Rheumatoid Arthritis: Keystone E

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.

Keystone E. · The Rebecca MacDonald Centre for Arthritis and Autoimmune Disease, University of Toronto, Toronto, Ontario, Canada. · Curr Opin Rheumatol. · Pubmed #19365267 No free full text.

Abstract: PURPOSE OF REVIEW: To provide an update on new concepts in the inhibition of radiographic progression with current and emerging biologic therapy. RECENT FINDINGS: The advent of biologic therapies for the treatment of rheumatoid arthritis has given rise to the concept of a disconnect between clinical and radiographic outcomes. Radiographic progression has been observed in patients in clinical remission, whereas inhibition of radiographic progression has been demonstrated in patients with clinically active disease. Moreover, imaging remission has been shown to be much easier to achieve than clinical remission. Biologics are superior to methotrexate (MTX) in inhibiting radiographic progression at every level of disease activity and response. The majority of patients receiving biologics and a significant proportion receiving MTX alone do not progress radiographically. The combination of a biologic and MTX inhibits radiographic progression more than either alone, reducing both the proportion of patients progressing and the degree of progression of those who do progress. Although biologics are similar in their ability to inhibit radiographic progression in most patients, they differ in inhibiting the progression in the rapid radiographic progressors. SUMMARY: The disconnect between clinical and radiographic outcomes demonstrated with biologics implies the need to monitor both outcomes in order to treat patients most effectively. The superiority of biologics over MTX in inhibiting radiographic progression suggests that the clinical target for a biologic may differ from that for MTX to prevent structural damage and preserve function. For most patients, radiographic inhibition should not affect the choice of a biologic.

Mader R, Keystone E. · Rebecca McDonald Centre for Arthritis and Autoimmune Diseases, Department of Medicine, University of Toronto, Toronto, Ontario, Canada. · J Rheumatol Suppl. · Pubmed #17985419 No free full text.

Abstract: Disability and joint damage in rheumatoid arthritis (RA) occur rapidly and early in the course of the disease. Disease activity is predominantly responsible for the disability in the early stages of RA. Nonreversible joint damage increases disability later in the course of RA. In recent years, several strategies that employed combination therapies with conventional disease modifying antirheumatic drugs (DMARD) were studied with the aim of rapidly bringing the disease under control. The ultimate goal was to alleviate symptoms and slow or halt the progression of joint damage. The introduction of highly efficient biologic agents allows introduction of a number of new strategies, including early administration of a biologic agent alone or in combination with high-dose methotrexate. Other options for the use of biologic therapies include the use of biologic agents for moderate disease, and early use of a biologic agent for induction of remission and subsequent treatment with a conventional DMARD. A strategy for tight control of disease with targeted outcomes for decision-making may offer further improvement in disease control irrespective of the treatment approach. The remarkably improved outcomes that can be achieved by initiating aggressive therapy early, with close monitoring of disease progression and modification of ineffective therapeutic strategies, support the use of biologics in the optimal management of RA.

Haraoui B, Keystone E. · Université de Montréal, RDU CHUM, Hôpital Notre-Dame, Montreal, Quebec, Canada. · Curr Opin Rheumatol. · Pubmed #16344625 No free full text.

Abstract: PURPOSE OF REVIEW: The anti-tumor necrosis factor agents are now widely used in the management of patients with rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis and juvenile inflammatory arthritis. One of the most common observations made during their use is the development of autoantibodies. The purpose of this paper is to review this phenomenon and its clinical implications. RECENT FINDINGS: While the development of different autoantibodies is a common encounter, rare cases of lupus-like syndromes have been reported. On the other hand, a variety of immune-mediated clinical manifestations have been described, including vasculitis and demyelinating syndromes. Rare cases of cytopenia and non-specific lung injuries have also been reported. SUMMARY: While these clinical complications are rare and isolated events, clinicians must be aware of their occurrence. The experience with the anti-tumor necrosis factor agents is rather short and new, unusual immune-mediated complications may still appear. Clinicians should be prepared to recognize them.

Smolen JS, Aletaha D, Keystone E. · Medical University of Vienna and Lainz Hospital, Vienna, Austria. · Arthritis Rheum. · Pubmed #16200577 links to  free full text

This publication has no abstract.

Keystone E. · Department of Medicine, University of Toronto, Ontario, Canada. · Arthritis Res Ther. · Pubmed #15960817 No free full text.

