Stable Dose Of Methotrexate Research Articles

Golimumab in patients with active rheumatoid arthritis after treatment with tumour necrosis factor α inhibitors (GO-AFTER study): a multicentre, randomised, double-blind, placebo-controlled, phase III trial

Tumour necrosis factor alpha (TNFalpha) inhibitors are frequently used to treat rheumatoid arthritis, but whether use of a different TNFalpha inhibitor can improve patient response is unknown. We assess the efficacy and safety of the TNFalpha inhibitor golimumab in patients with active rheumatoid arthritis who had previously received one or more TNFalpha inhibitors. 461 patients with active rheumatoid arthritis from 82 sites in 10 countries were randomly allocated by interactive voice response system, stratified by study site and methotrexate use, to receive subcutaneous injections of placebo (n=155), 50 mg golimumab (n=153), or 100 mg golimumab (n=153) every 4 weeks between Feb 21, 2006, and Sept 26, 2007. Allocation was double-blind. Eligible patients had been treated with at least one dose of a TNFalpha inhibitor previously. Patients continued stable doses of methotrexate, sulfasalazine, hydroxychloroquine, oral corticosteroids, and non-steroidal anti-inflammatory drugs. The primary endpoint was achievement at week 14 of 20% or higher improvement in American College of Rheumatology criteria for assessment of rheumatoid arthritis (ACR20). At week 16, patients who had less than 20% improvement in tender and swollen joint counts were given rescue therapy and changed treatment from placebo to 50 mg golimumab, or from 50 mg to 100 mg golimumab. Drug efficacy was assessed by intention to treat and safety was assessed according to the study drug given. This study is registered with ClinicalTrials.gov, number NCT00299546. Patients had discontinued previous TNFalpha inhibitors because of lack of effectiveness (269 [58%] patients) or reasons unrelated to effectiveness (246 [53%] patients), such as intolerance and accessibility issues. Patients had active disease, which was indicated by a median of 14.0 (IQR 9.0-22.0) swollen and 26.0 (16.0-41.0) tender joints for the whole group. 28 (18%) patients on placebo, 54 (35%) patients on 50 mg golimumab (odds ratio 2.5 [95% CI 1.5-4.2], p=0.0006), and 58 (38%) patients on 100 mg golimumab (2.8 [1.6-4.7], p=0.0001) achieved ACR20 at week 14. Two patients were never treated, and 57 patients did not complete the study because of adverse events, unsatisfactory treatment effect, loss to follow-up, death, or other reasons. 155 patients on placebo, 153 on 50 mg golimumab, and 153 on 100 mg golimumab were assessed for drug efficacy. For weeks 1-16, serious adverse events were recorded in 11 (7%) patients on placebo, 8 (5%) on 50 mg golimumab, and 4 (3%) on 100 mg golimumab. For weeks 1-24, after some patients were given rescue therapy, serious adverse events were recorded in 15 (10%) patients on placebo, 14 (5%) on 50 mg golimumab, and 8 (4%) on 100 mg golimumab. Golimumab reduced the signs and symptoms of rheumatoid arthritis in patients with active disease who had previously received one or more TNFalpha inhibitors. Centocor Research and Development and Schering-Plough Research Institute.

Alefacept with methotrexate for treatment of psoriatic arthritis: Open-label extension of a randomized, double-blind, placebo-controlled study

A single course of alefacept intramuscularly in combination with methotrexate (MTX) was effective in treating both psoriasis and psoriatic arthritis (PsA). We sought to determine the efficacy and safety of an additional course of alefacept intramuscularly in combination with MTX in patients with PsA. In this open-label extension study, patients with PsA on stable doses of MTX were treated with an additional 12 weekly intramuscular injections of alefacept followed by 12 weeks of observation. Efficacy of PsA treatment was measured as 20% reduction in American College of Rheumatology criteria (ACR20). At the end of the open-label extension phase, 86 of 160 (54%) patients achieved ACR20, of which 28 of 55 had received placebo plus MTX and 58 of 105 received alefacept plus MTX in the prior double-blind phase. Although there was no increase in the proportion of patients achieving ACR20 after a second course of alefacept plus MTX, those achieving ACR50 and ACR70 increased from 17% and 7%, respectively, in the double-blind phase to 32% and 12%, respectively, in the open-label extension phase. In this open-label extension phase of the study there was no control group and the effect on psoriasis in these patients was not measured. Patients with psoriasis and PsA on stable doses of MTX derive benefit for both conditions from one or more courses of alefacept, with further benefit in PsA apparent after a second course of treatment. No additional toxicity was observed.

