Treatment of rheumatoid arthritis with the selective costimulation modulator abatacept: Twelve‐month results of a phase iib,double‐blind,randomized, placebo‐controlled trial

Objective

To determine the clinical efficacy, safety, and immunogenicity of abatacept (CTLA‐4Ig), a selective costimulation modulator, in patients with rheumatoid arthritis (RA) that has remained active despite methotrexate (MTX) therapy.

Methods

This was a 12‐month, multicenter, randomized, double‐blind, placebo‐controlled study. A total of 339 patients with active RA despite MTX therapy were randomly assigned to receive 10 mg/kg abatacept (n = 115), 2 mg/kg abatacept (n = 105), or placebo (n = 119). This report focuses on the results observed at month 12 of a phase IIb trial.

Results

A significantly greater percentage of patients treated with 10 mg/kg abatacept met the American College of Rheumatology 20% improvement criteria (achieved an ACR20 response) at 1 year compared with patients who received placebo (62.6% versus 36.1%; P < 0.001). Greater percentages of patients treated with 10 mg/kg abatacept also achieved ACR50 responses (41.7% versus 20.2%; P < 0.001) and ACR70 responses (20.9% versus 7.6%; P = 0.003) compared with patients who received placebo. For patients treated with 10 mg/kg abatacept, there were also statistically significant and clinically important improvements in modified Health Assessment Questionnaire scores compared with patients who received placebo (49.6% versus 27.7%; P < 0.001). Abatacept at a dosage of 10 mg/kg elicited an increase in rates of remission (Disease Activity Score in 28 joints of <2.6) compared with placebo at 1 year (34.8% versus 10.1%; P < 0.001). The incidence of adverse events was comparable between the groups, and no significant formation of neutralizing antibodies was noted.

Conclusion

Abatacept was associated with significant reductions in disease activity and improvements in physical function that were maintained over the course of 12 months in patients with RA that had remained active despite MTX treatment. Abatacept was found to be well tolerated and safe over the course of 1 year. Abatacept in combination with MTX has the potential to play an important role in future RA therapy.

     

Treatment of rheumatoid arthritis with L-histidine: a randomized, placebo-controlled, double-blind trial.

A randomized cooperative double-blind trial of oral L-histidine for the treatment of rheumatoid arthritis was carried out. Patients were treated with either L-histidine 4.5 g daily, or placebo, for 30 weeks. None of the clinical measurements showed an advantage of histidine over placebo. A small decrease in rheumatoid factor titer and a small increase in hematocrit were found only in the histidine group. There was suggestive evidence of a beneficial effect of histidine in patients with more active and prolonged disease, based upon subjective doubld-blind evaluations by physicians and patients. No adverse effects of histidine therapy were noted. Histidine cannot be advocated as a therapeutic agent in rheumatoid arthritis, but further studies in certain groups of patients seem justified.     

Safety of the selective costimulation modulator abatacept in rheumatoid arthritis patients receiving background biologic and nonbiologic disease-modifying antirheumatic drugs: A one-year randomized, placebo-controlled study

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.     

Treatment of rheumatoid arthritis with ornidazole: a randomized, double-blind, placebo-controlled study

The aim of our study was to evaluate the clinical efficacy, safety, and tolerability of ornidazole in patients with rheumatoid arthritis (RA). This was 3 months, randomized, double-blind,placebo-controlled study. A total of 160 patients with active RA were randomly assigned to receive 1,000 mg ornidazole (n = 53), 500 mg ornidazole (n = 55), or placebo (n = 52). A significantly greater percentage of patients treated with 1,000 mg ornidazole met the American College of Rheumatology 20% improvement criteria (achieved an ACR20 response) at 3 months compared with patients who received placebo (62.0 vs. 32.4%; P < 0.001). Greater percentages of patients treated with 1,000 mg ornidazole also achieved ACR50 responses (38.3 vs. 10.9%; P < 0.001) and ACR70 responses (19.6 vs. 1.2%; P < 0.001) compared with patients who received placebo. Ornidazole treatment was also associated with significant reductions in pain and duration of morning stiffness, significant improvement in the quality of life and both the physician’s and patient’s global assessments, and significant reductions in disease activity as assessed by objective laboratory measures (erythrocyte sedimentation rate and C-reactive protein level). Ornidazole was well tolerated. There were no dose-limiting toxic effects. In this 3-month-trial ornidazole was safe, well tolerated, and associated with improvement in the inflammatory symptoms of RA.     