Abstract: Although the precise pathogenesis of rheumatoid arthritis (RA) remains unclear, many cell populations, including monocytes, macrophages, endothelial cells, fibroblasts and B cells, participate in the inflammatory process. Ongoing research continues to evaluate the critical roles played by B cells in sustaining the chronic inflammatory process of RA. These findings have contributed to the development of targeted therapies that deplete B cells, such as rituximab, as well as inhibitors of B lymphocyte stimulation, such as belimumab. In a phase I trial, belimumab treatment significantly reduced CD20+ levels in patients with systemic lupus erythematosus. Phase I and phase II trials of rituximab found that rituximab plus methotrexate achieved significantly better American College of Rheumatology 50% responses for patients with RA than those patients receiving monotherapy with methotrexate. These clinical trial data present promising evidence for B cell targeted therapies as future therapeutic options for RA.

Keystone E, Haraoui B. · Division of Advanced Therapeutics, The Rebecca MacDonald Centre for Arthritis and Autoimmune Disease, Mount Sinai Hospital, 60 Murray Street, University of Toronto, Toronto, Ontario, Canada M5G 1X5. · Rheum Dis Clin North Am. · Pubmed #15172045 No free full text.

Abstract: Adalimumab is a recombinant human immunoglobulin G1 monoclonal antibody that is specific for human tumor necrosis factor.Based on the data presented in this article, adalimumab administered alone or in patients partially responsive to methotrexate exhibits a rapid onset of action, provides a substantial reduction in signs and symptoms, and results in an improvement in physical function and health-related quality of life. Adalimumab has been demonstrated to inhibit progression of structural joint damage in patients who have long-standing rheumatoid arthritis. Taken together, the data support adalimumab as a new therapeutic option for patients with moderate to severe rheumatoid arthritis.

Keystone E. · The Centre for Advanced Therapeutics, Mount Sinai Hospital and University of Toronto, Canada. · Ann Rheum Dis. · Pubmed #12379620 links to  free full text

This publication has no abstract.

Russell A, Haraoui B, Keystone E, Klinkhoff A. · Department of Medicine, University of Alberta Hospital Site, Heritage Medical Research Centre, Edmonton, Canada. · Clin Ther. · Pubmed #11768835 No free full text.

Abstract: BACKGROUND: Rheumatoid arthritis (RA) is a physically debilitating disease that places an enormous burden not only on individuals and their families but also on the economy. Affecting -1% of the Canadian population, RA is characterized by pain and swelling of joints. Without effective treatment, RA results in joint destruction that often requires surgery. OBJECTIVE: This review summarizes the effect of current and new RA treatments on joint damage, with a focus on infliximab. The health-economic repercussions and potential impact of arresting the joint destruction of RA are discussed. METHODS: Information for inclusion in this review was identified through searches of the MEDLINE and HealthStar databases from 1995 to 2000. Search terms included rheumatoid arthritis, treatment guidelines, economics, and individual drug names. RESULTS: Standard initial RA drug therapy has been aimed at reducing pain and inflammation, whereas use of the more potent disease-modifying antirheumatic drugs (DMARDs) has been reserved for later stages of disease. More aggressive RA treatment involves introducing DMARDs at the earliest stage. The largest single direct cost of RA involves hospital admissions for the correction of joint deformities. Among newer therapies, the anti-tumor necrosis factor-alpha agent infliximab has been shown to arrest radiographic measures of disease progression. CONCLUSIONS: With early and aggressive treatment involving new drugs and drug combinations, it may be possible to ameliorate the physical, social, and economic effects of RA.

Haraoui B, Strand V, Keystone E. · Université de Montreal, Rheumatic Disease Unit, CHUM, Canada. · Curr Pharm Biotechnol. · Pubmed #11469381 No free full text.

Abstract: Advances in the understanding of the pathogenesis of rheumatoid arthritis (RA) as well as improved biotechnology has enabled selective targeting of the pathogenic elements of disease. Targeting cell recruitment through adhesion molecules has been shown to be successful in pre-clinical murine models. Results of studies of an anti-ICAM-1 monoclonal antibody and anti-sense oligonucleotides have been encouraging. An alternate approach to inhibiting recruitment has been the targeting of chemoattractant molecules ie. chemokines. Important advances have been made in cytokine directed therapy targeting TNFalpha and IL-1. TNF antagonists (anti-TNF monoclonal antibody/soluble TNF receptor Fc fusion protein) have resulted in rapid and substantial improvement in signs and symptoms of disease as well as disease modification, shown by slowing of radiological progression. IL-1 receptor antagonist protein appears to have a significant effect on radiological progression despite a modest effect on symptoms and signs. Studies using anti-inflammatory cytokines such as IL-10 are in progress. A more recent therapeutic approach has been to target T-cell activation by interfering with co-stimulatory complexes such as CD40L/CD40 and CD28/CD80 and CD86. Both pre-clinical and preliminary clinical studies in human subjects support the concept. Another approach involving T-cell receptor peptide vaccination with VB peptides over-utilized in RA synovium has shown to be beneficial. Targeting the cytokines driving T-cells in the RA synovium ie. IL-12 & IL-15 has also proven beneficial in animal studies. Recent attention has also been directed toward the invading synovial fibroblast using Fas-FasL mediated apoptosis. Pre-clinical studies in which angiogenesis and osteoclast activation are targeted have been encouraging. In conclusion, the proof of principle has been established that selective targeting of pathogenic elements of disease results in substantial improvement in signs and symptoms as well as disease progression. Improved efficacy is expected with more aggressive targeting of the pathogenic elements.

