Infliximab (chimeric anti-tumour necrosis factor α monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial Number needed to treat (NNT): implication in rheumatology clinical practice Patient reported outcomes in a trial of combination therapy with etanercept and methotrexate for rheumatoid arthritis: the TEMPO trial [Analysis of efficacy and safety of multiple intravenous infusion of anti-tumor necrosis factor-alpha monoclonal antibody (Remicade) combined with methotrexate compared with sodium aurothiomalate and intramuscular depot methylprednisolone in rheumatoid arthritis]. A trial of etanercept, a recombinant tumor necrosis factor receptor:Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. Infliximab in active early rheumatoid arthritis Rapid alleviation of signs and symptoms of rheumatoid arthritis with intravenous or subcutaneous administration of adalimumab in combination with methotrexate Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor alpha monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis. Infliximab treatment in combination with cyclosporin A in patients with severe refractory rheumatoid arthritis A randomised comparative study of the short term clinical and biological effects of intravenous pulse methylprednisolone and infliximab in patients with active rheumatoid arthritis despite methotrexate treatment. Chimeric anti-tumor necrosis factor-alpha monoclonal antibody treatment of patients with rheumatoid arthritis receiving methotrexate therapy. Adalimumab, a fully human anti-tumor necrosis factor alpha monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial. Very early treatment with infliximab in addition to methotrexate in early, poor-prognosis rheumatoid arthritis reduces magnetic resonance imaging evidence of synovitis and damage, with sustained benefit after infliximab withdrawal: results from a twelve-month randomized, double-blind, placebo-contro Etanercept versus methotrexate in patients with early rheumatoid arthritis: two-year radiographic and clinical outcomes. Combination of infliximab and methotrexate therapy for early rheumatoid arthritis: a randomized, controlled trial. Randomised double-blind comparison of chimeric monoclonal antibody to tumour necrosis factor α (cA2) versus placebo in rheumatoid arthritis Etanercept in combination with sulfasalazine, hydroxychloroquine, or gold in the treatment of rheumatoid arthritis. Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomised controlled trial [Therapy of refractory chronic polyarthritis with tumor necrosis factor alpha receptor fusion proteins (TNFR55-IgG1)--results of double-blind placebo-controlled studies over 3 months]. Once-weekly administration of 50 mg etanercept in patients with active rheumatoid arthritis: results of a multicenter, randomized, double-blind, placebo-controlled trial. Etanercept therapy in rheumatoid arthritis. A randomized, controlled trial. The safety of infliximab, combined with background treatments, among patients with rheumatoid arthritis and various comorbidities: a large, randomized, placebo-controlled trial. A multicenter, double-blind, randomized, placebo controlled trial of infliximab combined with low dose methotrexate in Japanese patients with rheumatoid arthritis. Sustained improvement over two years in physical function, structural damage, and signs and symptoms among patients with rheumatoid arthritis treated with infliximab and methotrexate. Health-related quality of life and functional status of patients with rheumatoid arthritis randomly assigned to receive etanercept or placebo. 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. Treatment of rheumatoid arthritis with a recombinant human tumor necrosis factor receptor (p75)-Fc fusion protein. Efficacy and safety of the fully human anti-tumour necrosis factor alpha monoclonal antibody adalimumab (D2E7) in DMARD refractory patients with rheumatoid arthritis: a 12 week, phase II study. The relationship of serum infliximab concentrations to clinical improvement in rheumatoid arthritis: results from ATTRACT, a multicenter, randomized, double-blind, placebo-controlled trial. Comparison of ultrasonographic assessment of synovitis and joint vascularity with radiographic evaluation in a randomized, placebo-controlled study of infliximab therapy in early rheumatoid arthritis. Efficacy and safety of adalimumab as monotherapy in patients with rheumatoid arthritis for whom previous disease modifying antirheumatic drug treatment has failed. The effectiveness of anti-tumor necrosis factor therapy in preventing progressive radiographic joint damage in rheumatoid arthritis: a population-based study. A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis. Radiographic, clinical, and functional outcomes of treatment with adalimumab (a human anti-tumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy: a randomized, placebo-controlled, 52-week trial. Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. Recombinant soluble tumor necrosis factor receptor (p80) fusion protein: toxicity and dose finding trial in refractory rheumatoid arthritis. A single dose, placebo controlled study of the fully human anti-tumor necrosis factor-alpha antibody adalimumab (D2E7) in patients with rheumatoid arthritis. Drug survival, efficacy and toxicity of monotherapy with a fully human anti-tumour necrosis factor-alpha antibody compared with methotrexate in long-standing rheumatoid arthritis. Adalimumab, a fully human anti tumor necrosis factor-alpha monoclonal antibody, and concomitant standard antirheumatic therapy for the treatment of rheumatoid arthritis: results of STAR (Safety Trial of Adalimumab in Rheumatoid Arthritis). A comparative study of etanercept plus methotrexate and methotrexate alone in Taiwanese patients with active rheumatoid arthritis: a 12-week, double-blind, randomized, placebo-controlled study. Repeated therapy with monoclonal antibody to tumour necrosis factor α (cA2) in patients with rheumatoid arthritis
BACKGROUND Not all patients with rheumatoid arthritis can tolerate or respond to methotrexate , a st and ard 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 .  METHODS 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 r and omised 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 . FINDINGS 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 . INTERPRETATION 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 Objective : To calculate the number needed to treat ( NNT ) and number needed to harm ( NNH ) from the data in rheumatology clinical trials and systematic review s. Methods : The NNTs for the clinical ly important outcome measures in the rheumatology systematic review s from the Cochrane Library , issue 2 , 2000 and in the original r and omised , double blind , controlled trials were calculated . The measure used for calculating the NNT in rheumatoid arthritis ( RA ) interventions was the American College of Rheumatology 20 % improvement or Paulus criteria ; in osteoarthritis ( OA ) interventions , the improvement of pain ; and in systemic sclerosis ( SSc ) interventions , the improvement of Raynaud 's phenomenon . The NNH was calculated from the rate of withdrawals due to adverse events from the treatment . Results : The data required for the calculation of the NNT were available in 15 systematic review s and 11 original articles . For RA interventions , etanercept treatment for six months had the smallest NNT ( 1.6 ; 95 % confidence interval ( CI ) 1.4 to 2.0 ) , whereas leflunomide had the largest NNH ( 9.6 ; 95 % CI 6.8 to 16.7 ) . For OA treatment options , only etodolac and tenoxicam produced significant pain relief compared with placebo ( NNT=4.4 ; 95 % CI 2.4 to 24.4 and 3.8 ; 95 % CI 2.5 to 7.3 , respectively ) . For SSc interventions , none were shown to be efficacious in improving Raynaud 's phenomenon because the 95 % CI of the NNT was infinite . Conclusions : The NNT and NNH are helpful for clinicians , enabling them to translate the results from clinical trials and systematic review s to use in routine clinical practice . Both NNT and NNH should be accompanied by a limited 95 % CI and adjusted for the individual subject 's baseline risk Objective : To compare patient reported measures of function , health related quality of life ( QoL ) , and satisfaction with medication among patients with rheumatoid arthritis ( RA ) treated with methotrexate ( MTX ) , etanercept , or both for up to 1 year . Methods : In a 52 week , double blind , clinical trial , patients with active RA were r and omised to receive etanercept 25 mg twice weekly , methotrexate up to 20 mg weekly , or combination therapy .  The Health Assessment Question naire ( HAQ ) disability index , EuroQoL health status visual analogue scale ( EQ-5D VAS ) , patient global assessment , and patient general health VAS were administered at baseline and weeks 2 , 4 , 8 , 12 , 16 , 20 , 24 , 32 , 40 , 48 , and 52 . Satisfaction with the medication was compared at 52 weeks . Results : Of 682 enrolled patients , 522 completed 52 weeks of treatment . Mean improvement from baseline in HAQ score was 0.65 , 0.70 , and 1.0 for MTX , etanercept , and the combination , respectively . The mean percentage and absolute improvement in the HAQ was significantly higher ( p<0.01 ) for combination therapy than for either of the monotherapies . Combination therapy produced significantly more rapid achievement of HAQ ⩽0.5 sustained for 6 months than either of the monotherapies ( p<0.01 ) . Compared with patients receiving monotherapy , those receiving combination therapy achieved a significantly better ( p<0.05 ) health state as measured by the EQ-5D VAS ( mean ( SD ) 63.7 ( 3.2 ) , 66.8 ( 3.2 ) , 72.7 ( 3.1 ) for MTX , etanercept , and the combination , respectively ) . Results were similar for other assessment s ( p<0.01 ) . Patients in combination and etanercept groups were significantly more likely ( p<0.0001 , p = 0.0009 , respectively ) to report satisfaction with the medication . Conclusions : Combination therapy with etanercept and methotrexate improved function , QoL , and satisfaction with the medication significantly more than monotherapy The objective of the paper was compare the effects and tolerability of combined therapy of multiple intravenous infusions of anti-tumour necrosis factor-alfa ( TNF-alfa ) monoclonal antibody ( Remicade ) with methotrexate versus treatment with sodium aurothiomalate and intramuscular depot methylprednisolone in rheumatoid arthritis ( RA ) . We investigate also the interval necessary to obtain the improvement in both treatment groups . 