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ID PMID Title PublicationDate abstract
15157004 Review of health economics modelling in rheumatoid arthritis. 2004 As the cost of drug treatment for rheumatoid arthritis (RA) constitutes only a small proportion of total costs of the disease to individuals and society, therapeutic interventions have the potential for significant economic benefit. To take advantage of this potential, clinicians need to gain a global, long-term perspective on patient care. Economic evaluations of RA therapies are critically important in influencing decisions regarding the role of costly, but highly effective new therapies, particularly in settings where there are financial constraints on healthcare provisions. Such evaluations, therefore, need to be methodologically similar with valid results to enhance their value to clinicians and policy decision-makers. This requires the use of appropriate elements in the numerator (i.e. total number of dollars spent on healthcare as a result of the intervention) and the denominator (net health effectiveness) components of the cost-effectiveness equation. Other important design factors also need to be managed properly to ensure validity of the evaluation. In this regard, the guidelines proposed by the Outcome Measures in Rheumatoid Arthritis Clinical Trials (OMERACT) Task Force represent a useful approach to help create common standards for economic evaluations in RA. Recently, the development of a number of decision analysis models in RA has helped predict the likely cost-effectiveness of new interventions such as the anti-tumour necrosis factor (TNF)-alpha agents, etanercept and infliximab, both of which have been found to be cost-effective relative to other disease-modifying anti-rheumatic drugs (DMARDs) using short-term efficacy endpoints. In comparisons of these two agents in patients with DMARD-resistant RA, etanercept has been shown to be more cost-effective than the combination of methotrexate and infliximab, administered in various dosages, over a period of 1 year using American College of Rheumatology (ACR) response rates as the primary efficacy measure. However, the criteria for determining clinical efficacy is paramount and other studies that use radiographic progression as a measure of clinical effectiveness show no difference between etanercept and infliximab in clinical efficacy. Important issues that need to be considered in developing economic models in RA include consideration of the connection between the prevention of radiographic progression and downstream economic consequences, and the need to employ lifetime models wherever possible because a long time period is necessary to determine the true cost-effectiveness of agents that modify radiographic progression of RA, such as etanercept, infliximab, and adalimumab. In doing so, it is hoped that such studies will provide optimal information to facilitate important decisions on resource allocation.
15823761 Anakinra: review of recombinant human interleukin-I receptor antagonist in the treatment o 2004 Dec BACKGROUND: Interleukin-1 (IL-1) plays an important role in the pathophysiology and progression of rheumatoid arthritis (RA) by contributing to destruction of cartilage, bone, and periarticular tissues. Inhibiting IL-1 synthesis or activity with the use of recombinant human IL-1 receptor antagonist (anakinra) may prove to be an effective approach to the treatment of RA. OBJECTIVE: The purpose of this article is to review the effects of anakinra in the treatment of RA. METHODS: A MEDLINE search from 1982 to 2003 was used to identify animal studies and randomized clinical trials of anakinra and other therapies that target IL-1. RESULTS: Clinical trials of anakinra have shown that it reduces the signs and symptoms of active disease and slows the rate of radiographic destruction in adults with RA. With anakinra 150 mg/d, 43% of patients achieved an American College of Rheumatology (ACR) 20% response, compared with 27% with placebo (P = 0.014). The ACR20 score indicates at least 20% improvement in the ACR composite score, which includes assessment of tender and swollen joint count, and other clinical end points such as pain and disability assessment. Patients treated with anakinra also experienced a 59% reduction in new bony erosion compared with controls (P < 0.001) and a 65% reduction in joint space narrowing as measured by the modified Sharp score (P = 0.020). Injection-site reactions were the most commonly reported adverse event, occurring in 50%, 73%, and 81% of patients receiving anakinra 30, 75, and 150 mg/d, respectively, compared with 25% of patients receiving placebo. Few serious adverse events were reported, and they typically occurred in patients receiving the highest daily dosage. CONCLUSIONS: IL-1 is an important cytokine in promoting the damage associated with RA. Anakinra is mildly to moderately effective and well tolerated in patients with active RA when used as monotherapy or in combination with methotrexate.
