Rheumatoid Arthritis: Moreland LW

Daniel CL, Moreland LW. · No affiliation provided · J Rheumatol. · Pubmed #11950000 links to  free full text

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Moreland LW, Bridges SL. · No affiliation provided · Am J Med. · Pubmed #11690579 No free full text.

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Abbott JD, Moreland LW. · University of Alabama at Birmingham, Department of Medicine; Division of Clinical Immunology and Rheumatology, 1717 6th Avenue South, SRC 068, Birmingham, AL 35294-7201, USA. · Expert Opin Investig Drugs. · Pubmed #15268638 No free full text.

Abstract: Rheumatoid arthritis (RA) is a chronic inflammatory disease that often results in significant morbidity, mortality and disability. Over the past 20 years a better understanding of the pathogenesis of RA has led to the development of new approaches to disease treatment. The recent introduction of biological agents has changed the treatment paradigm for RA. The success of early biological therapies including TNF-alpha and IL-1 antagonists has spurred interest in the development of additional novel targets in the treatment of RA. Biological therapies approved for other indications, such as rituximab, are now being evaluated for the treatment of rheumatic diseases such as RA. A co-stimulatory blocker, abatacept, is also in pivotal Phase III trials. This article reviews evolving pharmacological therapies in RA with an emphasis on the newer approaches to treatment including inhibition of cognate signalling and T- and B-cell targets.

Moreland LW. · University of Alabama at Birmingham, Department of Medicine, Division of Clinical Immunology and Rheumatology, Birmingham, Alabama 35294-7201, USA. · Pharmacoeconomics. · Pubmed #15157003 No free full text.

Abstract: 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.

Bridges SL, Hughes LB, Mikuls TR, Howard G, Tiwari HK, Alarcón GS, McNicholl JM, Moreland LW. · Departments of Medicine and Microbiology, Division of Clinical Immu-nology and Rheumatology, University of Alabama at Birmingham, 415 Lyons-Harrison Research Building, 701 19th Street South, Birmingham, Alabama 35294-0007, USA. · Clin Exp Rheumatol. · Pubmed #14969066 No free full text.

Abstract: African-Americans have been under-represented in genetic studies of rheumatoid arthritis (RA) susceptibility and severity. Genetic and non-genetic factors influencing the radiographic severity of RA and its response to treatment are poorly understood, particularly in African-Americans. The Consortium for the Longitudinal Evaluation of African-Americans with early RA (CLEAR) Registry, a collaborative effort among four institutions in the southeast USA, will hopefully provide a useful resource to study these issues.

Shanahan JC, Moreland LW, Carter RH. · Division of Clinical Immunology and Rheumatology, University of Alabama-Birmingham, Alabama, USA. · Curr Opin Rheumatol. · Pubmed #12707575 No free full text.

Abstract: The development of biologic agents has provided rheumatologists with a variety of new and effective treatment options. The success of early biologics, especially etanercept and infliximab for the treatment of rheumatoid arthritis, has spurred research into novel targets for the management of systemic inflammatory and autoimmune diseases. In addition, existing biologics approved for use in other diseases, such as rituximab, are now under study for the treatment of new indications. This article reviews ongoing research on the treatment of rheumatic diseases with new and existing biologic agents.

Mikuls TR, Moreland LW. · Department of Medicine, Section of Rheumatology and Immunology, University of Nebraska Medical Center, Omaha, Nebraska, USA. · Drug Saf. · Pubmed #12495361 No free full text.