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.

Keystone E, Heijde D, Mason D, Landewé R, Vollenhoven RV, Combe B, Emery P, Strand V, Mease P, Desai C, Pavelka K. · University of Toronto, Toronto, Ontario, Canada. · Arthritis Rheum. · Pubmed #18975346 No free full text.

Abstract: OBJECTIVE: To evaluate the efficacy and safety of 2 dosage regimens of lyophilized certolizumab pegol (a novel PEGylated anti-tumor necrosis factor agent) as adjunctive therapy to methotrexate (MTX) in patients with active rheumatoid arthritis (RA) with an inadequate response to MTX therapy alone. METHODS: In this 52-week, phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial, 982 patients were randomized 2:2:1 to receive treatment with subcutaneous certolizumab pegol at an initial dosage of 400 mg given at weeks 0, 2, and 4, with a subsequent dosage of 200 mg or 400 mg given every 2 weeks, plus MTX, or placebo plus MTX. Co-primary end points were the response rate at week 24 according to the American College of Rheumatology 20% criteria for improvement (ACR20) and the mean change from baseline in the modified total Sharp score at week 52. RESULTS: At week 24, ACR20 response rates using nonresponder imputation for the certolizumab pegol 200-mg and 400-mg groups were 58.8% and 60.8%, respectively, as compared with 13.6% for the placebo group. Differences in ACR20 response rates versus placebo were significant at week 1 and were sustained to week 52 (P < 0.001). At week 52, mean radiographic progression from baseline was reduced in patients treated with certolizumab pegol 200 mg (0.4 Sharp units) or 400 mg (0.2 Sharp units) as compared with that in placebo-treated patients (2.8 Sharp units) (P < 0.001 by rank analysis). Improvements in all ACR core set of disease activity measures, including physical function, were observed by week 1 with both certolizumab pegol dosage regimens. Most adverse events were mild or moderate. CONCLUSION: Treatment with certolizumab pegol 200 or 400 mg plus MTX resulted in a rapid and sustained reduction in RA signs and symptoms, inhibited the progression of structural joint damage, and improved physical function as compared with placebo plus MTX treatment in RA patients with an incomplete response to MTX.

Keystone E, Emery P, Peterfy CG, Tak PP, Cohen S, Genovese MC, Dougados M, Burmester GR, Greenwald M, Kvien TK, Williams S, Hagerty D, Cravets MW, Shaw T. · Division of Rheumatology, University of Toronto, Toronto, Canada. · Ann Rheum Dis. · Pubmed #18388156 No free full text.

Abstract: OBJECTIVE: To determine if treatment with a B cell-targeted therapy can inhibit the progression of structural joint damage in patients with rheumatoid arthritis (RA), exhibiting an inadequate response to tumour necrosis factor (TNF) inhibitors. METHODS: In this phase III study, patients with an inadequate response to a TNF inhibitor and receiving methotrexate were randomised to rituximab or placebo. Radiographs were obtained at baseline, week 24 and week 56 after randomisation. Patients with an inadequate response to their randomised therapy could receive rescue medication from week 16. From week 24, eligible patients from both treatment arms could receive open-label rituximab. Patients were analysed according to their original treatment group. Radiographs were scored using the Genant-modified Sharp method. The primary radiographic endpoint was change in total Genant-modified Sharp score at week 56. RESULTS: Rituximab treatment caused significant reduction in joint damage progression compared with placebo. The mean change from baseline in the total Genant-modified Sharp score at week 56 was significantly lower for patients treated with rituximab than for patients treated with placebo (1.00 vs 2.31; p = 0.005), and was supported by changes in erosion score (0.59 and 1.32 for rituximab plus methotrexate vs placebo plus methotrexate, respectively; p = 0.011) and joint space narrowing score (0.41 and 0.99, respectively; p<0.001). CONCLUSIONS: This study provides the first evidence that a B cell-targeted therapy-rituximab-can significantly inhibit the progression of structural joint damage in patients with RA with long-standing, active and treatment-resistant disease.