12617039 [Pharmacological profile of anti-human TNF alpha monoclonal antibody, infliximab (Remicade 2003 Jan TNF alpha (tumor necrosis factor-alpha) plays an important role in the pathogenesis of inflammatory diseases including Crohn's disease and rheumatoid arthritis. Infliximab (Remicade) is a chimeric monoclonal antibody that recognizes human TNF alpha. Clinical trials trials have been persuasive that infliximab is effective in both Crohn's disease and rheumatoid arthritis. Infliximab is an important treatment option in patients with active Crohn's disease who have not responded to conventional therapy and in patients with Crohn's disease who have fistulae. Moreover, infliximab plus methotrexate is effective in patients with active rheumatoid arthritis who have not responded adequately to traditional disease-modifying anti-rheumatic drugs, in terms of reducing symptoms and signs, inhibiting the progression of structural damage and improving physical function.
14969073 Methotrexate as the "anchor drug" for the treatment of early rheumatoid arthritis. 2003 Sep The two major advances over the 1990s in the treatment of rheumatoid arthritis (RA) were a shift in strategy from a "pyramid", in which disease modifying anti-rheumatic drugs (DMARDs) were deferred for several years, to the early aggressive use of DMARDs and widespread acceptance of methotrexate as the DMARD with the most long-term effectiveness and safety. Methotrexate courses are continued far longer than those of any other DMARD, an excellent indicator of greater effectiveness and safety. In one recent series, methotrexate was the first DMARD used in more than 80% of patients with RA. Studies which document the superiority of combinations of methotrexate with biological agents to methotrexate monotherapy select for only a minority of contemporary patients with RA who have severe disease activity and incomplete responses to methotrexate. In one locale, only 5% of patients met criteria for the Anti-Tumor Necrosis Factor Trial in RA with Concomitant Therapy (ATTRACT) trial and only 30% met the criteria for the Early Rheumatoid Arthritis (ERA) trial. In studies comparing methotrexate directly with biological agents, the biological agents have greater efficacy in patients with very severe disease, but the best results are seen in patients who take a combination of methotrexate and biologic agents. These data establish that methotrexate is the anchor drug and probably should be the first DMARD used in the majority of patients with RA at this time.
11955534 Methotrexate and mortality in patients with rheumatoid arthritis: a prospective study. 2002 Apr 6 BACKGROUND: Methotrexate is the most frequent choice of disease-modifying antirheumatic therapy for rheumatoid arthritis. Although results of studies have shown the efficacy of such drugs, including methotrexate, on rheumatoid arthritis morbidity measures, their effect on mortality in patients with the disease remains unknown. Our aim was to prospectively assess the effect on mortality of methotrexate in a cohort of patients with rheumatoid arthritis. METHODS: Our cohort included 1240 patients with rheumatoid arthritis seen at the Wichita Arthritis Center, an outpatient rheumatology facility. Patients' details were entered into a computerised database at the time of their first clinic visit. We also obtained and recorded demographic, clinical, laboratory, and self-reported data at each follow-up visit (average interval 3.5 months). We estimated the mortality hazard ratio of methotrexate with a marginal structural Cox proportional hazards model. FINDINGS: 191 individuals died during follow-up. Patients who began treatment with methotrexate (n=588) had worse prognostic factors for mortality. After adjustment for this confounding by indication, the mortality hazard ratio for methotrexate use compared with no methotrexate use was 0.4 (95% CI 0.2-0.8). Other conventional disease-modifying antirheumatic drugs did not have a significant effect on mortality. The hazard ratio of methotrexate use for cardiovascular death was 0.3 (0.2-0.7), whereas that for non-cardiovascular deaths was 0.6 (0.2-1.2). INTERPRETATION: Our data indicate that methotrexate may provide a substantial survival benefit, largely by reducing cardiovascular mortality. This survival benefit of methotrexate would set a standard against which new disease-modifying antirheumatic drugs could be compared.