Abstract: In the last decade, there have been substantial advances in the treatment of rheumatoid arthritis with the addition of several new disease-modifying agents to the therapeutic armamentarium. Biological agents targeting tumour necrosis factor (TNF) represent one such important addition. Infliximab, a chimeric anti-TNF monoclonal antibody, has shown remarkable promise in alleviating the signs and symptoms of rheumatoid arthritis in addition to retarding radiographic disease progression when used in combination with methotrexate. In its pivotal phase III trial, the addition of infliximab to patients with methotrexate-refractory disease was associated with substantial clinical benefit. Using American College of Rheumatology criteria for improvement, one-half of patients receiving infliximab (3 mg/kg every 8 weeks) plus methotrexate showed at least 20% improvement compared with only 20% of those receiving placebo plus methotrexate (p < 0.001) with over one-half of eventual responders obtaining criteria for improvement by the second week of observation. Although its use has been met with much deserved enthusiasm, recent reports have highlighted several potential serious adverse effects associated with infliximab (and other TNF antagonists), including infusion reactions, congestive heart failure, drug-induced lupus, and CNS demyelination. In addition, recent reports have cited the potential for reactivation of mycobacterial and fungal infection in patients receiving infliximab, mandating appropriate tuberculosis screening prior to drug initiation. Although the frequency of serious drug-related toxicity (requiring discontinuation of the agent) appears to be quite low, these reports underscore the need for caution and close surveillance with the administration of TNF inhibitors, particularly given that strategies aimed at preventing toxicity remain unproven. Despite its potential for toxicity, infliximab remains a valuable alternative for patients with rheumatoid arthritis.

Hughes LB, Moreland LW, Bridges SL. · Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, 35294-0007, USA. · Immunol Res. · Pubmed #12403341 No free full text.

Abstract: Rheumatoid arthritis is a common autoimmune disease characterized by inflammation of the synovial membrane of diarthrodial joints, which often leads to joint damage and disability. There are known associations between major histocompatibility complex class II alleles and susceptibility to rheumatoid arthritis and its severity in Caucasians. African Americans, an admixed population in the United States, has been underrepresented in genetic studies of the susceptibility and severity of rheumatoid arthritis. With the advent of biologic agents, which target specific molecules of the immune system (e.g., tumor necrosis factor, interleukin-1), biologic markers of treatment response in Caucasians and in African Americans would be clinically useful.

Moreland LW, O'Dell JR. · School of Medicine, University of Alabama at Birmingham, 1717 6th Avenue South, SRC 068, Birmingham, AL 35294-7201, USA. · Arthritis Rheum. · Pubmed #12384910 links to  free full text

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Misischia RJ, Moreland LW. · No affiliation provided · Expert Opin Investig Drugs. · Pubmed #12084003 No free full text.

Abstract: Rheumatoid arthritis (RA) is a chronic inflammatory disease that, despite recent advances in therapy, still results in significant morbidity, mortality and disability. The aetiology remains unknown and past therapies, although helpful for the majority of patients, have been suboptimal. The recent introduction of newer agents has changed the treatment paradigm of RA. COX-2 inhibitors, anti-TNF agents and interleukin-1 antagonists have allowed us to treat RA more effectively with relatively low risk of side effects. Investigations of other possible treatment pathways, such as inhibition of angiogenesis, may produce still better treatment and rapid unraveling of the immune system and how it relates to RA greatly enhances the opportunities for improved therapeutics in RA.

Robinson WH, Genovese MC, Moreland LW. · Stanford University School of Medicine, California 94305, USA. · Arthritis Rheum. · Pubmed #11592357 links to  free full text

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Moreland LW. · Department of Medicine, University of Alabama at Birmingham, Birmingham, AM, USA. · Isr Med Assoc J. · Pubmed #11574988 links to  free full text

Abstract: There is accumulating evidence that tumor necrosis factor plays a major role in the pathogenesis of rheumatoid arthritis. Recent biotechnological advances have allowed for the development of agents that directly target TNF, a proinflammatory cytokine. In the last 2 years, the U.S. Food and Drug Administration and the European Union's Commission of the European Communities have approved two biological agents for the treatment of refractory RA, etanercept and infliximab. Etanercept is a fusion protein, composed of the Fc portion of immunoglobulin G1 and the extracellular domain of a TNF receptor (p75). Infliximab is a chimeric monoclonal antibody composed of murine variable and human constant regions. In placebo-controlled trials, both agents have proven to be effective and well tolerated in RA patients.

