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 Targeting pathophysiological rhythms: prednisone chronotherapy shows sustained efficacy in rheumatoid arthritis Randomised comparison of combined step-down prednisolone, methotrexate and sulphasalazine with sulphasalazine alone in early rheumatoid arthritis Cost-effectiveness and cost-utility of combination therapy in early rheumatoid arthritis: randomized comparison of combined step-down prednisolone, methotrexate and sulphasalazine with sulphasalazine alone. COBRA Trial Group. Combinatietherapie Bij Reumatoïde Artritis. Hypothalamus-Pituitary-Adrenal Axis Function in Patients with Rheumatoid Arthritis Treated with Nighttime-Release Prednisone A simple model that suggests possible cost savings when modified-release prednisone 5 mg/day is added to current treatment in patients with active rheumatoid arthritis. Indirect and total costs of early rheumatoid arthritis: a randomized comparison of combined step-down prednisolone, methotrexate, and sulfasalazine with sulfasalazine alone. COBRA combination therapy in patients with early rheumatoid arthritis: long-term structural benefits of a brief intervention. Treatment of Very Early Rheumatoid Arthritis With Symptomatic Therapy, Disease-Modifying Antirheumatic Drugs, or Biologic Agents Cost-utility analysis of treatment strategies in patients with recent-onset rheumatoid arthritis.
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 Objective This 9-month open-label extension of the Circadian Administration of Prednisone in Rheumatoid Arthritis Study ( CAPRA 1 ) investigated the long-term safety and efficacy of prednisone chronotherapy with a novel modified-release ( MR ) prednisone for up to 12 months . Methods Of 288 patients with rheumatoid arthritis originally r and omised to MR or immediate-release ( IR ) prednisone , 249 continued with prednisone chronotherapy ( 2–10 mg/day ) in the 9-month open-label extension . Duration of morning stiffness of the joints ( MS ) , disease activity scores ( DAS28 ) , American College of Rheumatology ( ACR20 ) responses and plasma levels of interleukin 6 ( IL-6 ) were assessed . Safety was analysed from adverse event reports and laboratory investigations . Results During the 3-month double-blind phase , patients in the MR group achieved a reduction in MS of 33.1 % while no change was observed in the IR group . After 6 months of treatment , MS was reduced in the IR/MR group by 54 % and in the MR/MR group by 56 % . MS reduction after 12 months was 45 % ( IR/MR group ) and 55 % ( MR/MR group ) . Plasma levels of IL-6 declined on MR treatment . DAS28 was reduced from 5.8 to 4.8 ( MR/MR group ) and 4.9 ( IR/MR group ) , respectively . 37 % of the 219 patients who completed the 12-month study achieved improvement according to the ACR20 criteria . Adverse events did not differ from the known profile of low-dose prednisone . Conclusions Prednisone chronotherapy with the MR tablet was safe and well tolerated and provided a sustained improvement which result ed in a better benefit to risk ratio of low-dose glucocorticoid treatment for at least 12 months BACKGROUND The value of intensive combination therapy in early rheumatoid arthritis is unproven . In a multicentre , double-blind , r and omised trial ( COBRA ) , we compared the combination of sulphasalazine ( 2 g/day ) , methotrexate ( 7.5 mg/week ) , and prednisolone ( initially 60 mg/day , tapered in 6 weekly steps to 7.5 mg/day ) with sulphasalazine alone . METHODS 155 patients with early rheumatoid arthritis ( median duration 4 months ) were r and omly assigned combined treatment ( 76 ) or sulphasalazine alone ( 79 ) . Prednisolone and methotrexate were tapered and stopped after 28 and 40 weeks , respectively . The main outcomes were the pooled index ( a weighted change score of five disease activity measures ) and the Sharp/Van der Heijde radiographic damage score in h and s and feet . Independent health-care professionals assessed the main outcomes without knowledge of treatment allocation . FINDINGS At week 28 , the mean pooled index was 1.4 ( 95 % CI 1.2 - 1.6 ) in the combined treatment group and 0.8 ( 0.6 - 1.0 ) in the sulphasalazine group ( p < 0.0001 ) . At this time , 55 ( 72 % ) and 39 ( 49 % ) patients , respectively , were improved according to American College of Rheumatology criteria . The clinical difference between the groups decreased and was no longer