12734886 The responsiveness of generic health status measures as assessed in patients with rheumato 2003 May OBJECTIVE: We used a variety of health status measures in 2 groups of patients with rheumatoid arthritis (RA) to assess both the smallest distinguishable difference and the relative responsiveness to change of these measures, when used in clinical practice. METHODS: Two groups of patients were studied. Group 1: 24 patients with stable RA tested on 2 occasions; Group 2: 60 patients receiving methotrexate tested before and 14 weeks after treatment with infliximab. Assessments were made with self-completed questionnaires: the modified Health Assessment Questionnaire, Medical Outcomes Study Short Form-36 [SF-36 (SF-6D)], EuroQol, and, in some, the standard gamble. Group 2 also had joint counts, and measures of erythrocyte sedimentation rate, C-reactive protein, and hemoglobin. RESULTS: The limits-of-agreement (Bland-Altman) approach had greater confidence intervals (CI) than did CI based on +/- 2 standard errors of the measurement. Improvement with infliximab could be determined with all measures, however, but the standard gamble seemed least responsive to change. CONCLUSION: The various measures had different degrees of responsiveness, but with all it was possible to show improvement in Group 2 compared to Group 1. There was a closer association of the patient centered measures of improvement with changes in pain score than with joint counts.
15717805 [Seroprevalence of Helicobacter pylori in rheumatoid arthritis and its relationship to pha 2004 Dec GOAL: To find out a serology prevalence of Helicobacter pylori (Hp) infection in patients suffering from rheumatoid arthritis (RA) and to investigate its relationship to pharmacotherapy modes. METHOD: To determine Hp IgG class and IgA class antibodies by ELISA method in hospitalised patients with active RA according to ACR criteria (1987). RESULTS: 137 patients with RA were examined--20 men, 117 women, an average age was 54.6 +/- 13.1, an average length of RA in these patients was 12.46 +/- 9.75, positive RF/LFT had 88% of patients. Hp ELISA IgG antibodies were confirmed in 57% (78/137) of patients with RA, Hp ELISA IgA antibodies were confirmed in 60% of examined patients (82/137), and IgG + IgA antibodies simultaneously were found in 51% (70/137) of examined patients. A comparison of basic demographic data, specific parameters of the disease, and clinical signs has not confirmed any differences between groups of Hp positive and Hp negative patients. Patients with both types of Hp antibodies (IgG + IgA) had more frequent signs of RA in other places than joints (p = 0.046). RA patients with anti-Hp IgG antibodies more frequently used anticoagulation drugs (p = 0.029) while patients with anti-Hp IgA antibodies more frequently used methotrexate (p = 0.01). CONCLUSIONS: Results point out more frequent incidence of Hp IgA antibodies in RA patients treated with methotrexate and more frequent incidence of both IgG and IgA antibodies in patients with RA signs in other places than joints.
11842822 Patients chosen for treatment with cyclosporine because of severe rheumatoid arthritis are 2002 Feb OBJECTIVE: To determine whether patients with rheumatoid arthritis (RA) selected for treatment with cyclosporin A (CSA) because of severe disease are more likely to carry HLA-DRB1 alleles encoding the conserved "shared epitope" (SE) sequence. METHODS: The majority of patients (n = 178) were currently being treated with methotrexate (MTX), either alone or in combination with chloroquine and/or CSA. In about 30% of patients, treatment with CSA had been initiated because of limited response to MTX or MTX and chloroquine. Patients were treated as clinically indicated without knowledge of their HLA-DRB1 status. HLA-DRB1 typing was by a reverse dot blot method. RESULTS: Patients that had been treated with CSA were significantly more likely to carry an SE allele than patients not treated with CSA (81.5% vs 60.5%; OR 2.9, p = 0.006). Patients with 2 SE alleles were the most likely to have been treated with CSA. Results were still significant after correction for age, sex, and disease duration in a logistic regression model. There was no association between rheumatoid factor positivity and requirement for CSA therapy. Examination of individual SE alleles by multiple logistic regression analysis indicated that the strongest association was with presence of HLA-DRB1**0401 (p = 0.004). The DRB1*0401/*0404 genotype provided the greatest risk of requiring CSA treatment. Patients selected for CSA treatment had developed RA at a significantly earlier age than those not requiring CSA (44.4 vs 51.3 yrs; p = 0.004). CONCLUSION: Patients requiring treatment with CSA because of severe RA were significantly more likely to carry an SE allele than patients not requiring such treatment. CSA treated patients were also more likely to have had earlier age of disease onset. These data provide further evidence that bearing the SE (particularly 2 alleles) is associated with development of severe RA.