Gabriel SE, Coyle D, Moreland LW. · Health Sciences Research, Mayo Foundation, Rochester, Minnesota 55905, USA. · Pharmacoeconomics. · Pubmed #11548909 No free full text.

Abstract: Rheumatoid arthritis is one of the most common chronic systemic inflammatory diseases, affecting approximately 1% of the adult population. Disease-modifying antirheumatic drugs (DMARDs) have been the mainstay of treatment for rheumatoid arthritis when combined with physical therapy and aspirin (acetylsalicylic acid) or nonsteroidal anti-inflammatory drugs. Recently, a number of new biological therapies have been introduced for the treatment of this condition and will have a major impact on the future management of this disabling disease. In this review, we summarise data on the efficacy and tolerability of the currently available DMARDs, including gold compounds, antimalarials, penicillamine, cytotoxic drugs (azathioprine and cyclophosphamide), sulfasalazine, methotrexate, leflunomide, cyclosporin, anti-tumour necrosis factor agents, combination therapy and apheresis. A literature review and quality assessment of economic evaluations of DMARDs is presented, illustrating that there has been a paucity of economic evaluations on these agents and showing the variable quality of those studies that are available. The manuscript also addresses the pharmacoeconomic implications of the new agents for rheumatoid arthritis; the need for formal long term economic evaluations in order to determine the cost effectiveness of these costly, but highly effective, new treatments is emphasised.

Moreland LW, Russell AS, Paulus HE. · University of Alabama at Birmingham, 1717-6th Avenue South, SRC 068, Birmingham, AL 35294-7201, USA. · J Rheumatol. · Pubmed #11409142 No free full text.

Abstract: We review the historical highlights of the management of rheumatoid arthritis (RA). Studies of nonsteroidal antiinflammatory drugs, disease modifying antirheumatic drugs, and biological agents over 5 decades were evaluated and summarized. There is emphasis on drug therapy as it has developed and evolved from empirical relief of symptoms with salicylates to targeted intervention in the immunoinflammatory process with tumor necrosis factor inhibitors. A therapeutic paradigm has been proposed to rationalize the use of the available therapies. If one accepts the thesis that both the acute and chronic consequences of RA are due to persistent misdirected and inadequately controlled inflammation that causes tissue destruction and loss of function, then prolonged complete control of the abnormal inflammatory process is the fundamental first step in the management of all patients with RA. Unfortunately, even with the newest therapeutic options to treat RA, most patients achieve only partial suppression of inflammation and many lose therapeutic benefit after an initial good response. The management of persistent or recurrent rheumatoid inflammation and disability continues to be a challenge. It remains to be determined whether the future addition of more potent specific interventions in the immunoinflammatory process will be able to solve this problem without disarming host defenses against infections and tumors.

Wolfe F, Cush JJ, O'Dell JR, Kavanaugh A, Kremer JM, Lane NE, Moreland LW, Paulus HE, Pincus T, Russell AS, Wilskie KR. · National Data Bank for Rheumatic Diseases-Arthritis Research Center Foundation, Inc. and University of Kansas School of Medicine, Wichita, Kansas, USA. · J Rheumatol. · Pubmed #11409141 No free full text.

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Moreland LW. · Arthritis Clinical Intervention Program, Department of Medicine, Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, Alabama, USA. · Rheum Dis Clin North Am. · Pubmed #11396103 No free full text.

Abstract: The encouraging clinical results observed in trials using anti-TNF therapy clearly warrant further studies to determine whether TNF inhibitors are capable of modifying the destructive component of this disease in long-term follow-up studies as well as to assess the safety of long-term use (see the article by Keystone in this issue). It is also reasonable to propose that interfering with the cytokine cascade earlier in the course of disease may be of even greater therapeutic benefit. As the pathogenetic mechanisms in RA are more clearly defined, especially in early disease and in those individuals destined to develop severe disease, the potential of other biologic agents to specifically inhibit these critical pathways may provide better treatments for our patients. Many potential targets in the immune-mediated process of RA are currently being rigorously evaluated in clinical trials. Use of combinations of biologic therapies, perhaps in human patients with RA, should be of considerable interest in future trials.