Inflammatory and prothrombotic biomarkers in patients with rheumatoid arthritis: Effects of tumor necrosis factor-α blockade

Objective Increased cardiovascular (CV) risk is a rheumatoid arthritis (RA) hallmark and it has been mainly related to chronic systemic inflammation. Since inflammation is linked to coagulation perturbation, both may play a role in increasing CV risk. Treatment with tumor necrosis factor (TNF)-α blocking agents is effective in RA and reduces local and systemic inflammation but there is little information on its effect on coagulation. We therefore investigated inflammation and coagulation plasma biomarkers before and after infliximab treatment in RA patients. Methods We studied 20 patients with active RA and 40 healthy controls. Patients were treated with: a stable dose of methotrexate (10 mg/week), and infliximab (3 mg/kg) at weeks 0, 2, 6 and 14. At baseline and week 14, we determined: disease activity score (DAS-28), visual analogue scale pain, erythrocyte sedimentation rate (ESR), and plasma levels of C-reactive protein (CRP), TNF-α, interleukin (IL)-6, prothrombin fragment 1 + 2 (F1 + 2) and D-dimer. The same inflammation and coagulation parameters were evaluated 1 h after infliximab infusion in 10 patients. Results At baseline, ESR, CRP, TNF-α, IL-6, F1 + 2 and D-dimer levels were significantly higher in RA patients than in controls ( P = 0.0001). After 14 weeks of infliximab treatment, there was a significant clinical improvement and ESR and CRP, IL-6, F1 + 2 and D-dimer level decrease ( P = 0.001– P = 0.008). The levels of TNF-α, IL-6, F1 + 2 and D-dimer significantly decreased 1 h after infliximab infusion ( P = 0.005). Conclusions Infliximab decreases inflammation and coagulation biomarkers in RA patients. Such a combined effect may be pivotal in reducing the whole thrombotic risk in these patients.

The human anti-IL-1β monoclonal antibody ACZ885 is effective in joint inflammation models in mice and in a proof-of-concept study in patients with rheumatoid arthritis

IntroductionIL-1β is a proinflammatory cytokine driving joint inflammation as well as systemic signs of inflammation, such as fever and acute phase protein production.MethodsACZ885, a fully human monoclonal antibody that neutralizes the bioactivity of human IL-1β, was generated to study the potent and long-lasting neutralization of IL-1β in mechanistic animal models as well as in a proof-of-concept study in patients with rheumatoid arthritis (RA).ResultsThe mouse IL-1 receptor cross-reacts with human IL-1β, and it was demonstrated that ACZ885 can completely suppress IL-1β-mediated joint inflammation and cartilage destruction in mice. This observation prompted us to study the safety, tolerability and pharmacodynamic activity of ACZ885 in RA patients in a small proof-of-concept study – the first to be conducted in humans. Patients with active RA despite treatment with stable doses of methotrexate were enrolled in this dose escalation study. The first 32 patients were split into four cohorts of eight patients each (six were randomly assigned to active treatment and two to placebo). ACZ885 doses were 0.3, 1, 3 and 10 mg/kg, administered intravenously on days 1 and 15. To explore efficacy within 6 weeks of treatment, an additional 21 patients were randomly assigned to the 10 mg/kg cohort, resulting in a total of 20 patients dosed with 10 mg/kg and 15 patients treated with placebo. There was clinical improvement (American College of Rheumatology 20% improvement criteria) at week 6 in the 10 mg/kg treatment group; however, this did not reach statistical significance (P = 0.085). A statistically significant reduction in disease activity score was observed after 4 weeks in the 10 mg/kg group. Onset of action was rapid, because most responders exhibited improvement in their symptoms within the first 3 weeks. C-reactive protein levels decreased in patients treated with ACZ885 within 1 week. ACZ885 was well tolerated. Three patients receiving ACZ885 developed infectious episodes that required treatment. No anti-ACZ885 antibodies were detected during the study.ConclusionACZ885 administration to methotrexate-refractory patients resulted in clinical improvement in a subset of patients. Additional studies to characterize efficacy in RA and to determine the optimal dose regimen appear warranted.Trial RegistrationClinicalTrials.gov identifier NCT00619905.