15319231 Decreased prolactin response to hypoglycaemia in patients with rheumatoid arthritis: corre 2005 Mar OBJECTIVE: To compare basal and stimulated prolactin levels between patients with rheumatoid arthritis and healthy controls, and to assess the effects of antirheumatic treatment on prolactin concentrations. METHODS: Serum prolactin was assessed under basal conditions and during an insulin tolerance test (ITT) in 20 patients with recently diagnosed active rheumatoid arthritis and 20 age and sex matched controls. The patients were reassessed after two weeks' treatment with naproxen and after six months' additional treatment with either sulfasalazine or methotrexate. Disease activity was assessed by the disease activity score (DAS). RESULTS: Basal levels of prolactin were not significantly different between patients with rheumatoid arthritis and controls. Prolactin responses to hypoglycaemia were less in untreated rheumatoid patients than in controls. DAS scores correlated negatively with the area under the curve (AUC) for prolactin concentrations during the ITT. Treatment with naproxen for two weeks did not influence either basal or stimulated prolactin levels. After six months of antirheumatic treatment, prolactin responses to hypoglycaemia increased significantly to levels observed in controls. At the same time point, DAS had improved considerably. The improvement correlated with the increase in AUC of prolactin during the ITT (r = 0.48; p = 0.05). CONCLUSIONS: Patients with active rheumatoid arthritis have a decreased prolactin response to hypoglycaemia induced stress. The response recovers following treatment with antirheumatic drugs.
12453315 Effects of disease modifying agents and dietary intervention on insulin resistance and dys 2002 Patients with rheumatoid arthritis (RA) experience excess cardiovascular disease (CVD). We investigated the effects of disease-modifying antirheumatic drugs (DMARD) and dietary intervention on CVD risk in inflammatory arthritis. Twenty-two patients (17 women; 15 with RA and seven with spondyloarthropathy) who were insulin resistant (n = 20), as determined by the Homeostasis Model Assessment, and/or were dyslipidemic (n = 11) were identified. During the third month after initiation of DMARD therapy, body weight, C-reactive protein (CRP), insulin resistance, and lipids were re-evaluated. Results are expressed as median (interquartile range). DMARD therapy together with dietary intervention was associated with weight loss of 4 kg (0-6.5 kg), a decrease in CRP of 14% (6-36%; P < 0.006), and a reduction in insulin resistance of 36% (26-61%; P < 0.006). Diet compliers (n = 15) experienced decreases of 10% (0-20%) and 3% (0-9%) in total and low-density lipoprotein cholesterol, respectively, as compared with increases of 9% (6-20%; P < 0.05) and 3% (0-9%; P < 0.05) in diet noncompliers. Patients on methotrexate (n = 14) experienced a reduction in CRP of 27 mg/l (6-83 mg/l), as compared with a decrease of 10 mg/l (3.4-13 mg/l; P = 0.04) in patients not on methotrexate. Improved cardiovascular risk with DMARD therapy includes a reduction in insulin resistance. Methotrexate use in RA may improve CVD risk through a marked suppression of the acute phase response. Dietary intervention prevented the increase in total and low-density lipoprotein cholesterol upon acute phase response suppression.