Modulation of CCR2 in rheumatoid arthritis: a double-blind, randomized, placebo-controlled clinical trial

OBJECTIVE: CCR2 is a chemokine receptor expressed by monocytes, macrophages, and a subset of T cells. Its ligand, CCL2 (monocyte chemotactic protein 1), is abundantly present in the synovium of patients with rheumatoid arthritis (RA). Blocking CCR2 prevents CCL2-mediated chemotaxis in vitro and modulates arthritis in animal models of RA. In this study we examined the effects of CCR2 blockade on synovial inflammation in RA. METHODS: The study was designed as a phase IIa clinical trial with a human CCR2 blocking antibody (MLN1202) in patients with active RA. Thirty-two patients received 3 infusions, over a period of 6 weeks, with either placebo (n = 9) or anti-CCR2 monoclonal antibody at 0.5 mg/kg (n = 7), 1.5 mg/kg (n = 7), or 4.0 mg/kg (n = 9). Safety was monitored with laboratory tests, immunotoxicity assessments, and documenting of adverse events, and European League Against Rheumatism and American College of Rheumatology response criteria were used to assess clinical improvement. Synovial tissue was obtained at baseline and after 43 days of treatment, for pharmacodynamic analysis using immunohistochemistry and digital image analysis. The Kruskal-Wallis test was used to compare groups, and the Wilcoxon signed rank test was used to assess changes within the groups. RESULTS: All patients completed the study. Treatment with CCR2 blocking antibody reduced the levels of free CCR2 on CD14+ monocytes by at least 57% and up to 94% (P < 0.001), demonstrating the biologic activity of the compound. However, there was no reduction in the levels or expression of any of the synovial biomarkers. Accordingly, no clinical improvement was observed. CONCLUSION: Treatment with anti-CCR2 blocking antibody did not result in amelioration of synovial inflammation in active RA. The results do not support the notion that blockade of CCR2 may be sufficient to induce clinical improvement in RA.     

Efficacy of methotrexate treatment in patients with probable rheumatoid arthritis: a double-blind, randomized, placebo-controlled trial

OBJECTIVE: To determine whether patients with undifferentiated arthritis (UA; inflammatory, nontraumatic arthritis that cannot be diagnosed using current classification criteria) benefit from treatment with methotrexate (MTX). METHODS: The PRObable rheumatoid arthritis: Methotrexate versus Placebo Treatment (PROMPT) study was a double-blind, placebo-controlled, randomized, multicenter trial involving 110 patients with UA who fulfilled the American College of Rheumatology (ACR) 1958 criteria for probable RA. Treatment started with MTX (15 mg/week) or placebo tablets, and every 3 months the dosage was increased if the Disease Activity Score was >2.4. After 12 months, the study medication was tapered and discontinued. Patients were followed up for 30 months. When a patient fulfilled the ACR criteria for RA (primary end point), the study medication was changed to MTX. Joint damage was scored on radiographs of the hands and feet. RESULTS: In 22 of the 55 patients (40%) in the MTX group, UA progressed to RA compared with 29 of 55 patients (53%) in the placebo group. However, in the MTX group, patients fulfilled the ACR criteria for RA at a later time point than in the placebo group (P = 0.04), and fewer patients showed radiographic progression over 18 months (P = 0.046). CONCLUSION: This study provides evidence for the efficacy of MTX treatment in postponing the diagnosis of RA, as defined by the ACR 1987 criteria, and retarding radiographic joint damage in UA patients.     

