Tofacitinib (CP-690,550) in patients with rheumatoid arthritis receiving methotrexate: twelve-month data from a twenty-four-month phase III randomized radiographic study. Methodological aspects and the interpretation of clinical trial data: lessons from the TEAR trial. The safety and efficacy of a JAK inhibitor in patients with active rheumatoid arthritis: Results of a double-blind, placebo-controlled phase IIa trial of three dosage levels of CP-690,550 versus placebo. Low-dose prednisolone in addition to the initial disease-modifying antirheumatic drug in patients with early active rheumatoid arthritis reduces joint destruction and increases the remission rate: a two-year randomized trial. Efficacy of modified-release versus standard prednisone to reduce duration of morning stiffness of the joints in rheumatoid arthritis (CAPRA-1): a double-blind, randomised controlled trial Low-Dose Prednisone Inclusion in a Methotrexate-Based, Tight Control Strategy for Early Rheumatoid Arthritis Drug-free remission, functioning and radiographic damage after 4 years of response-driven treatment in patients with recent-onset rheumatoid arthritis Are changes in bone mineral density different between groups of early rheumatoid arthritis patients treated according to a tight control strategy with or without prednisone if osteoporosis prophylaxis is applied? A randomized, double-blind, parallel, single-site pilot trial to compare two different starting doses of methotrexate in methotrexate-naïve adult patients with rheumatoid arthritis. Early combination disease-modifying antirheumatic drug therapy and tight disease control improve long-term radiologic outcome in patients with early rheumatoid arthritis: the 11-year results of the Finnish Rheumatoid Arthritis Combination Therapy trial Induction therapy with a combination of DMARDs is better than methotrexate monotherapy: first results of the tREACH trial Remission induction therapy with methotrexate and prednisone in patients with early rheumatoid and undifferentiated arthritis (the IMPROVED study) Phase II study of tofacitinib (CP‐690,550) combined with methotrexate in patients with rheumatoid arthritis and an inadequate response to methotrexate The impact of four dynamic, goal-steered treatment strategies on the 5-year outcomes of rheumatoid arthritis patients in the BeSt study Very low-dose prednisolone in early rheumatoid arthritis retards radiographic progression over two years: a multicenter, double-blind, placebo-controlled trial. Phase IIb dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) or adalimumab monotherapy versus placebo in patients with active rheumatoid arthritis with an inadequate response to disease-modifying antirheumatic drugs. A comparative study of the effects of bucillamine and salazosulfapyridine in the treatment of rheumatoid arthritis The Stop Arthritis Very Early (SAVE) trial, an international multicentre, randomised, double-blind, placebo-controlled trial on glucocorticoids in very early arthritis A phase IIb dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) versus placebo in combination with background methotrexate in patients with active rheumatoid arthritis and an inadequate response to methotrexate alone. Leflunomide or methotrexate? Comparison of clinical efficacy and safety in low socio-economic rheumatoid arthritis patients In early rheumatoid arthritis, patients with a good initial response to methotrexate have excellent 2-year clinical outcomes, but radiological progression is not fully prevented: data from the methotrexate responders population in the SWEFOT trial Low-Dose Prednisone Therapy for Patients with Early Active Rheumatoid Arthritis: Clinical Efficacy, Disease-Modifying Properties, and Side Effects: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial Tofacitinib or adalimumab versus placebo in rheumatoid arthritis. Tofacitinib (CP-690,550) in combination with methotrexate in patients with active rheumatoid arthritis with an inadequate response to tumour necrosis factor inhibitors: a randomised phase 3 trial Treatment of rheumatoid arthritis with methotrexate and hydroxychloroquine, methotrexate and sulfasalazine, or a combination of the three medications: results of a two-year, randomized, double-blind, placebo-controlled trial. A randomized comparative effectiveness study of oral triple therapy versus etanercept plus methotrexate in early aggressive rheumatoid arthritis: the treatment of Early Aggressive Rheumatoid Arthritis Trial. Treatment of rheumatoid arthritis with methotrexate alone, sulfasalazine and hydroxychloroquine, or a combination of all three medications. Early disease control by low-dose prednisone comedication may affect the quality of remission in patients with early rheumatoid arthritis. The effect of glucocorticoids on joint destruction in rheumatoid arthritis. The Arthritis and Rheumatism Council Low-Dose Glucocorticoid Study Group. Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis. Methotrexate therapy in rheumatoid arthritis after failure to sulphasalazine: to switch or to add?
OBJECTIVE The purpose of this 24-month phase III study was to examine structural preservation with tofacitinib in patients with rheumatoid arthritis ( RA ) with an inadequate response to methotrexate ( MTX ) .  Data from a planned 12-month interim analysis are reported . METHODS In this double-blind , parallel-group , placebo-controlled study , patients receiving background MTX  were r and omized 4:4:1:1 to tofacitinib at 5 mg twice daily , tofacitinib at 10 mg twice daily , placebo to tofacitinib at 5 mg twice daily , and placebo to tofacitinib at 10 mg twice daily . At month 3 , nonresponder placebo-treated patients were advanced in a blinded manner to receive tofacitinib as indicated above ; remaining placebo-treated patients were advanced at 6 months . Four primary efficacy end points were all analyzed in a step-down procedure . RESULTS At month 6 , response rates according to the American College of Rheumatology 20 % improvement criteria for tofacitinib at 5 mg and 10 mg twice daily were higher than those for placebo ( 51.5 % and 61.8 % , respectively , versus 25.3 % ; both P < 0.0001 ) . At month 6 , least squares mean ( LSM ) changes in total modified Sharp/van der Heijde score for tofacitinib at 5 mg and 10 mg twice daily were 0.12 and 0.06 , respectively , versus 0.47 for placebo ( P = 0.0792 and P ≤ 0.05 , respectively ) . At month 3 , LSM changes in the Health Assessment Question naire disability index score for tofacitinib at 5 mg and 10 mg twice daily were -0.40 ( significance not declared due to step-down procedure ) and -0.54 ( P < 0.0001 ) , respectively , versus -0.15 for placebo . At month 6 , rates of remission ( defined as a value < 2.6 for the 4-variable Disease Activity Score in 28 joints using the erythrocyte sedimentation rate ) for tofacitinib at 5 mg and 10 mg twice daily were 7.2 % ( significance not declared due to step-down procedure ) and 16.0 % ( P < 0.0001 ) , respectively , versus 1.6 % for placebo . The safety profile was consistent with findings in previous studies . CONCLUSION Data from this 12-month interim analysis demonstrate that tofacitinib inhibits progression of structural damage and improves disease activity in patients with RA who are receiving MTX The approach to treatment of RA has evolved substantially in recent years with the introduction of highly effective novel therapies that have result ed in new treatment paradigms , such as treat-to-target and the treatment of patients earlier in their disease course [ 1 , 2 ] . Clinicians are very interested in studies that compare the effectiveness of medications that could help them achieve optimal treatment outcomes for their patients . Extrapolation of the results of such studies into clinical practice depends on accurate assessment of data from the clinical trials . This assessment has become increasingly challenging as study design s have become increasingly complex , with multiple arms and changes in treatments over the course of a trial . There are many methods to analyse a given set of data ; with the same data set , depending on the method of analysis , different conclusions can be reached . To help st and ardize this process , a European League Against Rheumatism (EULAR)/ACR committee created guidelines on reporting data from clinical trials [ 3 ] . The complexities of this analysis are illustrated by a recent example . The R and omized Comparative Effectiveness Study of Oral Triple Therapy versus Etanercept plus Methotrexate in the Early , Aggressive Rheumatoid Arthritis ( TEAR ) trial was design ed to address two important clinical questions : ( i ) is it better to intensively treat all early RA patients with multiple DMARDs  , or reserve this treatment only for those who do not appropriately respond to MTX monotherapy ? and ( ii ) is the combination therapy of MTX plus etanercept ( ETN ) superior to triple combination therapy of MTX , SSZ and HCQ ( TT ) , either initially or after insufficient efficacy of MTX at 6 months ? [ 4 ] . Patients with early RA were r and omly assigned to receive MTX monotherapy , MTX plus ETN or TT . At 6 months , patients treated with MTX monotherapy who did not achieve DAS28 < 3.2 were stepped up to add either ETN or move to TT and treated for 102 weeks . The primary outcome , by the protocol , was the area under the curve ( AUC ) of DAS28 