Dose titration using the Disease Activity Score (DAS28) in rheumatoid arthritis patients treated with anti-TNF-alpha. Full dose, reduced dose or discontinuation of etanercept in rheumatoid arthritis Discontinuation of adalimumab after achieving remission in patients with established rheumatoid arthritis: 1-year outcome of the HONOR study Relapse rates in patients with rheumatoid arthritis in stable remission tapering or stopping antirheumatic therapy: interim results from the prospective randomised controlled RETRO study Induction therapy with adalimumab plus methotrexate for 24 weeks followed by methotrexate monotherapy up to week 48 versus methotrexate therapy alone for DMARD-naïve patients with early rheumatoid arthritis: HIT HARD, an investigator-initiated study Benefits 8 years after a remission induction regime with an infliximab and methotrexate combination in early rheumatoid arthritis. Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor alpha monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis. Drug-free remission, functioning and radiographic damage after 4 years of response-driven treatment in patients with recent-onset rheumatoid arthritis 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. Discontinuation of etanercept after achievement of sustained remission in patients with rheumatoid arthritis who initially had moderate disease activity—results from the ENCOURAGE study, a prospective, international, multicenter randomized study Adjustment of therapy in rheumatoid arthritis on the basis of achievement of stable low disease activity with adalimumab plus methotrexate or methotrexate alone: the randomised controlled OPTIMA trial Comparison of joint destruction between standard- and low-dose etanercept in rheumatoid arthritis from the Prevention of Cartilage Destruction by Etanercept (PRECEPT) study. Assessment of long-term safety and efficacy of etanercept in a 5-year extension study in patients with rheumatoid arthritis. Sustained effect after lowering high-dose infliximab in patients with rheumatoid arthritis: a prospective dose titration study Disease activity guided dose reduction and withdrawal of adalimumab or etanercept compared with usual care in rheumatoid arthritis: open label, randomised controlled, non-inferiority trial Maintenance, reduction, or withdrawal of etanercept after treatment with etanercept and methotrexate in patients with moderate rheumatoid arthritis (PRESERVE): a randomised controlled trial Discontinuation of infliximab in rheumatoid arthritis patients in clinical remission Discontinuing treatment in patients with rheumatoid arthritis in sustained clinical remission: exploratory analyses from the BeSt study Judging disease activity in clinical practice in rheumatoid arthritis: first step in the development of a disease activity score. Step-down strategy of spacing TNF-blocker injections for established rheumatoid arthritis in remission: results of the multicentre non-inferiority randomised open-label controlled trial (STRASS: Spacing of TNF-blocker injections in Rheumatoid ArthritiS Study) Effects of half dose etanercept (25 mg once a week) on clinical remission and radiographic progression in patients with rheumatoid arthritis in clinical remission achieved with standard dose. Discontinuation of adalimumab treatment in rheumatoid arthritis patients after achieving low disease activity
OBJECTIVE Anti-tumour necrosis factor alpha ( TNF-alpha ) therapy yields high response rates shortly after institution of therapy in patients with rheumatoid arthritis ( RA ) , and on theoretical grounds large differences in the effective dose between patients can be expected . Together with the high costs , these differences warrant new approaches to the way patients are dosed . METHODS We used the Disease Activity Score ( DAS28 ) , a composite disease activity index , to titrate the dose of anti-TNF-alpha ( adalimumab , D2E7 ; Knoll ) in 21 patients with low disease activity in an open extension study lasting 40 weeks . The dose of anti-TNF-alpha was reduced stepwise and dosing intervals were kept stable . Disease activity and flares were assessed using the DAS28 . Patients who flared received the previous effective dose . RESULTS Dose reduction was accomplished in 15 patients . The total amount of anti-TNF-alpha  given to the patients was reduced by 67 % . At the end of the study the mean DAS28 had not changed and no patients dropped out because of persistent worsening of the RA . CONCLUSION Dose titration of anti-TNF-alpha treatment using the DAS28 is feasible and leads to overall dose reduction while maintaining clinical efficacy . This approach will save costs and possibly prevent long-term side-effects Background The aim of the Dose Reduction or Discontinuation of Etanercept in Methotrexate-Treated Rheumatoid Arthritis Patients Who Have Achieved a Stable Low Disease Activity-State study was to investigate the effect of etanercept ( ETN ) dose maintenance , reduction or withdrawal on patients with rheumatoid arthritis ( RA ) who had already achieved stable low disease activity ( LDA ) on ETN 50 mg+methotrexate ( MTX ) .  