36 patients commencing intramuscular sodium aurothiomalate therapy with intramuscular depot methylprednisolone acetate at weeks 0 , 4 , 8 and 12 in addition to chrysotherapy were compared in retrospective analysis with 32 patients starting with multiple intravenous infusions of infliximab , anti-TNF-alfa monoclonal antibody ( Remicade ) and methotrexate at a stable dose . Patients were assessed by composite clinical score ( DAS 28 ) and C-reactive protein during 22 weeks of therapy . At week 2 and 6 a significantly greater percentage of infliximab-treated than gold-treated RA patients achieved improvement in each clinical measurement of disease activity . At 22 week of treatment moderate and good response according to EULAR criteria was achieved in 91 % of infliximab-treated patients and 58 % gold treated patients ( p < 0.001 ) . Adverse events were more frequently observed in infliximab-treated patients , but only gold-treated patients discontinued treatment because adverse events ( 2 patients due to proteinuria , 2 patients due to mucocutaneous changes and one patient due to leucopenia ) . The higher percentage of adverse events in infliximab-treated patients was caused mainly by the occurrence of infusion reactions ( 23 reactions out of 160 infusions ) ; most of them were mild ( somnolentia and headache ) and transient . Viral infections ( including herpes simplex and zoster ) were more common in patients treated with infliximab and methotrexate . Combination therapy of infliximab and methotrexate is more effective in reducing clinical and biochemical disease activity than gold with methylprednisolone treatment in RA patients during 22 weeks of treatment , especially in the first 6 weeks BACKGROUND Patients treated with methotrexate for rheumatoid arthritis often improve but continue to have active disease . This study was undertaken to determine whether the addition of etanercept , a soluble tumor necrosis factor receptor (p75):Fc fusion protein ( TNFR : Fc ) , to methotrexate therapy would provide additional benefit to patients who had persistent rheumatoid arthritis despite receiving methotrexate .  METHODS In a 24-week , double-blind trial , we r and omly assigned 89 patients with persistently active rheumatoid arthritis despite at least 6 months of methotrexate therapy at a stable dose of 15 to 25 mg per week ( or as low as 10 mg per week for patients unable to tolerate higher doses ) to receive either etanercept ( 25 mg ) or placebo subcutaneously twice weekly while continuing to receive methotrexate . The primary measure of clinical response was the American College of Rheumatology criteria for a 20 percent improvement in measures of disease activity ( ACR 20 ) at 24 weeks . RESULTS The addition of etanercept to methotrexate therapy result ed in rapid and sustained improvement . At 24 weeks , 71 percent of the patients receiving etanercept plus methotrexate and 27 percent of those receiving placebo plus methotrexate met the ACR 20 criteria ( P<0.001 ) ; 39 percent of the patients receiving etanercept plus methotrexate and 3 percent of those receiving placebo plus methotrexate met the ACR 50 criteria ( for a 50 percent improvement ) ( P<0.001 ) . Patients receiving etanercept plus methotrexate had significantly better outcomes according to all measures of disease activity . The only adverse events associated with etanercept were mild injection-site reactions , and no patient withdrew from the study because of adverse events associated with etanercept . CONCLUSIONS In patients with persistently active rheumatoid arthritis , the combination of etanercept and methotrexate was safe and well tolerated and provided significantly greater clinical benefit than methotrexate alone 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 h and s 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 Objective : This r and omized , placebo‐controlled , double‐blind , Phase 1 study assessed the magnitude , onset , and duration of response with intravenous ( i.v . ) and subcutaneous ( s.c . ) adalimumab ( Humira ® , Abbott Laboratories ) combined with methotrexate ( MTX ) in patients with active rheumatoid arthritis ( RA ) despite previous MTX therapy . Methods : Fifty‐four patients were r and omized to two injections of i.v . or s.c . adalimumab ( 1 mg/kg ) or placebo while continuing on MTX ( mean dose , 15.7 mg/week ) . Dosing intervals were determined by the European League Against Rheumatism ( EULAR ) response criteria , and were allowed to range from 1 to 3 months . Efficacy was mainly assessed using the EULAR response criteria and the American College of Rheumatology ( ACR ) response criteria . Results : Moderate EULAR response was achieved at least once within 29 days after the first injection in 83 % and 61 % of patients receiving i.v . and s.c . adalimumab respectively , compared with 44 % for placebo [ probability (p)≤0.05 for i.v . adalimumab versus placebo ] . A 20 % improvement in disease activity according to the ACR criteria ( ACR20 response ) was achieved by 72 % and 67 % of patients receiving i.v . and s.c . adalimumab respectively , compared with 28 % for placebo ( p≤0.01 and p≤0.05 , respectively , versus placebo ) . By Day 15 after the first and second injections , statistically significant moderate EULAR and ACR20 response rates were achieved with either i.v . or s.c . adalimumab compared with placebo ( p ≤ 0.05 ) . The mean times to second injection  for i.v . adalimumab , s.c . adalimumab , and placebo were 42.2 days ( range : 27–84 days ) , 38.3 days ( range : 26–85 days ) , and 28.4 days ( range : 26–32 days ) , respectively ( minimum time allowed by the protocol between the first and second injections was 4 weeks ) . Adalimumab in combination with MTX  was well tolerated , with no patients being withdrawn because of adverse events . Conclusion : Either i.v . or s.c . adalimumab added to MTX  significantly improved the signs and symptoms of RA compared with MTX alone . Subcutaneously administered adalimumab appeared to provide a response that was as great , as rapid , and as enduring as that with i.v . adalimumab OBJECTIVE To evaluate the efficacy , pharmacokinetics , immunogenicity , and safety of multiple infusions of a chimeric monoclonal anti-tumor necrosis factor alpha antibody ( cA2 ) ( infliximab ; Remicade , Centocor , Malvern , PA ) given alone or in combination with low-dose methotrexate ( MTX ) in rheumatoid arthritis ( RA ) patients . METHODS In a 26-week , double-blind , placebo-controlled , multicenter trial , 101 patients with active RA exhibiting an incomplete response or flare of disease activity while receiving low-dose MTX were r and omized to 1 of 7 groups of 14 - 15 patients each . The patients received either intravenous cA2 at 1 , 3 , or 10 mg/kg , with or without MTX 7.5 mg/week , or intravenous placebo plus MTX 7.5 mg/week at weeks 0 , 2 , 6 , 10 , and 14 and were followed up through week 26 . RESULTS Approximately 60 % of patients receiving cA2 at 3 or 10 mg/kg with or without MTX achieved the 20 % Paulus criteria for response to treatment , for a median duration of 10.4 to > 18.1 weeks ( P < 0.001 versus placebo ) . Patients receiving cA2 at 1 mg/kg without MTX became unresponsive to repeated infusions of cA2 ( median duration 2.6 weeks ; P=0.126 versus placebo ) . However , coadministration of cA2 at 1 mg/kg with MTX appeared to be synergistic , prolonging the duration of the 20 % response in > 60 % of patients to a median of 16.5 weeks ( P < 0.001 versus placebo ; P=0.006 versus no MTX ) and the 50 % response to 12.2 weeks ( P < 0.001 versus placebo ; P=0.002 versus no MTX ) . Patients receiving placebo infusions plus suboptimal low-dose MTX continued to have active disease , with a Paulus response lasting a median of 0 weeks . A 70 - 90 % reduction in the swollen joint count , tender joint count , and C-reactive protein level was maintained for the entire 26 weeks in patients receiving 10 mg/kg of cA2 with MTX . In general , treatment was well tolerated and stable blood levels of cA2 were achieved in all groups , except for the group receiving 1 mg/kg of cA2 alone , at which dosage antibodies to cA2 were observed in approximately 50 % of the patients . CONCLUSION Multiple infusions of cA2 were effective and well tolerated , with the best results occurring at 3 and 10 mg/kg either alone or in combination with MTX in approximately 60 % of patients with active RA despite therapy with low-dose MTX . When cA2 at 1 mg/kg was given with low-dose MTX , synergy was observed . The results of the trial provide a strategy for further evaluation of the efficacy and safety of longer-term treatment with cA2 Objective : To investigate whether infliximab can be used in combination with cyclosporin A ( CsA ) in patients with refractory rheumatoid arthritis ( RA ) who can not tolerate methotrexate ( MTX ) .  Material s and methods : Eighteen patients with refractory RA receiving low dose CsA ( 2 mg/kg/day ) and prednisone ( 5 mg/day ) were treated with intravenous infliximab .  