from weeks 48 to 102 . Although many of the items suggested by a joint EULAR/ACR committee on reporting disease activity in clinical trials of patients [ 3 ] were reported , several facets of the methods of data analysis need to be fully understood in order to establish whether the reader concurs with the authors ’ conclusions that this study showed no difference in clinical outcomes at 2 years between patients initially treated with MTX plus ETN or TT . The data reported were an observed analysis only for patients who continued in the trial from week 48 to 102 patients had to have done well clinical ly and not had a significant adverse event to remain in the study through week 48 . A more traditional statistical analysis , such as a nonresponder imputation or last observation carried forward from day 0 to week 102 might have given different results . The first question posed , whether it is more effective to start either combination or MTX monotherapy , was not answered ; the results are not presented for those patients initially treated with MTX  who achieved DAS28 < 3.2 at week 26 and then continued to week 102 . The primary outcome reported in the manuscript was an observed group analysis of change in the mean DAS28-ESR from week 48 to 102 and not the AUC of the DAS28 during this time period . The authors stated that their statistical analysis plan was confirmed by their secondary analyses , which did include non-responder imputation and last observation carried forward . However , these analyses were also performed only on patients in the study from week 48 to 102 . In addition to design and statistical considerations , some of the data can be interpreted differently from the authors , and this might be worth some further examination . For instance , the authors reported that there was no difference in the change in DAS28 , or other clinical measures , between the patient groups studied . However , there was a treatment difference at week 102 between the ETN and TT groups for ACR70 ( 18.2 vs 11.3 % , P = 0.02 ) . This would suggest that ETN plus MTX was more effective in achieving a profound response . This difference in profound response may have led to the significant difference in radiographic progression reported with ETN and MTX treatment vs TT at week 102 . The radiographic difference was noted despite the fact that X-rays were not done in patients who withdrew early ; in other studies , results at the time of exit have been extrapolated to the final endpoint to allow comparison . In this case , radiological data are only in those observed or study completers ; by definition , such patients usually fare quite well and patients who do well have less progression of joint damage . Initial TT and initial MTX monotherapy with step-up had similar ACR20/50/70 response rates at 2 years , OBJECTIVE To determine the efficacy , safety , and tolerability of 3 different dosages of CP-690,550 , a potent , orally active JAK inhibitor , in patients with active rheumatoid arthritis ( RA ) in whom methotrexate , etanercept , infliximab , or adalimumab caused an inadequate or toxic response . METHODS Patients ( n = 264 ) were r and omized equally to receive placebo , 5 mg of CP-690,550 , 15 mg of CP-690,550 , or 30 mg of CP-690,550 twice daily for 6 weeks , and were followed up for an additional 6 weeks after treatment . The primary efficacy end point was the American College of Rheumatology 20 % improvement criteria ( ACR20 ) response rate at 6 weeks . RESULTS By week 6 , the ACR20 response rates were 70.5 % , 81.2 % , and 76.8 % in the 5 mg , 15 mg , and 30 mg twice daily groups , respectively , compared with 29.2 % in the placebo group ( P < 0.001 ) . Improvements in disease activity in CP-690,550-treated patients compared with placebo were seen in all treatment groups as early as week 1 . ACR50 and ACR70 response rates significantly improved in all treatment groups by week 4 . The most common adverse events reported were headache and nausea . The infection rate in both the 15 mg twice daily group and the 30 mg twice daily group was 30.4 % ( versus 26.2 % in the placebo group ) . No opportunistic infections or deaths occurred . Increases in mean low-density lipoprotein cholesterol and high-density lipoprotein cholesterol levels , and increases in mean serum creatinine level ( 0.04 - 0.06 mg/dl ) were seen in all CP-690,550 treatment arms . CONCLUSION Our findings indicate that CP-690,550 is efficacious in the treatment of RA , result ing in rapid , statistically significant , and clinical ly meaningful reductions in the signs and symptoms of RA . Further studies of CP-690,550 in RA are warranted OBJECTIVE To assess the efficacy of low-dose prednisolone on joint damage and disease activity in patients with early rheumatoid arthritis ( RA ) . METHODS At the start of their initial treatment with a disease-modifying antirheumatic drug ( DMARD ) , patients with early ( duration < or = 1 year ) active RA were r and omly assigned to receive either 7.5 mg/day prednisolone or no prednisolone for 2 years . Radiographs of the h and s and feet were obtained at baseline and after 1 and 2 years and scored according to the Sharp score as modified by van der Heijde . Remission was defined as a Disease Activity Score in 28 joints of < 2.6 . Bone mineral density was measured by dual x-ray absorptiometry at baseline and after 2 years . RESULTS Of the 250 patients included , 242 completed the study and 225 had radiographs available both at baseline and at 2 years . At 2 years , the median and interquartile range ( IQR ) change in total Sharp score was lower in the prednisolone group than in the no-prednisolone group ( 1.8 [ IQR 0.5 - 6.0 ] versus 3.5 [ IQR 0.5 - 10 ] ; P = 0.019 ) . In the prednisolone group , there were fewer newly eroded joints per patient after 2 years ( median 0.5 [ IQR 0 - 2 ] versus 1.25 [ IQR 0 - 3.25 ] ; P = 0.007 ) . In the prednisolone group , 25.9 % of patients had radiographic progression beyond the smallest detectable difference compared with 39.3 % of patients in the no-prednisolone group ( P = 0.033 ) . At 2 years , 55.5 % of patients in the prednisolone group had achieved disease remission , compared with 32.8 % of patients in the no-prednisolone group ( P = 0.0005 ) . There were few adverse events that led to withdrawal . Bone loss during the 2-year study was similar in the 2 treatment groups . CONCLUSION Prednisolone at 7.5 mg/day added to the initial DMARD retarded the progression of radiographic damage after 2 years in patients with early RA , provided a high remission rate , and was well tolerated . Therefore , the data support the use of low-dose prednisolone as an adjunct to DMARDs in early active RA BACKGROUND Circadian rhythms are changed in patients with rheumatoid arthritis . A new modified-release delivery system has been developed which adapts the release of the administered glucocorticoid to the circadian rhythms of endogenous cortisol and disease symptoms to improve the benefit-risk ratio of glucocorticoid therapy in rheumatoid arthritis . We aim ed to assess the efficacy and safety of a new modified-release prednisone tablet compared with immediate-release prednisone in patients with this disease . METHODS In a 12-week , multicentre , r and omised , double-blind trial , 288 patients with active rheumatoid arthritis were r and omly assigned to either a modified-release prednisone tablet ( n=144 ) or to an immediate-release prednisone tablet ( n=144 ) . The modified-release tablet was taken at bedtime and prednisone was released with a delay of 4 h after ingestion . This treatment was compared with morning administration of immediate-release prednisone as an active comparator . The primary outcome measure was duration of morning stiffness of the joints . Analysis was by intention to treat . This trial is registered with Clinical Trials.gov , number NCT00146640 . FINDINGS The mean relative change in duration of morning stiffness of the joints from baseline to end of treatment was significantly higher with modified-release prednisone than with immediate-release prednisone ( -22.7%vs -0.4 % ; difference=22.4 % [ 95 % CI 0.49 - 44.30 ] ; p=0.045 ) . Patients in the prednisone modified-release group achieved a mean reduction of 44.0 ( SD 136.6 ) min compared with baseline . The absolute difference between the treatment groups was 29.2 min ( 95 % CI -2.59 to 61.9 ) in favour of modified-release prednisone ( p=0.072 ) . The safety profile did not differ between treatments . INTERPRETATION Modified-release prednisone is well tolerated , convenient to administer , and produces a clinical ly relevant reduction of morning stiffness of the joints in addition to all known therapeutic effects of immediate-release prednisone BACKGROUND Treatment strategies for tight control of early rheumatoid arthritis ( RA ) are highly effective but can be improved . OBJECTIVE To investigate whether adding prednisone , 10 mg/d , at the start of a methotrexate (MTX)-based treatment strategy for tight control in early RA increases its effectiveness . DESIGN A 2-year , prospect i ve , r and omized , placebo-controlled , double-blind , multicenter trial ( CAMERA-II [ Computer Assisted Management in Early Rheumatoid Arthritis trial-II ] ) . ( International St and ard R and omised Controlled Trial Number : IS RCT N 70365169 ) SETTING 7 hospitals in the Netherl and s. PATIENTS 236 