Dose REduction strategy of subcutaneous TNF inhibitors in rheumatoid arthritis: design of a pragmatic randomised non inferiority trial, the DRESS study A tailored approach to reduce dose of anti-TNF drugs may be equally effective, but substantially less costly than standard dosing in patients with ankylosing spondylitis over 1 year: a propensity score-matched cohort study 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 Evaluation of abatacept administered subcutaneously in adults with active rheumatoid arthritis: impact of withdrawal and reintroduction on immunogenicity, efficacy and safety (phase Iiib ALLOW study) Clinical and radiographic outcomes at 2 years and the effect of tocilizumab discontinuation following sustained remission in the second and third year of the ACT-RAY study The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials Biologic-free remission of established rheumatoid arthritis after discontinuation of abatacept: a prospective, multicentre, observational study in Japan Discontinuation of adalimumab after attaining disease activity score 28-erythrocyte sedimentation rate remission in patients with rheumatoid arthritis (HONOR study): an observational study The BeSt way of withdrawing biologic agents. The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and non-randomised studies of health care interventions. Low doses of etanercept can be effective to maintain remission in ankylosing spondylitis patients Prospective evaluation of frequency of signs of systemic sclerosis in 76 patients with morphea. 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 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 Patient-tailored dose reduction of TNF-α blocking agents in ankylosing spondylitis patients with stable low disease activity in daily clinical practice. 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) Prediction of Relapse After Discontinuation of Biologic Agents by Ultrasonographic Assessment in Patients With Rheumatoid Arthritis in Clinical Remission: High Predictive Values of Total Gray‐Scale and Power Doppler Scores That Represent Residual Synovial Inflammation Before Discontinuation 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. Sustained remission with etanercept tapering in early rheumatoid arthritis. Discontinuation of adalimumab treatment in rheumatoid arthritis patients after achieving low disease activity Flares in Rheumatoid Arthritis: Frequency and Management. A Report from the BRASS Registry
Background Preliminary , mostly uncontrolled studies suggest that dose reduction or discontinuation of tumour necrosis factor blockers can be achieved in a relevant proportion of patients with RA without loss of disease control . However , long term safety , cost effectiveness and feasibility in clinical practice remain uncertain . Methods / Design This study is a 18-months pragmatic , non-inferiority , cost minimalisation , r and omized controlled trial on dose reduction and discontinuation of the subcutaneous tumour necrosis factor ( TNF ) blockers adalimumab and etanercept in RA patients with low disease activity . 180 RA patients with low disease activity ( DAS28 < 3.2 or clinical judgment of the rheumatologist ) are r and omized 2:1 to either increased spacing and eventually discontinuation after 6 months of the TNF blocker , and usual care . Implementation is done in routine daily care , using treat to target and feedback implementation in both treatment arms . The primary outcome is non-inferiority ( NI margin 20 % ) in cumulative incidence of persistent ( > 3 months ) RA flare , according to a recently vali date d DAS28 based flare criterion ( DAS28 change > 1.2 , or DAS28 increase of 0.6 and current DAS28 ≥ 3.2 ) . Secondary outcomes include mean disease activity , function , radiographic progression , safety and cost effectiveness . Cost per quality adjusted life year ( QALY ) differences between groups are expressed as a decremental cost effectiveness ratio ( DCER ) , i.e. saved costs divided by ( possible ) loss in QALY . Discussion The design of this study targeted several clinical and method ological issues on TNF blocker dose de-escalation , including how to taper the TNF blockers , the satisfactory control condition , how to define flare , implementation in clinical practice , and the choice of the non-inferiority margin . Pragmatic cost minimalisation studies using non-inferiority design s and DCERs will become more mainstream as cost effectiveness in healthcare gains importance .Trial registration Dutch Trial Register NTR3216 , The study has received ethical review board approval ( number NL37704.091.11 Objective To compare the effectiveness , safety and costs of st and ard versus individually tailored reduced doses of anti-tumour necrosis factor ( TNF ) drugs in patients with ankylosing spondylitis ( AS ) after achieving low-disease activity . Methods This was a single-centre prospect i ve observational study performed within the ATTRA registry . The anti-TNF dose tapering strategy was chosen by treating physicians , without prespecified protocol . We used propensity score ( PS ) methodology to identify two cohorts of patients matched for relevant baseline characteristics who were treated with either reduced ( n=53 ) or st and ard ( n=83 ) doses of TNF inhibitors .  