Keystone E, Fleischmann R, Emery P, Furst DE, van Vollenhoven R, Bathon J, Dougados M, Baldassare A, Ferraccioli G, Chubick A, Udell J, Cravets MW, Agarwal S, Cooper S, Magrini F. · Mount Sinai Hospital, and University of Toronto, 600 University Avenue, Toronto, Ontario, Canada. · Arthritis Rheum. · Pubmed #18050221 links to  free full text

Abstract: OBJECTIVE: To determine the safety and efficacy of additional courses of rituximab in patients with rheumatoid arthritis (RA). METHODS: An open-label extension analysis of RA patients previously treated with rituximab was conducted. Patients who had participated in any of 3 double-blind trials were eligible for additional courses (2 infusions of 1,000 mg given 2 weeks apart) if they exhibited a swollen joint count and tender joint count of > or =8 with > or =16 weeks elapsing after the previous course. Safety was assessed in patients receiving all or a portion of a rituximab course. Efficacy was assessed 24 weeks after each course, using the American College of Rheumatology 20% criteria for improvement (ACR20), ACR50, ACR70, European League Against Rheumatism (EULAR) response criteria, Disease Activity Score in 28 joints, the disability index of the Health Assessment Questionnaire, and Short Form 36 scores, stratified according to prior tumor necrosis factor (TNF) inhibitor exposure. RESULTS: A total of 1,039 patients received > or =1 course of rituximab. Of these, 570 received 2 courses, 191 received 3 courses, and 40 received 4 courses, for a total of 1,669 patient-years. Irrespective of prior TNF inhibitor exposure, ACR20 responses were comparable at week 24 after course 1 and at week 24 after course 2 (65% versus 72%), as were ACR50 and ACR70 responses. EULAR moderate/good responses were also comparable in course 2 relative to course 1 (88% versus 79%), with EULAR remission occurring in a 2-fold higher proportion of patients after course 2 than after course 1 (13% versus 6%). The most common adverse events, which were mild-to-moderate acute infusion-related events, decreased with each course. The serious infection rate after course 1 (5.1 per 100 patient-years) remained stable through additional courses. The proportion of patients with circulating IgM and IgG levels below the lower limit of normal (LLN) increased with subsequent courses; however, serious infection rates in these patients (5.6 per 100 patient-years in patients with low IgM levels and 4.8 per 100 patient-years in patients with low IgG levels were comparable with those in patients with immunoglobulin levels above the LLN (4.7 per 100 patient-years). Patients with human antichimeric antibody (9.2%) did not exhibit decreasing efficacy or present additional safety concerns. CONCLUSION: These findings indicate that patients treated with repeated courses of rituximab have sustained clinical responses with no new adverse events.

Antoni CE, Kavanaugh A, Kirkham B, Tutuncu Z, Burmester GR, Schneider U, Furst DE, Molitor J, Keystone E, Gladman D, Manger B, Wassenberg S, Weier R, Wallace DJ, Weisman MH, Kalden JR, Smolen J. · Friedrich-Alexander University, Erlangen-Nuremberg, Germany. · Arthritis Rheum. · Pubmed #15818699 links to  free full text