patients with early RA ( duration < 1 year ) . INTERVENTION Patients were r and omly assigned to an MTX-based , tight control strategy starting with either MTX and prednisone or MTX and placebo . Methotrexate treatment was tailored to the individual patient at monthly visits on the basis of predefined response criteria aim ing for remission . MEASUREMENTS The primary outcome was radiographic erosive joint damage after 2 years . Secondary outcomes included response criteria , remission , and the need to add cyclosporine or a biologic agent to the treatment . RESULTS Erosive joint damage after 2 years was limited and less in the group receiving MTX and prednisone ( n = 117 ) than in the group receiving MTX and placebo ( n = 119 ) . The MTX and prednisone strategy was also more effective in reducing disease activity and physical disability , achieving sustained remission , and avoiding the addition of cyclosporine or biologic treatment . Adverse events were similar in both groups , but some occurred less in the MTX and prednisone group . LIMITATION A tight control strategy for RA implies monthly visits to an outpatient clinic , which is not always feasible . CONCLUSION Inclusion of low-dose prednisone in an MTX-based treatment strategy for tight control in early RA improves patient outcomes . PRIMARY FUNDING SOURCE Catharijne Foundation 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 Summary Addition of 10 mg prednisone daily to a methotrexate-based tight control strategy does not lead to bone loss in early rheumatoid arthritis ( RA ) patients receiving preventive treatment for osteoporosis . A small increase in lumbar bone mineral density ( BMD ) during the first year of treatment was recorded , regardless of use of glucocorticoids . Introduction This study aims to describe effects on BMD of treatment according to EULAR guidelines with a methotrexate-based tight control strategy including 10 mg prednisone daily versus the same strategy without prednisone in early RA patients who received preventive therapy for osteoporosis . Methods Early RA patients were included in the CAMERA-II trial : a r and omized , placebo-controlled , double-blind 2-year trial , in which effects of addition of 10 mg prednisone daily to a methotrexate-based tight control strategy were studied . All patients received calcium , vitamin D and bisphosphonates . Disease activity was assessed every 4 weeks . Radiographs of h and s and feet and dual-energy X-ray absorptiometry of lumbar spine and left hip were performed at baseline and after 1 and 2 years of treatment . Results BMD increased significantly over time in both treatment groups at the lumbar spine with a mean of 2.6 % during the first year ( p < 0.001 ) , but not at the hip ; at none of the time points did BMD differ significantly between the prednisone and placebo group . Higher age and lower weight at baseline and higher disease activity scores during the trial , but not glucocorticoid therapy , were associated with lower BMD at both the lumbar spine and the hip in mixed-model analyses . Conclusion Addition of 10 mg prednisone daily to a methotrexate-based tight control strategy does not lead to bone loss in early RA patients on bisphosphonates . A small increase in lumbar BMD during the first year of treatment was found , regardless of use of glucocorticoids BACKGROUND Methotrexate ( MTX ) is a cornerstone in the treatment of rheumatoid arthritis . Despite its widespread use , expert opinions differ about the optimal MTX starting dosage to achieve rapid onset of action while averting increased occurrence of adverse effects . Plasma concentrations have not been assessed in previous studies that monitored clinical efficacy . OBJECTIVE This study was performed to compare the pharmacokinetic parameters and clinical response of a st and ard ( 15 mg ) and an accelerated ( 25 mg ) dosing regimen , each administered orally once a week . METHODS This r and omized , controlled , double-blind , parallel , single-site study included 19 MTX-naïve patients older than 18 years with rheumatoid arthritis . Patients participated for 16 weeks . Disease activity was assessed using the Disease Activity Score in 28 joints ( DAS-28 ) as the primary outcome parameter . Plasma MTX concentrations were measured using HPLC at weeks 1 , 5 , 10 , and 16 . Tolerability was assessed via routine blood analysis ( hematology and clinical chemistry ) and a patient question naire to monitor adverse events . Reported or observed adverse events were recorded along with information about their severity and causal relationship to the study medication . RESULTS Nineteen white patients ( 13 women and 6 men ; mean age , 56 years ; and mean weight , 74 kg ) participated . At study entry , mean ( SD ) DAS-28 - 4v ( erythrocyte sedimentation rate ) was 4.73 ( 1.02 ) . Health Assessment Question naire scores were 1.45 ( 0.85 ) ; for C-reactive protein , 11.45 ( 10.04 ) mg/dL ; for alkaline phosphatase , 73.58 ( 19.91 ) U/L ; for aspartate aminotransferase , 23.32 ( 7.13 ) U/L ; and for creatinine , 0.87 ( 0.22 ) mg/dL. Although pharmacokinetic parameters such as AUC and C(max ) were significantly higher after the accelerated dosing regimen , clinical activity scores ( DAS-28 ) and inflammation parameters ( C-reactive protein ) did not indicate a significant benefit of an accelerated starting regimen . Considering toxicity , no elevation in liver function enzymes and no decrease in renal function were observed using the accelerated dosing ( statistical significance set at P ≤ 0.05 ) . No serious adverse events were noted . All observed adverse events were classified as study related . Overall , adverse events were noted in 58 % of patients . Comparison of the two doses revealed that 60 % of patients receiving the st and ard dosing regimen and 56 % of patients receiving the accelerated dosing regimen reported adverse events , the most frequent being gastrointestinal . These events were generally self-limiting . CONCLUSIONS Differences in clinical response between these two small selected patient groups who received an initial oral dose of either 15 or 25 mg MTX per week did not reach the level of statistical significance . The overall incidence of adverse effects , all classified as study related , was 58 % , with 60 % of patients receiving the st and ard dosage and 56 % of patients receiving the accelerated dosing regimen reporting adverse effects . However , because of the small sample size , this study was not powered to detect differences in the incidence of adverse events between the two dosing groups . Clinical Trials.gov identifier : NCT00695188 Introduction Early treatment of rheumatoid arthritis ( RA ) has been shown to retard the development of joint damage for a period of up to 5 years . The aim of this study was to evaluate the radiologic progression beyond that time in patients with early RA initially treated with a combination of three disease-modifying antirheumatic drugs ( DMARDs ) or a single DMARD .  Methods A cohort of 199 patients with early active RA were initially r and omized to receive treatment with a combination of methotrexate , sulfasalazine , and hydroxychloroquine with prednisolone ( FIN-RACo ) , or treatment with a single DMARD ( initially , sulfasalazine ) with or without prednisolone ( SINGLE ) . After 2 years , the drug-treatment strategy became unrestricted , but still targeted remission . The radiographs of h and s and feet were analyzed by using the Larsen score at baseline , 2 , 5 , and 11 years , and the radiographs of large joints , at 11 years . Results Sixty-five patients in the FIN-RACo and 65 in the SINGLE group had radiographs of h and s and feet available at baseline and at 11 years . The mean change from baseline to 11 years in Larsen score was 17 ( 95 % CI , 12 to 26 ) in the FIN-RACo group and 27 ( 95 % CI , 22 to 33 ) in the SINGLE group ( P = 0.037 ) . In total , 87 % ( 95 % CI , 74 to 94 ) and 72 % ( 95 % CI , 58 to 84 ) of the patients in the FIN-RACo and the SINGLE treatment arms , respectively , had no erosive changes in large joints at 11 years . Conclusions Targeting to remission with tight clinical controls results in low radiologic progression in most RA patients . Patients treated initially with a combination of DMARDs have less long-term radiologic damage than do those treated initially with DMARD monotherapy . Trial registration Current Controlled Trials IS RCT N18445519 Objective To determine the most effective induction disease-modifying antirheumatic drug ( DMARD ) strategy in early rheumatoid arthritis ( RA ) , second to compare one single dose of intramuscular glucocorticoids ( GCs ) with daily oral GCs during the induction phase . Methods The 3-month data of a single-blinded clinical trial in patients with recent-onset arthritis ( tREACH ) were used . Patients were included who had a high probability ( > 70 % ) of progressing to persistent arthritis , based on the prediction model of Visser . Patients were r and omised into three induction therapy strategies : ( A ) combination therapy ( methotrexate ( MTX ) + sulfasalazine + hydroxychloroquine ) with GCs intramuscularly ; ( B ) combination therapy with an oral GC tapering scheme and ( C ) MTX with oral GCs similar to B. A total of 281 patients were r and omly assigned to strategy ( A ) ( n=91 ) , ( B ) ( n=93 ) or ( C ) ( n=97 ) . Results The Disease Activity Score ( DAS ) after 3 months was lower in patients receiving initial combination therapy than in those receiving MTX monotherapy ( 0.39 ( 0.67 to 0.11 , 95 % CI ) ) . DAS did not differ between the different GC bridging treatments . After 3 months 50 % fewer biological agents were prescribed in the combination therapy groups . Although the proportion of patients with medication adjustments differed significantly between the treatment arms , no differences were seen in these adjustments due to adverse events after stratification for drug . Conclusion Triple DMARD induction therapy is better than MTX monotherapy in early RA . Furthermore , no differences were seen in medication adjustments due to adverse events after stratification for drug . Intramuscular and oral GCs are equally effective as bridging treatments and both can be used Aim Classifying more patients as rheumatoid arthritis ( RA ) ( 2010 American College of Rheumatology/European League Against Rheumatism criteria for RA ) may improve treatment outcomes but may cause overtreatment in daily practice . The authors determined the efficacy of initial methotrexate ( MTX ) plus prednisone treatment in patients with 1987 or 2010 classified RA and undifferentiated arthritis ( UA ) . Method 610 recent onset RA or UA patients started with MTX 25 mg/week and prednisone 60 mg/day tapered to 7.5 mg/day in 7 weeks .  