11974488 [Health economics research in the area of chronic polyarthritis]. 2002 Feb Costs of illness are of major economic relevance in rheumatoid arthritis (RA) as in other chronic diseases. Overall costs of 15,000 Euro/year: 10,000 Euro indirect costs, and 5000 Euro direct costs are estimated, respectively. A further detailed analysis of direct costs underlines that inpatient care (50%) is the most prominent cost driver. Medication costs are also evaluated in detail since they are expected to gain importance with the introduction of the more expensive biologicals. While annual costs for regular disease modifying drugs (DMARDs) vary from 160 to 5000 Euro per patient, costs for the new biologicals amount up to 20,000 Euro (100-125% of the current estimated overall costs). For a comparison of different therapeutic strategies, costs are related to effectiveness in cost-effectiveness analyses. Based on present clinical trials, the ratios of medication costs and response according to the ACR 20-criteria of various DMARDs and biologicals are compared. The most cost-effective medication is sulfasalzine, followed by methotrexate, and leflunomide. Combining etanercept and methotrexate is preferable to methotrexate monotherapy and the combination of infliximab and methotrexate. This review shows that important economic issues in RA have already been addressed by applying cost-of-illness analyses and cost-effectiveness analyses. However, the knowledge about cost-effective therapeutic options is still scarce. Thus, primary data will have to be obtained using standardized approaches. These economic findings can be taken into account in the development of disease-management recommendations for RA-therapy.
11927833 Polymorphisms in the methylenetetrahydrofolate reductase gene were associated with both th 2002 Apr 5,10-Methylenetetrahydrofolate reductase (MTHFR), a key enzyme involved in folate metabolism, has two common polymorphisms that affect enzyme activity. The objective of this study was to examine whether there was a correlation between the genotype or haplotype of the MTHFR gene and the efficacy or toxicity of methotrexate (MTX) in the treatment of rheumatoid arthritis. MTX-treated rheumatoid arthritis patients (n = 106) were selected from outpatient clinics and used for a retrospective study to examine the correlation between genotypes or haplotypes concerning polymorphisms of the MTHFR gene, and the efficacy or toxicity of MTX. Estimation of the haplotype frequencies was performed by maximum likelihood estimation based on expectation maximization algorithm. Single locus analysis examining each locus separately showed that patients with 1298C were receiving significantly lower doses of MTX compared to patients without [P < 0.05, relative risk (RR) = 2.18, 95% confidence interval (CI) 1.17-4.06], while a higher rate of overall MTX toxicity was observed in patients with 677T than those without (P < 0.05, RR = 1.25, 95% CI 1.05-1.49). An estimation of haplotype frequencies showed that there was no 677T-1298C haplotype in the population. Posterior distribution of the diplotype configuration for each individual was concentrated on a single configuration. Patients with the 677C-1298C haplotype were receiving lower doses of MTX than those without (P < 0.05, RR = 2.14, 95% CI 1.13-4.07), while subjects with 677T-1298A had a higher frequency of side-effects from MTX (P < 0.05, RR = 1.42, 95% CI 1.11-1.82). Both single locus and haplotype analyses suggest that polymorphisms within the MTHFR gene are associated with both the efficacy and toxicity of MTX in rheumatoid arthritis patients. Pharmacokinetic studies are necessary to prove the association.