Rituximab

An important role for B cells in the immunopathogenesis of rheumatoid arthritis (RA) is recognized. Rituximab is a chimeric murine/human anti-CD20 monoclonal antibody that transiently depletes CD20+ B cells. A single course of rituximab (two intravenous infusions of 1,000mg given two weeks apart) with a stable dose of methotrexate significantly improved all measures of disease activity, fatigue, and health-related quality of life relative to placebo with methotrexate. This was demonstrated in the REFLEX trial, a 24-week, randomized, double-blind, double-dummy, international, phase III study in 520 patients who had active RA despite ongoing treatment with methotrexate and had experienced an inadequate response to anti-tumor necrosis factor (TNF) therapy. Patients in REFLEX (or other studies) who responded to, and required further treatment after, an initial course of rituximab continued to respond to subsequent courses of the drug. A small subgroup of patients in REFLEX continued to respond to their first course of rituximab through 48 weeks of follow-up. Long-term treatment (up to 56 weeks) with one or more courses of rituximab in REFLEX significantly inhibited joint structural damage, the first time this effect has been reported in patients with an inadequate response to TNF inhibitors. Rituximab was generally well tolerated; the majority of adverse events were related to the first infusion of the drug, were mild to moderate in severity, and were easily managed. The adverse event profile of rituximab was unchanged after repeat courses.

Alefacept plus methotrexate for psoriatic arthritis

Background Psoriatic arthritis (PsA) is a multifactorial condition that leads to chronic inflammation of the joints and entheses in around 10–30% of patients with psoriasis. Therapy for PsA is generally based around agents used to treat rheumatoid arthritis (RA), but toxicity and variability in treatment response limit their use, especially in the long term. Following recent research into the underlying immunologic nature of PsA, interest has focused on the modification of T-cell function. Alefacept, an inhibitor of T-cell activation approved for the treatment of chronic plaque psoriasis, has shown promising results in pilot studies in PsA. Objectives To investigate the efficacy and safety of alefacept in combination with methotrexate for the treatment of PsA. Design This was a placebo-controlled, double-blind, international phase II clinical trial. Eligible patients were 18–20 years old, with active PsA (greater than or equal to3 swollen joints and greater than or equal to3 tender joints), and were receiving stable doses of methotrexate (total duration of methotrexate treatment greater than or equal to3 months). Intervention Patients received weekly doses of either alefacept 15 mg or placebo intramuscularly for 12 weeks. This was followed by a 12-week, methotrexate-only observation period. All patients continued on their stable methotrexate dose (10–25 mg/week) throughout. Patients were stratified according to psoriasis body surface area (BSA) involvement (greater than or equal to3% or <3%) at baseline. Outcome measures The main study outcome was the proportion of patients achieving an ACR20 response (20% improvement in disease activity according to the American College of Rheumatology criteria) at week 24. Other outcome measures included changes in psoriasis BSA involvement, and safety parameters. Results In all, 185 patients were included in the study (alefacept n = 123, placebo n = 62). At week 24, significantly more patients in the alefacept group achieved an ACR20 response, compared with patients in the placebo group (54% vs 23%, respectively, P <0.001). Patients in the alefacept group showed a significantly greater decrease in tender joints (31%, mean reduction -8.0) and in swollen joints (46%, mean reduction -6.3), compared with patients in the placebo group (17%, mean reduction -4.5, and 35%, mean reduction -3.5, respectively). In the alefacept group, significantly more patients with psoriasis involving greater than or equal to3% of BSA showed a 50% reduction in psoriasis severity at week 14 compared with patients in the placebo group (53% vs 17%, respectively, P <0.001). Reported adverse events were mild-to-moderate in severity and similar in both groups. The incidence of serious adverse events was low (1.6%) and judged to be unrelated to study medication. Conclusion The results of this study suggest that alefacept in combination with methotrexate might be effective and safe for the treatment for PsA.