Treatment of rheumatoid arthritis with ornidazole. A randomized, double-blind, placebo-controlled study

SIR, In many previous studies, rheumatoid arthritis (RA) hasbeen found at high frequencies in individuals with periodontitis,and RA resembles periodontitis in many pathological aspects[1, 2]. HLA-DR4 tissue antigens are found at high frequenciesboth in patients with periodontitis and in those with RA. HLA-DR4tissue antigens and their subtypes are directly associated witheach disease [3, 4]. High levels of oral anaerobic bacterial antibodies and heat-shockproteins have been found in the     

The effects of intravenous doxycycline therapy for rheumatoid arthritis: a randomized, double-blind, placebo-controlled trial

OBJECTIVE: To determine the feasibility, safety, and potential clinical efficacy of intravenous (IV) doxycycline therapy for rheumatoid arthritis (RA), as well as its possible effects on serum and urinary markers of collagen breakdown. METHODS: The exploratory trial was designed as a 16-week, single-center, randomized, double-blind, placebo-controlled trial. Eligible subjects with active seropositive or erosive RA were randomly allocated into 3 treatment groups: doxycycline 200 mg IV, azithromycin 250 mg orally, or placebo. The blinded IV study drug was administered once daily for the first 3 weeks by home self-infusion and then weekly for the next 8 weeks, concurrent with the blinded oral study drug at the prescribed doses. The primary end points were the change between baseline and week 4 in the tender joint count, erythrocyte sedimentation rate, and urinary excretion of pyridinoline. RESULTS: The trial was stopped prematurely after enrollment of 31 patients. Three subjects were withdrawn because of worsening arthritis, and 1 patient was withdrawn when newly diagnosed with breast cancer. Infusion-related events occurred in 13 (42%) of 31 patients, but none were serious. There were 4 serious adverse events unrelated to the study drug, including a new diagnosis of breast cancer in 3 cases and hospitalization for abdominal pain in 1 case. No significant differences were observed across treatment groups in any of the 3 primary clinical end points. CONCLUSION: Although IV doxycycline therapy was generally well-tolerated by patients in this trial, it did not show any evidence of reducing disease activity or collagen crosslink production.     

Treatment of rheumatoid arthritis with humanized anti-interleukin-6 receptor antibody: a multicenter, double-blind, placebo-controlled trial

OBJECTIVE: Interleukin-6 (IL-6) is a pleiotropic cytokine that regulates the immune response, inflammation, and hematopoiesis. Overproduction of IL-6 plays pathologic roles in rheumatoid arthritis (RA), and the blockade of IL-6 may be therapeutically effective for the disease. This study was undertaken to evaluate the safety and efficacy of a humanized anti-IL-6 receptor antibody, MRA, in patients with RA. METHODS: In a multicenter, double-blind, placebo-controlled trial, 164 patients with refractory RA were randomized to receive either MRA (4 mg/kg body weight or 8 mg/kg body weight) or placebo. MRA was administered intravenously every 4 weeks for a total of 3 months. The clinical responses were measured using the American College of Rheumatology (ACR) criteria. RESULTS: Treatment with MRA reduced disease activity in a dose-dependent manner. At 3 months, 78% of patients in the 8-mg group, 57% in the 4-mg group, and 11% in the placebo group achieved at least a 20% improvement in disease activity according to the ACR criteria (an ACR20 response) (P < 0.001 for 8-mg group versus placebo). Forty percent of patients in the 8-mg group and 1.9% in the placebo group achieved an ACR50 response (P < 0.001). The overall incidences of adverse events were 56%, 59%, and 51% in the placebo, 4-mg, and 8-mg groups, respectively, and the adverse events were not dose dependent. A blood cholesterol increase was observed in 44.0% of the patients. Liver function disorders and decreases in white blood cell counts were also observed, but these were mild and transient. There was no increase in antinuclear antibodies or anti-DNA antibodies. Anti-MRA antibodies were detected in 2 patients. CONCLUSION: Treatment with MRA was generally well tolerated and significantly reduced the disease activity of RA.     