15157003 Drugs that block tumour necrosis factor: experience in patients with rheumatoid arthritis. 2004 Three biological response modifiers that inhibit tumour necrosis factor-alpha (TNF-alpha) are approved for treating rheumatoid arthritis (RA). Etanercept is a fusion protein comprising two soluble human TNF-alpha receptors linked to the Fc fragment of human immunoglobulin G1. Infliximab is a chimeric (human/mouse) monoclonal antibody and adalimumab is a humanised monoclonal antibody. In placebo-controlled trials in established disease-modifying antirheumatic drug (DMARD)-refractory RA, the anti-TNF-alpha agents have reduced disease activity, as monotherapy or in combination with methotrexate. In long-term, open-label studies with etanercept or adalimumab, clinical response was sustained for up to 5 years. In early RA, etanercept has similar efficacy to methotrexate. However, etanercept was more effective than methotrexate in preventing radiographic progression. Preventing or delaying disease progression and disability with etanercept therapy in early RA may reduce costs associated with long-term disease outcomes. Data also suggest a benefit of infliximab plus methotrexate or adalimumab plus methotrexate in early RA. All three agents have been shown to improve functionality as assessed by health assessment questionnaire (HAQ) disability scores. Health-related quality of life is also improved in terms of physical and mental health and vitality. Furthermore, etanercept and adalimumab are associated with a reduction in fatigue. Long-term etanercept or infliximab therapy is associated with increased job employment and etanercept also reduces healthcare utilisation. Mild, transient injection-site reactions occur in about 33% of patients treated with etanercept and 20% of patients treated with adalimumab. In patients treated with infliximab, 16-20% have infusion reactions. The incidence of serious infection associated with etanercept and infliximab was low, about 2-3% in etanercept studies of up to 5 years duration, and 5% in a survey of more than 10 infliximab trials. This paper reviews the evidence for efficacy, safety and effectiveness of anti-TNF-alpha agents in RA.
14711022 Newer approaches to the treatment of rheumatoid arthritis. 2003 Growing evidence suggests that rheumatoid arthritis should no longer be considered a benign disease. Considerable data suggest that this disease is associated with diminished long-term survival. Other studies have also shown that in patients with rheumatoid arthritis, bone damage can occur very early in the disease course. Older disease modifying agents for treating rheumatoid arthritis were limited by long-term toxicity. Newer agents, including methotrexate, leflunomide, and the biologic agents etanercept, infliximab, adalimumab, and anakinra have shown long-term efficacy and superior long-term tolerability. Newer approaches to treating this disease have stressed treatment early in the disease course, before irreversible joint damage occurs, using combinations of second line disease modifying agents.
15476252 Quantification of cortical bone loss and repair for therapeutic evaluation in collagen-ind 2004 Oct OBJECTIVE: Ex vivo and in vivo micro-computed tomography (micro-CT) combined with a novel image analysis algorithm were used to quantify cortical bone loss and periosteal new bone formation for therapeutic evaluation in a murine model of collagen-induced arthritis. METHODS: An automated algorithm was created to locate 5 metatarsophalangeal and 3 metacarpophalangeal joints in 3-dimensional micro-CT images of mouse paws for evaluation of joint cortical bone volume (JCBV) within close proximity of the joints as well as cortical bone mineral density and periosteal new bone formation within the paws. For validation, automated estimates of JCBV were compared with radiographic visual scores (RVS) in 4 treatment groups (n = 9 per group): rat anti-mouse CD11a monoclonal antibody, methotrexate (MTX), anti-CD11a plus MTX, and saline only. In a separate study, serial images of hind limbs were evaluated in 2 treatment groups: murine tumor necrosis factor receptor II-Fc fusion protein (mTNFRII; n = 10) and control antibody (n = 7). RESULTS: Automated estimates of the JCBV were significantly correlated with the RVS (hind paws R = -0.94, front paws R = -0.81, combined R = -0.87). The anti-CD11a group had significantly higher JCBV compared with controls. In the serial study, the automated estimate of JCBV detected significant treatment effects in the mTNFRII-Fc group compared with controls. Cortical bone mineral density was significantly higher in all treatment groups compared with controls. CONCLUSION: Micro-CT combined with a novel image analysis technique (estimation of JCBV) provides a fully automated means to quantify bone destruction in a mouse model of rheumatoid arthritis.
