***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Objectives Rituximab is an effective treatment in patients with established rheumatoid arthritis ( RA ) . The objective of the IMAGE study was to determine the efficacy of rituximab in the prevention of joint damage and its safety in combination with methotrexate ( MTX ) in patients initiating treatment with MTX .  Methods In this double-blind r and omised controlled phase III study , 755 MTX-naïve patients with active RA were r and omly assigned to MTX alone , rituximab 2 × 500 mg + MTX or rituximab 2 × 1000 mg + MTX . The primary end point at week 52 was the change in joint damage measured using a Genant-modified Sharp score . Results 249 , 249 and 250 patients were r and omly assigned to MTX alone , rituximab 2 × 500 mg + MTX or rituximab 2 × 1000 mg + MTX , respectively . At week 52 , treatment with rituximab 2 × 1000 mg + MTX compared with MTX alone was associated with a reduction in progression of joint damage ( mean change in total modified Sharp score 0.359 vs 1.079 ; p=0.0004 ) and an improvement in clinical outcomes ( ACR50 65 % vs 42 % ; p<0.0001 ) ; rituximab 2 × 500 mg + MTX  improved clinical outcomes ( ACR50 59 % vs 42 % ; p<0.0001 ) compared with MTX alone but did not significantly reduce the progression of joint damage . Safety outcomes were similar between treatment groups . Conclusions Treatment with rituximab 2 × 1000 mg in combination with MTX is an effective therapy for the treatment of patients with MTX-naïve RA . CLinical Trials.gov identifier NCT00299104 Objectives This phase III study evaluated the efficacy and safety of rituximab plus methotrexate ( MTX ) in patients with active rheumatoid arthritis ( RA ) who had an inadequate response to MTX and who were naïve to prior biological treatment . Methods Patients with active disease on stable MTX ( 10–25 mg/week ) were r and omised to rituximab 2 × 500 mg ( n=168 ) , rituximab 2 × 1000 mg ( n=172 ) , or placebo ( n=172 ) . From week 24 , patients not in remission ( Disease Activity Score ( 28 joints ) ≥2.6 ) received a second course of rituximab ; patients initially assigned to placebo switched to rituximab 2 × 500 mg . The primary end point was American College of Rheumatology 20 ( ACR20 ) response at week 24 . All patients were followed until week 48 . Results At week 24 , both doses of rituximab showed statistically superior efficacy ( p<0.0001 ) to placebo ( ACR20 : 54 % , 51 % and 23 % ; rituximab ( 2 × 500 mg ) + MTX , rituximab ( 2 × 1000 mg ) + MTX and placebo + MTX , respectively ) . Secondary end points were also significantly improved for both rituximab groups compared with placebo . Further improvements in both rituximab arms were observed from week 24 to week 48 . Rituximab + MTX was well tolerated , demonstrating comparable safety to placebo + MTX through to week 24 , and between rituximab doses through to week 48 . Conclusions Rituximab ( at 2 × 500 mg and 2 × 1000 mg ) plus MTX  significantly improved clinical outcomes at week 24 , which were further improved by week 48 . No significant differences in either clinical or safety outcomes were apparent between the rituximab doses BACKGROUND An open-label study indicated that selective depletion of B cells with the use of rituximab led to sustained clinical improvements for patients with rheumatoid arthritis . To confirm these observations , we conducted a r and omized , double-blind , controlled study . METHODS We r and omly assigned 161 patients who had active rheumatoid arthritis despite treatment with methotrexate  to receive one of four treatments : oral methotrexate ( > or = 10 mg per week ) ( control ) ; rituximab ( 1000 mg on days 1 and 15 ) ; rituximab plus cyclophosphamide ( 750 mg on days 3 and 17 ) ; or rituximab plus methotrexate . Responses defined according to the criteria of the American College of Rheumatology ( ACR ) and the European League against Rheumatism ( EULAR ) were assessed at week 24 ( primary analyses ) and week 48 ( exploratory analyses ) . RESULTS At week 24 , the proportion of patients with 50 percent improvement in disease symptoms according to the ACR criteria , the primary end point , was significantly greater with the rituximab-methotrexate combination ( 43 percent , P=0.005 ) and the rituximab-cyclophosphamide combination ( 41 percent , P=0.005 ) than with methotrexate alone ( 13 percent ) . In all groups treated with rituximab , a significantly higher proportion of patients had a 20 percent improvement in disease symptoms according to the ACR criteria ( 65 to 76 percent vs. 38 percent , P < or = 0.025 ) or had EULAR responses ( 83 to 85 percent vs. 50 percent , P < or = 0.004 ) . All ACR responses were maintained at week 48 in the rituximab-methotrexate group . The majority of adverse events occurred with the first rituximab infusion : at 24 weeks , serious infections occurred in one patient ( 2.5 percent ) in the control group and in four patients ( 3.3 percent ) in the rituximab groups . Peripheral-blood immunoglobulin concentrations remained within normal ranges . CONCLUSIONS In patients with active rheumatoid arthritis despite methotrexate treatment , a single course of two infusions of rituximab , alone or in combination with either cyclophosphamide or continued methotrexate , provided significant improvement in disease symptoms at both weeks 24 and 48 R and omized controlled trials often suffer from two major complications , i.e. , noncompliance and missing outcomes . One potential solution to this problem is a statistical concept called intention-to-treat ( ITT ) analysis . ITT analysis includes every subject who is r and omized according to r and omized treatment assignment . It ignores noncompliance , protocol deviations , withdrawal , and anything that happens after r and omization . ITT analysis maintains prognostic balance generated from the original r and om treatment