***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: Objective : To estimate the cost effectiveness of combination treatment with etanercept plus methotrexate in comparison with monotherapies in patients with active rheumatoid arthritis ( RA ) using a new model that incorporates both functional status and disease activity . Methods : Effectiveness data were based on a 2 year trial in 682 patients with active RA ( TEMPO ) . Data on re source consumption and utility related to function and disease activity were obtained from a survey of 616 patients in Sweden . A Markov model was constructed with five states according to functional status ( Health Assessment Question naire ( HAQ ) ) subdivided into high and low disease activity . The cost for each quality adjusted life year ( QALY ) gained was estimated by Monte Carlo simulation . Results : Disease activity had a highly significant effect on utilities , independently of HAQ . For re source consumption , only HAQ was a significant predictor , with the exception of sick leave . Compared with methotrexate alone , etanercept plus methotrexate over 2 years increased total costs by € 14 221 and led to a QALY gain of 0.38 . When treatment was continued for 10 years , incremental costs were € 42 148 for a QALY gain of 0.91 . The cost per QALY gained was € 37 331 and € 46 494 , respectively . The probability that the cost effectiveness ratio is below a threshold of € 50 000/QALY is 88 % . Conclusion : Incorporating the influence of disease activity into this new model allows better assessment of the effects of anti-tumour necrosis factor treatment on patients ’ general wellbeing . In this analysis , the cost per QALY gained with combination treatment with etanercept plus methotrexate compared with methotrexate alone falls within the acceptable range OBJECTIVE To assess cost-effectiveness of abatacept in patients with moderately to severely active RA and inadequate response to MTX .  METHODS We developed a simulation model to depict progression of disability [ in terms of the HAQ Disability Index ( HAQ-DI ) ] in women aged 55 - 64 yrs with moderately to severely active RA and inadequate response to MTX .  At model entry , patients were assumed to receive either only MTX or MTX plus abatacept . Patients were then tracked from model entry until death . Future health-state utilities and medical-care costs ( except study therapy ) were estimated based on predicted values of the HAQ-DI . The model was estimated using data from a Phase III clinical trial of abatacept plus various secondary sources . Cost-effectiveness was expressed in terms of incremental cost ( 2006 US$ ) per quality -adjusted life-year ( QALY ) gained over alternatively 10 yrs and a lifetime . Costs and health effects were both discounted at 3 % annually . RESULTS Over 10 yrs , abatacept would yield 1.2 additional QALYs ( undiscounted ) per patient ( 4.6 vs 3.4 for MTX ) at an incremental ( discounted ) cost of $ 51,426 ( $ 103,601 vs $ 52,175 , respectively ) ; over a lifetime , corresponding figures were 2.0 QALYS ( 6.8 vs 4.8 ) and $ 67,757 ( $ 147,853 vs $ 80,096 ) . Cost-effectiveness was [ mean ( 95 % CI ) ] $ 47,910 ( $ 44,641 , $ 52,136 ) per QALY gained over 10 yrs and $ 43,041 ( $ 39,070 , $ 46,725 ) per QALY gained over a lifetime . Findings were robust in sensitivity analyses . CONCLUSION Abatacept is cost-effective by current st and ards of medical practice in patients with moderately to severely active RA and inadequate response to MTX OBJECTIVE To evaluate the incremental cost effectiveness of rituximab in patients with rheumatoid arthritis that failed to respond adequately to tumour necrosis factor-alpha inhibitors ( biologic disease-modifying antirheumatic drugs ; bDMARDs ) . A cost-utility model has been developed to simulate the long-term incremental cost and benefits of rituximab using data from clinical trials and registries . METHODS The model estimates the lifetime disease progression of up to 10,000 hypothetical rheumatoid arthritis ( RA ) patients that failed one bDMARD . It compares cost and outcomes of two treatment sequences , representing the current UK st and ard both with and without rituximab . The population characteristics match those of the R and omised Evaluation of Long-term Efficacy of rituximab in RA ( REFLEX ) phase III r and omised control trial . Clinical outcomes were based on an indirect comparison of published American College of Rheumatology response rates , adjusted for differences in placebo . To estimate medical re source use , health assessment question naire ( HAQ ) scores were grouped into five categories with UK registry data informing the average cost for each category . Quality -adjusted life years ( QALYs ) gained were