Methods Patients with RA ( n=91 ) and stable LDA with ETN 50 mg once weekly (QW)+MTX were included . After 8 weeks with unchanged treatment , 73 patients were r and omised in a double-blind design to ETN 50 mg QW+MTX ( ETN50 ) , ETN 25 mg QW+MTX ( ETN25 ) or placebo QW+MTX ( PBO ) for 48 weeks . Patients who flared were declared failures and treated with open-label ETN50 until week 48 . The primary outcome was the proportion of patients on ETN50 versus PBO who were non-failures after 48 weeks . Results The proportion of non-failure patients was significantly lower with ETN50 ( 52 % ; p=0.007 ) and ETN25 ( 44 % ; p=0.044 ) versus PBO ( 13 % ) . Median time to failure was significantly shorter with PBO ( 6 weeks ) compared with ETN50 ( 48 weeks ; p=0.001 ) and ETN25 ( 36 weeks ; p<0.001 ) . The majority of patients who flared regained LDA with open-label ETN50 quickly . Adverse events were consistent with the known side effect profiles of these medications . Conclusions In patients with established RA who have achieved stable LDA on ETN50+MTX , continuing both is superior to PBO+MTX . Reduced dose ETN was also more effective than PBO in maintaining a favourable response , suggesting that a maintenance strategy with reduced dose ETN may be possible in a number of patients with established RA . Trial registration number NCT00858780 Objectives To investigate the possibility of discontinuing adalimumab ( ADA ) for 1 year without flaring ( DAS28-erythrocyte sedimentation rate ( ESR ) ≥3.2 ) , and to identify factors enabling established patients with rheumatoid arthritis ( RA ) to remain ADA-free . Methods Of 197 RA patients treated with ADA+methotrexate ( MTX ) , 75 patients who met the ADA-free criteria ( steroid-free and sustained DAS28-ESR remission for 6 months with stable MTX doses ) were studied for 1 year . Results The mean disease duration and DAS28-ESR score in 75 patients was 7.5 years and 5.1 at baseline , respectively . The proportion of patients who sustained DAS28-ESR < 2.6 ( 48 % ) and DAS28-ESR < 3.2 ( 62 % ) for 1 year were significantly lower in the ADA discontinuation group than in the ADA continuation group ; however , in patients with deep remission ( DAS28-ESR ≤1.98 ) identified by receiver operating characteristics analysis following logistic analysis , these rates increased to 68 % and 79 % , respectively , with no significant difference between both groups . Remarkably , ADA readministration to patients with flare was effective in returning DAS28-ESR to < 3.2 within 6 months in 90 % and 9 months in 100 % patients ; among the patients who sustained DAS28-ESR < 3.2 during ADA discontinuation , 100 % remained in structural remission and 94 % in functional remission . Conclusions The possibility of remaining ADA-free for 1 year was demonstrated in established patients with RA with outcomes that ADA can be discontinued without flaring in 79 % patients with deep remission , with similar rates in the ADA continuation group , and showed no functional or structural damage in patients with DAS28-ESR < 3.2 . ADA readministration to patients with flare during ADA discontinuation was effective Objective To prospect ively analyse the risk for disease relapses in patients with rheumatoid arthritis ( RA ) in sustained remission , either continuing , tapering or stopping disease-modifying antirheumatic drugs ( DMARDs ) in a prospect i ve r and omised controlled trial . Methods Reduction of Therapy in patients with Rheumatoid arthritis in Ongoing remission is a multicentre , r and omised controlled , parallel-group phase 3 trial evaluating the effects of tapering and stopping all conventional and /or biological DMARDs in patients with RA in stable remission . Patients ( disease activity score 28 (DAS28)<2.6 for least 6 months ) were r and omised into three arms , either continuing DMARDs ( arm 1 ) , tapering DMARDs by 50 % ( arm 2 ) or stopping DMARDs after 6 months tapering ( arm 3 ) . The primary endpoint was sustained remission during 12 months . Results In this interim analysis , the first 101 patients who completed the study were analysed . At baseline , all patients fulfilled DAS28 remission  and 70 % also American College of Rheumatology- European League Against Rheumatism Boolean remission . 82.2 % of the patients received methotrexate , 40.6 % biological DMARDs and 9.9 % other DMARDs . Overall , 67 patients ( 66.3 % ) remained in remission for 12 months , whereas 34 patients ( 33.7 % ) relapsed . The incidence of relapses was related to study arms ( p=0.007 ; arm 1 : 15.8 % ; arm 2 : 38.9 % ; arm 3 : 51.9 % ) . Multivariate logistic regression identified anticitrullinated protein antibodies ( ACPA ) positivity ( p=0.038 ) and treatment reduction ( in comparison to continuation ) as predictors for relapse ( arm 2 : p=0.012 ; arm 3 : p=0.003 ) . Conclusions This r and omised controlled study testing three different treatment strategies in patients with RA in sustained remission demonstrated that more than half of the patients maintain in remission after tapering or stopping conventional and biological DMARD treatment . Relapses occurred particularly in the first 6 months after treatment reduction and were associated with the presence of ACPA . Trial registration number 2009 - 015740 - 42 Objective To investigate the long-term effects of induction therapy with adalimumab ( ADA ) plus methotrexate ( MTX ) in comparison with placebo ( PBO ) plus MTX in DMARD-naïve patients with active early rheumatoid arthritis ( RA ) . Methods Patients with active early RA ( disease duration of ≤12 months ) were r and omly assigned to receive 40 mg ADA subcutaneously every other week ( eow ) plus MTX 15 mg/week subcutaneously