Abstract: OBJECTIVE: To investigate the efficacy and tolerability of infliximab therapy for the articular and dermatologic manifestations of active psoriatic arthritis (PsA). METHODS: One hundred four patients with PsA in whom prior therapy with at least 1 disease-modifying antirheumatic drug (DMARD) had failed were recruited into this investigator-initiated, multicenter, randomized, double-blind, placebo-controlled clinical trial. During the initial blinded portion of the study, patients received infusions of infliximab (5 mg/kg) or placebo at weeks 0, 2, 6, and 14. After week 16, patients initially assigned to receive placebo crossed over to receive infliximab 5 mg/kg every 8 weeks through week 50, while patients initially randomized to infliximab continued to receive active treatment at the same dose through week 50. The primary efficacy outcome was achievement of the American College of Rheumatology 20% criteria for improvement in rheumatoid arthritis (ACR20) at week 16. Additional predefined clinical efficacy assessments included the Psoriasis Area and Severity Index (PASI) score, the ACR50 and ACR70 criteria, the Disease Activity Score in 28 joints, the Health Assessment Questionnaire, ratings of enthesitis and dactylitis, and the Psoriatic Arthritis Response Criteria score. RESULTS: The proportion of infliximab-treated patients who achieved an ACR20 response at week 16 (65%) was significantly higher than the proportion of placebo-treated patients who achieved this response (10%). In addition, 46% of infliximab-treated patients achieved an ACR50 response, and 29% achieved an ACR70 response; no placebo-treated patient achieved these end points. Among patients who had PASI scores of >/=2.5 at baseline, 68% of infliximab-treated patients achieved improvement of >/=75% in the PASI score at week 16 compared with none of the placebo-treated patients. Continued therapy with infliximab resulted in sustained improvement in articular and dermatologic manifestations of PsA through week 50. The incidence of adverse events was similar between the treatment groups. CONCLUSION: Therapy with infliximab at a dose of 5 mg/kg significantly improved the signs and symptoms of arthritis, psoriasis, dactylitis, and enthesitis in patients with active PsA that had been resistant to DMARD therapy. With continued infliximab treatment, benefits were sustained through 50 weeks. The benefit-to-risk ratio appeared favorable in this study population.

St Clair EW, van der Heijde DM, Smolen JS, Maini RN, Bathon JM, Emery P, Keystone E, Schiff M, Kalden JR, Wang B, Dewoody K, Weiss R, Baker D, Anonymous00222. · Duke University Medical Center, Durham, North Carolina, USA. · Arthritis Rheum. · Pubmed #15529377 links to  free full text

Abstract: 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.

Kremer J, Genovese M, Cannon GW, Caldwell J, Cush J, Furst DE, Luggen M, Keystone E, Bathon J, Kavanaugh A, Ruderman E, Coleman P, Curtis D, Kopp E, Kantor S, Weisman M, Waltuck J, Lindsley HB, Markenson J, Crawford B, Fernando I, Simpson K, Strand V. · Center for Rheumatology, Albany, New York 12206, USA. · J Rheumatol. · Pubmed #15290730 No free full text.

Abstract: OBJECTIVE: To obtain additional safety and efficacy data on leflunomide (LEF) treatment in combination with methotrexate (MTX) therapy in an open-label extension study in patients with rheumatoid arthritis (RA). METHODS: Following a 24 week, randomized, double-blind trial of adding placebo (PLA) or LEF to stable MTX therapy, patients could enter a 24 week extension. Subjects randomized to LEF and MTX continued treatment [(LEF/LEF) + MTX]. Subjects randomized to PLA and MTX switched to LEF (10 mg/day, no loading dose) and MTX [(PLA/LEF) + MTX]. The double-blind regarding initial randomization was maintained. RESULTS: For subjects in the extension phase, American College of Rheumatology 20% (ACR20) responder rates for the (LEF/LEF) + MTX group were maintained from Week 24 (57/96, 59.4%) to Week 48 (53/96, 55.2%). ACR20 responder rates improved in patients switched to LEF from PLA at Week 24 [(PLA/LEF) + MTX] from 25.0% (24/96) at Week 24 to 57.3% (55/96) at Week 48. Patients in the extension who switched from PLA to LEF without a loading dose exhibited a lower incidence of elevated transaminases compared to patients initially randomized to LEF. Diarrhea and nausea were less frequent during the open-label extension in patients who did not receive a LEF loading dose. CONCLUSION: Response to therapy was maintained to 48 weeks of treatment in patients who continued to receive LEF and MTX during the extension. Importantly, ACR20 response rates after 24 weeks of LEF therapy were similar between patients switched from PLA to LEF without loading dose, and those who received a loading does of LEF (100 mg/day x 2 days) at randomization. Fewer adverse events were reported in patients switched to LEF without a loading dose.

Breedveld FC, Emery P, Keystone E, Patel K, Furst DE, Kalden JR, St Clair EW, Weisman M, Smolen J, Lipsky PE, Maini RN. · Department of Rheumatology, University of Leiden, Leiden, The Netherlands. · Ann Rheum Dis. · Pubmed #14722203 links to  free full text