allocation . In ITT analysis , estimate of treatment effect is generally conservative . A better application of the ITT approach is possible if complete outcome data are available for all r and omized subjects . Per- protocol population is defined as a subset of the ITT population who completed the study without any major protocol violations Background In the IMAGE study , rituximab plus methotrexate ( MTX ) inhibited joint damage and improved clinical outcomes at 1 year in MTX-naïve patients with early active rheumatoid arthritis . Objective The aim of this study was to assess joint damage progression and clinical outcomes over 2 years . Methods Patients ( n=755 ) were r and omised to receive rituximab 2 × 500 mg+MTX , 2 × 1000 mg+MTX or placebo+MTX . The placebo-controlled period continued to week 104 . Two-year end points were defined as secondary or exploratory and included change in total Genant-modified Sharp score ( mTSS ) , total erosion score and joint space narrowing score from baseline to week 104 . Clinical efficacy and physical function end points were also assessed . Results At 2 years , rituximab 2 × 1000 mg+MTX maintained inhibition of progressive joint damage  versus MTX alone ( mTSS change 0.41 vs 1.95 ; p<0.0001 ( 79 % inhibition ) ) , and a higher proportion of patients receiving rituximab 2 × 1000 mg+MTX had no radiographic progression over 2 years compared with those receiving MTX alone ( 57 % vs 37 % ; p<0.0001 ) . Contrary to 1-year results , exploratory analysis of rituximab 2 × 500 mg+MTX at 2 years showed that progressive joint damage was slowed by ∼61 % versus placebo+MTX ( mTSS , exploratory p=0.0041 ) . Improvements in clinical signs and symptoms and physical function seen after 1 year in rituximab-treated patients versus those receiving placebo were maintained at year 2 . Safety profiles were similar between groups . Conclusions Treatment with rituximab 2 × 1000 mg+MTX was associated with sustained improvements in radiographic , clinical and functional outcomes over 2 years . Clinical trials.gov identifier NCT00299104 Objective . To evaluate the efficacy and safety of three dosing and repeat treatment regimens of rituximab ( RTX ) plus MTX in patients with active RA . Methods . Patients with active RA despite stable MTX ( 10–25 mg/week ) were r and omly assigned to one of the three treatment regimens comprising two courses of RTX given 24 weeks apart : 2 × 500 and 2 × 500 mg ; 2 × 500 and 2 × 1000 mg ( dose escalation ) ; and 2 × 1000 and 2 × 1000 mg . The primary endpoint was proportion of patients achieving ACR20 at Week 48 . Results . At Week 48 , ACR20 responses were not statistically significantly different between the dose regimens . Compared with RTX 2 × 500 mg ( n = 134 ) or dose escalation ( n = 119 ) , ACR and European League Against Rheumatism ( EULAR ) outcomes in the RTX 2 × 1000 mg group ( n = 93 ) were consistently higher , with significantly more patients achieving EULAR responses ( P = 0.0495 ) . At Week 48 , rituximab 2 × 1000 mg was associated with a higher proportion of patients who , following retreatment , maintained or improved their Week 24 responses . Dose escalation from 2 × 500 to 2 × 1000 mg did not appear to be associated with improved outcomes compared with continual 2 × 500 mg . All RTX regimens demonstrated comparable safety .  Conclusions . RTX 2 × 500 and 2 × 1000 mg could not be clearly differentiated , although some efficacy outcomes suggest improved outcomes in the rituximab 2 × 1000 mg group . Retreatment from Week 24 result ed in a sustained suppression of disease activity through to Week 48 . Trial registration . Clinical Trials.gov , http:// clinical trials.gov/ , NCT00422383 OBJECTIVE To define clinical ly meaningful changes in 2 widely used health-related quality of life ( HQL ) instruments in studies of patients with rheumatoid arthritis ( RA ) . METHODS Patients with RA ( n = 693 ) who were enrolled in 2 double-blind , placebo-controlled clinical trials completed the Short Form 36 ( SF-36 ) modified health survey and the Health Assessment Question naire ( HAQ ) disability index at baseline and 6-week followup assessment s. Data on 5 RA severity measures were also collected at baseline and at 6 weeks ( patient and physician global assessment s , joint swelling and tenderness counts , and global pain assessment ) . Comparison of changes in the SF-36 scales and HAQ scores was made between groups of patients known to differ in the level of change on each RA severity measure . RESULTS With few exceptions , changes in the SF-36 and HAQ scores were different between patients who differed in the level of change on each RA severity measure . Changes in the SF-36 and HAQ scores were more strongly related to changes in the patient and physician global assessment s and patient pain assessment than to changes in the joint swelling and tenderness counts . CONCLUSION Based on these results , minimally important changes in the SF-36 scales and HAQ disability scores were determined , which will be useful in interpreting HQL results in clinical trials OBJECTIVE To examine the efficacy and safety of different rituximab doses plus methotrexate ( MTX ) , with or without glucocorticoids , in patients with active rheumatoid arthritis ( RA ) resistant to disease-modifying antirheumatic drugs ( DMARDs ) , including biologic agents . METHODS A total of 465 patients were r and omized into 9 treatment groups : 3 rituximab groups ( placebo [ n = 149 ] , 500 mg [ n = 124 ] , or 1,000 mg [ n = 192 ] on days 1 and 15 ) each also taking either placebo glucocorticoids , intravenous methylprednisolone premedication , or intravenous methylprednisolone premedication plus oral prednisone for 2 weeks . All patients received MTX ( 10 - 25 mg 
    Output:
    
CONCLUSION Low-dose RTX has similar effectiveness and met noninferiority criteria for most primary outcomes .