or PBO plus MTX subcutaneously at 15 mg/week over 24 weeks . Thereafter , all patients received MTX monotherapy up to week 48 . The primary outcome was the Disease Activity Score 28 ( DAS28 ) at week 48 . Secondary outcomes included proportions of patients in remission ( DAS28<2.6 ) , ACR responses , Health Assessment Question naire ( HAQ ) score and radiographic progression . Results 87 patients were assigned to ADA/MTX and 85 patients to PBO/MTX . At baseline , DAS28 was 6.2±0.8 in the ADA/MTX and 6.3±0.9 in the PBO/MTX groups . At week 24 , treatment with ADA/MTX compared with PBO/MTX result ed in a greater reduction in DAS28 ( 3.0±1.2 vs 3.6±1.4 ; p=0.009 ) and other secondary outcomes such as DAS28 remission rate ( 47.9 % vs 29.5 % ; p=0.021 ) and HAQ ( 0.49±0.6 vs 0.72±0.6 ; p=0.0014 ) . At week 48 , the difference in clinical outcomes between groups was not statistically significant ( DAS28 : 3.2±1.4 vs 3.4±1.6 ; p=0.41 ) . Radiographic progression at week 48 was significantly greater in patients administered PBO/MTX ( Sharp/van der Heijde score : ADA/MTX 2.6 vs PBO/MTX 6.4 ; p=0.03 , Ratingen score : 1.7 vs 4.2 ; p=0.01 ) . Conclusions A greater reduction in radiographic progression after initial combination therapy with ADA and MTX was seen at week 48 , even after discontinuation of ADA treatment at week 24 . This sustained effect was not found at the primary endpoint ( DAS28 reduction ) OBJECTIVE To ascertain whether a 1-year remission induction therapy with an infliximab-MTX ( INF-MTX ) combination in patients with early RA provided sustained benefit after INF cessation compared with conventional treatment . METHODS Twenty patients with poor prognosis RA of < 1 year of disease duration were r and omized to receive either INF and MTX or placebo infusions and MTX for 1 year . They then stepped down to MTX monotherapy and were treated according to st and ard clinical care . After 8 years , disease activity , function and quality of life ( QoL ) data were collected . RESULTS At follow-up , data were available for 18 patients ( 1 in each group had died ) . Median 28-joint DAS was significantly lower in the INF-MTX group compared with placebo-MTX group ( 2.7 vs 4.3 , P = 0.02 ) . Four patients in the INF-MTX group were in remission vs none in the placebo-MTX group . One patient in the INF-MTX group achieved drug-free remission . Both RAQoL and HAQ median scores were lower in the INF-MTX group ; however , this did not reach statistical significance ( median RAQoL 3 vs 8 , P = 0.18 ; median HAQ 1.0 vs 1.5 , P = 0.12 ) . CONCLUSION A remission induction regime with an INF-MTX combination for 1 year in early RA can improve long-term clinical outcomes . Larger studies will be required to confirm the implication s of these findings 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 Objectives : To compare the occurrence of drug-free remission , functional ability and radiological damage after 4 years of response-driven treatment according to four different treatment strategies for rheumatoid arthritis ( RA ) . Methods : Patients with recent-onset , active RA ( n = 508 ) were r and omly assigned to four different treatment strategies : ( 1 ) sequential monotherapy ; ( 2 ) step-up combination therapy ; ( 3 ) initial combination therapy with prednisone and ( 4 ) initial combination therapy with infliximab . Treatment was adjusted based on 3-monthly disease activity score ( DAS ) assessment s , aim ing at a DAS ⩽2.4 . From the third year , patients with a sustained DAS < 1.6 discontinued treatment . Results : In total , 43 % of patients were in remission ( DAS < 1.6 ) at 4 years and 13 % were in drug-free remission : 14 % , 12 % , 8 % and 18 % of patients in groups 1–4 , respectively . The absence of anti-cyclic citrullinated peptide antibodies , male gender and short symptom duration were independently associated with drug-free remission . Functional ability and remission were maintained in all four groups with the continuation of DAS-driven treatment , without significant differences between the groups . Significant progression of joint damage was observed in 38 % and 31 % of patients in groups 3 and 4 versus 51 % and 54 % of patients in groups 1 and 2 ( p<0.05 , group 4 versus groups 1 and 2 , group 3 versus group 2 ) . Conclusions : In patients with recent-onset active RA  , drug-free remission was achieved in up to 18 % of patients . DAS-driven treatment maintained clinical and functional improvement , independent of the treatment strategy . Joint damage progression remained significantly lower after initial combination therapy compared with initial monotherapy 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 Abstract Objectives : To investigate the efficacy and safety of etanercept ( ETN ) in patients with rheumatoid arthritis ( RA ) with moderate disease activity and the possibility to discontinue ETN  after achieving remission . Methods : Multicenter , r and omized , and open-label study was conducted in Japan and Korea . RA patients ( disease duration < 5 years ) with moderate disease activity despite methotrexate ( MTX ) treatment were allocated to either MTX or ETN + MTX ( Period 1 ) for 12 months . Patients who achieved sustained remission  defined as  DAS28  < 2.6 at both 6 and 12 months in the ETN + MTX group , were r and omized to either continue or discontinue ETN for 12 months ( Period 2 ) . Results : A total