Once-weekly administration of 50 mg etanercept in patients with active rheumatoid arthritis: results of a multicenter, randomized, double-blind, placebo-controlled trial

OBJECTIVE: To evaluate the safety, efficacy, and pharmacokinetics of 50 mg etanercept administered subcutaneously once weekly in adult patients with active rheumatoid arthritis (RA). METHODS: Four hundred twenty RA patients were randomized to receive, in a blinded manner, the study drug for up to 16 weeks: 214 patients received 50 mg etanercept once weekly, 153 received 25 mg etanercept twice weekly, and 53 received placebo for 8 weeks followed by 25 mg etanercept twice weekly for 8 weeks. Efficacy and safety were assessed at weeks 8 and 16. Pharmacokinetic analyses were performed on serum samples from patients at selected study sites. The primary efficacy end point was achievement of the American College of Rheumatology (ACR) 20% improvement criteria (ACR20 response) at week 8. RESULTS: An ACR20 response was achieved at week 8 by 50% of the patients receiving 50 mg etanercept once weekly, by 49% of the patients receiving 25 mg etanercept twice weekly, and by 19% of the patients in the placebo group (P 相似文献   

Denosumab treatment effects on structural damage, bone mineral density, and bone turnover in rheumatoid arthritis: a twelve-month, multicenter, randomized, double-blind, placebo-controlled, phase II clinical trial

OBJECTIVE: RANKL is essential for osteoclast development, activation, and survival. Denosumab is a fully human monoclonal IgG2 antibody that binds RANKL, inhibiting its activity. The aim of this multicenter, randomized, double-blind, placebo-controlled, phase II study was to evaluate the effects of denosumab on structural damage in patients with rheumatoid arthritis (RA) receiving methotrexate treatment. METHODS: RA patients received subcutaneous placebo (n = 75), denosumab 60 mg (n = 71), or denosumab 180 mg (n = 72) injections every 6 months for 12 months. The primary end point was the change from baseline in the magnetic resonance imaging (MRI) erosion score at 6 months. RESULTS: At 6 months, the increase in the MRI erosion score from baseline was lower in the 60-mg denosumab group (mean change 0.13; P = 0.118) and significantly lower in the 180-mg denosumab group (mean change 0.06; P = 0.007) than in the placebo group (mean change 1.75). A significant difference in the modified Sharp erosion score was observed as early as 6 months in the 180-mg denosumab group (P = 0.019) as compared with placebo, and at 12 months, both the 60-mg (P = 0.012) and the 180-mg (P = 0.007) denosumab groups were significantly different from the placebo group. Denosumab caused sustained suppression of markers of bone turnover. There was no evidence of an effect of denosumab on joint space narrowing or on measures of RA disease activity. Rates of adverse events were comparable between the denosumab and placebo groups. CONCLUSION: Addition of twice-yearly injections of denosumab to ongoing methotrexate treatment inhibited structural damage in patients with RA for up to 12 months, with no increase in the rates of adverse events as compared with placebo.     

Evaluation of immunogenicity of the T cell costimulation modulator abatacept in patients treated for rheumatoid arthritis

OBJECTIVE: The immunogenicity of abatacept, a selective costimulation modulator, administered intravenously, was assessed across Phase II and III trials in patients with rheumatoid arthritis (RA). METHODS: Two direct-format enzyme-linked immunosorbent assays evaluated antibody responses [whole abatacept molecule (CTLA-4 and Ig portion) and CTLA-4 portion only (Assay A)] in the Phase II trials. During the Phase III trials and 2-year open-label periods, a similar, but more sensitive, Assay B was employed. Serum samples collected prestudy, during treatment, and 56 and/or 85 days following the last dose were evaluated. Seropositive samples with anti-CTLA-4 reactivity and sufficiently low drug levels were further characterized for neutralizing activity (cell-based bioassay). RESULTS: A total of 2237 patients with both pre- and post-baseline serum samples were eligible for assessment. Of these, 62 (2.8%) patients demonstrated an anti-abatacept or anti-CTLA-4 response, determined using either Assay A or B. Using the more sensitive Assay B, 60 of 1990 patients (3.0%) demonstrated an antibody response to the whole abatacept molecule (n = 41, 2.1%) or the CTLA-4 portion (n = 19, 1.0%). Of the 1764 RA patients evaluated in the Phase III studies, 203 discontinued therapy and had sera collected 56 and/or 85 days after discontinuation. Patients who discontinued had a higher incidence of immunogenicity versus patients who did not discontinue (7.4% vs 2.6%, respectively). Of 20 patients positive for anti-CTLA-4 reactivity, 13 were eligible for assessment with the neutralization bioassay. Of these, 8 patients exhibited neutralizing activity. Seroconversion occurred with no adverse safety outcomes or effect on pharmacokinetic parameters. No consistent pattern was observed between antibody response and loss of efficacy (American College of Rheumatology 20 and Health Assessment Questionnaire responses). CONCLUSION: Abatacept was associated with a low incidence of immunogenicity in patients with RA and lacked any adverse sequelae.     