The patients were given infliximab ( 3 mg/kg weight ) at 0 , two , six , and every eight weeks thereafter for a total period of 12 months . Clinical improvement was evaluated according to the American College of Rheumatology ( ACR ) 20 % response criteria . Results : Eighty per cent of patients receiving the combination treatment with CsA and infliximab achieved the 20 % ACR criteria for response to treatment , whereas 39 % satisfied the 50 % response criteria . In addition , a 76 % reduction in swollen and tender joint count was found . Finally , a reduction in C reactive protein and erythrocyte sedimentation rate was maintained throughout the study . In general , treatment was well tolerated , with minimal adverse drug reactions . Two patients dropped out ; one because of an immediate hypersensitivity reaction and the other because of the development of pulmonary tuberculosis . Conclusion : Multiple infusions of infliximab and low doses of CsA improve patients with refractory RA . It seems that CsA may be an alternative disease modifying drug to be used in combination with infliximab in patients with refractory RA who can not tolerate MTX OBJECTIVES To compare the short term clinical and biological effects of intravenous ( i.v . ) pulse methylprednisolone ( MP ) and infliximab ( IFX ) in patients with severe active rheumatoid arthritis ( RA ) despite methotrexate ( MTX ) treatment . METHODS Patients with active RA despite MTX treatment were r and omly allocated to receive a single i.v . infusion of MP ( 1 g ) or three i.v . infusions of IFX ( 3 mg/kg ) on weeks 0 , 2 , and 6 . Patients were " blindly " evaluated for disease activity measures . Quality of life ( QoL ) was evaluated through the SF-36 health survey . Serum matrix metalloproteinase-3 ( MMP-3 ) titres were measured at baseline , weeks 2 and 6 . RESULTS Compared with baseline , significant improvement was noted in all activity measures , including serum C reactive protein ( CRP ) titres , in the IFX group only . At week 14 , 6/9 ( 67 % ) and 4/9 ( 44 % ) IFX patients met the ACR20 and 50 response criteria , while this was the case in only 1/12 ( 8 % ) and 0/12 ( 0 % ) MP patients , respectively ( p<0.05 ) . None of the QoL scales improved with MP treatment , whereas some did so in the IFX group . Serum MMP-3 titres significantly decreased ( 41 % drop ) at week 6 in the IFX group , while no changes were seen in patients given MP . CONCLUSION This short term r and omised comparative study demonstrates that TNF blockade is better than MP pulse therapy in a subset of patients with severe refractory RA , with improvement in not only clinical parameters of disease activity but also biological inflammatory indices , such as serum CRP and MMP-3 titres OBJECTIVE To evaluate the safety and efficacy of single and multiple doses of a chimeric anti-TNF-alpha monoclonal antibody ( infliximab ) in patients with rheumatoid arthritis ( RA ) who had active disease despite therapy with methotrexate ( MTX ) .  METHODS Twenty-eight patients with active RA despite receiving therapy with 10 mg/week of MTX  were r and omized to receive a single , blinded infusion of either placebo or 5 , 10 , or 20 mg/kg infliximab .  Twenty-three patients who completed the blinded study entered an open , multiple dose extension study in which they received up to 3 additional infusions of 10 mg/kg infliximab at Weeks 12 , 20 , and 28 . Safety , efficacy , and pharmacokinetics were evaluated during the blinded and open trial . RESULTS There were no serious infusion related reactions . In the blinded phase , 17 ( 81.0 % ) of 21 patients receiving infliximab achieved an American College of Rheumatology ( ACR ) 20 % response at some point during the 12 weeks of followup compared to one ( 14.3 % ) of 7 patients receiving placebo ( p = 0.003 ) . Clinical improvement was evident by the first week and was sustained through Week 12 . For the 19 patients who received infliximab during the blinded part of the trial and continued into the open label trial , 53 % maintained an ACR 20 % response with multiple infusions of 10 mg/kg infliximab through Week 40 . Three patients withdrew from the trial during the open continuation phase because of adverse events : cellulitis , infusion related dizziness and headache , and vasculitic rash .  Infliximab in doses of 5 to 20 mg/kg had a mean terminal half-life ranging from 9 to 12 days and was detectable in sera from most patients 8 to 12 weeks after dosing . CONCLUSION Infliximab is generally well tolerated during 40 weeks of therapy . A single infusion of 5 to 20 mg/kg infliximab significantly decreases the signs and symptoms of RA compared to placebo in patients with active disease receiving MTX . Multiple doses of infliximab produce sustained clinical benefit for up to 40 weeks OBJECTIVE To evaluate the efficacy and safety of adalimumab ( D2E7 ) , a fully human monoclonal tumor necrosis factor alpha antibody , in combination with methotrexate ( MTX ) in patients with active rheumatoid arthritis ( RA ) despite treatment with MTX .  METHODS In a 24-week , r and omized , double-blind , placebo-controlled study , 271 patients with active RA were r and omly assigned to receive injections of adalimumab ( 20 mg , 40 mg , or 80 mg subcutaneously ) or placebo every other week while continuing to take their long-term stable dosage of MTX . The primary efficacy end point was the American College of Rheumatology criteria for 20 % improvement ( ACR20 ) at 24 weeks . RESULTS An ACR20 response at week 24 was achieved by a significantly greater proportion of patients in the 20-mg , 40-mg , and 80-mg adalimumab plus MTX groups ( 47.8 % , 67.2 % , and 65.8 % , respectively ) than in the placebo plus MTX group ( 14.5 % ) ( P < 0.001 ) . ACR50 response rates with the 20-mg , 40-mg , and 80-mg adalimumab dosages ( 31.9 % , 55.2 % , and 42.5 % , respectively ) were significantly greater than that with placebo ( 8.1 % ) ( P = 0.003 , P < 0.001 , and P < 0.001 , respectively ) . The 40-mg and 80-mg doses of adalimumab were associated with an ACR70 response ( 26.9 % and 19.2 % , respectively ) that was statistically significantly greater than that with placebo ( 4.8 % ) ( P < 0.001 and P = 0.020 ) . Responses were rapid , with the greatest proportion of adalimumab-treated patients achieving an ACR20 response at the first scheduled visit ( week 1 ) . Adalimumab was safe and well tolerated ; comparable numbers of adalimumab-treated patients and placebo-treated patients reported adverse events . CONCLUSION The addition of adalimumab at a dosage of 20 mg , 40 mg , or 80 mg administered subcutaneously every other week to long-term MTX therapy  in patients with active RA provided significant , rapid , and sustained improvement in disease activity over 24 weeks compared with MTX plus placebo OBJECTIVE Anti-tumor necrosis factor alpha agents are among the most effective therapies for rheumatoid arthritis ( RA ) . However , their optimal use is yet to be determined . This 12-month double-blind study attempted remission induction using st and ard therapy with or without infliximab in patients with early , poor-prognosis RA . The primary end point was synovitis ( measured by magnetic resonance imaging [ MRI ] ) . Clinical observations continued to 24 months . METHODS All patients had fewer than 12 months of symptoms . Assessment s included full metrologic evaluation , laboratory tests , radiographs , functional evaluation using the Health Assessment Question naire ( HAQ ) , and quality of life measurement using the RA Quality of Life ( RAQoL ) question naire . MRI was performed at 0 , 4 , 14 , and 54 weeks ; MR images were scored blindly . Patients received methotrexate ( MTX ) and were r and omized to receive either infliximab or placebo for 12 months . RESULTS Twenty patients were recruited ( mean age 52 years , mean symptom duration 6 months , mean C-reactive protein level 42 mg/liter , and 65 % rheumatoid factor positive ) . At 1 year , all MRI scores were significantly better , with no new erosions in the infliximab plus MTX group ; a greater percentage of infliximab plus MTX-treated patients fulfilled the American College of Rheumatology ( ACR ) 50 % and 70 % improvement criteria ( 78 % versus 40 % in the placebo plus MTX group and 67 % versus 30 % , respectively ) and had a greater functional benefit ( P < 0.05 for all comparisons ) . Importantly , at 1 year after stopping induction therapy , response was sustained in 70 % of the patients in the infliximab plus MTX group , with a median Disease Activity Score in 28 joints ( DAS28 ) of 2.05 ( remission range ) . At 2 years , there were no significant between-group differences in the DAS28 , ACR response , or radiographic scores , but differences in the HAQ and RAQoL scores were maintained ( P < 0.05 ) . CONCLUSION Remission induction with infliximab plus MTX provided a significant reduction in MRI evidence of synovitis and erosions at 1 year . At 2 years , functional and quality of life benefits were sustained , despite withdrawal of infliximab therapy . These data may have significant implication s for the optimal use of expensive biologic therapies OBJECTIVE To compare the clinical and radiographic outcomes in patients with rheumatoid arthritis ( RA ) who received monotherapy with either etanercept or methotrexate ( MTX ) for 2 years and to assess the safety of this therapy . METHODS In the Enbrel ERA ( early rheumatoid arthritis ) trial , 632 patients with early , active RA were r and omized to receive either twice-weekly subcutaneous etanercept ( 10 mg or 25 mg ) or weekly oral MTX ( mean dosage 19 mg per week ) for at least 1 year in a double-blind manner . Following the blinded phase of the trial , 512 patients continued to receive the therapy to which they had been r and omized for up to 1 additional year , in an open-label manner . Radiograph readers remained blinded to treatment group assignment and the chronologic order of images . RESULTS At 24 months , more 25-mg