of 222 patients were enrolled in Period 1 and clinical remission was achieved in 106/157 ( 67.5 % ) and 5/28 ( 17.9 % ) patients in the ETN + MTX and MTX groups , respectively . In Period 2 , sixty-seven patients were r and omized and finally 28/32 ( 87.5 % ) and 15/28 ( 53.6 % ) patients who continued or discontinued  ETN maintained clinical remission . Baseline disease activity and the presence of comorbid diseases influenced the maintenance of remission after ETN discontinuation . Conclusions : ETN + MTX was efficient for RA patients with moderate disease activity into remission . After achieving sustained remission , a half of the patients who discontinued ETN could maintain remission for 1 year BACKGROUND Biological agents offer good control of rheumatoid arthritis , but the long-term benefits of achieving low disease activity with a biological agent plus methotrexate or methotrexate alone are unclear . The OPTIMA trial assessed different treatment adjustment strategies in patients with early rheumatoid arthritis attaining ( or not ) stable low disease activity with adalimumab plus methotrexate or methotrexate monotherapy . METHODS This trial was done at 161 sites worldwide . Patients with early ( < 1 year duration ) rheumatoid arthritis naive to methotrexate  were r and omly allocated ( by interactive voice response system , in a 1:1 ratio , block size four ) to adalimumab ( 40 mg every other week ) plus methotrexate ( initiated at 7·5 mg/week , increased by 2·5 mg every 1 - 2 weeks to a maximum weekly dose of 20 mg by week 8) or placebo plus methotrexate for 26 weeks ( period 1 ) . Patients in the  adalimumab plus methotrexate  group who completed period 1 and achieved the stable low disease activity target ( 28-joint disease activity score with C-reactive protein [DAS28]<3·2 at weeks 22 and 26 ) were r and omised to adalimumab-continuation or adalimumab-withdrawal for an additional 52 weeks ( period 2 ) . Patients achieving the target with initial methotrexate continued methotrexate-monotherapy . Inadequate responders were offered adalimumab plus methotrexate . All patients and investigators were masked to treatment allocation in period 1 . During period 2 , treatment reallocation of patients who achieved the target was masked to patients and investigators ; patients who did not achieve the target remained masked to original r and omisation , but were aware of the subsequent assignment . The primary endpoint was a composite measure of DAS28 of less than 3·2 at week 78 and radiographic non-progression from baseline to week 78 , compared between adalimumab-continuation and methotrexate-monotherapy  . Adverse events were monitored throughout period 2 . This trial is registered with Clinical Trials.gov , number NCT00420927 . FINDINGS The study was done between Dec 28 , 2006 , and Aug 3 , 2010 . 1636 patients were assessed and 1032 were r and omised in period 1 ( 515 to adalimumab plus methotrexate ; 517 to placebo plus methotrexate ) . 466 patients in the adalimumab plus methotrexate group completed period 1 ; 207 achieved the stable low disease activity target , of whom 105 were rer and omised to adalimumab-continuation . 460 patients in the placebo plus methotrexate group completed period 1 ; 112 achieved the stable low disease activity target and continued methotrexate-monotherapy . 73 of 105 ( 70 % ) patients in the adalimumab-continuation group and 61 of 112 ( 54 % ) patients in the methotrexate-monotherapy group achieved the primary endpoint at week 78 ( mean difference 15 % [ 95 % CI 2 - 28 % ] , p=0·0225 ) . Patients achieving the stable low disease activity target on adalimumab plus methotrexate who withdrew adalimumab mostly maintained their good responses . Overall , 706 of 926 patients in period 2 had an adverse event , of which 82 were deemed serious ; however , distribution of adverse events did not differ between groups . INTERPRETATION Treatment to a stable low disease activity target result ed in improved clinical , functional , and structural outcomes , with both adalimumab-continuation and methotrexate-monotherapy . However , a higher proportion of patients treated with initial adalimumab plus methotrexate achieved the low disease activity target compared with those initially treated with methotrexate alone . Outcomes were much the same whether adalimumab was continued or withdrawn in patients who initially responded to adalimumab plus methotrexate . FUNDING AbbVie OBJECTIVE To evaluate the prevention of joint destruction and clinical efficacy of low-dose etanercept ( ETN ) ( 25 mg/week ) compared with st and ard-dose ETN ( 50 mg/week ) in RA . METHODS In this prospect i ve , r and omized , open-label study , 70 patients were assigned to receive  ETN at either 50 or 25 mg/week for 52 weeks . The primary endpoint was the variation in modified total Sharp score ( mTSS ) , and secondary endpoints were variations in disease activity score in 28 joints ( DAS-28 ) , modified HAQ and adverse event rate . Values of mTSS were calculated at baseline and after 52 weeks . Non-progression was estimated as ΔmTSS ≤0.5 , and the non-progression rate was compared between groups . RESULTS Mean values at baseline were as follows : disease duration 9.2 years ; DAS-28 5.45 ; and annual progression of mTSS 26.1 . No significant differences in background were seen between groups . At 52 weeks , the non-progression rate was significantly