Rheumatoid Arthritis: Weinblatt M

Aletaha D, Landewe R, Karonitsch T, Bathon J, Boers M, Bombardier C, Bombardieri S, Choi H, Combe B, Dougados M, Emery P, Gomez-Reino J, Keystone E, Koch G, Kvien TK, Martin-Mola E, Matucci-Cerinic M, Michaud K, O'Dell J, Paulus H, Pincus T, Richards P, Simon L, Siegel J, Smolen JS, Sokka T, Strand V, Tugwell P, van der Heijde D, van Riel P, Vlad S, van Vollenhoven R, Ward M, Weinblatt M, Wells G, White B, Wolfe F, Zhang B, Zink A, Felson D, Anonymous00358, Anonymous00359. · Medical University of Vienna, Vienna, Austria. · Arthritis Rheum. · Pubmed #18821648 No free full text.

Abstract: OBJECTIVE: To make recommendations on how to report disease activity in clinical trials of rheumatoid arthritis (RA) endorsed by the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR). METHODS: The project followed the EULAR standardized operating procedures, which use a three-step approach: 1) expert-based definition of relevant research questions (November 2006); 2) systematic literature search (November 2006 to May 2007); and 3) expert consensus on recommendations based on the literature search results (May 2007). In addition, since this is the first joint EULAR/ACR publication on recommendations, an extra step included a meeting with an ACR panel to approve the recommendations elaborated by the expert group (August 2007). RESULTS: Eleven relevant questions were identified for the literature search. Based on the evidence from the literature, the expert panel recommended that each trial should report the following items: 1) disease activity response and disease activity states; 2) appropriate descriptive statistics of the baseline, the endpoints and change of the single variables included in the core set; 3) baseline disease activity levels (in general); 4) the percentage of patients achieving a low disease activity state and remission; 5) time to onset of the primary outcome; 6) sustainability of the primary outcome; 7) fatigue. CONCLUSION: These recommendations endorsed by EULAR and ACR will help harmonize the presentations of results from clinical trials. Adherence to these recommendations will provide the readership of clinical trials with more details of important outcomes, while the higher level of homogeneity may facilitate the comparison of outcomes across different trials and pooling of trial results, such as in meta-analyses.

Furst DE, Halbert RJ, Bingham CO, Fukudome S, Anderson L, Bonafede P, Bray V, Cohen SB, Sherrer YR, St Clair EW, Tesser JR, Weinblatt M, Dubois RW. · Geffen School of Medicine, University of California at Los Angeles, 1000 Veteran Ave Rm 32-59, Los Angeles, CA 90095-1670, USA. · Rheumatology (Oxford). · Pubmed #18178593 No free full text.

Abstract: OBJECTIVES: There is a lack of agreement on assessing disease activity in patients with RA and determining when the RA treatment should be changed or continued. A panel of rheumatologists was convened to develop guidelines to assess adequacy of disease control, focusing on the use of disease-modifying anti-rheumatic drugs. METHODS: The Research and Development/University of California in Los Angeles (RAND/UCLA) Appropriateness Method was used to evaluate disease control adequacy. After a literature review, 108 scenarios were developed to simulate situations most likely to be encountered in clinical practice and rated on a 9-point scale by a 10-member expert panel. RESULTS: Final appropriateness rankings for the scenarios were as follows: 37% 'appropriate', 48% 'inappropriate', and 16% 'neutral'. The panelists felt that patients with disease control in the 'appropriate' range have adequate control with their current therapy, whereas those in the 'inappropriate' range should be considered for a change in therapy. Those in 'neutral' areas should have their therapy reviewed carefully. The panelists recommended that the clinically active joint count should be considered the most important decision factor. In patients with no clinically active joints, regardless of other factors no change in therapy was felt to be warranted. Patients with five or more active joints should be considered inadequately treated, and in patients with one to four active joints other variables must be considered in the decision to change therapy. CONCLUSION: These preliminary guidelines will assist the clinician in determining when a patient's clinical situation warrants therapy escalation and when continuing the current regimen would be appropriate.

Furst DE, Breedveld FC, Burmester GR, Crofford L, Emery P, Feldman M, Kalden JR, Kavanaugh A, Keystone E, Lipsky PE, Maini RN, Moreland L, Smolen JS, Van De Putte L, Vischer T, Weinblatt M, Weissman M. · No affiliation provided · Ann Rheum Dis. · Pubmed #10577989 links to  free full text

This publication has no abstract.

