***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: Background Methotrexate is the most efficient anticancer drug in osteosarcoma . It requires individual exposure monitoring because of the high doses used , its wide interpatient pharmacokinetic variability and the existence of demonstrated relationships between efficacy , toxicity and serum drug concentrations . Objective To develop a maximum a posteriori ( MAP ) Bayesian estimator able to predict individual pharmacokinetic parameters and exposure indices such as area under the curve ( AUC ) for methotrexate from a few blood sample s , in order to prevent toxicity and facilitate further studies of the relationships between efficacy and exposure . Methods Methotrexate population pharmacokinetics were estimated by a retrospective analysis of concentration data from 40 children and young adults by using the nonparametric expectation maximisation method NPEM . A linear two-compartment model with elimination from the central compartment was assumed . Individual pharmacokinetic parameters and AUC were subsequently estimated in 30 other young patients , using MAP Bayesian estimation as implemented in two programs , ADAPT II and an inhouse program Winphar ® . Results The pharmacokinetic parameters used in the model were the volume of the central compartment ( V1 ) and the transfer constants ( k10 , k12 and k21 ) . The mean values ( with percentage coefficient of variation ) obtained were : 18.24L ( 54.1 % ) and 0.41 ( 42.3 % ) , 0.0168 ( 68.7 % ) , and 0.1069 ( 61.3 % ) h-1 , respectively . Bayesian forecasting enabled nonbiased estimation of AUC and systemic clearance using a schedule with two sampling times ( 6 and 24 hours after the beginning of the infusion ) and either program . Collection of a third sample at 4 hours improved the precision . Conclusion The Bayesian adaptive method developed herein allows accurate estimation of individual exposure to methotrexate and can easily be used in clinical practice OBJECTIVE To evaluate the safety and activity of an immunoconjugate of ricin A chain and anti-CD5 monoclonal antibody ( anti-CD5 IC ) , with and without concomitant methotrexate and /or azathioprine , in the treatment of rheumatoid arthritis ( RA ) . METHODS Seventy-nine patients with active RA were enrolled in 2 prospect i ve open-label protocol s. RESULTS Using composite criteria , response rates were 50 - 68 % at 1 month and 22 - 25 % at 6 months . Transient depletion of CD3/CD5 T cells was observed on days 2 and 5 of treatment , with reconstitution on day 15 or day 29 . Treatment-associated adverse effects were common but resolved rapidly without sequelae . CONCLUSION These findings suggest activity of anti-CD5 IC in active RA and warrant confirmation in a multicenter r and omized study ( currently underway ) Objectives The aim of this 12-week Phase IIb study was to assess the efficacy and safety of olokizumab ( OKZ ) , a humanised anti-IL6 monoclonal antibody , in patients with rheumatoid arthritis ( RA ) with moderate-to-severe disease activity who had previously failed tumour necrosis factor ( TNF ) inhibitor therapy . The dose-exposure-response relationship for OKZ was also investigated . Methods Patients were r and omised to one of nine treatment arms receiving placebo ( PBO ) or OKZ ( 60 , 120 or 240 mg ) every 4 weeks ( Q4W ) or every 2 weeks ( Q2W ) , or 8 mg/kg tocilizumab ( TCZ ) Q4W . The primary endpoint was change from baseline in DAS28(C-reactive protein , CRP ) at Week 12 . Secondary efficacy endpoints were American College of Rheumatology 20 ( ACR20 ) , ACR50 and ACR70 response rates at Week 12 . Exploratory analyses included comparisons of OKZ efficacy with TCZ . Results Across 221 r and omised patients , OKZ treatment produced significantly greater reductions in DAS28(CRP ) from baseline levels at Week 12 , compared to PBO ( p<0.001 ) , at all the OKZ doses tested ( 60 mg OKZ p=0.0001 , 120 and 240 mg OKZ p<0.0001 ) . Additionally , ACR20 and ACR50 responses were numerically higher for OKZ than PBO ( ACR20 : PBO=17.1–29.9 % , OKZ=32.5–60.7 % ; ACR50 : PBO=1.3–4.9 % , OKZ=11.5–33.2 % ) . OKZ treatment , at several doses , demonstrated similar efficacy to TCZ across multiple endpoints . Most adverse events were mild or moderate and comparable between OKZ and TCZ treatment groups . Pharmacokinetic/pharmacodynamic modelling demonstrated a shallow dose/exposure response relationship in terms of percentage of patients with DAS28(CRP ) < 2.6 . Conclusions OKZ produced significantly greater reductions in DAS28(CRP ) from baseline at Week 12 compared with PBO . Reported AEs were consistent with the safety profile expected of this class of drug , with no new safety signals identified . Trial register number : NCT01242488 OBJECTIVE To investigate the safety , tolerability , pharmacokinetics , and efficacy of apilimod mesylate , an oral interleukin-12 (IL-12)/IL-23 inhibitor , in patients with rheumatoid arthritis ( RA ) . METHODS We performed a phase IIa , r and omized , double-blind , placebo-controlled proof-of-concept study of apilimod , in combination with methotrexate , in 29 patients with active RA ( 3:1 ratio of apilimod-treated to placebo-treated patients ) in 3 stages . Patients received apilimod 100 mg/day or placebo for 4 weeks ( stage 1 ) or 8 weeks ( stage 2 ) . In stage 3 , patients received apilimod 100 mg twice a day or placebo for 8 weeks , with an optional extension of 4 weeks . Clinical response ( Disease Activity Score in 28 joints [ DAS28 ] and American College of Rheumatology [ ACR ] criteria ) was assessed throughout ; synovial tissue sample s collected at baseline and on day 29 ( stages 1 and 2 ) or day 57 ( stage 3 ) were stained for cellular markers and cytokines for immunohistochemistry analysis . RESULTS While only mild adverse events were observed in stages 1 and 2 , in stage 3 , all patients experienced headache and /or nausea . Among apilimod-treated patients ( 100 mg/day ) , there was a small , but significant , reduction in the DAS28 on day 29 and day 57 compared with baseline . ACR20 response was reached in only 6 % of patients on day 29 and 25 % of patients on day 57 , similar to the percentage of responders in the placebo group . Increasing the dosage ( 100 mg twice a day ) did not improve clinical efficacy . Consistent with clinical results , apilimod did not have an effect on expression of synovial biomarkers . Of importance , we also did not observe an effect of apilimod on synovial IL-12 and IL-23 expression . CONCLUSION Our results do not support the notion that IL-12/IL-23 inhibition by apilimod is able to induce robust clinical improvement in RA Objective To evaluate the efficacy and safety of golimumab 50 and 100 mg monotherapy in Japanese patients with active rheumatoid arthritis ( RA ) despite treatment with disease-modifying antirheumatic drugs ( DMARDs ) . Methods A total of 316 patients were r and omised to receive subcutaneous injections every 4 weeks of placebo ( group 1 ) , golimumab 50 mg ( group 2 ) or golimumab 100 mg ( group 3 ) ; group 1 crossed over to golimumab 50 mg at week 16 . The primary end point was the proportion of patients achieving ≥20 % improvement in the American College of Rheumatology criteria ( ACR20 ) at week 14 . ACR50 and ACR70 response rates were also measured . Adverse events ( AEs ) were monitored throughout the study . Results Demographics were similar across groups ; the mean age was 52 years and 81.8 % of patients ( 252/308 ) were female .  Week 14 ACR20 response rates were significantly greater in groups 2 ( 51/101 ( 50.5 % ) ) and 3 ( 60/102 ( 58.8 % ) ) than in group 1 ( 20/105 ( 19.0 % ) ; p<0.0001 for both ) , as were ACR50 and ACR70 response rates . After placebo crossover at week 16 , week 24 ACR response rates were similar in groups 1 and 2 . Through week 16 , 63.8 % of patients in group 1 , 62.4 % in group 2 and 60.8 % in group 3 had AEs and 1.9 % , 1.0 % and 2.0 % had serious AEs . After week 16 , one malignancy was reported ( breast cancer , group 3 ) . Infections were the most common AEs . No deaths or cases of tuberculosis were reported through week 24 . Conclusions Golimumab monotherapy ( 