Mikuls TR, Moreland LW. · Division of Clinical Immunology and Rheumatology, University of Birmingham, 1813 6th Ave South, MEB 625, Birmingham, AL 35294, USA. · Expert Opin Pharmacother. · Pubmed #11336570 No free full text.

Abstract: There is accumulating evidence that tumour necrosis factor (TNF) plays a major role in the pathogenesis of rheumatoid arthritis (RA). Recent biotechnological advances have allowed for the development of agents that directly target TNF, a pro-inflammatory cytokine. In the last 2 years, the US FDA and the EU's Commission of the European Communities have approved two biological agents for the treatment of refractory RA, etanercept and infliximab. Etanercept is a fusion protein, composed of the Fc portion of IgG1 and the extracellular domain of the TNF receptor (p75). Infliximab is a chimeric monoclonal antibody (mAb) composed of murine variable and human constant regions. In placebo-controlled trials, both agents have proven to be effective and well-tolerated in RA patients. This review evaluates the available TNF inhibitors, summarises pertinent clinical trials and underscores differences between the two agents in terms of molecular structure, efficacy, safety data, antigenicity and pharmacokinetics.

Jones RE, Moreland LW. · Department of Medicine, University of Alabama at Birmingham, USA. · Bull Rheum Dis. · Pubmed #10408141 No free full text.

Abstract: Tumor necrosis factor antagonists such as infliximab and etanercept represent a new and powerful approach to managing RA. In studies published to date, TNF antagonists appear to be safe and effective agents for short-term therapeutic use in RA. Defining when in the course of RA to use TNF antagonists and determining the effectiveness of combinations of these biologic agents with DMARDs or other cytokine antagonists are areas of current and future studies. Other cytokine antagonists that may be promising subjects for further study are IL-1 antagonists. Like TNF, IL-1 is a member of the inflammatory cascade, but may play a different role in the development of inflammatory arthritis. In animal models, inhibition of TNF suppressed the inflammatory response while IL-1 antagonism prevented joint destruction (2). These results imply that combination therapy providing inhibition of both IL-1 and TNF might be an effective treatment in humans with RA, but clinical trials in humans have not yet been performed. Studies are underway in people with early RA to determine if the new TNF inhibitors are more effective or safer than currently available therapies, such as methotrexate. Other agents that inhibit TNF activity are also being tested at this time in people with RA.

Moreland LW. · Department of Medicine, University of Alabama at Birmingham, USA. · Cleve Clin J Med. · Pubmed #10375846 No free full text.

Abstract: Infliximab and etanercept, both approved by the FDA in 1998, are examples of a new class of disease-modifying antirheumatic drugs that interfere with the action of tumor necrosis factor alpha, one of the key cytokines that promote inflammation. Infliximab is approved for Crohn disease and etanercept for rheumatoid arthritis. Both show promise in treating rheumatoid arthritis, although the long-term risks and benefits of these drugs are not yet known.

Moreland LW. · Department of Medicine, Multipurpose Arthritis Center, University of Alabama at Birmingham, 35294-7201, USA. · J Rheumatol Suppl. · Pubmed #10328137 No free full text.

Abstract: Clinical trials of tumor necrosis factor (TNF) inhibitors for rheumatoid arthritis (RA) have produced consistently outstanding results with no major side effects in patients refractory to other available treatments. The improvement, determined using either the Paulus or the American College of Rheumatology evaluation criteria, is rapid and has persisted over the 2 years of followup data currently available. Trials of 2 drugs are reviewed--infliximab, currently approved for treatment of Crohn's disease, and etanercept, recently approved for RA therapy.