Percentage remissions after 4 months were compared between RA ( 1987 or 2010 criteria ) and UA . Predictors for remission were identified . Results With the 2010 criteria , 19 % more patients were classified as RA than with the 1987 criteria , but similar remission rates were achieved : 291/479 ( 61 % ) 2010 classified RA and 211/264 ( 58 % ) 1987 classified RA patients ( p=0.52 ) , and 79/122 ( 65 % ) UA patients ( p=0.46 ) . Anticitrullinated protein antibodies ( ACPA ) positive RA patients achieved more remission ( 66 % ) than ACPA negative RA patients ( 51 % , p=0.001 ) , but also had a lower mean baseline Disease Activity Score ( DAS ) ( 3.2 vs 3.6 , p<0.001 ) . Independent predictors for remission were male sex , low joint counts , DAS and Health Assessment Question naire , low body mass index and ACPA positivity . Conclusion Initial treatment with MTX and a tapered high dose of prednisone results in similarly high remission percentages after 4 months ( about 60 % ) in RA patients , regardless of fulfilling the 1987 or 2010 criteria , and in UA patients . Independent predictors indicate that initiating treatment while disease activity is relatively low results in more remission To compare the efficacy , safety , and tolerability of 4 doses of oral tofacitinib ( CP‐690,550 ) with placebo in Japanese patients with active rheumatoid arthritis ( RA ) receiving stable background methotrexate ( MTX ) who had an inadequate response to MTX alone Objective To compare clinical and radiological outcomes of four dynamic treatment strategies in recent-onset rheumatoid arthritis ( RA ) after 5 years follow-up . Methods 508 patients with recent-onset RA were r and omly assigned into four treatment strategies : sequential monotherapy ; step-up combination therapy ; initial combination with prednisone ; initial combination with infliximab . Treatment adjustments were made based on 3-monthly disease activity score ( DAS ) measurements ( if DAS > 2.4 next treatment step ; if DAS ≤2.4 during ≥6 months taper to maintenance dose ; if DAS < 1.6 during ≥6 months stop antirheumatic treatment ) . Primary and secondary outcomes were functional ability , joint damage progression , health-related quality of life and ( drug-free ) remission percentages . Results After 5 years , 48 % of patients were in clinical remission ( DAS < 1.6 ) and 14 % in drug-free remission , irrespective of initial treatment . After an earlier improvement in functional ability and quality of life with initial combination therapy , from 1 year onwards clinical outcomes were comparable across the groups and stable during 5 years . The initial combination groups showed less joint damage in year 1 . In years 2–5 annual progression was comparable across the groups . After 5 years , initial combination therapy result ed in significantly less joint damage progression , reflecting the earlier clinical response . Conclusion Irrespective of initial treatment , an impressive improvement in clinical and radiological outcomes of RA patients can be achieved with dynamic treatment aim ed at reducing disease activity , leading to 48 % remission , 14 % drug-free remission and sustained functional improvement . Starting with combination therapy result ed in earlier clinical improvement and less joint damage without more toxicity OBJECTIVE To assess the effect of 5 mg/day prednisolone on disease progression in patients with early rheumatoid arthritis ( RA ) receiving st and ardized disease-modifying antirheumatic drug ( DMARD ) therapy .  METHODS Patients with active RA of < 2 years ' duration were r and omly assigned in a double-blinded manner to receive prednisolone or placebo while starting concomitant DMARD therapy ( gold sodium thiomalate or methotrexate ) . H and and foot radiographs were taken at baseline and at 6 , 12 , and 24 months and were evaluated according to the Ratingen score and the total modified Sharp/van der Heijde score ( SHS ) . RESULTS Of 192 included patients , 166 were available for the intent-to-treat analysis ( ITT ) . Seventy-six patients completed the study per protocol ( PP ) . Radiographic progression ( increase in the Ratingen score ) was significantly less with prednisolone than with placebo . The difference in the progression rate between the groups was greatest in the first 6 months . At 24 months in the ITT population , the least squares ( LS ) mean difference was 3.14 ( 95 % confidence interval [ 95 % CI ] 0.94 , 5.34 ) , P = 0.006 . The results were confirmed by the total SHS in the ITT population ( LS mean difference 7.20 [ 95 % CI 0.93 , 13.47 ] , P = 0.022 ) and with the PP population . Clinical and functional outcomes tended to be better and the rate of remissions was higher in the prednisolone group . Side effects were observed more frequently in the prednisolone group than in the control group : weight gain ( 4 versus 0 patients ) , hypertension ( 6 versus 2 patients ) , glaucoma ( 3 versus 0 patients ) , Cushing 's syndrome ( 5 versus 0 patients ) , gastric distress ( 9 versus 4 patients ) , and gastric ulcers ( only with concomitant nonsteroidal antiinflammatory drug therapy ; 3 versus 0 patients ) . No new lumbar fractures were found in either group . CONCLUSION The very low daily dose of 5 mg prednisolone given over 2 years in combination with background DMARD therapy substantially decreased radiographic progression in early RA at low risk OBJECTIVE To compare the efficacy , safety , and tolerability of 5 doses of oral tofacitinib ( CP-690,550 ) or adalimumab monotherapy with placebo for the treatment of active rheumatoid arthritis ( RA ) in patients with an inadequate response to disease-modifying antirheumatic drugs . METHODS In this 24-week , double-blind , phase IIb study , patients with RA ( n = 384 ) were r and omized to receive placebo , tofacitinib at 1 , 3 , 5 , 10 , or 15 mg administered orally twice a day , or adalimumab at 40 mg injected subcutaneously every 2 weeks ( total of 6 injections ) followed by oral tofacitinib at 5 mg twice a day for 12 weeks . The primary end point was the responder rate according to the American College of Rheumatology 20 % improvement criteria ( ACR20 ) at week 12 . RESULTS Treatment with tofacitinib at a dose of ≥3 mg twice a day result ed in a rapid response with significant efficacy when compared to placebo , as indicated by the primary end point ( ACR20 response at week 12 ) , achieved in 39.2 % ( 3 mg ; P ≤ 0.05 ) , 59.2 % ( 5 mg ; P < 0.0001 ) , 70.5 % ( 10 mg ; P < 0.0001 ) , and 71.9 % ( 15 mg ; P < 0.0001 ) in the tofacitinib group and 35.9 % of patients in the adalimumab group ( P = 0.105 ) , compared with 22.0 % of patients receiving placebo . Improvements were sustained at week 24 , according to the ACR20 , ACR50 , and ACR70 response rates as well as classifications of remission according to the 3-variable Disease Activity Score in 28 joints ( DAS28 ) using C-reactive protein and the 4-variable DAS28 using the erythrocyte sedimentation rate . The most common treatment-emergent adverse events ( AEs ) in patients across all tofacitinib treatment arms ( n = 272 ) were urinary tract infection ( 7.7 % ) , diarrhea ( 4.8 % ) , headache ( 4.8 % ) , and bronchitis ( 4.8 % ) . CONCLUSION Tofacitinib monotherapy at ≥3 mg twice a day was efficacious in the treatment of patients with active RA over 24 weeks and demonstrated a manageable safety profile Bucillamine ( Buc ) , developed in Japan , is a disease-modifying antirheumatic drug ( DMARD ) which has been used to treat numerous patients with rheumatoid arthritis ( RA ) in Japan and Korea with favorable results . However , it has not been used globally . In the present study , we compared the timing of onset of efficacy and the usefulness of this drug with that of the globally accepted agent salazosulfapyridine ( SASP ) . There were 26 patients in the Buc group and 23 in the SASP group . We compared changes in the number of swollen joints , number of painful joints , duration of morning stiffness , grip strength , levels of inflammatory