significant after prednisolone was stopped , and there were no further changes after methotrexate was stopped . At 28 weeks , the radiographic damage score had increased by a median of 1 ( range 0 - 28 ) in the combined-therapy group and 4 ( 0 - 44 ) in the sulphasalazine group ( p < 0.0001 ) . The increases at week 56 ( 2 [ 0 - 43 ] vs 6 [ 0 - 54 ] , p = 0.004 ) , and at week 80 ( 4 [ 0 - 80 ] vs 12 [ 0 - 72 ] , p = 0.01 ) were also significant . Further analysis suggests that combined therapy immediately suppressed damage progression , whereas sulphasalazine did so less effectively and with a lag of 6 to 12 months . There were fewer withdrawals in the combined therapy than the sulphasalazine group ( 6 [ 8 % ] vs 23 [ 29 % ] ) , and they occurred later . INTERPRETATION This combined-therapy regimen offers additional disease control over and above that of sulphasalazine alone that persists for up to a year after corticosteroids are stopped . Although confirmatory studies and long-term follow-up are needed , this approach may prove useful in the treatment of early rheumatoid arthritis OBJECTIVE Assessment of the cost-effectiveness and cost-utility of early intervention in rheumatoid arthritis ( RA ) patients , with combined step-down prednisolone , methotrexate and sulphasalazine , compared to sulphasalazine alone . METHODS Multicentre 56 week r and omized double-blind trial with full economic analysis of direct costs and utility analysis with rating scale and st and ard gamble measurement techniques . RESULTS The combined-treatment group included 76 patients and the sulphasalazine group 78 patients . The mean total costs per patient in the first 56 weeks of follow-up were $ 5519 for combined treatment and $ 6511 for treatment with sulphasalazine alone ( P = 0.37 ) . Out-patient care , in-patient care and non-health care each contributed about one-third to the total costs . The combined-treatment group appeared to generate savings in the length of hospital stay for RA , non- protocol drugs and costs of home help , but comparisons were not statistically significant . Protocol drugs and monitoring were slightly more expensive in the combined-treatment group . Clinical , radiographic and functional outcomes significantly favoured combined treatment at week 28 ( radiography also at week 56 ) . Utility scores also favoured combined treatment . CONCLUSION Combined treatment is cost-effective due to enhanced efficacy at lower or equal direct costs Objective . To investigate the effects of longterm low-dose chronotherapy with modified-release ( MR ) prednisone for rheumatoid arthritis ( RA ) on the hypothalamus-pituitary-adrenal ( HPA ) axis as part of the Circadian Administration of Prednisone in Rheumatoid Arthritis ( CAPRA-1 ) study . This consisted of a 3-month active-controlled phase and a 9-month open-label extension with MR prednisone  including patients previously treated with prednisone  ( Clinical Trials.gov number NCT00146640 ) . Methods .  Corticotropin-releasing hormone ( CRH ) tests were performed on 28 patients at 3 timepoints : at baseline on pre study immediate-release ( IR ) prednisone , after the 3-month double-blind phase on either IR prednisone or MR prednisone , and after the 9-month open-label extension on MR prednisone . Changes of cortisol were assessed and compared to individual patients ’ efficacy and safety data . Results . The increase ( mean , SD ) of cortisol plasma concentrations after injection of corticorelin was 5.5 ( 4.37 ) μg/dl on IR prednisone at baseline ( n = 21 ) and 5.3 ( 4.07 ) μg/dl on MR prednisone at 12 months ( n = 22 ) . Numbers of normal/suppressed/no response reactions did not differ among treatments . Switching from IR to MR prednisone did not influence responses , nor did longterm treatment of up to 12 months with MR prednisone . No worsening of adrenal impairment was observed on treatment with nighttime-release prednisone in patients with low responsiveness to CRH testing before the treatment with MR prednisone . Conclusion . Treatment with nighttime-release prednisone did not change adrenocortical function over 12 months . We presume that chronotherapy with this nighttime-release prednisone may improve the efficacy of longterm low-dose glucocorticoid treatment in patients with RA OBJECTIVE The effects of a 12-week treatment with modified-release prednisone ( MR-pred ) on the costs of drug treatment of