etanercept patients than MTX patients met American College of Rheumatology 20 % improvement criteria ( 72 % and 59 % , respectively ; P = 0.005 ) , and more had no increase in total score and erosion scores on the Sharp scale ( P = 0.017 and P = 0.012 , respectively ) . The mean changes in total Sharp score and erosion score in the 25-mg etanercept group ( 1.3 and 0.66 units , respectively ) were significantly lower than those in the MTX group ( 3.2 and 1.86 units , respectively ; P = 0.001 ) . Significantly more patients in the 25-mg etanercept group ( 55 % ) than in the MTX group ( 37 % ) had at least 0.5 units of improvement in the Health Assessment Question naire disability index ( P < 0.001 ) . Fewer patients in the etanercept group than in the MTX group experienced adverse events or discontinued treatment because of adverse events . CONCLUSION Etanercept as monotherapy was safe and was superior to MTX in reducing disease activity , arresting structural damage , and decreasing disability over 2 years in patients with early , aggressive RA 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 thous and forty-nine patients were r and omly 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 Tumour necrosis factor alpha ( TNF alpha ) is a critical inflammatory mediator in rheumatoid arthritis , and may therefore be a useful target for specific immunotherapy . In support of this hypothesis , we previously observed beneficial responses in patients with active rheumatoid arthritis after open-label administration of a  chimeric monoclonal antibody to TNF alpha ( cA2 ) . We now report the results of a four-centre , r and omised double-blind trial of a single infusion of 1 or 10 mg/kg cA2 compared with placebo in 73 patients with active rheumatoid arthritis . The primary endpoint of the study was the achievement at week 4 of a Paulus 20 % response , an amalgam of six clinical , observational , and laboratory variables . Intention-to-treat analysis of data from individual patients showed only 2 of 24 placebo recipients responding at this time , compared with 11 of 25 patients treated with low-dose cA2 ( p = 0.0083 ) and 19 of 24 patients treated with high-dose cA2 ( p < 0.0001 ) . Over half of the high-dose cA2 patients responded by the more stringent 50 % Paulus criteria at this time ( p = 0.0005 ) . The magnitude of these responses was impressive , with maximum mean improvements in individual disease-activity assessment s , such as tender or swollen-joint counts and in serum C-reactive protein , exceeding 60 % for patients on high-dose treatment . There were two severe adverse events . 1 patient on 1 mg/kg cA2 developed pneumonia ( " possibly " treatment-related ) and 1 on 10 mg/kg had a fracture ( " probably not " treatment-related ) . The results provide the first good evidence that specific cytokine blockade can be effective in human inflammatory disease and define a new direction for the treatment of rheumatoid arthritis OBJECTIVE To prospect ively determine the efficacy and safety of etanercept in combination with sulfasalazine ( SSZ ) , hydroxychloroquine ( HCQ ) , and gold in the treatment of rheumatoid arthritis ( RA ) . METHODS A prospect i ve open-label study enrolled 119 patients with RA who had active disease despite stable therapy with SSZ ( n = 50 ) , HCQ ( n = 50 ) , or intramuscular gold ( n = 19 ) . Primary efficacy endpoints consisted of American College of Rheumatology responses at 24 and 48 weeks . Safety was established at regularly scheduled visits . RESULTS Patients in each etanercept combination showed significant improvement at both 24 and 48 weeks . Toxicity withdrawals by 48 weeks included gold ( n = 1 ) : proteinuria ; HCQ  ( n = 5 ) : septic wrist and bilateral pneumonia , rash , optic neuritis , breast cancer , squamous cancer of the tongue ; and  SSZ  ( n = 5 ) : otitis media , elevated liver function indicators , pericarditis , rash , and gastroenteritis . The most common adverse events not requiring discontinuation from the study were injection site reactions ( 43 % of patients ) and upper respiratory type infections ( 34 % ) . CONCLUSION This study is the first to prospect ively evaluate the safety of etanercept in combination with SSZ , HCQ , and gold in patients with RA .  Etanercept in combination with SSZ , HCQ , or gold was efficacious and well tolerated , with a discontinuation rate of 9 % ( 11/119 ) for adverse events at 48 weeks BACKGROUND Etanercept and methotrexate are effective in the treatment of rheumatoid arthritis but no data exist on concurrent initiation or use of the combination compared with either drug alone . We aim ed to assess combination treatment with etanercept and methotrexate versus the monotherapies in patients with rheumatoid arthritis . METHODS In a double-blind , r and omised , clinical efficacy , safety , and radiographic study , 686 patients with active rheumatoid arthritis were r and omly allocated to treatment with etanercept 25 mg ( subcutaneously twice a week ) , oral methotrexate ( up to 20 mg every week ) , or the combination . Clinical response was assessed by criteria of the American College of Rheumatology ( ACR ) . The primary efficacy endpoint was the numeric index of the ACR response ( ACR-N ) area under the curve ( AUC ) over the first 24 weeks . The primary radiographic endpoint was change from baseline to week 52 in total joint damage and was assessed with the modified Sharp score . Analysis was by intention to treat . FINDINGS Four patients did not receive any drug ; thus 682 were studied .  ACR-N AUC at 24 weeks was greater for the combination group compared with etanercept alone and methotrexate alone ( 18.3%-years [ 95 % CI 17.1 - 19.6 ] vs 14.7%-years [ 13.5 - 16.0 ] , p<0.0001 , and 12.2%-years [ 11.0 - 13.4 ] , p<0.0001 ; respectively ) . The mean difference in ACR-N AUC between combination and methotrexate alone was 6.1 ( 95 % CI 4.5 - 7.8 , p<0.0001 ) and between etanercept and methotrexate was 2.5 ( 0.8 - 4.2 , p=0.0034 ) . The combination was more efficacious than methotrexate or etanercept alone in retardation of joint damage ( mean total Sharp score -0.54 [ 95 % CI -1.00 to -0.07 ] vs 2.80 [ 1.08 to 4.51 ] , p<0.0001 , and 0.52 [ -0.10 to 1.15 ] , p=0.0006 ; respectively ) . The mean difference in total Sharp score between combination and methotrexate alone was -3.34 ( 95 % CI -4.86 to -1.81 , p<0.0001 ) and between etanercept and methotrexate was -27 ( -3.81 to -0.74 , p=0.0469 ) . The number of patients reporting infections or adverse events was similar in all groups . INTERPRETATION The combination of etanercept and methotrexate was significantly better in reduction of disease activity , improvement of functional disability , and retardation of radiographic progression compared with methotrexate or etanercept alone . These findings bring us closer to achievement of remission and repair of structural damage in rheumatoid arthritis UNLABELLED AIM OF STUDIES : To determine the optimal dose regimen for i.v . TNFR55-IgG1 in refractory rheumatoid arthritis . METHODS 218 patients with refractory rheumatoid arthritis were enrolled for two double-blind placebo-controlled multicenter trials ( Europe and USA ) . They were treated with monthly i.v . placebo , 0.01 , 0.05 , 0.1 or 0.5 mg/kg TNFR55-IgG1 after a 4 week wash-out of DMARDs . An additional German trial compared biweekly i.v . 20 mg TNFR55-IgG1 and monthly 50 mg following a loading does of 100 mg in 60 patients . RESULTS TNFR55-IgG1 induced a substantial improvement already apparent one day after the first infusion . A maximal , dose dependent effect was reached after two weeks . Later , efficacy declined in parallel to an increase in anti-TNFR55-IgG1 antibodies result ing in an increased drug clearance . The drug was well tolerated with predominantly mild or moderate adverse events . CONCLUSION Intravenous TNFR55-IgG1 was well tolerated and effective in refractory rheumatoid arthritis but the treatment schedules tested could not stabilise the initial improvement 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 r and omized 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 sample s 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 < /= 0.0001 for each etanercept group versus placebo ) . Similarly , achievement of the ACR50 response was attained by 18 % of patients in each of the 2 etanercept groups , compared with 6 % of patients in the placebo group ( P < 0.03 for each comparison ) . Pharmacokinetics of the 2 etanercept regimens were similar at steady state . No clinical ly significant differences in efficacy or safety were observed between the 2 etanercept groups . CONCLUSION Safety , efficacy , and pharmacokinetics were comparable between the 2 etanercept dosing regimens . Thus , comparable clinical outcomes are to be expected when patients are treated with etanercept administered either as 50 mg once weekly or as 25 mg twice weekly BACKGROUND In a phase II study , etanercept ( recombinant human tumor necrosis factor receptor [p75]:Fc fusion protein ) safely produced rapid , dose-dependent improvement in rheumatoid arthritis over 3 months . OBJECTIVE To confirm the benefit of etanercept therapy of longer duration and simplified dosing in patients with rheumatoid arthritis . DESIGN R and omized , double-blind , placebo-controlled trial with blinded joint assessors . SETTING 13 North American centers . PATIENTS 234 patients with active rheumatoid arthritis who had an inadequate response to disease-modifying antirheumatic drugs . INTERVENTION Twice-weekly subcutaneous injections of etanercept , 10 or 25 mg , or placebo for 6 months . MEASUREMENTS The primary end points were 20 % and 50 % improvement in disease activity according to American College of Rheumatology ( ACR ) responses at 3 and 6 months . Other end points were 70 % ACR responses at 3 and 6 months and other measures of disease activity at 3 and 6 months . RESULTS Etanercept significantly reduced disease activity in a dose-related fashion . At 3 months , 62 % of the patients receiving 25 mg of etanercept and 23 % of the placebo recipients achieved 20 % ACR response ( P < 0.001 ) . At 6 months , 59 % of the 25-mg group and 11 % of the placebo group achieved a 20 % ACR response ( P < 0.001 ) ; 40 % and 5 % , respectively , achieved a 50 % ACR response ( P < 0.01 ) . The respective mean percentage reduction in the number of tender and swollen joints at 6 months was 56 % and 47 % in the 25-mg group and 6 % and -7 % in the placebo group ( P < 0.05 ) . Significantly more etanercept recipients achieved a 70 % ACR response , minimal disease status ( 0 to 5 affected joints ) , and improved quality of life .  