Abstract: OBJECTIVE: To examine the impact of the combination of infliximab plus methotrexate (MTX) on the progression of structural damage in patients with early rheumatoid arthritis (RA). METHODS: Subanalyses were carried out on data for patients with early RA in the Anti-TNF Therapy in RA with Concomitant Therapy (ATTRACT) study, in which 428 patients with active RA despite MTX therapy received placebo with MTX (MTX-only) or infliximab 3 mg/kg or 10 mg/kg every (q) 4 or 8 weeks with MTX (infliximab plus MTX) for 102 weeks. Early RA was defined as disease duration of 3 years or less; 82 of the 428 patients (19%) met this definition. Structural damage was assessed with the modified van der Heijde-Sharp score. The changes from baseline to week 102 in total modified van der Heijde-Sharp score were compared between the infliximab plus MTX groups and the MTX-only group. RESULTS: The erosion and joint space narrowing scores from baseline to week 102 in the cohort of patients with early RA decreased significantly in each infliximab dose regimen compared with the MTX-only regimen. Consistent benefit was seen in the joints of both hands and feet. CONCLUSIONS: Infliximab combined with MTX inhibited the progression of structural damage in patients with early RA during the 2 year period of treatment. Early intervention with infliximab in patients with active RA despite MTX therapy may provide long term benefits by preventing radiographic progression and preserving joint integrity.

Kremer JM, Genovese MC, Cannon GW, Caldwell JR, Cush JJ, Furst DE, Luggen ME, Keystone E, Weisman MH, Bensen WM, Kaine JL, Ruderman EM, Coleman P, Curtis DL, Kopp EJ, Kantor SM, Waltuck J, Lindsley HB, Markenson JA, Strand V, Crawford B, Fernando I, Simpson K, Bathon JM. · The Center for Rheumatology, LLP, 1367 Washington Avenue, Suite 101, Albany, NY 12206, USA. · Ann Intern Med. · Pubmed #12416946 links to  free full text

Abstract: BACKGROUND: Disease-modifying antirheumatic drugs may confer greater benefits when combined with the antimetabolite methotrexate. OBJECTIVE: To evaluate the efficacy and safety of leflunomide versus placebo when added to ongoing, stable-dose methotrexate therapy in patients with persistently active rheumatoid arthritis. DESIGN: 24-week, multicenter, randomized, double-blind, placebo-controlled trial. SETTING: 20 centers in the United States and Canada. PATIENTS: Patients with persistent rheumatoid arthritis, as defined by American College of Rheumatology (ACR) criteria, despite receiving methotrexate for at least 6 months. INTERVENTION: Leflunomide or matching placebo added to existing methotrexate therapy. MEASUREMENTS: The primary efficacy variable was the rate of achievement of 20% improvement in ACR criteria (ACR20) at the end of the study. The Health Assessment Questionnaire Disability Index was assessed at each visit, and the Medical Outcomes Study 36-Item Short Form was completed as an end point analysis. RESULTS: In the leflunomide and placebo groups, 46.2% and 19.5% of patients, respectively, met ACR20 criteria at 24 weeks (P < 0.001). Clinical improvement was demonstrated by statistically significant mean changes in individual components of the ACR20 response criteria. Discontinuation rates were similar in both treatment groups (23.1% in the leflunomide group and 24.8% in the placebo group), as were the overall incidences of adverse events (89.2% vs. 89.5%, respectively). Adverse events were predominantly mild or moderate. CONCLUSIONS: Combination therapy with leflunomide and methotrexate provides statistically significant clinical benefit in patients with active rheumatoid arthritis who are receiving methotrexate therapy. Leflunomide plus methotrexate is generally well tolerated and can be used safely with appropriate liver enzyme and hematologic monitoring.

Mason U, Aldrich J, Breedveld F, Davis CB, Elliott M, Jackson M, Jorgensen C, Keystone E, Levy R, Tesser J, Totoritis M, Truneh A, Weisman M, Wiesenhutter C, Yocum D, Zhu J. · GlaxoSmithKline Pharmaceuticals, Greenford, Middlesex, UK. · J Rheumatol. · Pubmed #11838838 No free full text.

Abstract: OBJECTIVE: Double blind studies were conducted with the anti-CD4 monoclonal antibody (Mab) keliximab in patients with active, stable rheumatoid arthritis (RA), to confirm preliminary evidence of efficacy and safety from open. uncontrolled studies. METHODS: We enrolled 136 and 186 patients into 2 consecutive, randomized, double blind trials, with similar populations [apart from inclusion of disease modifying antirheumatic drug (DMARD)-naïve patients in Study 2]. Patients received 4 weeks intravenous placebo or keliximab [40, 80, 120, or 140 mg twice weekly (bw), or 240 mg once weekly (ow)].The primary endpoint was the American College of Rheumatology (ACR) 20 response criteria, one week after the end of treatment. RESULTS: ACR 20 response rates in Study I were 19%, 42%, 51%*, and 69%* (*p < 0.05 compared to placebo), with placebo, 40, 80, or 140 mg keliximab bw, respectively. The response rates in Study 2 were 30%, 39%, 46% and 47% with placebo, 80 or 120 mg bw, or 240 mg keliximab ow, respectively. In the 2 studies, there was a dose dependent increase in peripheral blood CD4+ T cell coating with keliximab, but a different pattern of CD4 depletion was seen. While only 12% of keliximab treated patients in Study I had CD4 counts below 250 cells/mm3 at the end of the treatment period, 47% fell below this level in Study 2. Clinical response was not correlated with CD4 depletion, but was correlated with CD4+ T cell coating with keliximab. CONCLUSION: Coating of peripheral blood CD4+ T cells with keliximab, but not CD4 depletion, is a determinant of clinical response.