Weinblatt M, Schiff M, Goldman A, Kremer J, Luggen M, Li T, Chen D, Becker JC. · Rheumatology and Immunology, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA. · Ann Rheum Dis. · Pubmed #16935912 No free full text.

Abstract: OBJECTIVE: To investigate the efficacy and safety of abatacept in combination with etanercept in patients with active rheumatoid arthritis during a 1-year, randomised, placebo-controlled, double-blind phase, followed by an open-label, long-term extension (LTE). METHODS: Patients continued etanercept (25 mg twice weekly) and were randomised to receive abatacept 2 mg/kg (n = 85) or placebo (n = 36). As the effective dose of abatacept was established as 10 mg/kg in a separate trial, all patients received abatacept 10 mg/kg and etanercept during the LTE. RESULTS: A total of 121 patients were randomised; 80 completed double-blind treatment and entered the LTE. During double-blind treatment, the difference in the percentage of patients achieving the primary end point (modified American College of Rheumatology (ACR) 20 response at 6 months) was not significant between groups (48.2% v 30.6%; p = 0.072). At 1 year, no notable changes in modified ACR responses were observed. Subsequent to the dosing change, similar modified ACR responses were seen during the LTE. Significant improvements in quality of life were observed with abatacept and etanercept versus placebo and etanercept in five of the eight short-form 36 subscales at 1 year. More abatacept and etanercept-treated patients experienced serious adverse events (SAEs) at 1 year than patients receiving placebo and etanercept (16.5% v 2.8%), with 3.5% v 0% experiencing serious infections. CONCLUSION: The combination of abatacept (at a dose of 2 mg/kg during the double-blind phase and 10 mg/kg during the LTE) and etanercept was associated with an increase in SAEs, including serious infections, with limited clinical effect. On the basis of the limited efficacy findings and safety concerns, abatacept in combination with etanercept should not be used for rheumatoid arthritis treatment.

Furst DE, Weisman M, Paulus HE, Bulpitt K, Weinblatt M, Polisson R, Zaug M, Kneer J, Van der Auwera P, Stevens RM. · Virginia Mason Research Center, Seattle, Washington, USA. · J Rheumatol. · Pubmed #14528504 No free full text.

Abstract: OBJECTIVE: To determine the optimal dose regimen of intravenous (IV) Ro 45-2081 (lenercept), a tumor necrosis factor receptor p55-Fc IgG1 fusion protein, in patients with active rheumatoid arthritis (RA) METHODS: In a double-blind, placebo-controlled, parallel-group, multicenter trial, adult patients with long-standing active RA stabilized on conventional therapy were randomly assigned to receive 3 IV infusions, one every 4 weeks, of one of the following: (a) placebo, (b) lenercept 0.01 mg/kg (maximum 1 mg), (c) lenercept 0.05 mg/kg (maximum 5 mg), (d) lenercept 0.2 mg/kg (maximum 20 mg), or (e) lenercept 0.5 mg/kg (maximum 50 mg). The material utilized in the study had a lower relative bioavailability [lower area under the time-concentration curve (AUC) per mg infused] than that used in a recent similar trial. Efficacy variables included change from baseline in number of swollen joints and tender joints, scores on physician and patient assessments of disease activity, and patient assessment of pain. RESULTS: Patients treated with lenercept exhibited improvement as early as one day after the first IV infusion. The treatment benefit, however, was modest, maximized by 2 weeks and then diminished or vanished as non-neutralizing anti-lenercept antibody concentrations increased. The majority of adverse experiences were mild or moderate and not considered related to study drug. CONCLUSION: Our results showed that lenercept administered by IV infusion every 4 weeks is well tolerated, but only transiently effective in patients with long-standing RA, likely due to both the low relative bioavailability of the material used in the study and the formation of non-neutralizing anti-lenercept antibodies.

Moreland LW, Cohen SB, Baumgartner SW, Tindall EA, Bulpitt K, Martin R, Weinblatt M, Taborn J, Weaver A, Burge DJ, Schiff MH. · Arthritis Clinical Intervention Program, Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, 1717-6th Avenue South, Room 068, Birmingham, AL 35294-7201, USA. · J Rheumatol. · Pubmed #11409115 No free full text.