Etanercept was well tolerated , with no dose-limiting toxic effects . CONCLUSIONS Etanercept can safely provide rapid , significant , and sustained benefit in patients with active rheumatoid arthritis OBJECTIVE To assess the risk of serious infections following 22 weeks of infliximab therapy , and to further characterize the safety profile of infliximab in combination with background treatments during 1 year in patients with rheumatoid arthritis ( RA ) with various comorbidities . METHODS Patients with active RA despite receiving methotrexate ( MTX )  were r and omly assigned to receive infusions of placebo ( group 1 , n=363 ) , 3 mg/kg infliximab ( group 2 , n=360 ) , or 10 mg/kg infliximab ( group 3 , n=361 ) at weeks 0 , 2 , 6 , and 14 . At week 22 , patients in placebo group 1 began receiving 3 mg/kg infliximab , and patients in group 3 continued to receive an infliximab dose of 10 mg/kg . Patients in group 2 who failed to meet predefined response criteria received increasing doses of infliximab in increments of 1.5 mg/kg . RESULTS At week 22 , the relative risk of developing serious infections in groups 2 and 3 , compared with group 1 , was 1.0 ( 95 % confidence interval [ 95 % CI ] 0.3 - 3.1 , P=0.995 ) and 3.1 ( 95 % CI 1.2 - 7.9 , P=0.013 ) , respectively . The incidence of serious adverse events was 7.8 % in groups 2 and 3 compared with 7.5 % in group 1 . From week 22 to week 54 , 11.8 % , 9.9 % , and 10.3 % of patients in groups 1 , 2 , and 3 , respectively , reported occurrences of serious adverse events . Through week 54 , 1 patient in group 1 , 2 patients in group 2 , and 4 patients in group 3 developed active tuberculosis . CONCLUSION The risk of serious infections in patients receiving the approved infliximab  dose of 3 mg/kg plus MTX was similar to that in patients receiving MTX alone . Patients receiving the unapproved induction regimen of 10 mg/kg infliximab plus MTX followed by a 10 mg/kg maintenance regimen had an increased risk of serious infections through week 22 OBJECTIVE A placebo controlled , double-blind trial ( DBT ) was conducted for Japanese patients with active rheumatoid arthritis ( RA ) despite treatment with low dose methotrexate ( MTX ) to evaluate the efficacy and safety of infliximab . Extended treatment with infliximab was conducted in an open-label trial ( OLT ) . METHODS In the DBT , 147 patients were r and omly assigned and treated with a placebo or 3 mg/kg or 10 mg/kg infliximab at Weeks 0 , 2 and 6 , combined with MTX . In the OLT , 129 patients from the DBT received 3 mg/kg infliximab  every 8 weeks . RESULTS The mean dose of MTX was 7.2 + /- 2.0 mg/week . Significantly more patients receiving 3 mg/kg ( 61.2 % ) and 10 mg/kg (52.9%)infliximab achieved a 20 % improvement according to the American College of Rheumatology ( ACR ) criteria at Week 14 , compared to placebo ( 23.4 % ) ( p < 0.001 ) . There was no significant difference in incidence of adverse events among the treatment groups . In patients receiving infliximab in the DBT , 11.6 % of patients with serum infliximab just before the OLT developed antibodies to infliximab ( ATI ) in the OLT , whereas 62.2 % of patients without serum infliximab did . In patients receiving placebo in the DBT , 43.9 % developed ATI . CONCLUSION The efficacy and safety of infliximab combined with low dose MTX were similar to those of the ATTRACT study . The data from the DBT and OLT also supported the importance of an induction treatment of infliximab , followed by a maintenance treatment without a long interval , giving stable serum concentrations in order to prevent formation of ATI OBJECTIVE To evaluate the efficacy and safety of repeated administration of infliximab plus methotrexate ( MTX ) over a 2-year period in patients with rheumatoid arthritis ( RA ) who previously experienced an incomplete response to MTX .  METHODS Four hundred twenty-eight patients were r and omly assigned to receive MTX plus placebo or infliximab at a dose of 3 or 10 mg/kg plus MTX for 54 weeks , with an additional year of followup . The protocol was later amended to allow for continued treatment during the second year . Of 259 patients who entered the second year of treatment , 216 continued to receive infliximab plus MTX for 102 weeks . Ninety-four of these 259 patients experienced a gap in therapy of > 8 weeks before continuing therapy . Infusions were administered at weeks 0 , 2 , and 6 , followed by treatment every 4 weeks or every 8 weeks ( alternating with placebo infusions in the interim 4-week visits ) at a dose of 3 or 10 mg/kg for a total of 102 weeks ( including the gap in therapy ) . For safety and efficacy assessment s , data on the patients who were r and omized to receive treatment , irrespective of whether treatment was administered for 102 weeks , were evaluated using all actual observations available . The efficacy measures included the Health Assessment Question naire ( HAQ ) ( physical function ) , Short Form 36 health survey ( SF-36 ) ( health-related quality of life ) , total radiographic scores ( structural damage ) , and the American College of Rheumatology 20 % improvement criteria ( ACR20 ) ( signs and symptoms ) . RESULTS The infliximab plus MTX regimens result ed in significantly greater improvement in HAQ scores ( P < or = 0.006 ) and SF-36 physical component summary scores ( P < or = 0.011 ) compared with the MTX-only group . There also was stability in the SF-36 mental component summary score among patients who received the infliximab plus MTX regimens . Median changes from baseline to week 102 in the total radiographic score were 4.25 for patients who received the MTX-only regimen and 0.50 for patients who received the infliximab plus MTX regimen . The proportion of patients achieving an ACR20 response at week 102 varied from 40 % to 48 % for the infliximab plus MTX groups compared with 16 % for the MTX-only group . CONCLUSION Throughout 102 weeks of therapy , infliximab plus MTX provided significant , clinical ly relevant improvement in physical function and quality of life , accompanied by inhibition of progressive joint damage and sustained improvement in the signs and symptoms of RA among patients who previously had an incomplete response to MTX alone OBJECTIVE To compare the functional status and well-being of patients with rheumatoid arthritis ( RA ) who were r and omly assigned to receive placebo , etanercept  10 mg , or etanercept 25 mg during a 26-week , phase III , double-blind clinical trial . BACKGROUND No single indicator of disease activity , severity , or therapeutic efficacy has been established for RA . During the past decade , health-related quality of life , a multidimensional way to assess physical , emotional , and social aspects of a disease or its treatment , has become an important outcome in RA studies and in assessment s of RA drug therapies . METHODS A total of 234 patients completed the Health Assessment Question naire ( HAQ )  , the  Short-Form 36 ( SF-36 ) ( n = 48 patients ) , items assessing energy and mental health from the Medical Outcomes Study ( MOS ) , and a single-item rating scale assessing current health ( feeling thermometer ) at baseline and several times during 6 months . RESULTS Significant improvements from baseline to last assessment were reported with etanercept versus placebo and in the HAQ Disability Index score ( ie , the total HAQ score ) and all 8 HAQ categories ( P < 0.05 ) , with the exception of grip . Significant improvements with etanercept in the MOS energy and mental health subscales , current health ( from the feeling thermometer ) , and mental and physical function components of the SF-36 were reported ( P < 0.05 ) . CONCLUSIONS Patients receiving 10- or 25-mg doses of etanercept reported significantly better functional status and well-being than did patients receiving placebo 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 , r and omized , 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 > or =3 months before enrollment with an inadequate response were r and omly assigned to receive 2 single doses of either adalimumab 0.25 , 0.5 , 1 , 3 , or 5 mg/kg i.v . 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 i.v . 