less in the 25 mg/week group ( 36.7 % ) than in the 50 mg/week group ( 67.7 % ) ( P = 0.041 ) . Mean ΔmTSS was higher at 25 mg/week ( 1.03 ) than at 50 mg/week ( -0.13 ) . DAS-28 was significantly improved at 4 weeks , and the effect of treatment lasted for 52 weeks in both groups . No differences in adverse event rates were seen between groups . CONCLUSION Low-dose ETN is not inferior to st and ard-dose ETN in terms of effects on clinical manifestations . However , in terms of the radiographic non-progression rate , the effects of low-dose ETN may be inferior to the effects of st and ard-dose ETN . TRIAL REGISTRATION UMIN Clinical Trials Registry , http://www.umin.ac.jp/ctr/ , UMIN000001798 OBJECTIVES To evaluate long-term safety and efficacy of etanercept ( ETN ) in patients with rheumatoid arthritis ( RA ) without concomitant disease-modifying antirheumatic drug therapy . METHODS A total of 549 patients enrolled in this 5-year , open-label extension after completing 1 of 2 r and omised controlled studies ; all patients received ETN 25 mg twice weekly during the extension . Safety assessment s included physical exams , adverse events ( AEs ) , vital signs , laboratory tests , and autoantibody evaluations . Key efficacy endpoints included numbers of responders achieving the American College of Rheumatology ( ACR ) criteria , low disease activity scores , and disease remission . RESULTS Three hundred and eight ( 56 % ) patients completed the 5-year extension study . Total ETN exposure , including that received during the double-blind studies was 2212 patient-years . Withdrawals for efficacy- and safety-related reasons were 12 % and 19 % , respectively . The most common AE was upper respiratory infection ( 44 % ) . Rates of serious infections decreased over the 5-year period ; one case of suspected tuberculosis was reported . Rates of malignancies remained generally consistent during the 5-year period . There were no reports of demyelinating disease , serious blood dyscrasias , or opportunistic infections . The relationship between autoantibody titres and clinical events was not statistically significant . Less than 5 % of patients tested positive for anti-etanercept antibodies and all antibodies were non-neutralising . After 5 years , ACR 20 , 50 , and 70 response rates were 78 % , 51 % , and 32 % , respectively ; the mean percentage of patients achieving low disease activity score ( DAS ≤ 2.4 ) and remission ( DAS ≤ 1.6 ) were 44 % and 20 % , respectively . CONCLUSIONS ETN maintained a favourable safety profile and consistent efficacy throughout the 5-year study duration Objectives : In clinical trials only a small subset of patients with rheumatoid arthritis ( RA ) benefits from higher than st and ard dose of infliximab ( > 3 mg/kg/8 weeks ) . However , dose escalation of infliximab is frequently applied in clinical practice . Individual adjustment of infliximab treatment based on actual disease activity , instead of subjective clinical judgement , could prevent possible unwarranted dose escalation . Methods : The infliximab dose of all patients with RA treated at our centre was decreased from 5 mg/kg to 3 mg/kg , leaving dosing intervals unaltered . Subsequently patients were followed for at least three infusions . At every visit , 28-joint Disease Activity Score ( DAS28 ) , infliximab serum trough levels and anti-infliximab antibody levels were assessed . Inversed European League Against Rheumatism ( EULAR ) criteria ( flare criteria ) were used as the endpoint . Results : A total of 18 patients were included in the study .  Mean ( SD ) DAS28 scores before dose reduction and after first and second low dose were 3.2 ( 1.2 ) , 3.2 ( 1.8 ) and 3.3 ( 1.2 ) , respectively ( values not significant ) . One patient ( 6 % , 95 % CI 0 % to 17 % ) developed a persistent flare that subsided after increasing infliximab doses and one patient stopped infliximab because of a lupus-like reaction . In all other patients ( n = 16 ) lowering infliximab result ed in unaltered disease activity . Infliximab levels showed that most patients had either low- ( < 1 mg/litre ) or high ( > 5 mg/litre ) serum trough levels . Anti-infliximab antibodies were detected in four patients . Conclusion : Infliximab dosages of 5 mg/kg can be lowered in the majority of patients with RA using DAS28-guided dose titration without increase of disease activity . Lowering the dose of infliximab should be considered in every patient receiving higher doses infliximab Objective To evaluate whether a disease activity guided strategy of dose reduction of two tumour necrosis factor ( TNF ) inhibitors , adalimumab or etanercept , is non-inferior in maintaining disease control in patients with rheumatoid arthritis compared with usual care . Design R and omised controlled , open label , non-inferiority strategy trial . Setting Two rheumatology outpatient clinics in the Netherl and s , from December 2011 to May 2014 . Participants 180 patients with rheumatoid arthritis and low disease activity using adalimumab or etanercept ;  121 allocated to the dose reduction strategy , 59 to usual care . Interventions Disease activity guided dose reduction ( advice to stepwise increase the injection interval every three months , until flare of disease activity or discontinuation ) or usual care ( no dose reduction advice ) . Flare was defined as increase in DAS28-CRP ( a composite score measuring