mapped from disease severity ( HAQ scores ) . RESULTS Compared to a st and ard UK treatment sequence ( assuming the sequential use of bDMARDs ) the introduction of rituximab led to a QALY gain of 0.526 years . The incremental cost-effectiveness ratios ( ICERs ) based on total direct medical cost were 11,601 pounds . Adding rituximab to a treatment sequence with no sequential use of biologic generates an ICER of 14,690 pounds . CONCLUSION Rituximab has lower average annual treatment costs compared to other bDMARDs and is a highly cost-effective treatment option for patients who have failed to respond adequately to one bDMARD . The cost per QALY gained of rituximab falls well below commonly accepted thresholds within the UK . Potential weaknesses of the model include the paucity of data on the efficacy of bDMARDs or non-biologic DMARDs when used as second-line options ; the lack of consensus about the most appropriate therapy in patients who fail all available bDMARDs ; probable underestimation of the non-drug related medical costs ; indirect measurement of QALY gains with rituximab therapy ; and the necessity of synthesis ing data from a number of clinical trials with different population s and study drugs PURPOSE To estimate the cost-effectiveness of infliximab plus methotrexate for active , refractory rheumatoid arthritis . METHODS We projected the 54-week results from a r and omized controlled trial of infliximab into lifetime economic and clinical outcomes using a Markov computer simulation model . Direct and indirect costs , quality of life , and disability estimates were based on trial results ; Arthritis , Rheumatism , and Aging Medical Information System ( ARAMIS ) data base outcomes ; and published data . Results were discounted using the st and ard 3 % rate . Because most well-accepted medical therapies have cost-effectiveness ratios below $ 50,000 to $ 100,000 per quality -adjusted life-year ( QALY ) gained , results below this range were considered to be " cost-effective . " RESULTS At 3 mg/kg , each infliximab infusion would cost $ 1393 . When compared with methotrexate alone , 54 weeks of infliximab plus methotrexate decreased the likelihood of having advanced disability from 23 % to 11 % at the end of 54 weeks , which projected to a lifetime marginal cost-effectiveness ratio of $ 30,500 per discounted QALY gained , considering only direct medical costs . When applying a societal perspective and including indirect or productivity costs , the marginal cost-effectiveness ratio for infliximab was $ 9100 per discounted QALY gained . The results remained relatively unchanged with variation of model estimates over a broad range of values . CONCLUSIONS Infliximab plus methotrexate for 54 weeks for rheumatoid arthritis should be cost-effective with its clinical benefit providing good value for the drug cost , especially when including productivity losses . Although infliximab beyond 54 weeks will likely be cost-effective , the economic and clinical benefit remains uncertain and will depend on long-term results of clinical trials Context It remains unclear whether the optimal treatment strategy for early rheumatoid arthritis ( RA ) is to step care from nonsteroidal anti-inflammatory drugs and other symptomatic treatments to glucocorticoids and then to disease-modifying antirheumatic drugs ( DMARDs ) only after 1 year , or to use more aggressive therapy early after diagnosis . Contribution The investigators used available data to estimate the cost-effectiveness of initial treatment strategies for RA . Compared with stepped care , early DMARDs or early biologic agents seem to improve outcomes , but only DMARDs do so at a cost per year of life saved that society typically considers acceptable . Caution Assumptions were based on limited data on early RA treatment with DMARDs and biologics . The Editors The treatment of rheumatoid arthritis ( RA ) has changed dramatically in the past decade with the introduction of new biologic therapies , particularly tumor necrosis factor inhibitors . Growing evidence suggests a benefit of aggressive treatment very early in the course of the disease and the existence of a critical therapeutic window of opportunity within which antirheumatic therapy is more effective and has a more durable effect than later in the course of the disease ( 1 , 2 ) . Very early initiation of disease-modifying antirheumatic drug ( DMARD ) or biologic therapy has a demonstrated prolonged benefit on RA progression and may permanently modify the disease to a milder course ( 1 , 3 ) . Emerging data also suggest that if RA is detected and treated very early , long-term control or remission may be possible and continuing treatment may not be necessary ( 46 ) . Although