Westhovens R, Kremer JM, Moreland LW, Emery P, Russell AS, Li T, Aranda R, Becker JC, Qi K, Dougados M. · Department of Rheumatology, KU Leuven, Herestraat 49, B 3000 Leuven, Belgium. · J Rheumatol. · Pubmed #19273451 No free full text.

Abstract: OBJECTIVE: To evaluate the safety and efficacy of abatacept plus methotrexate (MTX) over 5 years in patients with rheumatoid arthritis. METHODS: Patients were randomized to abatacept 10 or 2 mg/kg or placebo, plus MTX. Patients completing the 1-year, double-blind period entered the longterm extension, where all patients received a fixed dose of abatacept ~10 mg/kg. We describe safety analyses for all patients who received at least 1 dose of abatacept and efficacy analyses for the original ~10 mg/kg abatacept-treated group, over 5 years. RESULTS: Of the 235 abatacept- or placebo-treated patients completing the double-blind period, 219 entered the longterm extension; 130 (59.4%) were continuing at Year 5. No unexpected safety events were observed during the longterm extension compared with the double-blind period. Incidence rates of adverse events (AE) and serious AE were 489.7 and 20.0/100 patient-years in Year 1 versus 374.9 and 18.9/100 patient-years in the cumulative period, respectively. Using exploratory analyses, improvements observed at Year 1 in the 10 mg/kg group were maintained at Year 5, as assessed by ACR responses (ACR20=77.1% vs 82.7%; ACR50=53.0% vs 65.4%; ACR70=28.9% vs 40.4% at Years 1 and 5, respectively) and disease activity (Low Disease Activity State=48.2% vs 58.5%; Disease Activity Score-28-defined remission=25.3% vs 45.3% at Years 1 and 5, respectively). CONCLUSION: Abatacept maintained the efficacy observed at Year 1 over 5 years of treatment, and demonstrated consistent safety and tolerability. These data, along with relatively high retention rates, support the longterm clinical benefit provided by selective T cell costimulation modulation. Clinical trial registry: ClinicalTrials.gov; clinical trial registration number: NCT00254293.

Kremer JM, Genant HK, Moreland LW, Russell AS, Emery P, Abud-Mendoza C, Szechiński J, Li T, Teng J, Becker JC, Westhovens R. · Center for Rheumatology, Albany Medical College, Albany, New York 12206, USA. · Arthritis Rheum. · Pubmed #18383390 links to  free full text

Abstract: OBJECTIVE: To evaluate the efficacy, radiographic changes, and safety of abatacept and methotrexate therapy through 2 years in a long-term extension of a previously published 1-year study. METHODS: Patients who received placebo during year 1 were switched to abatacept. Patients taking abatacept continued to take it. Efficacy and safety were assessed through 2 years. RESULTS: Of 539 patients enrolled in the initial 1-year study, 488 completed 1 year of the long-term extension (2% discontinued for lack of efficacy). At 2 years, patients taking abatacept had maintained their responses on the American College of Rheumatology (ACR) improvement criteria and the Disease Activity Score in 28 joints (DAS28; using the C-reactive protein [CRP] level), as well as their physical function (according to the Health Assessment Questionnaire [HAQ] disability index [DI]) and health-related quality of life (HRQOL; assessed with the Short Form 36 [SF-36] health survey), that were observed at the end of the double-blind period (year 1 versus year 2 values were 81.9% versus 80.3% for ACR 20% improvement, 25.4% versus 30.9% for a DAS28 [CRP] of <2.6, 71.8% versus 66.8% for the HAQ DI, and 9.7 versus 10.6 and 7.3 versus 7.2, respectively, for the mean change in the physical and mental components summary scores of the SF-36). In the abatacept group, post hoc analysis demonstrated further inhibition of radiographic progression during year 2 (57% reduction in mean change of total score in year 2 versus year 1; P<0.0001), and minimal radiographic progression was observed (mean change in total score from baseline was 1.1 and 1.6 at year 1 and 2, respectively). Rates of adverse events (AEs) and severe AEs were consistent throughout the cumulative period. CONCLUSION: The improvements in signs and symptoms, physical function, and HRQOL observed after 1 year of abatacept treatment were maintained through 2 years of treatment. This durability was accompanied by a safety profile consistent with that in the double-blind portion of the study. Radiographic progression was further inhibited in year 2 compared with year 1, suggesting an increasing effect of abatacept on the inhibition of structural damage in year 2.