The efficacy and safety of rituximab in patients with active rheumatoid arthritis despite methotrexate treatment: results of a phase IIB randomized, double-blind, placebo-controlled, dose-ranging trial

OBJECTIVE: To examine the efficacy and safety of different rituximab doses plus methotrexate (MTX), with or without glucocorticoids, in patients with active rheumatoid arthritis (RA) resistant to disease-modifying antirheumatic drugs (DMARDs), including biologic agents. METHODS: A total of 465 patients were randomized into 9 treatment groups: 3 rituximab groups (placebo [n = 149], 500 mg [n = 124], or 1,000 mg [n = 192] on days 1 and 15) each also taking either placebo glucocorticoids, intravenous methylprednisolone premedication, or intravenous methylprednisolone premedication plus oral prednisone for 2 weeks. All patients received MTX (10-25 mg/week); no other DMARDs were permitted. RESULTS: Significantly more patients who received 2 500-mg or 2 1,000-mg infusions of rituximab met the American College of Rheumatology 20% improvement criteria (achieved an ACR20 response) at week 24 (55% and 54%, respectively) compared with placebo (28%; P < 0.0001). ACR50 responses were achieved by 33%, 34%, and 13% of patients, respectively (P < 0.001), and ACR70 responses were achieved by 13%, 20%, and 5% of patients (P < 0.05). Changes in the Disease Activity Score in 28 joints (-1.79, -2.05, -0.67; P < 0.0001) and moderate to good responses on the European League Against Rheumatism criteria (P < 0.0001) reflected the ACR criteria responses. Glucocorticoids did not contribute significantly to the primary efficacy end point, ACR20 response at 24 weeks. Intravenous glucocorticoid premedication reduced the frequency and intensity of first infusion-associated events; oral glucocorticoids conferred no additional safety benefit. Rituximab was well tolerated; the type and severity of infections was similar to those for placebo. CONCLUSION: Both rituximab doses were effective and well tolerated when added to MTX therapy in patients with active RA. The primary end point (ACR20 response) was independent of glucocorticoids, although intravenous glucocorticoid premedication improved tolerability during the first rituximab infusion.     

艾拉莫德治疗类风湿关节炎多中心随机双盲安慰剂对照研究

目的 研究艾拉莫德片（T-614）治疗类风湿关节炎（RA）的疗效和安全性。方法 280例活动期RA患者分别采用T-61450mg／d（25mg／次，每天2次）、25mg／d（25mg／次，每天1次）和安慰剂治疗。疗程为24周，并在2、6、12、18、24周时进行疗效及观察指标评估。结果 直到用药后6周治疗组达到ACR20及ACR50的比例才显著高于安慰剂组（P〈0．05），而12周、18周和24周的疗效观察显示治疗组的疗效随时间推移而逐渐增高，在24周时，25mg组、50mg组和安慰剂组的ACR20分别为39．1％、61．3％和24．2％，ACR50分别为23．9％、31．2％和7．4％，ACR20及ACR50治疗组优于安慰剂组．50mg组优于25mg组（P〈0．05）。治疗组在红细胞沉降率、C反应蛋白、类风湿因子改善程度差值组间比较有统计学意义。T-614治疗组耐受性良好。结论 艾拉莫德治疗RA具有良好的安全性和显著的疗效。