One-year outcomes and costs of anti-TNF drugs  were compared between both PS-matched cohorts . Results In the reduced dosing group , the median dose of TNF inhibitor corresponded to 0.67 and 0.5 of the st and ard dose initially and at 12 months respectively , and 21 % of patients required return to st and ard dosing regimen . The mean change per year in Bath Ankylosing Spondylitis Activity Index , C-reactive protein , Health Assessment Question naire Disability Index and Bath AS functional index , as well as quality -adjusted life-year area under the curve were no different between both groups . The HR ( 95 % CI ) of reduced versus st and ard dosing group for relapse and any adverse event was 1.46 ( 0.66 to 3.19 ) and 0.56 ( 0.22 to 1.44 ) , respectively . Mean difference ( 95 % CI ) in cost of anti-TNF drugs  was € −4214 ( −4707 to −3701 ) per year of treatment in favour of reduced dosing strategy . Conclusions In patients with AS after reaching low-disease activity , a tailored approach to reduce doses of anti-TNF drugs produced similar clinical outcomes at 1 year , but was substantially less costly 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 ) Objectives To assess the effect of a temporary interruption in subcutaneous ( SC ) abatacept on immunogenicity , safety and efficacy in patients with active rheumatoid arthritis despite methotrexate in a phase III trial . Methods Following a 12-week open-label introduction ( period I ; intravenous abatacept loading dose and weekly fixed-dose SC abatacept 125 mg ) , patients were r and omised 2:1 to double-blind SC placebo or SC abatacept for 12 weeks ( period II ) . At the end of period II , patients receiving SC abatacept continued treatment and patients on placebo were reintroduced to SC abatacept ( 12-week open-label period III ) . The co- primary end points were ELISA-detected immunogenicity rate and safety at the end of period II . Efficacy was also monitored . Results Of 167 patients entering period I , 72 % qualified for period II ; during periods II and III , three patients discontinued treatment . Mean ( SD ) disease duration was 6.6 ( 6.5 ) years and Disease Activity Score 28 was 4.8 ( 0.8 ) . The primary end point was met , with a non-significant increase in immunogenicity upon withdrawal ( 7/73 placebo vs 0/38 abatacept in period II ; p=0.119 ) which was reversed upon re introduction of SC abatacept ( 2/73 vs 1/38 , end period III ) . Safety was comparable regardless of withdrawal , with no unexpected events upon re introduction . Two patients experienced reactions at the SC injection site . On withdrawal , patients experienced slight worsening in efficacy which improved following re introduction . Conclusions Overall immunogenicity to SC abatacept is low , consistent with intravenous abatacept , and is not significantly affected by a 3-month interruption and re introduction . This stop – start schedule was well tolerated , with little impact on safety and efficacy . These are important considerations for the clinical use of SC abatacept . Clinical Trials gov Identifier Objective To assess the efficacy and safety of tocilizumab ( TCZ ) plus methotrexate/placebo ( MTX/PBO ) over 2 years and the course of disease activity in patients who discontinued TCZ due to sustained remission . Methods ACT-RAY was a double-blind 3-year trial . Patients with active rheumatoid arthritis despite MTX were r and omised to add  TCZ  to ongoing MTX  ( add-on strategy ) or switch to  TCZ plus PBO  ( switch strategy ) . Using a treat-to-target approach , open-label conventional synthetic disease-modifying antirheumatic drugs ( csDMARDs ) , other than MTX , were added from week 24 if Disease Activity Score in 28 joints based on erythrocyte sedimentation rate ( DAS28-ESR ) > 3.2 . Between weeks 52 and 104 , patients in sustained clinical remission ( DAS28-ESR < 2.6 at two consecutive visits 12 weeks apart ) discontinued TCZ and were assessed every 4 weeks for 1 year . If sustained remission was maintained , added csDMARDs , then MTX/PBO , were discontinued . Results Of the 556 r and omised patients , 76 % completed year 2 . Of patients entering year 2 , 50.4 % discontinued TCZ after achieving sustained remission and 5.9 % achieved drug-free remission . Most patients who discontinued TCZ ( 84.0 % ) had a subsequent flare , but responded well to TCZ re introduction . Despite many patients temporarily stopping TCZ  , radiographic