marker [ erythrocyte sedimentation rate ( ESR ) and C-reactive protein ( CRP ) ] , rheumatoid factor ( RF ) , physician ’s rating by visual analogue scale ( VAS ) , patient ’s rating of pain , patient ’s overall rating ( VAS ) , and improvement according to European League against Rheumatism ( EULAR ) criteria ( DAS28-CRP , DAS28-ESR ) in these two groups of patients . Both Buc and SASP were shown to be efficacious within 3 months after the start of treatment . Both drugs were found to be suitable as first-line treatment of early RA . Signs of efficacy tended to occur earlier with Buc than with SASP , and Buc also tended to have higher efficacy than SASP Background Glucocorticoids ( GCs ) are often used as early arthritis treatment and it has been suggested that they induce remission or at least delay the development of rheumatoid arthritis ( RA ) and the need to start disease-modifying antirheumatic drugs ( DMARDs ) . Objective To test the effect of GCs on patients with very early arthritis ( symptom duration of < 16 weeks ) in a r and omised controlled trial . Methods Patients received a single intramuscular injection of 120 mg methylprednisolone or placebo ( PL ) and were followed up for 52 weeks . Primary end point was drug-free clinical remission , both at weeks 12 and 52 . Among secondary outcomes were fulfilment of remission criteria at weeks 2 , 12 or 52 , time course of ‘ core set variables ’ and proportion of patients starting DMARDs .  Results 17.0 % of all analysed subjects ( 65/383 ) achieved persistent remission : 17.8 % ( 33/185 ) of the PL group , 16.2 % ( 32/198 ) of the patients receiving methylprednisolone ( OR=1.13 , 95 % CI 0.66 to 1.92 , p=0.6847 ) . Analyses of secondary end points showed significant clinical benefits of the GC only at week 2 . These differences subsequently disappeared . DMARDs were started in 162 patients : 50.3 % methylprednisolone and 56.7 % PL patients had to start DMARD treatment ( OR=0.78 , 95 % CI 0.49 to 1.22 , p=0.30 ) . Significantly more patients with polyarthritis than with oligoarthritis received  DMARDs  ( OR=2.84 , 95 % CI 1.75 to 4.60 , p<0.0001 ) . Conclusions Neither remission nor development of RA is delayed by GC treatment . Remission is rare in the first year of very early arthritis , occurring in < 20 % of the patients . Also , the need to start DMARDs was not influenced by GC treatment OBJECTIVE To compare the efficacy , safety , and tolerability of 6 dosages of oral tofacitinib ( CP-690,550 ) with placebo for the treatment of active rheumatoid arthritis ( RA ) in patients receiving a stable background regimen of methotrexate ( MTX ) who have an inadequate response to MTX monotherapy . METHODS In this 24-week , double-blind , phase IIb study , patients with active RA ( n = 507 ) were r and omized to receive placebo or tofacitinib ( 20 mg/day , 1 mg twice daily , 3 mg twice daily , 5 mg twice daily , 10 mg twice daily , or 15 mg twice daily ) . All patients continued to receive a stable dosage of MTX . The primary end point was the American College of Rheumatology 20 % improvement criteria ( ACR20 ) response rate at week 12 . RESULTS At week 12 , ACR20 response rates for patients receiving all tofacitinib dosages ≥3 mg twice daily ( 52.9 % for 3 mg twice daily , 50.7 % for 5 mg twice daily , 58.1 % for 10 mg twice daily , 56.0 % for 15 mg twice daily , and 53.8 % for 20 mg/day ) were significantly ( P ≤ 0.05 ) greater than those for placebo ( 33.3 % ) . Improvements were sustained at week 24 for the ACR20 , ACR50 , and ACR70 responses , scores for the Health Assessment Question naire disability index , the 3-variable Disease Activity Score in 28 joints using the C-reactive protein level ( DAS28-CRP ) , and a 3-variable DAS28-CRP of < 2.6 . The most common treatment-emergent adverse events occurring in > 10 % of patients in any tofacitinib group were diarrhea , upper respiratory tract infection , and headache ; 21 patients ( 4.1 % ) experienced serious adverse events . Sporadic increases in transaminase levels , increases in cholesterol and serum creatinine levels , and decreases in neutrophil and hemoglobin levels were observed . CONCLUSION In patients with active RA in whom the response to MTX has been inadequate , the addition of tofacitinib at a dosage ≥3 mg twice daily showed sustained efficacy and a manageable safety profile over 24 weeks In order to compare the efficacy and toxicity of methotrexate and leflunomide for the treatment of rheumatoid arthritis , a double-blind r and omized clinical trial was carried out at the Department of Medicine , Jinnah Medical College Hospital , Korangi , Karachi . The sample size was 240 patients and the duration of the study was 1 year . The patients enrolled were r and omly divided into two groups ( methotrexate and leflunomide ) . RA activity was clinical ly assessed by noting changes in the four primary ( tender joint count , swollen joint count , physician and patient global assessment score ) and three secondary ( morning stiffness , pain intensity , HAQ ) clinical efficacy end-points . Data were expressed as the mean ± SD . A P value of < 0.05 , calculated by paired t test , was considered significant . A total of 368 subjects were enrolled in this study . Of these , 128 subjects were withdrawn during the screening phase . Of the 240 subjects who were r and omized and treated , 129 received leflunomide and 111 received methotrexate . The difference between the baseline and 12 month end-point measurements of all primary clinical efficacy end-points was significantly greater in methotrexate-treated than in leflunomide-treated subjects . Both leflunomide and methotrexate result ed in significant improvements in all secondary clinical efficacy end-points after 1 year of treatment . In both treatment groups , the most common reason for withdrawal during the treatment was adverse events . The results of this study indicate that both leflunomide and methotrexate are effective drugs for the long-term treatment of RA . It was concluded that methotrexate , which is a much cheaper drug than leflunomide , is the drug of choice , especially for patients who belong to low socioeconomic groups Objective To investigate the 2-year clinical and radiological outcomes of patients with early rheumatoid arthritis ( RA ; symptom duration < 1 year ) who had initially responded well to methotrexate monotherapy .  Methods In the SWEFOT trial , all 487 patients started methotrexate ( target dose 20 mg/week ) . After 3–4 months , 147 had low disease activity , 28-joint based disease activity score ( DAS28 ) ≤3.2 . These patients were not r and omly selected but were followed in regular care for 2 years . Clinical outcomes and radiographic progression according to the van der Heijde modified Sharp ( SvdH ) score were analysed . Results The majority of the 147 patients continued on methotrexate monotherapy . After 1 and 2 years , DAS28 remission was achieved in 59.6 % and 71.8 % and mean observed DAS28 values were 2.53 and 2.25 , respectively . Despite the favourable clinical course , a proportion of the patients progressed radiographically with a mean ( SD ) increase in the SvdH score after 2 years of 3.90 ( 6.84 ) . There was no significant difference in progression between patients in DAS28 remission versus not in remission ( p=0.73 ) . At baseline , approximately half the patients had no radiographic damage , while after 2 years the proportion was approximately 20 % . Conclusion Most early RA patients who achieve low disease activity after 3–4 months of methotrexate monotherapy continue to have low disease activity during 2 years follow-up , and additional treatment is needed infrequently . Some radiological progression occurs in most patients , and may be marked or severe in some , even despite sustained DAS28 remission . Close monitoring for radiological progression is thus warranted Drug treatment for rheumatoid arthritis usually consists of a combination of a nonsteroidal anti-inflammatory drug ( NSAID ) and a disease-modifying antirheumatic drug ( for example , sulfasalazine , methotrexate , gold salt , or a combination ) . New biological agents , such as tumor necrosis factor- blocking agents and interleukin-1 receptor antagonists , appear promising ( 1 , 2 ) . Glucocorticoids have had a special place in the treatment of rheumatoid arthritis since the publication of the report by Hench and coworkers showing that cortisone dramatically alleviated the symptoms of rheumatoid arthritis by inhibiting inflammation ( 3 ) . This period of enthusiasm in the 1950s was followed by a long period in which glucocorticoids were applied cautiously for rheumatoid arthritis because of their many side effects and the recognition that inhibition of inflammation is not necessarily associated with retardation of joint damage ( 4 ) . Ongoing research on glucocorticoids in rheumatoid arthritis focused on both inflammation and joint damage . Some recent studies showed that glucocorticoids reduced the progression of joint damage when added to therapy with disease-modifying antirheumatic drugs . These findings suggested that glucocorticoids might also have disease-modifying properties . If this could be confirmed , glucocorticoids might be used more often , especially since potential serious adverse effects of glucocorticoid therapy are more easily managed today ( 5 ) . Secondary osteoporosis is inhibited