility complex (MHC). Given the extensive linkage equilibrium in the region and known risk of HLA-DRB1 alleles, we then applied conditional analyses to ascertain independent signals for RA susceptibility among these 200 candidate SNPs. Conditional analyses incorporating risk categories of the HLA-DRB1 "shared epitope" revealed three SNPs having independent associations with RA (conditional p < 0.001). This supports the presence of significant effects on RA susceptibility in the MHC in addition to the shared epitope.
20035687 [Monoclonal antibodies in chronic autoimmune inflammatory diseases]. 2009 Dec Among chronic inflammatory diseases, rheumatoid arthritis is a common inflammatory and destructive arthropathy, characterized by the release of potent proinflammatory cytokines mostly TNFa and IL-1, which both mediate systemic effects and contribute to joint destruction. Many therapeutic agents have been proposed to antagonise these cytokines, among which monoclonal antibodies. Thus twenty years ago the anti-TNFa infliximab was the first monoclonal antibody to be proposed in a non-cancerous indication, rheumatoid arthritis. Since then, several other monoclonal antibodies and/or antagonists either targeting cytokines (IL-1, IL-6, RANKL), but also immune cellular effectors T and B cells, have been evaluated not only in rheumatoid arthritis, but also in systemic lupus, Crohn's disease, multiple sclerosis, or ankylosing spondylitis. Clinical benefit has been unambiguously demonstrated, but before these novel molecules enter routine clinical practice, several parameters will have to be accurately documented such as their safety, long term efficacy, and economical cost.
20018035 A combinatorial approach for detecting gene-gene interaction using multiple traits of Gene 2009 Dec 15 Rheumatoid arthritis is inherited in a complex manner. So far several single susceptibility genes, such as PTPN22, STAT4, and TRAF1-C5, have been identified. However, it is presumed that some genes may interact to have a significant effect on the disease, while each of them only plays a modest role. We propose a new combinatorial association test to detect the gene-gene interaction in the rheumatoid arthritis data using multiple traits: disease status, anti-cyclic citrullinated peptide, and immunoglobulin M. Existing gene-gene interaction tests only use the information on a single trait at a time. In this article, we propose a new multivariate combinatorial searching method that utilizes multiple traits at the same time. Multivariate combinatorial searching method is conducted by incorporating the multiple traits with various techniques of feature selection to search for a set of disease-susceptibility genes that may interact. By analyzing three panels of markers, we have identified a significant gene-gene interaction between PTPN22 and TRAF1-C5.
20018010 Simultaneous genome-wide association studies of anti-cyclic citrullinated peptide in rheum 2009 Dec 15 Genome-wide associations between single-nucleotide polymorphisms and clinical traits were simultaneously conducted using penalized orthogonal-components regression. This method was developed to identify the genetic variants controlling phenotypes from a massive number of candidate variants. By investigating the association between all single-nucleotide polymorphisms to the phenotype of antibodies against cyclic citrullinated peptide using the rheumatoid arthritis data provided by Genetic Analysis Workshop 16, we identified genetic regions which may contribute to the pathogenesis of rheumatoid arthritis. Bioinformatic analysis of these genomic regions showed most of them harbor protein-coding gene(s).
20558853 Seronegative polyarthritis as severe systemic disease. 2010 Jun BACKGROUND: Severe extra-articular disease is associated with high levels of rheumatoid factor (RF ) in patients with seropositive rheumatoid arthritis (RA ) and a poor prognosis. It is said that patients with seronegative rheumatoid arthritis have a more benign course and less destructive disease. We observed several patients with seronegative non-rheumatoid polyarthritis, with aggressive extra-articular systemic disease. OBJECTIVES: Review of seronegative systemic polyarthritis with clinical presentation of typical cases. METHODS: Medline search for systemic manifestations of seronegative polyarthritis. CLINICAL PRESENTATIONS: 1. A 56-year-old woman was admitted to the cardiac intensive care unit with stabbing presternal chest pain aggravated by breathing and progressive dyspnoea, which gradually developed over a period of two weeks with one episode of fever at 38.0 degrees C. She had suffered chronic pain in her buttocks for three years with polyarthralgia and evanescent palmar-plantar rash. Imaging showed bilateral sacroiliitis (HLA B27 negative) and a large pericardial effusion. Extra-articular manifestations of SAPHO syndrome were proposed and she was successfully treated with combined therapy: pulse methylprednisolone, azathioprine, colchicine and prednisone. 2. A 47-year-old woman with psoriatic arthropathy developed high fever with leucocytosis and thrombocytosis and lung infiltrates during exacerbation of her joint disease . She was treated with pulse methylprednisolone followed by corticosteroid tapering, anti-TNF (infliximab) and methotrexate with complete resolution. 3. A 19-year-old man with inflammatory bowel disease developed acute pericarditis with response to 6-mercaptopurine, salazopyrine and prednisone. RESULTS: We discuss a range of seronegative arthritis diseases with possible systemic manifestations including the main procedures for early diagnosis. Infection, malignancy, hypersensitivity, granulomatous disease and other collagen diseases such as systemic lupus erythematosus should be excluded, but investigations for an underlying disease should not delay early corticosteroid and immunosuppressive therapy. CONCLUSION: A high level of suspicion of extra-articular disease should always be maintained when treating active seronegative polyarthritis.