Infliximab versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a preliminary study from China

AbstractAim: To report the efficacy and safety of infliximab in the treatment of active rheumatoid arthritis (RA) in Chinese patients.Methods: This is a multicentre double‐blind placebo controlled study. Patients with active RA despite being on a stable dose of methotrexate were randomly assigned to receive either infliximab 3 mg/kg body weight or placebo infusion at weeks 0, 2, 6 and 14. All patients continued their stable dose of methotrexate throughout the study. Patients were assessed at weeks 0, 2, 6, 14 and 18 for the American College of Rheumatology (ACR) 20%, 50% and 70% response (ACR20, 50 and 70, respectively). Health assessment questionnaire (HAQ), erythrocyte sedimentation rate (ESR), c‐reactive protein (CRP), duration of morning stiffness and adverse effects were monitored.Results: Infliximab was effective in improving the disease activity of RA with significant ACR20 response observed at week 2 (infliximab vs. placebo 52.87%vs. 13.95%, P &lt; 0.05). Significant differences in the ACR20 and ACR50 response rates between the two treatment groups were also observed at week 18 (75.86% and 43.68% of patients receiving infliximab vs. 48.84% and 25.58% and 13.95% of patients on placebo, P = 0.0003 and P = 0.011, respectively). Infliximab was generally well tolerated. The rate of adverse events and withdrawal due to adverse events were similar between the two groups. Most adverse reactions were transient. One patient in the infliximab group developed tuberculosis during the study. One patient in the placebo group developed antinuclear antibodies without obvious signs of systemic lupus erythematosus.Conclusion: In this preliminary study, infliximab infusions, at a dose of 3 mg/kg body weight given at various intervals over 14 weeks, were effective in controlling the signs and symptoms of active RA in Chinese. Infliximab also appeared to be well tolerated. Further studies involving a larger number of patients over a more prolonged period will further evaluate the long‐term efficacy and safety of infliximab in this group of patients.

Infliximab Therapy for Patients With Active and Refractory Spondyloarthropathies at the Dose of 3 mg/kg

: Infliximab at the dose of 5 mg/kg per infusion has been shown effective for the treatment of active spondyloarthropathies. It is not clear if the 5 mg/kg is required in most patients. : To evaluate the long-term efficacy and safety of infliximab at the lower dose of 3 mg/kg in patients with active and refractory ankylosing spondylitis (AS) and psoriatic arthritis (PsA). : Thirty patients were enrolled in a 78-week, single-center, prospective, open-label pilot study, including 16 patients with severe and active AS and 14 patients with active and refractory PsA. Infliximab (3 mg/kg, in combination with a stable dose of methotrexate was administered intravenously at 0, 2 and 6 weeks, and q8 weeks thereafter (schedule-A) and the improvement of Bath Ankylosing Spondylitis Disease Activity Index (BASDAI; for AS patients) and Patient Global Assessment of Disease Activity (PDA; for PsA patients) was monitored at baseline and at every visit (primary variables). Patients who did not respond sufficiently at 14 weeks, as well as patients who relapsed at any time during follow-up, received infliximab every 4 weeks (treatment schedule-B). Three different statistical approaches (per-protocol, last observation carried forward and by intention-to-treat) were applied. : Ten patients discontinued treatment for various reasons, including 3 (10.0%) because of allergic reactions. Twenty patients (66.7%, 9 with AS and 11 with PsA) had completed 78 weeks of treatment (schedule-A, 11 patients; schedule-B, 9 patients). Of these patients, 18 (90.0%) showed optimal response (improvement >/=50%), including 13 (65.0%) with improvement >/=70%. ASsessments in AS (ASAS) 50% was attained by 7/9 AS patients (77.8%). At 78 weeks of treatment, statistically significant improvement of indices of disease activity, function and quality of life was observed by all statistical approaches applied. : Infliximab at 3 mg/kg every 8 weeks or, if needed, every 4 weeks appears to be an effective and rather safe treatment of patients with active and refractory AS and PsA after 78 weeks of treatment.