15103253 Rheumatoid arthritis and malignant lymphomas. 2004 May PURPOSE OF REVIEW: The reason for the increased lymphoma risk in patients with rheumatoid arthritis (RA) has remained unclear. Reports of lymphomas in patients treated with TNF-blockers have brought renewed interest in this issue. This review summarizes data on possible associations between RA and lymphomas, including different treatments and RA disease related risk factors. RECENT FINDINGS: Some recent studies reported increased lymphoma risks linked to RA disease activity. The hypothesis that disease-modifying drugs, and in particular methotrexate, would increase the lymphoma risk receives little support. Observation times for the TNF-blocking therapies are still short, but so far no clear increased risk for lymphoma has been observed. Presence of Epstein-Barr virus, as analyzed with EBER in situ hybridization, appears to be uncommon in RA related lymphomas. Hypothetically, an increased proliferative drive caused by self or non-self antigens may play a role in lymphoma development in RA patients, but this has to be further studied. SUMMARY: Rheumatologists need to be aware of the increased lymphoma risk in their RA patients. The reason for the increased lymphoma risk in RA patients is still unclear, but available studies rather support the hypothesis of a link between RA disease severity and the risk of lymphoma than increased risks associated with specific treatment regimens. To facilitate the future evaluation of lymphoma risks in connection with treatment, we suggest that patients treated with new drugs should be subject to structured surveillance. Collected information should include data about RA disease activity and severity.
15529377 Combination of infliximab and methotrexate therapy for early rheumatoid arthritis: a rando 2004 Nov OBJECTIVE: To compare the benefits of initiating treatment with methotrexate (MTX) and infliximab (anti-tumor necrosis factor alpha [anti-TNFalpha] monoclonal antibody) with those of MTX treatment alone in patients with rheumatoid arthritis (RA) of < or =3 years' duration. METHODS: RA patients were eligible if they had active disease and no prior treatment with MTX or a TNFalpha inhibitor. One thousand forty-nine patients were randomly assigned in a 4:5:5 ratio to 3 treatment groups: MTX-placebo, MTX-3 mg/kg infliximab, and MTX-6 mg/kg infliximab. MTX dosages were rapidly escalated to 20 mg/week, and infliximab or placebo infusions were given at weeks 0, 2, and 6, and every 8 weeks thereafter through week 46. RESULTS: At week 54, the median percentage of American College of Rheumatology improvement (ACR-N) was higher for the MTX-3 mg/kg infliximab and MTX-6 mg/kg infliximab groups than for the MTX-placebo group (38.9% and 46.7% versus 26.4%, respectively; P < 0.001 for both comparisons). Patients in the MTX-3 mg/kg infliximab and MTX-6 mg/kg infliximab groups also showed less radiographic progression than those receiving MTX alone (mean +/- SD changes in van der Heijde modification of the total Sharp score at week 54: 0.4 +/- 5.8 and 0.5 +/- 5.6 versus 3.7 +/- 9.6, respectively; P < 0.001 for each comparison). In addition, physical function improved significantly more in the MTX-3 mg/kg infliximab and MTX-6 mg/kg infliximab groups than in the MTX-placebo group. Infliximab therapy was associated with a significantly higher incidence of serious infections, especially pneumonia. CONCLUSION: For patients with active RA in its early stages, combination therapy with MTX and infliximab provides greater clinical, radiographic, and functional benefits than treatment with MTX alone.
12665969 Current drug therapy for rheumatoid arthritis. 2003 The etiology of rheumatoid arthritis (RA) remains unclear at present, but advances have been made in the drug therapy for RA. Recent attention has been focused on selective cyclooxygenase-2 (COX-2) inhibitors, nonsteroidal antiinflammatory drugs (NSAIDs) that inhibit a subtype of cyclooxygenase. Various clinical studies have confirmed that the selective COX-2 inhibitors cause fewer severe gastrointestinal complications, although an increased incidence of myocardial infarction was suggested. Terminal enzymes of the arachidonic acid cascade, such as membrane-associated prostaglandin E synthase, might be a target for new NSAIDs in the near future. Low-dose glucocorticoid treatment for RA has been reconsidered possibly to prevent articular destruction of RA. Special attention for glucocorticoid-induced osteoporosis by concomitant administration of bisphosphonates might be necessary. Disease-modifying antirheumatic drugs should be effective in delaying the progression of joint destruction and physical disability. Methotrexate, sulfasalazine, and leflunomide have shown such an effect. Inhibition of articular destruction was also proven by administration of the biologic agents etanercept and infliximab plus methotrexate. Tuberculosis complicated with infliximab therapy is one of the most important concerns in Japan. Agents that improve the quality of life of patients with RA are still needed.