progression was minimal , with differences favouring add-on treatment . Rates of serious adverse events and serious infections per 100 patient-years were 12.2 and 4.4 in add-on and 15.0 and 3.7 in switch patients . In patients with normal baseline values , alanine aminotransferase elevations > 3 × upper limit of normal were more frequent in add-on ( 14.3 % ) versus switch patients ( 5.4 % ) . Conclusions Treat-to-target strategies could be successfully implemented with TCZ to achieve sustained remission , after which TCZ was stopped . Biologic-free remission was maintained for about 3 months , but most patients eventually flared . TCZ restart led to rapid improvement . Trial registration number NCT00810199 Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more Objective . The aim of this study was to determine whether biologic-free remission of RA is possible with discontinuation of abatacept . Methods . Japanese RA patients in 28-joint DAS with CRP ( DAS28-CRP ) remission ( < 2.3 ) after > 2 years of abatacept treatment in a phase II study and its long-term extension entered this 52 week , multicentre , non-blinded , prospect i ve , observational study . At enrolment , the patients were offered the option to continue abatacept or not . The primary endpoint was the proportion of patients who remained biologic-free at 52 weeks after discontinuation . Clinical , functional and structural outcomes were compared between those who continued and those who discontinued abatacept . Results . Of 51 patients enrolled , 34 discontinued and 17 continued abatacept treatment . After 52 weeks , 22 of the 34 patients ( 64.7 % ) remained biologic-free . Compared with the continuation group , the discontinuation group had a similar remission rate ( 41.2 % vs 64.7 % , P = 0.144 ) although they had a significantly higher mean DAS28-CRP score at week 52 ( 2.9 vs 2.0 , P = 0.012 ) . The two groups were also similar with regard to mean HAQ Disability Index ( HAQ-DI ) score ( 0.6 for both , P = 0.920 ) , mean change in total Sharp score ( ΔTSS ; 0.80 vs 0.32 , P = 0.374 ) and proportion of patients in radiographic remission ( ΔTSS ≤ 0.5 ) at the endpoint ( 64.3 % vs 70.6 % , P = 0.752 ) . Those attaining DAS28-CRP < 2.3 or < 2.7 without abatacept at the endpoint had significantly lower HAQ-DI score and /or CRP at enrolment . Non-serious adverse events occurred in three patients who continued or resumed abatacept . Conclusion . Biologic-free remission of RA is possible in some patients after attaining clinical remission with abatacept . Lower baseline HAQ-DI or CRP may predict maintenance of remission or low disease activity after discontinuation of abatacept . Trial registration : UMIN Clinical Trials Registry , http://www.umin.ac.jp/ctr/ ( UMIN000004137 ) Introduction Evidence s of biologics-free disease control after discontinuing adalimumab ( ADA ) in rheumatoid arthritis ( RA ) patients in clinical practice have not been sufficiently investigated . Purpose of this study is to investigate whether disease activity score 28 (DAS28)- erythrocyte sedimentation rate ( ESR ) remission was preserved after discontinuation of ADA in patients with RA . Methods This is an observational but not a r and omized controlled study . Among 197 RA patients who initiated with combination of ADA with concomitant MTX , 69 ( 35 % ) acquired DAS28 ( ESR ) < 2.6 for at least 24 weeks . Of those 69 patients , 51 went on ADA discontinuation with their consent , and finally 50 of those with follow-up of > 24 weeks were evaluated . The effect of discontinuing ADA on clinical disease activity , functional disability and radiographic progression were evaluated by DAS28 ( ESR ) , the clinical disease activity index ( CDAI ) and the simplified disease activity index ( SDAI ) , by a health assessment question naire-disability index ( HAQ-DI ) and by the modified total Sharp score ( mTSS ) , respectively . Results The mean age of the participants was 59.5 years with the mean disease duration of 7.1 years . Out of the 50 patients , 29 ( 58 % ) were maintained in DAS28 ( ESR ) < 2.6 at 24 weeks after discontinuing ADA . A logistic regression analysis showed that DAS28 ( ESR ) at baseline significantly predicted a DAS28 ( ESR ) < 2.6 maintained after discontinuation of ADA , and a receiver-operating characteristic ( ROC ) analysis showed that the cut-off value of DAS28 ( ESR ) at discontinuation was 2.16 . The mean HAQ-DI at six months after discontinuing ADA was 0.1 in patients who kept in DAS28 ( ESR ) < 2.6 , and 94.9 % ( 37/39 ) showed no evidence of radiographic progression ( > 0.5 per year of a change in mTSS ) at 1 year . Conclusions It was possible to maintain DAS28 ( ESR ) < 2.6 after discontinuation of ADA without functional and radiographic progression and very low DAS28 ( ESR ) at the discontinuation was associated with successful