Alefacept in combination with methotrexate for treatment of active psoriatic arthritis: rationale and design of a randomized, double-blind, placebo-controlled study

Psoriatic arthritis (PsA) is a chronic inflammatory arthritis associated with psoriasis that may result in considerable joint damage if left untreated. Although the pathogenesis of PsA is uncertain, evidence suggests that T cells play an important role in this inflammatory disease. Alefacept selectively reduces memory (CD45RO+) T cells by interacting with the CD2 receptor. It is efficacious in moderate to severe plaque psoriasis—clinical improvements correlate with reductions in the memory T-cell subset. Preliminary data in active PsA showed that alefacept was well tolerated. Patients who responded with 20%, 50%, or 70% reduction in global assessments of disease activity had the greatest reductions in memory T cells, both in the circulation and synovial tissue. Based on these favorable results, a randomized, double-blind, placebo-controlled study is underway to further evaluate the efficacy and safety of alefacept when administered in combination with methotrexate in a larger population of patients with PsA. It is anticipated that the combination of alefacept and methotrexate will be used in clinical practice. Eligible patients must be 18-70 years of age, have CD4+ T-cell counts at or above the lower limit of normal, and have active PsA (at least 3 swollen joints and at least 3 tender joints) despite treatment with methotrexate (10 mg/week up to 25 mg/week) for at least 3 months before the study. The dose of methotrexate must be stable for at least 4 weeks before enrollment. Randomization will be stratified based on body surface area (BSA) involvement of chronic plaque psoriasis (3% or greater, <3%) to maintain a 2:1 ratio of alefacept versus matching placebo. Alefacept 15 mg and placebo will be administered by intramuscular injection once weekly for 12 weeks followed by a 12-week observation period. All patients will continue to receive their stable dose of methotrexate for the entire 24-week study period. Stable doses of NSAIDs and steroids (up to 10 mg/day) will be permitted. The primary efficacy endpoint will be the proportion of patients achieving ACR 20, ACR 50, and ACR 70 responses at 24 weeks and at any time during the study. Additional efficacy evaluations will include PASI and PGA for psoriasis patients with BSA involvement of at least 3%, erythrocyte sedimentation rate, and C-reactive protein. Safety will be assessed by adverse events, infections, hematology, blood chemistry, urinalysis, vital signs, physical examinations, and anti-alefacept antibodies.

Efficacy, pharmacokinetic, and safety assessment of adalimumab, a fully human anti-tumor necrosis factor-alpha monoclonal antibody, in adults with rheumatoid arthritis receiving concomitant methotrexate: A pilot study