Keystone E, Freundlich B, Schiff M, Li J, Hooper M. · Mount Sinai Hospital, The Rebecca MacDonald Centre for Arthritis and Autoimmunity, Toronto, ON M5G 1X5, Canada. · J Rheumatol. · Pubmed #19228659 No free full text.

Abstract: OBJECTIVE: This analysis examined clinical and radiographic responses to methotrexate (MTX), etanercept (ETN), and combination ETN and MTX in patients with moderate versus severe rheumatoid arthritis (RA) in both early and late disease. METHODS: Data from the Trial of Etanercept and Methotrexate With Radiographic Patient Outcomes (TEMPO) and the Early Rheumatoid Arthritis trials were used. Patients were classified with moderate or severe RA based on Disease Activity Score including 28-joint count (DAS28). Outcomes included DAS28 remission, DAS28 low disease activity, Health Assessment Questionnaire (HAQ), American College of Rheumatology (ACR) scores, Total Sharp Score (TSS) progression, no radiographic progression (annualized change in TSS > or = 0), change from baseline in TSS, and the change in TSS for patients who had radiographic progression (TSS > 0). RESULTS: Patients with moderate disease generally achieved better clinical outcomes than patients with severe disease, including significant differences in DAS28 remission, low disease activity, and HAQ < or =0.5 at Month 12. Patients with baseline severe disease had higher ACR and DAS responses than patients with moderate disease. CONCLUSION: Patients with severe RA disease activity achieved substantial clinical improvement with high-dose MTX and/or ETN treatment, but patients with moderate disease were more likely to reach a lower disease activity state. These findings were independent of disease duration. The results support the opportunity for excellent clinical outcomes, particularly with combination therapy, in patients with moderate RA.

Karonitsch T, Aletaha D, Boers M, Bombardieri S, Combe B, Dougados M, Emery P, Felson D, Gomez-Reino J, Keystone E, Kvien TK, Martin-Mola E, Matucci-Cerinic M, Richards P, van Riel P, Siegel J, Smolen JS, Sokka T, van der Heijde D, van Vollenhoven R, Ward M, Wells G, Zink A, Landewe R. · Division of Rheumatology, Medical University of Vienna, Vienna, Austria. · Ann Rheum Dis. · Pubmed #18791056 No free full text.

Abstract: OBJECTIVE: To use an evidence-based and consensus-based approach to elaborate recommendations on how to report disease activity in clinical trials of patients with rheumatoid arthritis (RA) endorsed by the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR). METHODS: After an initial expert meeting, during which relevant research questions were identified, a systematic literature search was performed using Medline, Embase and the Cochrane Library as sources. To ensure literature retrieved was comprehensive, we emphasised search algorithms that were sensitive rather than specific. The results of the literature search were discussed by the expert panel, modified and expanded, and were used as the basis for the elaboration of the recommendation in the consensus process. Finally, an independent ACR panel approved these items with some minor modifications. RESULTS: The following pieces of evidence were obtained from the literature search: (1) timing and the sustaining of a response is relevant to achieve better outcomes; (2) composite disease activity indices have been used to define low disease activity and remission and these definitions have been validated as has the American Rheumatism Association (ARA) remission criteria. The "patient-reported symptom state" (PASS) is not yet well validated; (3) evidence was obtained to identify those measures, scales and patient-reported instruments, for which there is a documented association with relevant outcomes; (4) baseline disease activity is associated with disease activity levels at the end of follow-up; and (5) there was not sufficient evidence relating the added benefit of MRI or ultrasound over clinical assessments. Most data stemmed from observational studies rather than clinical trials and literature review was supplemented by input from experts. The results served as the basis for the elaboration of the seven recommendations by the experts. CONCLUSIONS: The approach based on scientific evidence from the literature as well as on expert input provided sufficient information to derive recommendations on reporting disease activity in RA clinical trials. The methodology, results and conclusions of this project were endorsed by EULAR and the ACR.