ADA-free DAS28 ( ESR ) < 2.6 in patients with RA.Trial registration University Hospital Medical Information Network Identifier : UMIN000006669 OBJECTIVES Treat-to-target strategies in the management of patients with rheumatoid arthritis ( RA ) involve intensifying medication as long as low disease activity or remission is not achieved . Our aim was to discuss reasons and opportunities for tapering and discontinuing medication when the target is achieved , in particular of biological agents . METHODS Data from the Beh and el Strategieën ( BeSt ) study are presented , a multicentre r and omised clinical trial comparing 4 treatment strategies in patients with recent onset active RA ( 1987 criteria ): 1 . Sequential monotherapy , 2 . Step up to combination therapy ( both starting with methotrexate ( MTX ) monotherapy ) , 3 . Initial combination therapy with MTX , sulfasalazine and prednisone and 4 . Initial combination therapy with MTX and infliximab . Treatment adjustments involving dose increases , drug changes or expansion to combination therapy occurred based on three-monthly calculations of the Disease Activity Score ( DAS ) , with a target of ≤2.4 . If this was achieved for 2 consecutive evaluations , treatment was tapered ( combinations to monotherapy , monotherapy to maintenance dose ) . Prednisone and infliximab ( either as part of initial treatment or as delayed treatment after failure on earlier therapies in arms 1 , 2 and -for infliximab- 3 ) were always tapered and discontinued before other drugs . The outcomes of discontinuation of infliximab  are presented . RESULTS 77/120 ( 64 % ) of patients who started initial infliximab were able to discontinue infliximab , whereas 27/109 ( 25 % ) of patients who started delayed infliximab in arms 1 - 3 could discontinue infliximab . Discontinuation was independent of previous dose increases in order to achieve low DAS . After discontinuation of infliximab , 16 of 27 patients ( 59 % ) in arms 1 - 3 and 34 of 77 patients ( 44 % ) in arm 4 suffered a DAS flare > 2.4 and had to restart treatment . Median time without infliximab  treatment was 17 ( IQR 3 - 47 ) months , and 29 of the 61 patients ( 58 % ) who needed to restart had been at least 1 year without infliximab . Restarting infliximab result ed in DAS ≤2.4 in all patients , and there was no progression of radiological damage . Presence of shared epitope , smoking , and a long treatment with infliximab  were independent predictors of infliximab restart . CONCLUSIONS Data on infliximab discontinuation in the BeSt study suggest that this possible in 1 in 4 patients , or more if infliximab was the initial treatment , who have had at least 6 consecutive months of low disease activity . While MTX is continued , about 50 % of patients can permanently stop infliximab without radiological damage progression , the others regain low disease activity after restarting infliximab . Treat to target strategies using biologic agents should include strategies for discontinuation OBJECTIVE : To test the feasibility of creating a valid and reliable checklist with the following features : appropriate for assessing both r and omised and non-r and omised studies ; provision of both an overall score for study quality and a profile of scores not only for the quality of reporting , internal validity ( bias and confounding ) and power , but also for external validity . DESIGN : A pilot version was first developed , based on epidemiological principles , review s , and existing checklists for r and omised studies . Face and content validity were assessed by three experienced review ers and reliability was determined using two raters assessing 10 r and omised and 10 non-r and omised studies . Using different raters , the checklist was revised and tested for internal consistency ( Kuder-Richardson 20 ) , test-retest and inter-rater reliability ( Spearman correlation coefficient and sign rank test ; kappa statistics ) , criterion validity , and respondent burden . MAIN RESULTS : The performance of the checklist improved considerably after revision of a pilot version . The Quality Index had high internal consistency ( KR-20 : 0.89 ) as did the subscales apart from external validity ( KR-20 : 0.54 ) . Test-retest ( r 0.88 ) and inter-rater ( r 0.75 ) reliability of the Quality Index were good . Reliability of the subscales varied from good ( bias ) to poor ( external validity ) . The Quality Index correlated highly with an existing , established instrument for assessing r and omised studies ( r 0.90 ) . There was little difference between its performance with non-r and omised and with r and omised studies . Raters took about 20 minutes to assess each paper ( range 10 to 45 minutes ) . CONCLUSIONS : This study has shown that it is feasible to develop a checklist that can be used to assess the method ological quality not only of r and