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 vali date d 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 < or = 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 BACKGROUND Tumor necrosis factor ( TNF ) is a proinflammatory cytokine involved in the pathogenesis of rheumatoid arthritis , and antagonism of TNF may reduce the activity of the disease . This study evaluated the safety and efficacy of a novel TNF antagonist - a recombinant fusion protein that consists of the soluble TNF receptor ( p75 ) linked to the Fc portion of human IgG1 ( TNFR : Fc ) . METHODS In this multicenter , double-blind trial , we r and omly assigned 180 patients with refractory rheumatoid arthritis to receive subcutaneous injections of placebo or one of three doses of TNFR : Fc ( 0.25 , 2 , or 16 mg per square meter of body-surface area ) twice weekly for three months . The clinical response was measured by changes in composite symptoms of arthritis defined according to American College of Rheumatology criteria . RESULTS Treatment with TNFR : Fc led to significant reductions in disease activity , and the therapeutic effects of TNFR : Fc were dose-related . At three months , 75 percent of the patients in the group assigned to 16 mg of TNFR : Fc per square meter had improvement of 20 percent or more in symptoms , as compared with 14 percent in the placebo group ( P<0.001 ) . In the group assigned to 16 mg per square meter , the mean percent reduction in the number of tender or swollen joints at three months was 61 percent , as compared with 25 percent in the placebo group ( P<0.001 ) . The most common adverse events were mild injection-site reactions and mild upper respiratory tract symptoms . There were no dose-limiting toxic effects , and no antibodies to TNFR : Fc were detected in serum sample s. CONCLUSIONS In this three-month trial TNFR : Fc was safe , well tolerated , and associated with improvement in the inflammatory symptoms of rheumatoid arthritis OBJECTIVES To evaluate efficacy , dose response , safety , and tolerability of adalimumab ( D2E7 ) in disease modifying antirheumatic drug ( DMARD ) refractory patients with longst and ing , active rheumatoid arthritis ( RA ) . METHODS During a 12 week , double blind , placebo controlled study , 284 patients were r and omly allocated to receive weekly subcutaneous injections of adalimumab 20 mg ( n = 72 ) , 40 mg ( n = 70 ) , or 80 mg ( n = 72 ) or placebo ( n = 70 ) without concomitant DMARDs . RESULTS Adalimumab significantly improved the signs and symptoms of RA for all efficacy measures . ACR20 responses with adalimumab were significant at each assessment versus placebo ( p</=0.01 ) . Additionally , ACR responses with adalimumab were achieved more rapidly than with placebo , with 82/115 ( 71 % ) of the ultimate ACR20 response rate to adalimumab treatment achieved at week 2 . At week 12 , for adalimumab 20 , 40 , and 80 mg , ACR20 response rates were 50.7 % , 57.1 % , and 54.2 % , respectively , versus 10.0 % for placebo ( p</=0.001 for all comparisons ) ; ACR50 rates were 23.9 % , 27.1 % , and 19.4 % , respectively , versus 1.4 % for placebo ( p</=0.001 for all comparisons ) ; and ACR70 rates were 11.3 % , 10.0 % , and 8.3 % , respectively , versus 0.0 % for placebo ( p</=0.05 for all comparisons ) . All adalimumab doses significantly improved all ACR core criteria at all assessment s. The 40 mg and 80 mg doses provided similar benefit . Adalimumab at all doses was generally well tolerated , with only mild or moderate adverse events . Completion rates were 87 % for adalimumab and 67 % for placebo . CONCLUSIONS Adalimumab given as monotreatment to patients with longst and ing , severe RA refractory to traditional DMARDs produced a rapid , sustained response and was safe and well tolerated , with no dose limiting side effects OBJECTIVE To investigate the relationship between serum concentrations of infliximab , a monoclonal anti-tumor necrosis factor alpha antibody , and clinical improvement from infliximab therapy for rheumatoid arthritis ( RA ) . METHODS Multiple blood sample s were obtained from each of 428 subjects with active RA who were enrolled in a multicenter , r and omized , double-blind , placebo-controlled trial ( ATTRACT [ Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy ] ) evaluating the clinical efficacy and safety of infliximab therapy .  Serum levels of infliximab  were measured by enzyme-linked immunosorbent assay . Dose-response trends were analyzed using generalized logistic regression techniques . Pharmacokinetic modeling was used to predict the serum concentrations of infliximab after simulated infusions using doses and dosing intervals not evaluated in the trial . RESULTS At week 54 , 26 % of the subjects receiving 3 mg/kg infliximab every 8 weeks had undetectable trough serum levels of infliximab  , a significantly greater proportion than in the other 3 treatment groups ( P < 0.001 ) . Increased magnitude of American College of Rheumatology ( ACR ) response ( measured by the ACR-N , a continuous measure of clinical improvement derived from the ACR 20 % response criteria ) and greater reduction from baseline in serum C-reactive protein level were both associated with higher trough serum concentrations of infliximab  ( P < 0.001 ) , as was less progression of radiographic joint damage ( P = 0.004 ) , providing support for a dose-response relationship . Pharmacokinetic models predicted that decreasing the dosing interval from 8 weeks to 6 weeks would yield higher trough serum levels of infliximab  than increasing the dose by 100 mg . CONCLUSION These results suggest that some patients with RA may benefit from infliximab given at higher doses than 3 mg/kg or more frequently than every 8 weeks OBJECTIVE To investigate sensitive ultrasonographic imaging methods for detection of synovial thickness and vascularity to discriminate between patients with early rheumatoid arthritis ( RA ) receiving infliximab + methotrexate ( MTX ) versus placebo + MTX over 18 weeks , and to compare the relationship between synovial thickening and vascularity at baseline and radiologic damage to joints of the h and s and feet at 54 weeks . METHODS Patients with early RA ( duration <3 years ) receiving stable dosages of MTX  were r and omly assigned to receive blinded infusions of 5 mg/kg infliximab ( n = 12 ) or placebo ( n = 12 ) at weeks 0 , 2 , 6 , and then every 8 weeks until week 46 . At baseline and week 18 , clinical assessment s were performed , and metacarpophalangeal joints were assessed by high-frequency ultrasonography and power Doppler ultrasonography measurements . Radiographs of the h and s and feet taken at baseline and at 54 weeks were evaluated using the van der Heijde modification of the Sharp method ( vdH-Sharp score ) . RESULTS Using changes in the total vdH-Sharp score over 54 weeks and changes in synovial thickening and joint vascularity at 18 weeks , we were able to distinguish those patients receiving infusions of infliximab + MTX from those receiving placebo + MTX . Sonographic measurements of synovial thickening and vascularity at baseline in the placebo + MTX group demonstrated clear relationships with the magnitude of radiologic joint damage at week 54 . Infliximab + MTX treatment abolished these relationships . CONCLUSION The delay or reversal of inflammatory and joint-destructive mechanisms in patients with early RA was already apparent following 18 weeks of treatment with infliximab + MTX and was reflected in radiologic changes at 54 weeks OBJECTIVE To evaluate the efficacy and safety of monotherapy with adalimumab in patients with RA for whom previous DMARD treatment has failed . METHODS In a 26 week , double blind , placebo controlled , phase III trial , 544 patients with RA were r and omised to monotherapy with adalimumab 20 mg every other week , 20 mg weekly , 40 mg every other week , 40 mg weekly , or placebo . The primary efficacy end point was > or = 20 % improvement in the ACR core criteria ( ACR20 response ) . Secondary efficacy end points included ACR50 , ACR70 , EULAR responses , and the Disability Index of the Health Assessment Question naire ( HAQ DI ) . RESULTS After 26 weeks , patients treated with adalimumab 20 mg every other week , 20 mg weekly , 40 mg every other week , and 40 mg weekly had significantly better response rates than those treated with placebo :  ACR20 ( 35.8 % , 39.3 % , 46.0 % , 53.4 % , respectively v 19.1 % ; p < or = 0.01 ) ; ACR50 ( 18.9 % , 20.5 % , 22.1 % , 35.0 % v 8.2 % ; p < or = 0.05 ) ; ACR70 ( 8.5 % , 9.8 % , 12.4 % , 18.4 % v 1.8 % ; p < or = 0.05 ) . Moderate EULAR response rates were significantly greater with adalimumab than with placebo ( 41.5 % , 48.2 % , 55.8 % , 63.1 % v 26.4 % ; p < or = 0.05 ) . Patients treated with adalimumab achieved better improvements in mean HAQ DI than those receiving placebo ( -0.29 , -0.39 , -0.38 , -0.49 v -0.07 ; p < or = 0.01 ) . No significant differences were found between adalimumab and placebo treated patients for serious adverse events , serious infections , or malignancies . Injection site reaction occurred in 10.6 % and 0.9 % of adalimumab and placebo treated patients , respectively ( p < or = 0.05 ) . CONCLUSION Among patients with RA for whom previous DMARD treatment had failed , adalimumab monotherapy achieved significant , rapid , and sustained improvements in disease activity and improved physical function and was safe and well tolerated OBJECTIVE To compare the effectiveness of 3 therapeutic strategies in preventing progressive joint damage  , in a population -based cohort . The 3 strategies were infliximab with concomitant disease-modifying antirheumatic drugs ( DMARDs ) , etanercept with concomitant DMARDs , and etanercept alone . METHODS We used sequential radiographs to assess all patients who were treated with infliximab or etanercept for > 10 months . The rates of erosion progression and joint space narrowing ( JSN ) were analyzed using multivariate regression models for longitudinal data , with adjustment for potential confounders . RESULTS A total of 372 patients treated with anti-tumor necrosis factor ( TNF ) therapies met the inclusion criteria . The baseline characteristics of the patients assigned to the 3 strategies were not significantly different , except that , as expected , more patients were receiving combination therapy with infliximab . The combination of infliximab plus DMARDs was significantly more effective than etanercept alone for controlling erosion progression ( P < 0.001 ) , but the effectiveness of the 2 combination-treatment strategies was similar ( P = 0.07 ) . The combination of infliximab plus DMARDs was also more effective at controlling progressive JSN compared with etanercept alone ( P = 0.04 ) or etanercept plus DMARDs ( P = 0.02 ) . Treatment with anti-TNF agents ( infliximab or etanercept ) plus concomitant DMARDs was more effective than treatment with etanercept alone for controlling erosion progression ( P = 0.045 ) . CONCLUSION When combined with traditional DMARDs , both etanercept and infliximab appear to offer similar protection against progressive structural joint damage , and combination therapy with either of these agents appears to be more effective than treatment with etanercept alone BACKGROUND Etanercept , which blocks the action of tumor necrosis factor , reduces disease activity in patients with long-st and ing rheumatoid arthritis . Its efficacy in reducing disease activity and preventing joint damage in patients with active early rheumatoid arthritis is unknown . METHODS We treated 632 patients with early rheumatoid arthritis with either twice-weekly subcutaneous etanercept  ( 10 or 25 mg ) or weekly  oral methotrexate ( mean , 19 mg per week ) for 12 months . Clinical response was defined as the percent improvement in disease activity according to the criteria of the American College of Rheumatology . Bone erosion and joint-space narrowing were measured radiographically and scored with use of the Sharp scale . On this scale , an increase of 1 point represents one new erosion or minimal narrowing . RESULTS As compared with patients who received methotrexate , patients who received the 25-mg dose of etanercept had a more rapid rate of improvement , with significantly more patients having 20 percent , 50 percent , and 70 percent improvement in disease activity during the first six months ( P<0.05 ) . The mean increase in the erosion score during the first 6 months was 0.30 in the group assigned to receive 25 mg of etanercept and 0.68 in the methotrexate group ( P= 0.001 ) , and the respective increases during the first 12 months were 0.47 and 1.03 ( P=0.002 ) . Among patients who received the 25-mg dose of etanercept , 72 percent had no increase in the erosion score , as compared with 60 percent of patients in the methotrexate group ( P=0.007 ) . This group of patients also had fewer adverse events ( P=0.02 ) and fewer infections ( P= 0.006 ) than the group that was treated with methotrexate . CONCLUSIONS As compared with oral methotrexate , subcutaneous [ corrected ] etanercept acted more rapidly to decrease symptoms and slow joint damage in patients with early active rheumatoid arthritis OBJECTIVE Tumor necrosis factor ( TNF ) is an important proinflammatory cytokine that mediates inflammatory synovitis and articular matrix degradation in rheumatoid arthritis ( RA ) . We investigated the ability of adalimumab , a human anti-TNF monoclonal antibody , to inhibit the progression of structural joint damage , reduce the signs and symptoms , and improve physical function in patients with active RA receiving concomitant treatment with methotrexate ( MTX ) .  METHODS In this multicenter , 52-week , double-blind , placebo-controlled study , 619 patients with active RA who had an inadequate response to MTX were r and omized to receive adalimumab 40 mg subcutaneously every other week ( n = 207 ) , adalimumab 20 mg subcutaneously every week ( n = 212 ) , or placebo ( n = 200 ) plus concomitant MTX . The primary efficacy end points were radiographic progression at week 52 ( total Sharp score by a modified method [ TSS ] ) , clinical response at week 24 ( improvements of at least 20 % in the American College of Rheumatology core criteria [ ACR20 ] ) , and physical function at week 52 ( disability index of the Health Assessment Question naire [ HAQ ] ) . RESULTS At week 52 , there was statistically significantly less radiographic progression , as measured by the change in TSS , in the patients receiving adalimumab either 40 mg every other week ( mean + /- SD change 0.1 + /- 4.8 ) or 20 mg weekly ( 0.8 + /- 4.9 ) as compared with that in the placebo group ( 2.7 + /- 6.8 ) ( P < or = 0.001 for each comparison ) . In addition , there were statistically significant changes in the components of the TSS . At week 24 , ACR20 responses were achieved by 63 % and 61 % of patients in the adalimumab 40 mg every other week and 20 mg weekly groups , respectively , versus 30 % of patients in the placebo group ( P < or = 0.001 for each comparison ) . At week 52 , ACR20 responses were achieved by 59 % and 55 % of patients taking adalimumab 40 mg every other week and 20 mg weekly , respectively , versus 24 % of patients taking placebo ( P < or = 0.001 for each comparison ) . At week 52 , physical function as measured by the HAQ demonstrated statistically significant improvement with adalimumab 40 mg every other week and 20 mg weekly compared with placebo ( mean change in HAQ score -0.59 and -0.61 , respectively , versus -0.25 ; P < or = 0.001 for each comparison ) . A total of 467 patients ( 75.4 % ) completed 52 weeks of treatment . Adalimumab was generally well tolerated . Discontinuations occurred in 22.0 % of adalimumab-treated patients and in 30.0 % of placebo-treated patients . The rate of adverse events ( both serious and nonserious ) was comparable in the adalimumab and placebo groups , although the proportion of patients reporting serious infections was higher in patients receiving adalimumab ( 3.8 % ) than in those receiving placebo ( 0.5 % ) ( P < or = 0.02 ) , and was highest in the patients receiving 40 mg every other week . CONCLUSION In this 52-week trial , adalimumab was more effective than placebo at inhibiting the progression of structural joint damage , reducing the signs and symptoms , and improving physical function in patients with active RA who had demonstrated an incomplete response to MTX BACKGROUND Neutralization of tumor necrosis factor a ( TNF-alpha ) for three to six months reduces the symptoms and signs of rheumatoid arthritis . However , the capacity of this approach to effect a more sustained benefit and its effect on joint damage are not known . METHODS We treated 428 patients who had active rheumatoid arthritis despite methotrexate therapy with placebo or infliximab , a chimeric monoclonal antibody against TNF-alpha  , in intravenous doses of 3 or 10 mg per kilogram of body weight every 4 or 8 weeks in combination with oral methotrexate for 54 weeks . We assessed clinical responses with use of the criteria of the American College of Rheumatology , the quality of life with a health-status question naire , and the effect on joint damage radiographically . RESULTS The combination of infliximab and methotrexate was well tolerated and result ed in a sustained reduction in the symptoms and signs of rheumatoid arthritis that was significantly greater than the reduction associated with methotrexate therapy alone ( clinical response , 51.8 percent vs. 17.0 percent ; P<0.001 ) . The quality of life was also significantly better with infliximab plus methotrexate than with methotrexate alone . Radiographic evidence of joint damage increased in the group given methotrexate , but not in the groups given infliximab and methotrexate ( mean change in radiographic score , 7.0 vs. 0.6 , P<0.001 ) . Radiographic evidence of progression of joint damage was absent in infliximab-treated patients whether or not they had a clinical response . CONCLUSIONS In patients with persistently active rheumatoid arthritis despite methotrexate therapy , repeated doses of infliximab in combination with methotrexate provided clinical benefit and halted the progression of joint damage OBJECTIVE To determine the safety and pharmacokinetics of recombinant human tumor necrosis factor receptor ( p80 ) fusion protein ( rhTNFR : Fc ) administered as a single intravenous ( iv ) loading dose followed by subcutaneous ( sc ) maintenance injections twice weekly for one month in patients with refractory rheumatoid arthritis ( RA ) . METHODS Four dose groups were evaluated with 4 patients with RA per group : 3 received active drug and one received placebo injection . After each dose group completed 4 weeks of treatment , the patient who received placebo was allowed to receive the active drug for one month . After these 16 patients completed the study , 3 additional patients received the highest dose and 3 additional patients received the lowest dose in an open label study to obtain more safety data ( total of 22 patients treated ) . RESULTS There were no serious adverse effects . Drug related events include mild injection site reactions in 4 patients that did not necessitate discontinuation of the drug . There was no clearcut dose response among the treatment groups . At Week 4 , there was 45 % mean improvement in total pain and total joint scores in patients receiving active drug ( n = 12 ) , compared to 22 % mean improvement in patients receiving placebo ( n = 4 ) . C-reactive protein ( CRP ) levels decreased substantially in patients treated with drug compared to placebo , 30 vs 13 % , respectively . The decrease in CRP was most pronounced in the highest dose group . CONCLUSION This initial experience with rhTNFR : Fc fusion protein in RA justifies further evaluation of this agent in a larger placebo controlled trial OBJECTIVE To assess the pharmacokinetics , safety profile , and efficacy of the fully human anti-tumor necrosis factor-alpha ( anti-TNF-alpha ) monoclonal antibody adalimumab ( D2E7 ) in patients with long-st and ing , active rheumatoid arthritis ( RA ) . METHODS This was a r and omized , double blind , placebo controlled study of single intravenous injections of ascending doses ( 0.5 to 10 mg/kg ) of adalimumab in 5 cohorts of 24 patients each ( 18 adalimumab and 6 placebo in all cohorts except the 0.5 mg/kg cohort of 17 adalimumab , 7 placebo ) . A total of 120 patients participated ( adalimumab 89 , placebo 31 ) . The clinical response was measured by changes in composite scores defined by the criteria of the European League Against