disease activity ) greater than 1.2 , or increase greater than 0.6 and current score of at least 3.2 . In the case of flare , TNF inhibitor use was restarted or escalated . Main outcome measures Difference in proportions of patients with major flare ( DAS28-CRP based flare longer than three months ) between the two groups at 18 months , compared against a non-inferiority margin of 20 % . Secondary outcomes included TNF inhibitor use at study end , functioning , quality of life , radiographic progression , and adverse events . Results Dose reduction of adalimumab or etanercept was non-inferior to usual care ( proportion of patients with major flare at 18 months , 12 % v 10 % ; difference 2 % , 95 % confidence interval −12 % to 12 % ) . In the dose reduction group , TNF inhibitor use could successfully be stopped in 20 % ( 95 % confidence interval 13 % to 28 % ) , the injection interval successfully increased in 43 % ( 34 % to 53 % ) , but no dose reduction was possible in 37 % ( 28 % to 46 % ) . Functional status , quality of life , relevant radiographic progression , and adverse events did not differ between the groups , although short lived flares ( 73 % v 27 % ) and minimal radiographic progression ( 32 % v 15 % ) were more frequent in dose reduction than usual care . Conclusions A disease activity guided , dose reduction strategy of adalimumab or etanercept to treat rheumatoid arthritis is non-inferior to usual care with regard to major flaring , while result ing in the successful dose reduction or stopping in two thirds of patients . Trial registration Dutch trial register ( www.trialregister.nl ) , NTR 3216 BACKGROUND Clinical remission and low disease activity are essential treatment targets in patients with rheumatoid arthritis . Although moderately active rheumatoid arthritis is common , treatment effects in moderate disease have not been well studied . Additionally , optimum use of biologics needs further investigation , including the use of induction , maintenance , and withdrawal treatment strategies . The aim of the PRESERVE trial was to assess whether low disease activity would be sustained with reduced doses or withdrawal of etanercept in patients with moderately active disease . METHODS In a r and omised controlled trial , patients aged between 18 and 70 years with moderately active rheumatoid arthritis ( disease activity score in 28 joints [ DAS28 ] > 3.2 and ≤5.1 ) despite treatment with methotrexate were enrolled at 80 centres in Europe , Latin America , Asia , and Australia between March 6 , 2008 , and Sept 9 , 2009 . To be eligible , patients had to have been receiving 15 - 25 mg of methotrexate every week for at least 8 weeks . In an open-label period of 36 weeks , all patients were given 50 mg etanercept plus methotrexate every week . To be eligible for a subsequent double-blind period of 52 weeks , participants had to have achieved sustained low disease activity . These patients were r and omly assigned ( 1:1:1 ) by an interactive voice-response system to one of three treatment groups : 50 mg etanercept plus methotrexate , 25 mg etanercept plus methotrexate , or placebo plus methotrexate . Patients were stratified in blocks of three by DAS28 response ( low disease activity or remission ) at week 36 . Patients , investigators , data analysts , and study staff were all masked to treatment allocation . The primary endpoint was the proportion of patients with low disease activity at week 88 in the groups given 50 mg etanercept or placebo in the double-blind period . A conditional primary endpoint was the proportion of patients receiving 25 mg etanercept who achieved low disease activity . Modified intention-to-treat population s were used for analyses . This trial is registered with Clinical Trials.gov , number NCT00565409 . FINDINGS 604 ( 72.4 % ) of 834 enrolled patients were eligible for the double-blind period , of whom 202 were assigned to 50 mg etanercept plus methotrexate , 202 to 25 mg etanercept plus methotrexate , and 200 to placebo plus methotrexate . At week 88 , 166 ( 82.6 % ) of 201 patients who had received at least one dose of 50 mg etanercept and one or more DAS28 evaluations had low disease activity , compared with 84 ( 42.6 % ) of 197 who had received placebo ( mean difference 40.8 % , 95 % CI 32.5 - 49.1 % ; p<0.0001 ) . Additionally , 159 ( 79.1 % ) of 201 patients given 25 mg etanercept had low disease activity at week 88 ( mean difference from placebo 35.9 % , 27.0 - 44.8 % ; p<0.0001 ) . INTERPRETATION Conventional or reduced doses of etanercept with methotrexate in patients with moderately active rheumatoid arthritis more effectively maintain low disease activity than does methotrexate alone after withdrawal of etanercept . FUNDING Pfizer Biologic drugs are effective but are also expensive , and it is difficult to evaluate the duration of treatment . Infliximab , an anti-TNFα antibody , suppresses arthritic activity and inhibits bone destruction in patients with rheumatoid arthritis ( RA ) . Here , we document that infliximab could be discontinued after clinical remission in RA patients . Among 172 patients with RA who reached clinical remission following infliximab ( 3 mg/kg ) and methotrexate ( MTX , > 6 mg/w ) , nine patients with sustained remission discontinued it . Clinical assessment was based on a disease activity score ( DAS ) that included a 28-joint count/erythrocyte sedimentation rate ( DAS28-ESR ) . The disease was assessed before and after the start of infliximab treatment , and concomitant drug treatment — in the order of corticosteroid , nonsteroidal anti-inflammatory drugs ( NSAIDs ) , and disease-modifying anti-rheumatic drugs ( DMARDs ) other than MTX — was gradually discontinued . We considered patients for discontinuation of infliximab treatment after remission ( DAS28-ESR < 2.6 ) had been sustained for more than 24 weeks . The nine patients able to discontinue treatment were all females , with a mean age of 53.8 years ; eight patients were at stage I or II .  