Weisman MH, Durez P, Hallegua D, Aranda R, Becker JC, Nuamah I, Vratsanos G, Zhou Y, Moreland LW. · Division of Rheumatology, Cedars-Sinai Medical Center, 8700 Beverly Blvd., B-131, Los Angeles, CA 90048, USA. · J Rheumatol. · Pubmed #17014006 No free full text.

Abstract: OBJECTIVE: Abatacept, a soluble selective costimulation modulator, selectively modulates T cell activation via the CD80/CD86:CD28 costimulation pathway. Data from a Phase II trial showed efficacy in patients with active rheumatoid arthritis (RA) and inadequate response to methotrexate when treated with abatacept (10 mg/kg or 2 mg/kg). To determine the mechanism of action of abatacept, we analyzed changes in the serum levels of inflammatory biomarkers in the patients enrolled in this trial. RESULTS: Following 12 months' treatment, serum levels of interleukin 6 (IL-6), soluble IL-2 receptor, C-reactive protein, soluble E-selectin, and soluble intercellular adhesion molecule-1 were significantly lower in patients receiving abatacept 10 mg/kg versus placebo. Smaller reductions in tumor necrosis factor-a and rheumatoid factor were also observed in the abatacept 10 mg/kg group compared with the placebo group. Although there was no evidence for efficacy of the 2 mg/kg dose, small reductions in inflammatory biomarkers at this dosage support the biologic effect of this therapy. CONCLUSION: These findings reveal the antiinflammatory and immunomodulatory effects of abatacept in patients with RA, and are consistent with the concept that modulating T cell activation improves clinical signs and symptoms and inhibits the progression of structural damage. These data suggest that selective modulation of the CD80/CD86:CD28 pathway with abatacept may affect several inflammatory cell types and cytokines that are involved in the proinflammatory cascade.

Kremer JM, Genant HK, Moreland LW, Russell AS, Emery P, Abud-Mendoza C, Szechinski J, Li T, Ge Z, Becker JC, Westhovens R. · Center for Rheumatology, Albany, New York, USA. · Ann Intern Med. · Pubmed #16785475 links to  free full text