Rheumatism ( EULAR ) and the American College of Rheumatology . RESULTS Single doses of adalimumab showed a rapid onset of clinical effect ( 24 hours to 1 week ) , with peak efficacy at 1 to 2 weeks that was sustained for at least 4 weeks and for as long as 3 months in some patients . EULAR response was seen at least once during the 4 week period after drug injection in 29 % of patients in the placebo group as well as in 41 % , 78 % , 72 % , 89 % , and 100 % in the 0.5 , 1 , 3 , 5 , and 10 mg/kg groups , respectively . No dose related increases in adverse events were observed in the adalimumab patients compared with the placebo group . Adalimumab systemic drug exposure ( AUC0- ( ) ) increased linearly with an increase in dose . The mean total serum clearance was 0.012 to 0.017 l/h , and the steady-state volume of distribution ranged from 4.7 to 5.5 l. The estimated mean terminal half-life ranged from 10.0 to 13.6 days for the 5 cohorts , with an overall mean half-life of 12 days . CONCLUSION Treatment with the fully human Mab adalimumab was safe and well tolerated when administered as a single intravenous injection at doses up to 10 mg/kg , and was associated with a clinical ly significant improvement in the signs and symptoms of active RA OBJECTIVES To compare the 48-week drug survival , efficacy and toxicity of monotherapy with a fully human anti-tumour necrosis factor-alpha ( TNF-alpha ) monoclonal antibody ( moAb ) and methotrexate ( MTX ) in patients with active long-st and ing rheumatoid arthritis ( RA ) . Secondary aims were to identify potential predictors for clinical response . METHODS Patients with RA , enrolled in phase I trials with a human anti-TNF-alpha moAb and followed for at least 48 weeks at our centre , were compared with patients receiving MTX monotherapy without folate supplementation .  The first 6 weeks of anti-TNF therapy were placebo-controlled and followed by an open-label study . Patients treated with MTX participated in a 48-week , double-blind , phase III study of MTX alone vs MTX with folate supplementation , which was co-ordinated by our department . The studies with anti-TNF-alpha and MTX were performed in the same period and had very similar inclusion , exclusion , response and stop criteria . RESULTS Sixty-one patients treated with anti-TNF-alpha moAb were compared with 137 receiving MTX monotherapy . At baseline , patients in the anti-TNF-alpha group had a longer disease duration ( median 108 vs 50 months , P=0.0001 ) and a more protracted history of second-line anti-rheumatic drugs than those treated with MTX ( median 4 vs 1 , P=0.0001 ) . The 48-week dropout rate was lower among patients treated with anti-TNF ( 23 vs 45 % in the MTX group , P<0.005 ) . Proportional hazard analysis showed a significantly lower dropout risk among anti-TNF-treated patients [ relative risk ( 95 % confidence interval ) : 0.28 ( 0.12 - 0.6 ) uncorrected and 0.17 ( 0.06 - 0.45 ) corrected for confounders ) . The 48-week area under the curve for the disease activity score ( DAS ) was smaller in the anti-TNF-alpha group than in the MTX group ( P=0.005 ) . The percentage of responders was higher in the anti-TNF-alpha group over the whole study period . The median percentage of visits in which a patient fulfilled the European League Against Rheumatism ( EULAR ) response criteria was 83 % in the anti-TNF-alpha group vs 40 % in the MTX group ( P=0.0001 ) . Clinical and demographic characteristics were , in general , poor predictors for response to therapy at week 48 . The clinical response after the first anti-TNF-alpha dose tended to increase the chance of prolonged efficacy of this approach [ relative risk ( 95 % confidence interval ) : 2 ( 0.75 - 6.0 ) ] . The previous number of second-line drugs was the only predictive variable for response to  MTX to which it was inversely related [ relative risk ( 95 % confidence interval ) : -0.71 ( -0.57 to -0.88 ) ] . CONCLUSIONS In patients with active , long-st and ing RA , blocking TNF-alpha is more effective and better tolerated than MTX monotherapy . An early response increases the chance of a sustained effect of anti-TNF-alpha . In contrast to MTX , the response to anti-TNF-alpha is not affected by previous disease-modifying anti-rheumatic drug history OBJECTIVE This study , known as STAR ( Safety Trial of Adalimumab in Rheumatoid Arthritis ) , evaluated the safety and efficacy of adalimumab ( Humira ) , a fully human monoclonal tumor necrosis factor-alpha ( TNF-a ) antibody , when given with st and ard antirheumatic therapy in patients with active rheumatoid arthritis ( RA ) not adequately responding to such therapies .  St and ard antirheumatic therapy included traditional disease modifying antirheumatic drugs ( DMARD ) , low dose corticosteroids , nonsteroidal antiinflammatory drugs ( NSAID ) , and /or analgesics . METHODS In this 24-week , double-blind , placebo-controlled study , 636 patients with RA were r and omly assigned to receive adalimumab 40 mg subcutaneously ( sc ) every other week ( n = 318 ) or placebo ( n = 318 ) while continuing st and ard antirheumatic therapy . The frequencies of adverse events , serious adverse events , severe or life-threatening adverse events , adverse events leading to withdrawal , infection , or serious infection were the primary endpoints . Secondary endpoints were determined by American College of Rheumatology ( ACR ) response criteria . RESULTS During the study , the majority of patients received concomitant traditional DMARD ( 83.5 % ) and /or corticosteroids , NSAID , and /or analgesics ( 97.3 % ) . Overall , 56.0 % of patients continued treatment with one , 23.6 % with 2 , and 3.9 % with > or = 3 traditional DMARD . At 24 weeks , there were no statistically significant differences between the adalimumab and placebo groups in their respective rates of adverse events ( 86.5 % vs 82.7 % ) , serious adverse events ( 5.3 % vs 6.9 % ) , severe or life-threatening adverse events ( 11.9 % vs 15.4 % ) , or those leading to withdrawal ( 2.8 % vs 2.2 % ) . There were also no statistically significant differences in the rates of infections ( 52.2 % vs 49.4 % ) or serious infections ( 1.3 % vs 1.9 % ) between the groups . The incidence and types of adverse events did not vary between adalimumab- and placebo-treated patients by the number of concomitant traditional DMARD ( 0 , 1 , or 2 ) . Adalimumab-treated patients compared with placebo-treated patients achieved statistically superior ACR20 ( 52.8 % vs 34.9 % ) , ACR50 ( 28.9 % vs 11.3 % ) , and ACR70 ( 14.8 % vs 3.5 % ) response rates at Week 24 ( p < or = 0.001 ) . CONCLUSION This study demonstrated that addition of adalimumab 40 mg given sc every other week to concomitant st and ard antirheumatic therapy is well tolerated and provides significant improvements in signs and symptoms of RA . The data indicate that adalimumab is a safe and effective therapeutic option in patients with active RA who have an inadequate response to st and ard antirheumatic therapy , including one or more traditional DMARD  , corticosteroids , NSAID , and analgesics BACKGROUND AND PURPOSE Etanercept ( Enbrel ) , a recombinant tumor necrosis factor receptor fusion protein , has been shown to be effective in the treatment of patients with rheumatoid arthritis ( RA ) . The purpose of this study was to compare the efficacy and safety of etanercept in combination with methotrexate ( MTX ) and MTX alone in Taiwanese patients with active RA . METHODS In this double-blind study , 58 patients with active RA who were maintained on MTX therapy at a stable dose of 12.5 to 20 mg per week for 4 weeks were r and omized to receive either etanercept 25 mg ( n = 29 ) or placebo ( n = 29 ) by subcutaneous injection twice weekly over a period of 12 weeks . The primary endpoint was the reduction of tender and swollen joint counts by 20 % ( ACR 20 ) , 50 % ( ACR 50 ) , and 70 % ( ACR 70 ) as determined by the American College of Rheumatology criteria at the 12th week . RESULTS The addition of etanercept to MTX result ed in a greater reduction in the number of tender ( 7.00 vs 2.45 , p = 0.012 ) and swollen joints ( 8.55 vs 3.86 , p = 0.017 ) , and in serum levels of C-reactive protein ( 1.26 mg/dL vs 0.45 mg/dL , p = 0.014 ) compared to MTX alone after 12 weeks of therapy . In addition , the global assessment of disease activity by both physicians and patients , duration of morning stiffness , pain visual analog scale score , and Health Assessment Question naire were all improved by etanercept plus MTX therapy . Results for the overall improvement in disease activity assessed by ACR 20 ( 90 % vs 34 % ) , ACR 50 ( 66 % vs 10 % ) and ACR 70 ( 24 % vs 0 % ) all favored the etanercept plus MTX group . However , the adverse events were comparable between the 2 treatment groups . CONCLUSION Etanercept in combination with MTX was well tolerated and provided significantly more clinical benefit than MTX alone in Taiwanese patients with active RA Our in-vitro , animal , and early clinical data suggest that tumour necrosis factor alpha ( TNF alpha ) is an important target for specific biological therapy in rheumatoid arthritis . We report the results of repeated treatment with a chimeric monoclonal antibody to TNF alpha ( cA2 ) in patients having disease flares . 7 patients originally enrolled in an open-label trial completed two to four cycles , each of which was followed by a good clinical response , with median improvements in the swollen-joint count and C-reactive protein exceeding 80 % . cA2 may be useful therapy in the control of acute disease flares in rheumatoid arthritis and treatment programmes including cA2 may be effective in the long-term management of this disease
Background To analyse available evidence on the efficacy and safety of anti-TNFα drugs ( infliximab , etanercept and adalimumab ) for treating rheumatoid arthritis ( RA ) .