The mean duration of disease was 28.7 months , and these patients were on corticosteroid treatment equivalent to a mean of 2.28 mg prednisolone ( PSL ) . These nine patients all met the remission st and ard — that DAS28-ESR < 2.6 for ≥24 weeks ) — and so their treatment with concomitant drugs was discontinued . After the discontinuation of infliximab , the mean period of sustained remission was 14.2 months and the longest period was 29 months . The duration of disease was significantly shorter and the points from Steinbrocker ’s stage-classification were significantly lower in the infliximab-discontinued group than in the infliximab-continued group . Strategic reductions and /or discontinuations of concomitant treatment were performed in RA patients who attained clinical remission ( DAS28 < 2.6 ) through treatment with infliximab and MTX . Nine patients successfully discontinued infliximab after maintaining clinical remission for more than 24 weeks . After infliximab was discontinued , clinical remission and suppression of joint destruction were maintained with MTX alone , especially in early RA patients Objectives To determine the relapse rate after discontinuing treatment in patients with rheumatoid arthritis ( RA ) in sustained clinical remission , to identify predictors of a relapse and to evaluate treatment response after restarting treatment . Methods Five-year data from the BeSt study were used , in which 508 patients with recent-onset RA were r and omised into four dynamic treatment strategies , aim ing at a disease activity score ( DAS ) ≤2.4 . When DAS was < 1.6 for ≥6 months , the last disease-modifying antirheumatic drug ( DMARD ) was tapered and discontinued . If DAS increased to ≥1.6 , the last DMARD was immediately reintroduced . Results During a 5-year period , 115/508 patients ( 23 % ) achieved drug-free remission . Of these , 53 patients ( 46 % ) restarted treatment because the DAS was ≥1.6 after a median of 5 months , 59 patients ( 51 % ) remained in drug-free remission for a median duration of 23 months and 3 ( 3 % ) were lost to follow-up . In those who restarted treatment , mean ( SD ) DAS increased from 1.13 ( 0.73 ) at remission before tapering to 2.18 ( 0.65 ) at restart , reflecting an increase in all four components of DAS . Multivariable predictors for restarting treatment were anti-cyclic citrullinated peptide ( anti-CCP ) , last DMARD sulfasalazine , low baseline Health Assessment Question naire score and high mean DAS until remission . Of the 53 patients who restarted treatment , 39 ( 74 % ) again achieved remission 3–6 months after the restart . The median ( IQR ) damage progression in those who restarted treatment during the year of DAS increase was 0 ( 0–1 ) Sharp-van der Heijde units . Conclusion During 5 years DAS steered treatment , nearly 25 % of patients with RA achieved drug-free remission ; 46 % restarted DMARD monotherapy because of a relapse , the majority of whom again achieved clinical remission within 3–6 months without showing radiological progression during the relapse An investigation of clinical and laboratory variables which might form the basis for judging disease activity in clinical practice was made by six rheumatologists in a prospect i ve study of up to three years ' duration of 113 patients with early rheumatoid arthritis . Decisions to start treatment with slow acting antirheumatic drugs were equated with moments of high disease activity . If treatment with slow acting antirheumatic drugs was not started or if the slow acting antirheumatic drug remained unchanged for at least one year or if treatment was stopped because of disease remission , this was equated with periods of low disease activity . Two groups , one with high and one with low disease activity according to the above criteria , were formed . Factor analysis was performed to enable easy h and ling of the large number of clinical and laboratory variables without loss of information ; this result ed in five factors . Next , discriminant analysis was done to determine to what extent each factor contributed to discrimination between the two groups of differing disease activity . Finally , a multiple regression analysis was carried out to determine which laboratory and clinical variables underlie the factors of the discriminant function , result ing in a ' disease activity score ' . This score consisted of the following variables : Ritchie index , swollen joints , erythrocyte sedimentation rate , and general health , in declining importance . The rheumatologists ' decisions to prescribe slow acting antirheumatic drugs , or not , were mainly based on articular symptoms Tumour necrosis factor (TNF)-blocker tapering has been proposed for patients with rheumatoid arthritis ( RA ) in remission . Objective The trial aims to compare the