Abstract: OBJECTIVE: Patients with rheumatoid arthritis (RA) treated with etanercept (Enbrel) in controlled studies of 3 to 6 months' duration had rapid and sustained improvement of their disease, with minimal safety issues. In this study, we examine safety and clinical benefit after longer term treatment with etanercept. METHODS: All adult patients with RA with a previously inadequate response to one or more disease modifying antirheumatic drugs, and who received at least one dose of etanercept as monotherapy in controlled or open label clinical trials were evaluated for safety and clinical benefit. Adverse event rates were compared as was evidence of continued benefit over time. RESULTS: Etanercept continued to be safe and well tolerated in 628 adult patients treated for a median of 25 mo (maximum 43 mo; 1109 patient-years). Nine percent of patients withdrew due to lack of efficacy and 7% due to adverse events. Most adverse events were mild, and no statistically significant increases in frequency of events were seen when patients received etanercept over longer periods of time. Clinical benefit was maintained with longterm therapy. A 100% improvement in individual disease activity measures was achieved by 17% to 28% of the patients. Fifty-five percent of patients who were taking corticosteroids (mean dose at baseline 6.6 mg/day) decreased or discontinued corticosteroid therapy while maintaining control of their arthritis symptoms. CONCLUSION: Etanercept continued to be safe and well tolerated, and its clinical benefit was sustained for a median of 25 mo and for as long as 43 mo in patients with RA.

Aletaha D, Landewe R, Karonitsch T, Bathon J, Boers M, Bombardier C, Bombardieri S, Choi H, Combe B, Dougados M, Emery P, Gomez-Reino J, Keystone E, Koch G, Kvien TK, Martin-Mola E, Matucci-Cerinic M, Michaud K, O'Dell J, Paulus H, Pincus T, Richards P, Simon L, Siegel J, Smolen JS, Sokka T, Strand V, Tugwell P, van der Heijde D, van Riel P, Vlad S, van Vollenhoven R, Ward M, Weinblatt M, Wells G, White B, Wolfe F, Zhang B, Zink A, Felson D. · Division of Rheumatology, Medical University of Vienna, Vienna, Austria. · Ann Rheum Dis. · Pubmed #18791055 No free full text.

Abstract: OBJECTIVE: To make recommendations on how to report disease activity in clinical trials of rheumatoid arthritis (RA) endorsed by the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR). METHODS: The project followed the EULAR standardised operating procedures, which use a three-step approach: (1) expert-based definition of relevant research questions (November 2006); (2) systematic literature search (November 2006 to May 2007); and (3) expert consensus on recommendations based on the literature search results (May 2007). In addition, since this is the first joint EULAR/ACR publication on recommendations, an extra step included a meeting with an ACR panel to approve the recommendations elaborated by the expert group (August 2007). RESULTS: Eleven relevant questions were identified for the literature search. Based on the evidence from the literature the expert panel recommended that each trial should report the following items: (1) disease activity response and disease activity states; (2) appropriate descriptive statistics of the baseline, the endpoints and change of the single variables included in the core set; (3) baseline disease activity levels (in general); (4) the percentage of patients achieving a low disease activity state and remission; (5) time to onset of the primary outcome; (6) sustainability of the primary outcome; (7) fatigue. CONCLUSIONS: These recommendations endorsed by EULAR and ACR will help harmonise the presentations of results from clinical trials. Adherence to these recommendations will provide the readership of clinical trials with more details of important outcomes, while the higher level of homogeneity may facilitate the comparison of outcomes across different trials and pooling of trial results, such as in meta-analyses.

Johnsen AK, Plenge RM, Butty V, Campbell C, Dieguez-Gonzalez R, Gomez-Reino JJ, Shadick N, Weinblatt M, Gonzalez A, Gregersen PK, Benoist C, Mathis D. · Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA. · Arthritis Rheum. · Pubmed #18576312 links to  free full text