antirheumatic therapy should be initiated as early as possible after disease onset , the optimal strategy has not been determined . Early treatment with  biologics  seems to be superior to treatment with conventional DMARDs  in terms of hard outcomes , such as radiographic structural joint damage , but not necessarily in terms of disease activity ( 7 ) . Biologics are generally prescribed only after therapy with 1 or more conventional DMARDs has failed . However , r and omized , controlled trials ( RCTs ) have demonstrated improved efficacy of biologics in early disease ( 811 ) , and the pharmaceutical industry promotes early initiation of biologic therapy for RA . Because early therapy may change the natural course of the disease ( 4 ) , biologics could be most useful in early RA ( 4 , 12 , 13 ) . Although evidence supports the cost-effectiveness of biologic therapy  in DMARD-resistant severe RA ( 14 , 15 ) , its long-term cost-effectiveness in very early RA is unknown . The diagnosis of RA can be problematic very early in the course of disease ( 16 ) . An early diagnosis carries the risk for prescribing expensive and potentially toxic drugs to patients who might have spontaneous remission . Patients may incur time lost from work because of treatment or drug-related toxicities or may die because of treatment ( 13 ) . In addition , early antirheumatic therapy increases treatment costs ; in particular , biologics cost up to 10 times more than conventional DMARDs . However , patients may benefit from early therapy , endure fewer disability days , have less productivity loss , require fewer days in the hospital , and need fewer subsequent joint replacements ( 13 ) . It is therefore important to consider the total long-term costs associated with various therapeutic strategies . Health policy analyses use the incremental cost effectiveness ratio ( ICER ) to compare a particular treatment or strategy with competing treatment strategies to inform the allocation of health care re sources ( 17 ) . To determine whether the increased costs of treatment strategies that involve biologics in very early RA are warranted by health gains , we assessed the cost-effectiveness of major therapeutic strategies by examining different scenarios based on emerging data . Methods Decision Model Structure Our base-case analysis considers adults with very early RA , operationally defined as symptoms of less than 3 months in duration a definition commonly used in the literature for very early RA ( 18 , 19 ) . The classification criteria for RA require that signs and symptoms be present for at least 6 weeks ( 20 ) , and studies of patients with early RA suggest a median duration of illness of 11 to 23 weeks at diagnosis ( 21 , 22 ) . However , RA can not be reliably diagnosed at an early stage in all patients with inflammatory polyarthritis . A significant proportion of patients with undifferentiated arthritis will have spontaneous remission or receive diagnoses of other conditions ( 23 , 24 ) . Evolving diagnostic techniques , such as biomarkers ( 25 ) or improved clinical prediction rules for identifying which patients who present with undifferentiated polyarthritis will progress to RA , enable individualized decisions about initiation of treatment with DMARDs ( 23 , 26 ) . We used an individual sampling model ( 27 ) to track the course of disease over time , with changes in important variables ( principally radiographic joint damage and functional disability ) at time points at which events ( toxicities , treatment initiation , treatment discontinuation , or death ) occur . We estimated the expected lifetime costs and benefits for U.S. patients , expressed as quality -adjusted life-years ( QALYs ) , from both a health care provider and a societal perspective . Our models explore 5 conceivable strategies , but we focus on the 3 most plausible and clinical ly relevant strategies for very early RA . Although these may vary in actual practice , we simplified the choices to model the problem . In the pyramid strategy , initial nonsteroidal anti-inflammatory drugs 
    Output:
    
Rituximab was found to be the most cost-effective alternative compared to other biologics among the patients with an insufficient response to TNFi .
When 35,000 € /QALY is considered as a threshold for the ICER , TNFis do not seem to be cost-effective among cDMARD naïve patients and patients with an insufficient response to cDMARDs .
With thresholds of 50,000 to 100,000 € /QALY biologics might be cost-effective among patients with an inadequate response to cDMARDs .
St and ardization of multiattribute utility instruments and a vali date d st and ard conversion method for missing utility measures would enable better comparison between CUAs