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.

Mease PJ, Hobbs K, Chalmers A, El-Gabalawy H, Bookman A, Keystone E, Furst DE, Anklesaria P, Heald AE. · Seattle Rheumatology Associates/Swedish Medical Center Research, Seattle, Washington, USA. · Ann Rheum Dis. · Pubmed #18678578 No free full text.

Abstract: OBJECTIVE: To examine the safety and tolerability of a single intra-articular injection of rAAV2-TNFR:Fc, an adenoassociated virus serotype 2 vector containing the cDNA for the human tumour necrosis factor-immunoglobulin Fc fusion gene (tgAAC94), in subjects with inflammatory arthritis. METHODS: In a double-blind, placebo-controlled, phase 1, dose-escalation study, 15 subjects with inflammatory arthritis (14 with rheumatoid arthritis and 1 with ankylosing spondylitis) not receiving tumour necrosis factor alpha (TNFalpha) inhibitors with persistent moderate (grade 2) or severe (grade 3) swelling in a target joint due to inflammatory arthritis received a single intra-articular injection of rAAV2-TNFR:Fc at 1 x 10(10) (n = 5) or 1 x 10(11) (n = 6) DNase resistant particles per ml joint volume or placebo (n = 4) into a knee (n = 14) or ankle (n = 1). Safety was assessed through adverse event monitoring. As a secondary objective, changes in injected joint tenderness and swelling scores, each measured on a four-point scale, were evaluated. RESULTS: Intra-articular injections of rAAV2-TNFR:Fc were well tolerated with no major safety issues. One event, mild knee pruritis, was considered probably related. Synovial fluid TNFR:Fc protein was not detected (nor expected) at the doses used. At 12 weeks after injection, a two-point decrease in swelling was noted in 2/11 and 2/4 subjects injected with rAAV2-TNFR:Fc and placebo, respectively. CONCLUSION: A single dose of intra-articular rAAV2-TNFR:Fc appears to be safe and well tolerated in subjects without concurrent systemic TNFalpha antagonist use. It is thus feasible to proceed with larger trials to further test the safety and efficacy of local TNFR:Fc gene transfer as a therapeutic modality for patients with inflammatory arthritis.

Emery P, Keystone E, Tony HP, Cantagrel A, van Vollenhoven R, Sanchez A, Alecock E, Lee J, Kremer J. · Leeds Teaching Hospitals Trust, University of Leeds, Leeds, UK. · Ann Rheum Dis. · Pubmed #18625622 No free full text.

Abstract: OBJECTIVES: The phase III RADIATE study examined the efficacy and safety of tocilizumab, an anti-IL-6 receptor monoclonal antibody in patients with rheumatoid arthritis (RA) refractory to tumour necrosis factor (TNF) antagonist therapy. METHODS: 499 patients with inadequate response to one or more TNF antagonists were randomly assigned to receive 8 mg/kg or 4 mg/kg tocilizumab or placebo (control) intravenously every 4 weeks with stable methotrexate for 24 weeks. ACR20 responses, secondary efficacy and safety endpoints were assessed. RESULTS: ACR20 was achieved at 24 weeks by 50.0%, 30.4% and 10.1% of patients in the 8 mg/kg, 4 mg/kg and control groups, respectively (less than p<0.001 both tocilizumab groups versus control). At week 4 more patients achieved ACR20 in 8 mg/kg tocilizumab versus controls (less than p = 0.001). Patients responded regardless of most recently failed anti-TNF or the number of failed treatments. DAS28 remission (DAS28 <2.6) rates at week 24 were clearly dose related, being achieved by 30.1%, 7.6% and 1.6% of 8 mg/kg, 4 mg/kg and control groups (less than p = 0.001 for 8 mg/kg and p = 0.053 for 4 mg/kg versus control). Most adverse events were mild or moderate with overall incidences of 84.0%, 87.1% and 80.6%, respectively. The most common adverse events with higher incidence in tocilizumab groups were infections, gastrointestinal symptoms, rash and headache. The incidence of serious adverse events was higher in controls (11.3%) than in the 8 mg/kg (6.3%) and 4 mg/kg (7.4%) groups. CONCLUSION: Tocilizumab plus methotrexate is effective in achieving rapid and sustained improvements in signs and symptoms of RA in patients with inadequate response to TNF antagonists and has a manageable safety profile. TRIAL REGISTRATION NUMBER: NCT00106522.