effect of progressive spacing of TNF-blocker injections ( S-arm ) to their maintenance ( M-arm ) for established patients with RA in remission . Methods The study was an 18-month equivalence trial which included patients receiving etanercept or adalimumab at stable dose for ≥1 year , patients in remission on 28-joint Disease Activity Score ( DAS28 ) for ≥6 months and patients with stable joint damage . Patients were r and omised into two arms : maintenance or injections spacing by 50 % every 3 months up to complete stop . Spacing was reversed to the previous interval in case of relapse , and eventually reattempted after remission was reachieved . The primary outcome was the st and ardised difference of DAS28 slopes , based on a linear mixed-effects model ( equivalence interval set at ±30 % ) . Results 64 and 73 patients were included in the S-arm and M-arm , respectively , which was less than planned . In the S-arm , TNF blockers were stopped for 39.1 % , only tapered for 35.9 % and maintained full dose for 20.3 % . The equivalence was not demonstrated with a st and ardised difference of 19 % ( 95 % CI −5 % to 46 % ) . Relapse was more common in the S-arm ( 76.6 % vs 46.5 % , p=0.0004 ) . However , there was no difference in structural damage progression . Conclusions Tapering was not equivalent to maintenance strategy , result ing in more relapses without impacting structural damage progression . Further studies are needed to identify patients who could benefit from such a strategy associated with substantial cost savings . Trial registration number : Clinical Trials.gov : NCT00780793 ; EudraCT identifier : 2007 - 004483 - 41 OBJECTIVES This prospect i ve long-term follow-up study evaluated the effects of half-dose etanercept ( 25 mg weekly ) on clinical remission and radiographic progression in a large cohort of patients with rheumatoid arthritis ( RA ) in clinical remission after etanercept 25 mg bi-weekly . METHODS 524 biologic-naïve RA patients were treated with etanercept 25 mg bi-weekly after failure of conventional drugs . Patients achieving remission ( DAS28 < 2.6 ) for ≥12 months were r and omised to receive etanercept 25 mg  weekly or  25 mg bi-weekly . Patients were assessed at baseline and every 12 weeks . Remission rates , radiographic progression , incidence of infections and costs of the regimens were compared . RESULTS After a mean follow-up of 18±11 months , 347 patients ( 66.2 % ) achieved DAS28 remission ; 323 were r and omised to one of two dose regimens : etanercept 25 weekly ( group A , 159 patients ) and etanercept 25 mg bi-weekly ( group B , 164 patients ) . At the end of follow-up , 81.8 % patients of group A maintained remission for a mean of 3.6±1.5 years . Radiographic progression occurred in a small number of patients of group A and the rate of radiographic progression ( TSS > 0 ) was not significantly different in the two groups ( 18.85 % vs. 19.0 % after the first year and 16.9 % vs. 21.6 % after the second year , respectively ) . The incidence ratio of severe infections was 2.3/1.000 patient-years in group A. Etanercept half-dose regimen result ed in a saving of € 3.190.545 with a cost saving up to € 827.318 per year . CONCLUSIONS Clinical remission and arrest of radiographic progression persisted in a substantial percentage of patients with RA even after reduction of st and ard-dose etanercept Objective We implemented a retrospective study to explore discontinuation of therapy with adalimumab ( ADA ) without exacerbation in rheumatoid arthritis ( RA ) patients who had achieved low disease activity ( LDA ) with the biological agent . Methods We enrolled 46 RA patients who had completed open extension of a double-blind , placebo-controlled trial of ADA monotherapy in Japan and who had LDA ( DAS28-CRP < 2.7 ) at the last administration of ADA in the extension trials ; this date was defined as week 0 in the present study . Treatment of RA was at the discretion of the attending physician after week 0 . The primary endpoint of this study was the percentage of patients who maintained discontinuation of biological agents and LDA for 52 weeks . Results Twenty-four of the enrolled patients continued ADA while the rest discontinued ADA after the administration of the drug at week 0 . Fourteen of the 22 patients did not restart biological agents , and 4 ( 18.2 % ) of these maintained LDA through week 52 . All 4 of these patients had received ADA monotherapy before week 0 . ConclusionS ome RA patients who have achieved LDA with ADA monotherapy  can discontinue the biologic without incurring increased disease activity . A prospect i ve r and omized study is required to confirm the results of our study
BACKGROUND Anti-tumor necrosis factor ( TNF ) agents are effective in treating patients with rheumatoid arthritis ( RA ) , but they are associated with ( dose-dependent ) adverse effects and high costs .
To prevent overtreatment , several trials have assessed the effectiveness of down-titration compared with continuation of the st and ard dose .
OBJECTIVES To evaluate the benefits and harms of down-titration ( dose reduction , discontinuation or disease activity guided dose tapering ) of anti-TNF agents ( adalimumab , certolizumab pegol , etanercept , golimumab , infliximab ) on disease activity , functioning , costs , safety and radiographic damage compared with usual care in patients with RA and low disease activity .