Abstract: OBJECTIVE: It has been suggested that polymorphisms in IL1 are correlated with severe and/or erosive rheumatoid arthritis (RA), but the implicated alleles have differed among studies. The aim of this study was to perform a broad and well-powered search for association between allelic polymorphism in IL1A and IL1B and the susceptibility to or severity of RA. METHODS: Key coding and regulatory regions in IL1A and IL1B were sequenced in 24 patients with RA, revealing 4 novel single-nucleotide polymorphisms (SNPs) in IL1B. These and a comprehensive set of 24 SNPs tagging most of the underlying genetic diversity were genotyped in 3 independent RA case-control sample sets and 1 longitudinal RA cohort, totaling 3,561 patients and 3,062 control subjects. RESULTS: No fully significant associations were observed. Analysis of the discovery case-control sample sets indicated a potential association of IL1B promoter region SNPs with susceptibility to RA (for RA3/A, odds ratio [OR] 1.27, P = 0.0021) or with the incidence of radiographic erosions (for RA4/C, OR 1.56, P = 0.036), but these findings were not replicated in independent case-control samples. No association with rheumatoid factor, anti-cyclic citrullinated peptide, or the Disease Activity Score in 28 joints was found. None of the associations previously observed in other studies were replicated here. CONCLUSION: In spite of a broad and highly powered study, we observed no robust, reproducible association between IL1A/B variants and the susceptibility to or severity of RA in white individuals of European descent. Our results provide evidence that, in the majority of cases, polymorphism in IL1A and IL1B is not a major contributor to genetic susceptibility to RA.

Weinblatt M, Combe B, Covucci A, Aranda R, Becker JC, Keystone E. · Rheumatology and Immunology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA. · Arthritis Rheum. · Pubmed #16947384 links to  free full text

Abstract: OBJECTIVE: To assess the safety of abatacept, a selective costimulation modulator, in patients with active rheumatoid arthritis (RA) who had been receiving > or =1 traditional nonbiologic and/or biologic disease-modifying antirheumatic drugs (DMARDs) approved for the treatment of RA for at least 3 months prior to entry into the study. METHODS: This was a 1-year, multicenter, randomized, double-blind, placebo-controlled trial. Patients were randomized 2:1 to receive abatacept at a fixed dose approximating 10 mg/kg by weight range, or placebo. RESULTS: The abatacept and placebo groups exhibited similar frequencies of adverse events (90% and 87%, respectively), serious adverse events (13% and 12%, respectively), and discontinuations due to adverse events (5% and 4%, respectively). Five patients (0.5%) in the abatacept group and 4 patients (0.8%) in the placebo group died during the study. Serious infections were more frequent in the abatacept group than in the placebo group (2.9% versus 1.9%). Fewer than 4% of patients in either group experienced a severe or very severe infection. The incidence of neoplasms was 3.5% in both groups. When evaluated according to background therapy, serious adverse events occurred more frequently in the subgroup receiving abatacept plus a biologic agent (22.3%) than in the other subgroups (11.7-12.5%). CONCLUSION: Abatacept in combination with synthetic DMARDs was well tolerated and improved physical function and physician- and patient-reported disease outcomes. However, abatacept in combination with biologic background therapies was associated with an increase in the rate of serious adverse events. Therefore, abatacept is not recommended for use in combination with biologic therapy.

van der Heijde D, Simon L, Smolen J, Strand V, Sharp J, Boers M, Breedveld F, Weisman M, Weinblatt M, Rau R, Lipsky P. · Department of Internal Medicine, University Hospital Maastricht, Maastricht, The Netherlands. · Arthritis Rheum. · Pubmed #11954017 No free full text.

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Cush JJ, Tugwell P, Weinblatt M, Yocum D. · University of Texas Southwestern Medical School, Dallas, USA. · J Rheumatol. · Pubmed #10332987 No free full text.

Abstract: Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease that often leads to irreversible joint damage and loss of function. Although there are numerous treatment options, it is difficult to manage the disease in most patients. Use of cyclosporin A (CsA) for RA was first reported in 1979, and since that time many trials have investigated CsA use for this disease. Based on clinical evidence, CsA is an efficacious second-line agent for patients with active RA who have not responded adequately to methotrexate (MTX). In addition, CsA has been shown to provide clinical benefit when used in combination with MTX in patients responding inadequately to MTX monotherapy. Side effects associated with CsA treatment are manageable if dosing, monitoring, and intervention guidelines are followed. The purpose of this review is to provide recommendations for the use of CsA in severe RA to physicians experienced in the management of systemic immunosuppressive therapy for RA. Where possible and appropriate, recommendations are based on evidence available in the literature.

Roubenoff R, Beckman E, Weinblatt M, Shadick N, Gregersen PK. · No affiliation provided · Ann Intern Med. · Pubmed #18316760 links to  free full text

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Alarcón GS, Kremer J, Weinblatt M. · No affiliation provided · Arthritis Rheum. · Pubmed #15334490 links to  free full text

This publication has no abstract.