15476226 Characterization of pristane-induced arthritis, a murine model of chronic disease: respons 2004 Oct OBJECTIVE: To characterize chronic murine pristane-induced arthritis (PIA) with regard to the response to antirheumatic agents, expression levels of proinflammatory cytokines, and immunopathologic features. METHODS: Male DBA/1 mice were injected intraperitoneally with pristane oil to induce a chronic polyarthritis, which was monitored by visual scoring. Serum antibody and splenocyte responses to a panel of putative joint-derived autoantigens were measured. Whole paws were evaluated postmortem for changes in the levels of proinflammatory cytokines tumor necrosis factor alpha (TNFalpha), interleukin-1beta (IL-1beta), and IL-6 by enzyme-linked immunosorbent assay, and standard histopathology techniques were used to determine joint structural changes. Therapeutic studies were performed for up to 8 weeks of dosing with prednisolone, methotrexate, 3 nonsteroidal antiinflammatory drugs (celecoxib, diclofenac, and indomethacin), a p38 MAPK inhibitor, SB242235, and human soluble TNF receptor (sTNFR; etanercept) and murine sTNFR fusion proteins. RESULTS: Antibody and cellular responses to the putative joint autoantigens revealed a broad extent of autoimmunity in PIA. TNFalpha, IL-1beta, and IL-6 were all persistently up-regulated in PIA joints. Prednisolone, methotrexate, celecoxib, indomethacin, and SB242235 all significantly reduced the arthritis scores. Etanercept was ineffective in reducing the arthritis scores, whereas murine sTNFR produced a significant, but nonsustained, benefit. Only prednisolone significantly reduced the expression of TNFalpha, IL-1beta, and IL-6 in the joints. Prednisolone and methotrexate demonstrated the most effective joint protection. CONCLUSION: We have markedly extended the characterization of PIA as a murine model of chronic inflammatory arthritis by demonstrating cellular and humoral autoantigenicity, elevation of clinically precedented joint cytokines, and variation in the response to several antirheumatic therapies. PIA offers significant potential for the long-term study of immunopathologic mechanisms and novel therapies in rheumatoid arthritis.
15103246 Management of extra-articular disease manifestations in rheumatoid arthritis. 2004 May PURPOSE OF REVIEW: To discuss the rationale for various treatment strategies in rheumatoid arthritis with extra-articular manifestations, and to review advances in understanding the impact of extra-articular rheumatoid arthritis and its management. RECENT FINDINGS: Recent epidemiologic studies of extra-articular rheumatoid arthritis manifestations have emphasized their major role as predictors of premature mortality in patients with rheumatoid arthritis, and provide a rationale for aggressive ant-rheumatic treatment of extra-articular rheumatoid arthritis. Previous uncontrolled or nonrandomized studies favor the use of cyclophosphamide in patients with systemic rheumatoid vasculitis, and methotrexate in the case of other manifestations of extra-articular rheumatoid arthritis. Recent case reports indicate that patients with rheumatoid lung disease may respond to cyclosporine or tumor necrosis factor inhibitors, and that tumor necrosis factor blocking therapy also may be successful in cases of treatment-resistant vasculitis. By contrast, it has been suggested that tumor necrosis factor inhibitors may induce some manifestations of extra-articular rheumatoid arthritis. Data indicating a high risk of serious infections and cardiovascular disease in patients with extra-articular rheumatoid arthritis underline the importance of carefully monitoring such patients. SUMMARY: Extra-articular rheumatoid arthritis is a serious condition, and rheumatoid arthritis patients with extra-articular manifestations should be aggressively treated and monitored. Advances in the understanding of the pathogenesis of rheumatoid arthritis and developments of new, more specific drugs may be of particular benefit to patients with extra-articular disease.
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