Background: Because traditional therapies for rheumatoid arthritis (RA) such as methotrexate (MTX) do not produce an adequate response in many patients, newer therapies that block the proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) are increasingly being used in combination with MTX. Objective: This study evaluated the efficacy, pharmacokinetics, and safety profile of adalimumab, a fully human anti-TNF alpha monoclonal antibody, when added to continuing MTX therapy. Methods: This Phase I, randomized, dose-titration study consisted of a 4-week, double-blind, placebo-controlled treatment phase and a 26-month, open-label continuation phase. Patients with RA who had been taking stable doses of MTX (mean dose, 17 mg/wk) for ≥3 months before enrollment with an inadequate response were randomly assigned to receive 2 single doses of either adalimumab 0.25, 0.5, 1, 3, or 5 mg/kg IV or placebo in the double-blind phase. In the open-label phase, patients received treatment with 1 of the doses of adalimumab every other week or monthly for 18 months; patients were then switched to adalimumab 40 mg IV or SC every other week or monthly. The main efficacy end point was 20% improvement in American College of Rheumatology response criteria (ACR20). Other efficacy end points included 50% (ACR50) and 70% improvements in ACR response criteria. Pharmacokinetic parameters were analyzed for adalimumab and MTX during both phases of the study. Serum adalimumab concentrations were analyzed using a validated enzyme-linked immunosorbent assay relying on the double-antigen principle. Peak and trough concentrations were determined from observed concentration-time data, and a modeling approach was used to estimate total serum clearance, mean apparent terminal half-life, apparent volume of distribution at steady state, and area under the concentration-time curve. Results: Sixty patients entered the double-blind phase, 45 receiving adalimumab and 15 receiving placebo; 1 placebo recipient chose not to continue into the open-label phase. Overall, the study population included 47 (78.3%) women and 13 (21.7%) men. The mean age was 52.9 years (range, 24–73 years), and the mean body weight was 69.7 kg (range, 43–98 kg). ACR20 and ACR50 responses were achieved on at least 1 assessment during the 4-week double-blind phase by a respective 29 (64.4%) and 11 (24.4%) of 45 patients receiving active treatment and by 4 (26.7%) and none of the 15 patients receiving placebo. Responses to adalimumab were rapid, with 10 (22.2%) of 45 patients achieving an ACR20 response within 24 hours of dosing. Of 29 adalimumab recipients who had an ACR20 response, 18 (62.1%) had a duration of response (time from first occurrence of a response to first occurrence of a nonresponse) of 1 to 2 weeks, and 11 (37.9%) had a duration of response of 3 to 13 weeks. The pharmacokinetic properties of adalimumab appeared to be linear. The mean apparent terminal half-life after a single intravenous dose of adalimumab ranged from 15 to 19 days in the 5 dose groups. Repeated administration of adalimumab had no statistically significant effect on the pharmacokinetics of MTX, indicating that dose adjustment of MTX is not necessary. Adalimumab was well tolerated, and there were no dose-related adverse events. Conclusions: Among patients with active RA who had not had an adequate response to MTX, addition of adalimumab to MTX achieved statistically significant, long-term improvement compared with placebo plus MTX ( P ≤ 0.05), as indicated by ACR responses at 26 months. The combination was well tolerated. Adalimumab exhibited linear pharmacokinetics. In this selected patient population, adalimumab's long half-life of 15 to 19 days supports every-other-week dosing. Coadministration of adalimumab did not alter serum levels of MTX.

Infliximab (chimeric anti-tumour necrosis factor α monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial

Not all patients with rheumatoid arthritis can tolerate or respond to methotrexate, a standard treatment for this disease. There is evidence that antitumour necrosis factor alpha (TNFalpha) is efficacious in relief of signs and symptoms. We therefore investigated whether infliximab, a chimeric human-mouse anti-TNFalpha monoclonal antibody would provide additional clinical benefit to patients who had active rheumatoid arthritis despite receiving methotrexate. In an international double-blind placebo-controlled phase III clinical trial, 428 patients who had active rheumatoid arthritis, who had received continuous methotrexate for at least 3 months and at a stable dose for at least 4 weeks, were randomised to placebo (n=88) or one of four regimens of infliximab at weeks 0, 2, and 6. Additional infusions of the same dose were given every 4 or 8 weeks thereafter on a background of a stable dose of methotrexate (median 15 mg/week for > or =6 months, range 10-35 mg/wk). Patients were assessed every 4 weeks for 30 weeks. At 30 weeks, the American College of Rheumatology (20) response criteria, representing a 20% improvement from baseline, were achieved in 53, 50, 58, and 52% of patients receiving 3 mg/kg every 4 or 8 weeks or 10 mg/kg every 4 or 8 weeks, respectively, compared with 20% of patients receiving placebo plus methotrexate (p<0.001 for each of the four infliximab regimens vs placebo). A 50% improvement was achieved in 29, 27, 26, and 31% of infliximab plus methotrexate in the same treatment groups, compared with 5% of patients on placebo plus methotrexate (p<0.001). Infliximab was well-tolerated; withdrawals for adverse events as well as the occurrence of serious adverse events or serious infections did not exceed those in the placebo group. During 30 weeks, treatment with infliximab plus methotrexate was more efficacious than methotrexate alone in patients with active rheumatoid arthritis not previously responding to methotrexate.