50 and 100 mg ) was effective in reducing the signs and symptoms of RA in Japanese patients with active disease despite DMARD treatment Infliximab , a chimeric anti-TNF alpha antibody , showed in two double-blind placebo-controlled trials efficacy in combination with methotrexate ( MTX ) in patients with severe rheumatoid arthritis ( RA ) . Whereas in the first trial low-dose MTX or placebo was compared to infliximab alone and in combination , the second trial compared infliximab to placebo in patients with active RA despite maximal tolerated MTX treatment . Infliximab showed synergistic effects in combination with MTX . The immunogenicity of infliximab  was reduced by the combination . Infliximab in combination with high-dose MTX  is effective and safe in long-term treatment up to 54 weeks BACKGROUND Tumor necrosis factor ( TNF ) is an important mediator of cachexia , and its blockade prevents catabolism in animal models . However , little evidence shows that anti-TNF therapy is effective in treating cachexia in humans . OBJECTIVE The main aim of this study was to investigate the effect of etanercept , a synthetic soluble TNF receptor , on body composition in patients with early rheumatoid arthritis ( RA ) . DESIGN Twenty-six patients were r and omly assigned to 24 wk of treatment with  etanercept or methotrexate ; the latter is the first-line therapy for RA . Body composition , physical function , disease activity , systemic inflammation , and the circulating insulin-like growth factor ( IGF ) system were measured at baseline ( week 0 ) and at follow-up ( weeks 12 and 24 ) . Twelve patients in each treatment group ( 9 F , 3 M ) completed the study . RESULTS Overall , no important changes in body composition were observed , despite a transient increase in IGF-I at week 12 ( P < 0.01 ) . However , the secondary analysis of those patients ( 6/treatment group ) who gained weight during follow-up showed a significant effect of etanercept on the composition of the weight gained : 44 % of weight gained in the etanercept group was fat-free mass , as compared with only 14 % in the methotrexate group ( P = 0.04 ) . Etanercept and methotrexate were equally effective in controlling the disease and improving physical function . CONCLUSIONS Anti-TNF therapy with etanercept is not superior to that with methotrexate for the treatment of rheumatoid cachexia over a period of 6 mo . However , TNF blockade seems to normalize the anabolic response to overfeeding and , if these findings are confirmed , may be useful in conditions characterized by anorexia and weight loss OBJECTIVE Induction of immune tolerance to maintain clinical control with a minimal drug regimen is a current research focus in rheumatoid arthritis ( RA ) . Accordingly , we are developing a tolerization approach to dnaJP1 , a peptide part of a pathogenic mechanism that contributes to autoimmune inflammation in RA . We undertook this study to test 2 hypotheses : 1 ) that mucosal induction of immune tolerance to dnaJP1 would lead to a qualitative change from a proinflammatory phenotype to a more tolerogenic functional phenotype , and 2 ) that immune deviation of responses to an inflammatory epitope might translate into clinical improvement . METHODS One hundred sixty patients with active RA and with immunologic reactivity to dnaJP1 were enrolled in a pilot phase II trial . They received oral doses of 25 mg of dnaJP1 or placebo daily for 6 months . RESULTS The dnaJP1 peptide was safe and well-tolerated . In response to treatment with dnaJP1 , there was a significant reduction in the percentage of T cells producing tumor necrosis factor alpha and a corresponding trend toward an increased percentage of T cells producing interleukin-10 . Coexpression of a cluster of molecules ( programmed death 1 and its lig and s ) associated with T cell regulation was also 
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Conclusion The one adaptive design review ed here , and a simulation study found in the search , both indicate that adaptive design s can be applied to early phase trials in RA .