by potent bisphosphonates , and gastrointestinal complications of glucocorticoid therapy , especially in combination with NSAIDs , can be reduced by misoprostol , proton-pump inhibitors , or cyclooxygenase-2 selective NSAIDs . As yet , disease-modifying properties of low-dose glucocorticoids as monotherapy for patients with early rheumatoid arthritis have not been investigated . The aim of our study was to investigate the clinical efficacy , disease-modifying properties , and side effects of low-dose glucocorticoids as monotherapy for previously untreated patients with early active rheumatoid arthritis . Methods Patients From October 1992 through October 1995 , all consecutive out patients at the rheumatology departments of the Deventer and Zutphen Hospitals , the Netherl and s , who were at least 18 years of age and had early previously untreated rheumatoid arthritis ( disease duration < 1 year ) that satisfied classification criteria were invited to participate in the study [ 6 ] . To be included , patients had to have active disease , which was defined as the presence of at least two of the following three criteria : 1 ) early-morning stiffness lasting 30 minutes or longer , 2 ) 28-joint score for tenderness and 28-joint score for swelling of 3 or more , and 3 ) Westergren erythrocyte sedimentation rate of 28 mm or higher after 1 hour ( 7 , 8) . Exclusion criteria were contraindications to prednisone  or NSAIDs  , active gastrointestinal problems , serious complicating diseases , severe hypertension , hemorrhagic diathesis , treatment with cytotoxic or immunosuppressive drugs , alcohol or drug abuse , and psychiatric or mental problems . Informed consent was obtained from all patients before participation . Of the 118 eligible patients , 37 declined to participate ( Figure 1 ) . Figure 1 . Trial profile . Intervention Pharmacy personnel at Deventer Hospital used a computer-generated r and omization procedure to r and omly assign the 81 participating patients , in blocks of 10 , to one of two treatment groups . One group received two tablets of prednisone , 5 mg , once daily at breakfast , and one group received placebo . The pharmacology department at Deventer Hospital prepared and labeled the prednisone and placebo tablets , which were identical in shape and color , and distributed them to patients in unlabeled boxes . Only the pharmacist could access the allocation table . Both groups of patients received 500 mg of elementary calcium in the evening . The code of r and omization was broken after 2 years of treatment , and the prednisone dosage was tapered . Surplus tablets of the study medication were counted at every visit , and adherence was satisfactory ( 96 % ) . Use of NSAIDs  was not regulated . Local glucocorticoid injections were permitted only when absolutely necessary . Physical therapy and additional use of paracetamol were allowed . After 6 months , sulfasalazine ( 2 g/d ) could be prescribed as rescue medication . The decision to add sulfasalazine was made on clinical grounds ( activity of rheumatoid arthritis ) . Design and Setting The ethics committees of the University Medical Center Utrecht and the Deventer and Zutphen Hospitals approved the trial . The study was considered ethically acceptable when it was design ed ( 19891991 ) ; later , however , it became clear that irreversible joint damage is an early feature of rheumatoid arthritis . With our present knowledge , it would probably be considered unethical to compare the effects of prednisone and placebo in patients who did not receive a disease-modifying antirheumatic drug for at least 6 months . In our study , sulfasalazine could be prescribed as rescue medication only after 6 months to avoid obscuring the effects of prednisone monotherapy . Measurements All clinical outcome measurements , except those for disability and radiologic outcomes , were performed at baseline and every 3 months . Disability , which was assessed with the Health Assessment Question naire , and radiologic outcomes were measured every 6 months . Early-morning stiffness was recorded in minutes ( maximum , 720 minutes ) . Morning pain and general well-being were assessed on a horizontal visual analogue scale ranging from 0 to 100 mm , with 0 representing the best score ( no problems ) and 100 representing the worst score . Swelling and tenderness were assessed with the 28-joint score ( 7 , 8) . Grip strength was measured in kPa with a vigorimeter ( range , 0 to 200 kPa ) ; the mean of three measurements was calculated for each h and . Disability was assessed with a vali date d Dutch version of the Health Assessment Question naire ( Vragenlijst Dagelijks Functioneren ) ( 9 ) , which had a range of 0 to 3 ( 0 represented the best score [ no problems ] , and 3 represented the worst score ) . Serum C-reactive protein level was measured in mg/L. To investigate the possible sparing effect of the trial medication , we recorded the use of NSAIDs and analgesics , the frequency of intra-articular corticosteroid injections , and the use of physiotherapy . The patients recorded the use of NSAIDs , analgesics  , and physical therapy in st and ardized patient diaries . To calculate the use of NSAIDs and to compare different NSAIDs , we arbitrarily chose naproxen as a reference . One thous and mg of naproxen was defined as 1 unit and was considered to be approximately equivalent to 600 mg of azapropazone , 100 mg of diclofenac , 200 mg of flurbiprofen , 1600 mg of ibuprofen , 100 mg of indomethacin , 200 mg of ketoprofen , 15 mg of meloxicam , 1000 mg of nabumetone , 20 mg of piroxicam , and 600 mg of tiaprofenic acid . Every 3 months , the first author recorded use of intra-articular corticosteroid injections . Radiologic outcome measures were erosions , joint space narrowing , and the total score for both ( range , 0 to 448 ) . The total score is the sum of the erosions and narrowing scores in 44 joints in the h and s and feet , assessed on plain radiography and scored with the van der Heijde modification of the Sharp method ( 10 , 11 ) . Radiologic outcome measures also included the number of patients with erosive disease in each group and the number of radiologically affected joints per patient . Radiographs were taken at entry and every 6 months . An assistant prepared the radiographs to be read , and all identifying patient data on the radiographs were concealed from the readers . The readers had no knowledge of patient identity when they scored the radiographs . Radiographs were read in r and om patient order and were scored for each patient in temporal order . Scoring in temporal order clearly has advantages , as a comparative study has shown ( 11 ) . However , with this method , scores can either be stable or increase ; a decrease ( indicating improvement ) is not possible . The first author and an independent radiologist viewed all available radiographs  at one center . When the readers ' total scores for individual cases differed by 25 % or more , agreement was reached through discussion . Joint damage was defined as a score that exceeded 0 . To correct for possible differences between the two treatment groups in the number of patients who developed little or no joint damage , we also analyzed data only from patients who developed joint damage . Furthermore , radiologic damage was also analyzed with a cutoff point of 4 modified Sharp units . A score of 0 to 3 was interpreted as no damage , and scores of 4 or greater were interpreted as joint damage . This cutoff point seems to reflect clinical ly relevant change ( 12 ) and was also used in our study to define erosive rheumatoid arthritis . At the start of the study and every 3 months for 2 years , st and ardized lists were used to document adverse effects . We noted the occurrence of infections and the use of antibiotics ; the latter was checked at the patient 's pharmacy . For hypertension , the first author used a single device to measure blood pressure in mm Hg . For steroid diabetes , serum glucose level was measured in mmol/L. Hyperglycemia was defined according to the World Health Organization st and ard : postpr and ial , a glucose level of at least 11.0 mmol/L ( 198 mg/dL ) , and fasting , at least 6.6 mmol/L ( 119 mg/dL ) . Urinary glucose level was measured by using a semiquantitative method ( dipstick ) . A value less than 2.7 mmol/L ( 49 mg/dL ) was considered negative , a value of 2.7 to 5.5 mmol/L ( 50 to 99 mg/dL ) was considered a trace , a value of 5.6 to 16.6 mmol/L ( 100 to 299 mg/dL ) was considered 1 + , a value of 16.7 to 54.9 mmol/L ( 300 to 989 mg/dL ) was considered 2 + , and a value of 55 mmol/L or greater ( 990 mg/dL ) was considered 3 + . To assess weight gain , BACKGROUND Tofacitinib ( CP-690,550 ) is a novel oral Janus kinase inhibitor that is being investigated for the treatment of rheumatoid arthritis . METHODS In this 12-month , phase 3 trial , 717 patients who were receiving stable doses of methotrexate were r and omly assigned to 5 mg of tofacitinib twice daily , 10 mg of tofacitinib twice daily , 40 mg of adalimumab once every 2 weeks , or placebo . At month 3 , patients in the placebo group who did not have a 20 % reduction from baseline in the number of swollen and tender joints were switched in a blinded fashion to either 5 mg or 10 mg of tofacitinib twice daily ; at month 6 , all patients still receiving placebo were switched to