Abstract: BACKGROUND: The selective co-stimulation modulator abatacept demonstrated efficacy for treating rheumatoid arthritis in early clinical studies. OBJECTIVE: To evaluate the effects of abatacept in patients with persistent, active rheumatoid arthritis despite methotrexate treatment. DESIGN: One-year, multicenter, randomized, double-blind, placebo-controlled trial (November 2002 to October 2004). SETTING: 116 centers worldwide. PATIENTS: 652 patients with active rheumatoid arthritis despite methotrexate treatment. INTERVENTION: Once-monthly infusion of a fixed dose of abatacept, approximately 10 mg/kg of body weight, or placebo. MEASUREMENTS: Co-primary end points were a 20% improvement in American College of Rheumatology (ACR) response criteria (ACR 20) at 6 months, clinically meaningful improvements in physical function, and change from baseline in joint erosion score at 1 year. RESULTS: Four hundred thirty-three and 219 patients were randomly assigned to abatacept or placebo, respectively, and 385 (89%) and 162 (74%), respectively, completed 1 year of treatment. In a modified intention-to-treat analysis, 6-month ACR 20, ACR 50, and ACR 70 responses were 67.9% for abatacept versus 39.7% for placebo (difference, 28.2 percentage points [95% CI, 19.8 to 36.7 percentage points]), 39.9% for abatacept versus 16.8% for placebo (difference, 23.0 percentage points [CI, 15.0 to 31.1 percentage points]), and 19.8% for abatacept versus 6.5% for placebo (difference, 13.3 percentage points [CI, 7.0 to 19.5 percentage points]), respectively. At 1 year, the responses increased to 73.1% for abatacept versus 39.7% for placebo (difference, 33.4 percentage points [CI, 25.1 to 41.7 percentage points]), 48.3% for abatacept versus 18.2% for placebo (difference, 30.1 percentage points [CI, 21.8 to 38.5 percentage points]), and 28.8% for abatacept versus 6.1% for placebo (difference, 22.7 percentage points [CI, 15.6 to 29.8 percentage points]), respectively (P < 0.001 for all). Physical function significantly improved in 63.7% versus 39.3% of patients (P < 0.001). At 1 year, abatacept statistically significantly slowed the progression of structural joint damage compared with placebo. Abatacept-treated patients had a similar incidence of adverse events (87.3% vs. 84.0%; difference, 3.3 percentage points [CI, -2.5 to 9.1 percentage points]) and a higher incidence of prespecified serious infections (2.5% vs. 0.9%; difference, 1.6 percentage points [CI, -0.3 to 3.6 percentage points]) and infusion reactions (acute, 8.8% vs. 4.1%; difference, 4.7 percentage points [CI, 0.9 to 8.4 percentage points]; peri-infusional, 24.5% vs. 16.9%; difference, 7.6 percentage points [CI, 1.2 to 14.0 percentage points]) compared with placebo recipients. LIMITATIONS: The study involved only 1 group of patients over 1 year. CONCLUSIONS: Abatacept statistically significantly reduced disease activity in patients with rheumatoid arthritis and an inadequate response to methotrexate. Longer treatment in different patient populations is needed to establish its appropriate role in rheumatoid arthritis.

Fleischmann RM, Cohen SB, Moreland LW, Schiff M, Mease PJ, Smith DB, Keenan G, Kremer JM, Anonymous00083. · Radiant Research--Dallas, University of Texas, Southwestern Medical Center at Dallas, Dallas, TX 75235, USA. · Curr Med Res Opin. · Pubmed #16083527 No free full text.

Abstract: OBJECTIVE: Infliximab plus methotrexate (MTX) is approved for the treatment of rheumatoid arthritis (RA). Based on the benefit/risk profile of this combination therapy, lower doses of MTX would be preferable when infliximab efficacy can be maintained. We evaluated the ability of patients receiving infliximab plus MTX to achieve and maintain a clinical response while the dose of MTX was tapered. METHODS: Infliximab infusions were administered at a minimum dosage of 3 mg/kg at 8-week intervals (following three loading doses at weeks 0, 2, and 6) to patients who had an inadequate response to MTX. MTX tapering was initiated at week 22 or later when at least a 40% improvement in the combined tender and swollen joint count was achieved; dosages were reduced by 5 mg every 8 weeks to a protocol-specified minimum dosage of 5 mg per week. If the required dosage of MTX after a flare was greater than the baseline dosage, the patient was considered a treatment failure. RESULTS: Of the 210 patients enrolled, 159 (76%) achieved a 40% or better improvement in the combined tender and swollen joint count and had their MTX doses tapered. In these 159 responders, the median (mean) dose of MTX was reduced from 15 (16.5) mg per week at baseline to 5 (7.1) mg per week at week 54. From the time of initial response, 79% of these patients had a zero- or a one-vial increase in infliximab, corresponding to an approximate dose increase of 1 mg/kg, through week 54. CONCLUSION: Approximately 75% of the patients participating in this trial achieved at least a 40% reduction in the combined swollen and tender joint count (correlating with an American College of Rheumatology 20% [ACR20] response in 83% of patients) while reducing the mean MTX dose by 57%.