27077058 ASSESMENT OF ARTHROSCOPIC ELBOW SYNOVECTOMY OUTCOMES IN PATIENTS WITH RHEUMATOID ARTHRITIS 2009 Jan OBJECTIVE: To review functional outcomes of arthroscopic elbow synovectomy in patients with rheumatoid arthritis. METHODS: Between May 1999 and December 2005, 15 patients were submitted to elbow synovectomy using an arthroscopic approach. Three cases were bilateral, totaling 18 elbows. There were two male and 13 female patients. The mean age was 44 years and five months. The mean time of previous diagnosis was six years and eight months. All patients reported preoperative pain, and on seven elbows, instability was present. The mean preoperative values for joint motion were: flexion, 118°; extension, -24°, supine, 80°, and; prone, 71°. RESULT: The mean postoperative follow-up time was 39 months. The mean postoperative joint motion was 133° for flexion, -20° for extension, 84° supine, and 78° prone. On nine elbows (50%) an improved postoperative range of motion was reported, reaching functional levels. Twelve cases (66.6%) showed pain resolution or improvement to a level not interfering on the activities of daily life. According to Bruce's assessment method, the results were as follows: seven excellent, three good, two fair and six poor results, with an average of 85.5 points. Synovitis recurrence was found in six cases (33.3%), and evolution to osteoarthrosis was found in four (22.2%). CONCLUSION: Arthroscopic elbow synovectomy in patients with rheumatoid arthritis leads to pain improvement in 66.6% of the cases; however, it does not cause a significant range of motion improvement.
21794644 [Management of difficult clinical situations in rheumatoid arthritis: hepatitis]. 2009 Apr Treatment of patients with Rheumatoid Arthritis (RA) who also present a chronic infection by the hepatitis B or C virus represents a therapeutic challenge due to the possibility that treatments used for RA can aggravate or reactivate hepatitis, either due to the drugs hepatic toxicity or the increase in viral replication after immunosuppresive treatment. The problem of reactivation of hepatitis has assumed a larger importance in the past 5 years with the publication of several cases of reactivation of hepatitis B associated with anti-TNF therapy. In this article we revise both problems, hepatotoxicity and the increase of viral replication, as well as the better strategies to treat these patients.
18766426 Anakinra in the treatment of polyarticular-course juvenile rheumatoid arthritis: safety an 2009 Feb This study assessed the safety and preliminary efficacy of the interleukin-1 receptor antagonist anakinra in patients with polyarticular-course juvenile rheumatoid arthritis (JRA). Eighty-six patients entered a 12-week open-label run-in phase (1 mg/kg anakinra daily, < or =100 mg/day). Fifty responders were randomized to anakinra or placebo in a 16-week blinded phase, followed by a 12-month open-label extension (N = 44). Due to low enrollment, the primary endpoint was changed from efficacy to safety. The incidence and nature of adverse events were similar across all study phases, with the exception of injection site reactions, which were mild to moderate and decreased with time. Anakinra produced a nonsignificant (P = 0.11) reduction in disease flares compared with placebo. When normalized to 1 mg/kg dose, anakinra plasma concentrations were similar to values in adult patients with rheumatoid arthritis. These results indicate that anakinra 1 mg/kg once daily (< or =100 mg/day) is safe and well tolerated in patients with JRA.