tofacitinib in a blinded fashion . The three primary outcome measures were a 20 % improvement at month 6 in the American College of Rheumatology scale ( ACR 20 ) ; the change from baseline to month 3 in the score on the Health Assessment Question naire-Disability Index ( HAQ-DI ) ( which ranges from 0 to 3 , with higher scores indicating greater disability ) ; and the percentage of patients at month 6 who had a Disease Activity Score for 28-joint counts based on the erythrocyte sedimentation rate ( DAS28 - 4[ESR ] ) of less than 2.6 ( with scores ranging from 0 to 9.4 and higher scores indicating greater disease activity ) . RESULTS At month 6 , ACR 20 response rates were higher among patients receiving 5 mg or 10 mg of tofacitinib ( 51.5 % and 52.6 % , respectively ) and among those receiving adalimumab ( 47.2 % ) than among those receiving placebo ( 28.3 % ) ( P<0.001 for all comparisons ) . There were also greater reductions in the HAQ-DI score at month 3 and higher percentages of patients with a DAS28 - 4(ESR ) below 2.6 at month 6 in the active-treatment groups than in the placebo group . Adverse events occurred more frequently with tofacitinib than with placebo , and pulmonary tuberculosis developed in two patients in the 10-mg tofacitinib group . Tofacitinib was associated with an increase in both low-density and high-density lipoprotein cholesterol levels and with reductions in neutrophil counts . CONCLUSIONS In patients with rheumatoid arthritis receiving background methotrexate , tofacitinib was significantly superior to placebo and was numerically similar to adalimumab in efficacy . ( Funded by Pfizer ; ORAL St and ard Clinical Trials.gov number , NCT00853385 . ) BACKGROUND Rheumatoid arthritis is a heterogeneous chronic disease , and no therapeutic agent has been identified which is universally and persistently effective in all patients . We investigated the effectiveness of tofacitinib ( CP-690,550 ) , a novel oral Janus kinase inhibitor , as a targeted immunomodulator and disease-modifying therapy for rheumatoid arthritis . METHODS We did a 6-month , double-blind , parallel-group phase 3 study at 82 centres in 13 countries , including North America , Europe , and Latin America . 399 patients aged 18 years or older with moderate-to-severe rheumatoid arthritis and inadequate response to tumour necrosis factor inhibitors ( TNFi ) were r and omly assigned in a 2:2:1:1 ratio with an automated internet or telephone system to receive twice a day treatment with : tofacitinib 5 mg ( n=133 ) ; tofacitinib 10 mg ( n=134 ) ; or placebo ( n=132 ) , all with methotrexate . At month 3 , patients given placebo advanced to either tofacitinib 5 mg twice a day ( n=66 ) or 10 mg twice a day ( n=66 ) . Primary endpoints included American College of Rheumatology (ACR)20 response rate , mean change from baseline in Health Assessment Question naire-Disability Index ( HAQ-DI ) , and rates of disease activity score (DAS)28 - 4(ESR ) less than 2·6 ( referred to as DAS28<2·6 ) , all at month 3 . The full analysis set for the primary analysis included all r and omised patients who received at least one dose of study medication and had at least one post-baseline assessment . This trial is registered with www . Clinical Trials.gov , number NCT00960440 . FINDINGS At month 3 , ACR20 response rates were 41·7 % ( 55 of 132 [ 95 % CI vs placebo 6·06 - 28·41 ] ; p=0·0024 ) for tofacitinib 5 mg twice a day and 48·1 % ( 64 of 133 ; [ 12·45 - 34·92 ] ; p<0·0001 ) for tofacitinib 10 mg twice a day versus 24·4 % ( 32 of 131 ) for  placebo . Improvements from baseline in HAQ-DI were -0·43 ( [ -0·36 to -0·15 ] ; p<0·0001 ) for 5 mg twice a day and -0·46 ( [ -0·38 to -0·17 ] ; p<0·0001 ) for 10 mg twice a day tofacitinib versus -0·18 for placebo ; DAS28<2·6 rates were 6·7 % ( eight of 119 ; [ 0 - 10·10 ] ; p=0·0496 ) for 5 mg twice a day tofacitinib and 8·8 % ( 11 of 125 [ 1·66 - 12·60 ] ; p=0·0105 ) for 10 mg twice a day tofacitinib versus 1·7 % ( two of 120 ) for  placebo . Safety was consistent with phase 2 and 3 studies . The most common adverse events in months 0 - 3 were diarrhoea ( 13 of 267 ; 4·9 % ) , nasopharyngitis ( 11 of 267 ; 4·1 % ) , headache ( 11 of 267 ; 4·1 % ) , and urinary tract infection ( eight of 267 ; 3·0 % ) across tofacitinib groups , and nausea ( nine of 132 ; 6·8 % ) in the placebo group . INTERPRETATION In this treatment-refractory population  , tofacitinib with methotrexate had rapid and clinical ly meaningful improvements in signs and symptoms of rheumatoid arthritis and physical function over 6 months with manageable safety . Tofacitinib could provide an effective treatment option in patients with an inadequate response to TNFi . FUNDING Pfizer OBJECTIVE To compare the efficacy of combination therapy with methotrexate ( MTX ) and hydroxychloroquine ( HCQ ) , MTX and sulfasalazine ( SSZ ) , and MTX , HCQ , and SSZ in patients with rheumatoid arthritis ( RA ) . METHODS RA patients ( n = 171 ) who had not previously been treated with combinations of the study medications were r and omized to receive 1 of the 3 treatment combinations in this 2-year , double-blind , placebo-controlled protocol . HCQ was given at a dosage of 200 mg twice a day . The dosage of MTX was accelerated from 7.5 mg/week to 17.5 mg/week in all patients who were not in remission . Similarly , the dosage of SSZ was escalated from 500 mg twice a day to 1 gm twice a day in patients who were not in remission . The primary end point of the study was the percentage of patients who had a 20 % response to therapy according to the American College of Rheumatology ( ACR ) criteria at 2 years . RESULTS Intent-to-treat analysis revealed that patients receiving the triple combination responded best , with 78 % achieving an ACR 20 % response at 2 years , compared with 60 % of those treated with MTX and HCQ ( P = 0.05 ) and 49 % of those treated with MTX and SSZ ( P = 0.002 ) . Similar trends were seen for the ACR 50 % response , with 55 % , 40 % , and 29 % of patients in the 3 treatment groups , respectively , achieving these results at 2 years ( P = 0.005 for the triple combination group versus the MTX and SSZ group ) . All combination treatments were well-tolerated .  Fourteen patients ( evenly distributed among the 3 groups ) withdrew from the protocol because of symptoms that were potentially related to the study medication . CONCLUSION The triple combination of MTX , SSZ , and HCQ is well-tolerated , and its efficacy is superior to that of the double combination of MTX and SSZ and is marginally superior to that of the double combination of MTX and HCQ OBJECTIVE To assess whether it is better to intensively treat all patients with early rheumatoid arthritis ( RA ) using combinations of drugs or to reserve this approach for patients who do not have an appropriate response ( as determined by a Disease Activity Score in 28 joints using the erythrocyte sedimentation rate [ DAS28-ESR ] of ≥ 3.2 at week 24 )  to methotrexate ( MTX ) monotherapy , and to assess whether combination therapy with MTX plus etanercept is superior to the combination of MTX plus sulfasalazine plus hydroxychloroquine . METHODS The Treatment of Early Aggressive Rheumatoid Arthritis ( TEAR ) study is a 2-year , r and omized , double-blind trial . A 2 × 2 factorial design was used to r and omly assign subjects to 1 of 4 treatment arms : immediate treatment with MTX plus etanercept , immediate oral triple therapy ( MTX plus sulfasalazine plus hydroxychloroquine ) , or step-up from MTX monotherapy to one of the combination therapies ( MTX plus etanercept or MTX plus sulfasalazine plus hydroxychloroquine ) at week 24 if the DAS28-ESR was ≥ 3.2 . All treatment arms included matching placebos . The primary outcome was an observed-group analysis of DAS28-ESR values from week 48 to week 102 . RESULTS At week 24 ( beginning of the step-up period ) , subjects in the 2 immediate-treatment groups demonstrated a greater reduction in the DAS28-ESR compared with those in the 2 step-up groups ( 3.6 versus 4.2 ; P < 0.0001 ) ; no differences between the combination-therapy regimens were observed . Between week 48 and week 102 , subjects r and omized to the step-up arms had a DAS28-ESR clinical response that was not different from that of subjects who initially received combination therapy , regardless of the treatment arm . There was no significant difference in the DAS28-ESR between subjects r and omized to oral triple therapy and those r and omized to receive MTX plus etanercept . By week 102 , there was a statistically significant difference in the change in radiographic measurements from baseline between the group receiving MTX plus etanercept and the group receiving oral triple therapy ( 0.64 versus 1.69 ; P = 0.047 ) . CONCLUSION There were no differences in the mean DAS28-ESR during weeks 48 - 102 between subjects r and omized to receive MTX plus etanercept and those r and omized to triple therapy , regardless of whether they received immediate combination treatment or step-up from MTX monotherapy . At 102 weeks , immediate combination treatment with either strategy was more effective than MTX monotherapy prior to the initiation of step-up therapy . Initial use of MTX monotherapy with the addition of sulfasalazine plus hydroxychloroquine ( or etanercept , if necessary , after 6 months ) is a reasonable therapeutic strategy for patients with early RA . Treatment with the combination of MTX plus etanercept result ed in a statistically significant radiographic benefit compared with oral triple therapy BACKGROUND Rheumatoid arthritis is a common disease that causes substantial morbidity and mortality . The responses of patients with rheumatoid arthritis to treatment with a single so-called disease-modifying drug , such as methotrexate , are often suboptimal . Despite limited data , many patients are treated with combinations of these drugs . METHODS We enrolled 102 patients with rheumatoid arthritis and poor responses to at least one disease-modifying drug in a two-year , double-blind , r and omized study of treatment with methotrexate alone  ( 7.5 to 17.5 mg per week ) , the combination of sulfasalazine ( 500 mg twice daily ) and hydroxychloroquine ( 200 mg twice daily ) , or all three drugs . The dose of methotrexate was adjusted in an attempt to achieve remission in all patients . The primary and point of the study was the successful completion of two years of treatment with 50 percent improvement in composite symptoms of arthritis and no evidence of drug toxicity . RESULTS Fifty of the 102 patients had 50 percent improvement at nine months and maintained at least that degree of improvement for two years without evidence of major drug toxicity . Among them were 24 of 31 patients treated with all three drugs ( 77 percent ) , 12 of 36 patients treated with methotrexate alone ( 33 percent , P < 0.001 for the comparison with the three-drug group ) , and 14 of 35 patients treated with sulfasalazine and hydroxychloroquine ( 40 percent ) , P = 0.003 for the comparison with the three-drug group ) . Seven patients in the methotrexate group and three patients in each of the other two groups discontinued treatment because of drug toxicity . CONCLUSIONS In patients with rheumatoid arthritis , combination therapy with methotrexate , sulfasalazine , and hydroxychloroquine is more effective than either methotrexate alone or a combination of sulfasalazine , and hydroxychloroquine In order to identify rate and stability of remission induced by low-dose prednisone comedication in early rheumatoid arthritis ( RA ) , we evaluated patients with early RA ( < 1 year ) who were r and omized to receive ( P ) or not ( non-P ) low-dose prednisone in association with step-up disease-modifying antirheumatic drug therapy over 2 years .  Prevalence and duration of clinical remission were evaluated in the first and second year . Each treatment group included 105 patients ; no significant differences were found at baseline . During the first year , P patients achieved higher rates of clinical remission with a time-averaged odds ratio ( OR ) of 1.965 ( CI 95 % 1.214 - 3.182 , P= 0.006 ) . Moreover , they showed a higher probability of sustained remission during the second year ( OR 4.480 , CI 95 % 1.354 - 14.817 , P= 0.014 ) . In conclusion , we found as in early RA low-dose prednisone comedication is associated with higher rate of clinical remission , earlier disease activity control and more stable remission over time BACKGROUND Oral glucocorticoids are widely used to treat patients with rheumatoid arthritis , but their effect on joint destruction , as assessed radiologically , is uncertain . METHODS We conducted a r and omized , double-blind trial comparing oral prednisolone ( 7.5 mg daily for two years ) with placebo in 128 adults with active rheumatoid arthritis of less than two years ' duration . Except for systemic corticosteroids , other treatments could be prescribed . The primary outcome variables were the progression of damage as seen on radiographs of the h and after one and two years , as measured by the Larsen index , and the appearance of erosions in h and s that had no erosions at base line . The radiographs were viewed jointly by a radiologist and a rheumatologist who were unaware of the treatment assignment and the time point at which the films were obtained . RESULTS The statistical analysis of radiologically detected changes was based on 106 patients for whom there were films obtained at base line and two years later . After two years , the Larsen scores increased by a mean of 0.72 unit in the prednisolone group , indicating very little change , and by 5.37 units in the placebo group , indicating substantial joint destruction ( P = 0.004 ) . Of the 212 h and s of these patients , 147 ( 69.3 percent ) had no erosions at the start of the study . At two years , 15 of the 68 such h and s in the prednisolone group ( 22.1 percent ) and 36 of the 79 such h and s in the placebo group ( 45.6 percent ) had acquired erosions ( difference , 23.5 percentage points ; 95 percent confidence interval , 5.9 to 40.7 ; P = 0.007 ) . The patients in the prednisolone group had greater reductions than the patients in the placebo group in scores on an articular index and for pain and disability at 3 months ; for pain at 6 months ; and for disability at 6 , 12 , and 15 months ( all P < 0.05 ) . There was no difference between groups in st and ardized scores for the acute-phase response . The adverse events were typical of those encountered with antirheumatoid drugs . CONCLUSIONS In patients with early , active rheumatoid arthritis , prednisolone ( 7.5 mg daily ) given for two years in addition to other treatments substantially reduced the rate of radiologically detected progression of disease BACKGROUND Tofacitinib ( CP-690,550 ) is a novel oral Janus kinase inhibitor that is being investigated as a targeted immunomodulator and disease-modifying therapy for rheumatoid arthritis . METHODS In this phase 3 , double-blind , placebo-controlled , parallel-group , 6-month study , 611 patients were r and omly assigned , in a 4:4:1:1 ratio , to 5 mg of tofacitinib twice daily , 10 mg of tofacitinib twice daily , placebo for 3 months followed by 5 mg of tofacitinib twice daily , or placebo for 3 months followed by 10 mg of tofacitinib twice daily . The primary end points , assessed at month 3 , were the percentage of patients with at least a 20 % improvement in the American College of Rheumatology scale ( ACR 20 ) , the change from baseline in Health Assessment Question naire-Disability Index ( HAQ-DI ) scores ( which range from 0 to 3 , with higher scores indicating greater disability ) , and the percentage of patients with a Disease Activity Score for 28-joint counts based on the erythrocyte sedimentation rate ( DAS28 - 4[ESR ] ) of less than 2.6 ( with scores ranging from 0 to 9.4 and higher scores indicating more disease activity ) . RESULTS At month 3 , a higher percentage of patients in the tofacitinib groups than in the placebo groups met the criteria for an ACR 20 response ( 59.8 % in the 5-mg tofacitinib group and 65.7 % in the 10-mg tofacitinib group vs. 26.7 % in the combined placebo groups , P<0.001 for both comparisons ) . The reductions from baseline in HAQ-DI scores were greater in the 5-mg and 10-mg tofacitinib groups than in the placebo groups ( -0.50 and -0.57 points , respectively , vs. -0.19 points ; P<0.001 ) . The percentage of patients with a DAS28 - 4(ESR ) of less than 2.6 was not significantly higher with tofacitinib than with placebo ( 5.6 % and 8.7 % in the 5-mg and 10-mg tofacitinib groups , respectively , and 4.4 % with placebo ; P=0.62 and P=0.10 for the two comparisons ) . Serious infections developed in six patients who were receiving tofacitinib . Common adverse events were headache and upper respiratory tract infection . Tofacitinib treatment was associated with elevations in low-density lipoprotein cholesterol levels and reductions in neutrophil counts . CONCLUSIONS In patients with active rheumatoid arthritis , tofacitinib monotherapy was associated with reductions in signs and symptoms of rheumatoid arthritis and improvement in physical function . ( Funded by Pfizer ; ORAL Solo Clinical Trials.gov number , NCT00814307 . ) OBJECTIVES MTX , either alone or in combination with SSZ , is effective in the treatment of RA . Trials have shown that , after SSZ failure , the addition of MTX to SSZ is more effective than a switch to MTX . Whether this is also the case in daily practice has not been analysed yet . In this study , we compared the efficacy of a switch to MTX monotherapy with that of the addition of MTX to SSZ in the daily clinical practice of RA patients who had failed SSZ monotherapy in the Nijmegen RA Inception Cohort . METHODS For this study , 230 patients who failed to SSZ monotherapy were followed for up to 52 weeks . A total of 124 underwent a switch to MTX alone , whereas 106 patients received the combination of MTX and SSZ . The primary outcome measure was the mean change in the disease activity score ( DAS28 ) after 24 weeks . RESULTS Both treatment groups showed a significant decrease in DAS28 after 24 weeks , which was similar in both groups . Drug survival analysis showed that the chance to stop with a DMARD within 52 weeks was higher in the MTX-SSZ group ( P < 0.01 ) . CONCLUSIONS In RA patients who failed to SSZ  the clinical efficacy of a switch to MTX monotherapy was similar to that of the addition of MTX , suggesting that in daily clinical practice a switch to MTX is a good option for patients with an inadequate response to SSZ
Objectives To up date a previous systematic review assessing the efficacy of conventional synthetic disease-modifying antirheumatic drugs ( csDMARDs ) in rheumatoid arthritis ( RA ) .