omised controlled trials but also non-r and omised studies . It has also shown that it is possible to produce a checklist that provides a profile of the paper , alerting review ers to its particular method ological strengths and weaknesses . Further work is required to improve the checklist and the training of raters in the assessment of external validity We wanted to do a prospect i ve open-label study to evaluate if ankylosing spondylitis ( AS ) patients in clinical remission with twice weekly etanercept ( ETN ) 25 mg therapy could be changed to weekly regimen or even to every other week regimen without increased dose for injection . Thirty-eight AS patients self-administered 25 mg of ETN ( Wyett ) subcutaneously . According to the protocol , patients who were in clinical partial remission with twice weekly ETN 25 mg at week 12 and 16 changed to a weekly regimen without a change of the dose . If clinical remission , despite the reduction of the dose , persists at week 24 and 28 , patients changed to an every-other-week regimen , continuing with this administration schedule for the entire duration of the study if at week 36 and 46 clinical remission was maintained . At the end of the study , 18 patients ( 47 % ) were still in remission , 4 ( 10 % ) with a weekly regimen , and 14 ( 37 % ) with an every-other-weekly regimen . Our study indicates that a consistent percentage of subjects with AS , treated with ETN 25 mg twice weekly , achieved clinical remission within the first 3 months of therapy , and also , a substantial percentage of these patients maintains the partial remission with an every other week regimen OBJECTIVES Some authors consider that morphoea and systemic sclerosis ( SSc ) could be part of the same disease spectrum . The aim of this study was to analyse the prevalence of signs indicative of SSc in a cohort of patients with morphoea . METHODS This is a prospect i ve multi-centre study performed in four French academic dermatology departments : 76 patients with morphoea and 101 age- and sex-matched controls , who underwent complete clinical examination , were enrolled . A systemic search for signs indicative of SSc ( e.g. Raynaud 's phenomenon , reflux ) was performed with the help of a st and ardised question naire . RESULTS There were 58 women and 18 men ( ration=3/1 ) with a median age of 59 years . Mean age at diagnosis was 54 years ( extremes , 13 - 87 ) . 49 subjects had plaque morphoea , 9 had generalised morphoea and 18 had linear morphoea . Mean duration of morphoea was 7.9 years . Signs possibly indicative of SSc were noted in four patients of the control group and in 8 patients with morphoea . This difference was not statistically significant ( p=0.129 ) . Further investigations ruled out SSc in all patients . CONCLUSIONS Signs indicative of SSc are statistically not more frequently present in patients with morphoea than in controls and this study does not support the view that those 2 entities are part of a common disease spectrum 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 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 OBJECTIVES Tumour necrosis factor-alpha ( TNF-α ) blocking agents are very effective in controlling systemic inflammation and improving clinical assessment s in ankylosing spondylitis ( AS ) . In view of potential side effects and high costs of long-term treatment , our aim was to investigate whether dose reduction of TNF-α blocking agents is possible without loss of effectiveness in AS patients in daily clinical practice . METHODS Patients from the prospect i ve observational GLAS cohort , fulfilling the modified New York criteria for AS , with active disease before start of TNF-α blocking therapy and stable ( ≥6 months ) low disease activity on the conventional dose regimen , who started with dose reduction of TNF-α blocking therapy before June 2011 were studied . Dose reduction was patient-tailored ( step-by-step approach ) and consisted of lowering the dose and /or extending the interval between doses . RESULTS Between June 2005 and March 2011 , 58 AS patients started dose reduction of etanercept ( n=39 ) ,  infliximab  ( n=10 ) , or adalimumab ( n=9 ) . Of all patients , 74 % , 62 % , and 53 % maintained their reduced dose or dosing frequency after 6 , 12 , and 24 months , respectively . The mean dose  of TNF-α blocking therapy over time corresponded to 62 % of the st and ard dose regimen . Disease activity remained low in the majority of patients who maintained dose reduction after 24 months ( 94 % had BASDAI<4 ) . If there was recurrence of disease symptoms , patients achieved good clinical response after returning to the conventional regimen ( 88 % reached BASDAI<4 ) . CONCLUSIONS In this observational cohort , patient-tailored dose reduction of TNF-α blocking agents  was successful preserving stable low disease activity over 24 months in approximately half of the AS patients 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 This prospect i ve study aim ed to determine whether the comprehensive ultrasonographic assessment of synovial inflammation predicts relapse after discontinuation of treatment with a biologic agent in patients with rheumatoid arthritis ( RA ) in clinical remission 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 BACKGROUND We assessed the effects of reduction and withdrawal of treatment in patients with rheumatoid arthritis who had a remission while receiving etanercept-plus-methotrexate therapy .  METHODS Patients with early active disease who had not previously received methotrexate or biologic therapy received 50 mg of etanercept plus methotrexate weekly for 52 weeks ( open-label phase ) . We then r and omly assigned patients who had qualifying responses at weeks 39 and 52 to receive 25 mg of etanercept plus methotrexate ( combination-therapy group ) , methotrexate alone , or placebo for 39 weeks ( double-blind phase ) . Patients who had qualifying responses at week 39 of the double-blind phase had all treatment withdrawn at that time and were followed to week 65 ( treatment-withdrawal phase ) . The primary end point was the proportion of patients with sustained remission in the double-blind phase . RESULTS Of 306 patients enrolled , 193 underwent r and omization in the double-blind phase ; 131 qualified for the treatment-withdrawal phase . More patients in the combination-therapy group than in the methotrexate-alone group or the placebo group met the criterion for the primary end point ( 40 of 63 [ 63 % ] vs. 26 of 65 [ 40 % ] and 15 of 65 [ 23 % ] , respectively ; P=0.009 for combination therapy vs. methotrexate alone ; P<0.001 for combination therapy vs. placebo ) . At 65 weeks , 28 patients ( 44 % ) who had received combination therapy , 19 ( 29 % ) who had received methotrexate alone , and 15 ( 23 % ) who had received placebo were in remission ( P=0.10 for combination therapy vs. methotrexate alone ; P=0.02 for combination therapy vs. placebo ; P=0.55 for methotrexate alone vs. placebo ) . No significant between-group differences were observed in radiographic progression of disease . Serious adverse events were reported in 3 patients ( 5 % ) in the combination-therapy group , 2 ( 3 % ) in the methotrexate-alone group , and 2 ( 3 % ) in the placebo group . CONCLUSIONS In patients with early rheumatoid arthritis who had a remission while receiving full-dose etanercept-plus-methotrexate therapy , continuing combination therapy at a reduced dose result ed in better disease control than switching to methotrexate alone or placebo , but no significant difference was observed in radiographic progression . ( Funded by Pfizer ; Clinical Trials.gov number , NCT00913458 . ) 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 Objective . To describe the frequency , duration , and management of flares as reported by patients with rheumatoid arthritis ( RA ) . Methods . Data were collected in a prospect i ve observational study of patients with RA recruited from a single academic center and treated according to the rheumatologists ’ discretion . Every 6 months , patients reported the number and duration of RA flares and described how these were managed in terms of adding or changing medication and use of nonpharmacologic strategies . Results . Of patients who reported flares at least once during the study , 74 % reported having flares 6 months prior to study entry and 59 % reported flares prior to the first 6-month visit . At subsequent visits , 54–57 % reported having > 1 flare . Thirty percent of patients in remission reported flares . Flare duration lasted ≥ 2 weeks in 30 % , 1–2 weeks in 13 % , and < 1 week in 57 % . Forty percent reported medication changes at the time of their flare ; 16 % changed medication and used nonpharmacologic strategies and 26 % of patients reported no changes in treatment as a result of flares . Longer duration of flare was associated with changes in disease-modifying therapy . Conclusion . Patients with RA  experienced flares more often when noted to be in higher disease activity states than when in remission and reported changes in disease-modifying antirheumatic drugs or biologics more frequently when flares were of longer duration . There is a need to prospect ively study symptom intensity and duration of flare in relation to disease activity and consider self-management strategies in the development of a measure of flare
Abstract The effectiveness of biologic therapies now means that remission or low disease activity are realistic targets for treatment .
However , after achieving remission/low disease activity , the next steps remain unclear .
The aim of this publication was to conduct a broad systematic literature review to evaluate dosing down of biologics .