RA were modelled . METHODS With the results of a recent r and omized trial as source data , we expressed the effect of treatment ( MR-pred vs placebo ) on the decrease in the proportion of RA patients meeting disease activity thresholds for reimbursement of biologic treatment . RESULTS The results showed 11 - 13 % more patients on MR-pred than on placebo dropped below reimbursement thresholds for The Netherl and s , Belgium and the UK . Assuming 1 year of biologics cost € 15,000 and MR-pred costs € 1/day , € 396 are saved in each patient delaying biologic treatment by 12 weeks . CONCLUSION Despite a considerably higher cost than conventional prednisone , MR-pred is a cost-effective option for RA patients not on glucocorticoids who are eligible for therapy with biologic agents OBJECTIVE To describe the effect of indirect costs for patients with early rheumatoid arthritis ( RA ) within the COBRA trial ( Combinatietherapie Bij Reumatoide Artritis ) on the cost-effectiveness of both therapies . Analyses of the efficacy and direct costs of the treatments have already been reported . METHODS Patients with early RA selected for the 56-week trial were r and omly assigned to prednisolone , methotrexate , and sulfasalazine ( the COBRA combination ) ( n = 76 , tapered after 28 weeks ) or to sulfasalazine ( SSZ ; n = 79 , of which 78 patients were evaluable ) alone . The main efficacy outcomes were a pooled index and radiographic damage score in h and s and feet , and utilities . Direct and indirect costs were measured ( from a societal perspective ) by means of cost diaries and interviews completed by patients during the intervention phase and the followup phase , each lasting 28 weeks . Differences in mean costs between groups and cost-utility ratios were evaluated by applying nonparametric bootstrapping techniques . RESULTS In the first 28 weeks , indirect costs per patient totaled US $ 2,578 and US $ 3,638 for COBRA and SSZ therapy , respectively ( p = 0.09 ) . The total costs were $ 5,931 and $ 7,853 , respectively ( p < 0.05 ) . These differences were lost in the second 28 weeks . For the total period the mean total costs per patient were $ 10,262 and $ 12,788 , respectively ( p = 0.11 ) . Sensitivity analyses showed robustness of the data . The point estimate of the cost per quality -adjusted life-year based on the rating scale was negative at $ -385 , suggesting dominance of COBRA ( more effect at lower cost ) . CONCLUSION COBRA therapy adds additional disease control ( improvements in disease activity , physical function , and rate of damage progression ) at lower or equal cost compared to SSZ in early RA OBJECTIVE The Combinatietherapie Bij Reumatoide Artritis ( COBRA ) trial demonstrated that step-down combination therapy with prednisolone , methotrexate , and sulfasalazine ( SSZ ) was superior to SSZ monotherapy for suppressing disease activity and radiologic progression of rheumatoid arthritis ( RA ) . The current study was conducted to investigate whether the benefits of COBRA therapy were sustained over time , and to determine which baseline factors could predict outcome . METHODS All patients had participated in the 56-week COBRA trial . During followup , they were seen by their own rheumatologists and were also assessed regularly by study nurses ; no treatment protocol was specified . Disease activity , radiologic damage , and functional ability were the primary outcome domains . Two independent assessors scored radiographs in sequence according to the Sharp/van der Heijde method . Outcomes were analyzed by generalized estimating equations on the basis of intent-to-treat , starting with data obtained at the last visit of the COBRA trial ( 56 weeks after baseline ) . RESULTS At the beginning of followup , patients in the COBRA group had a significantly lower mean time-averaged 28-joint disease activity score ( DAS28 ) and a significantly lower median radiologic damage ( Sharp ) score compared with those in the SSZ monotherapy group . The functional ability score ( Health Assessment Question naire [ HAQ ] ) was similar in both groups . During the 4 - 5 year followup period , the time-averaged DAS28 decreased 0.17 points per year in the SSZ group and 0.07 in the COBRA group . The Sharp progression rate was 8.6 points per year in the SSZ group and 5.6 in the COBRA group . After adjustment for differences in treatment and disease activity during followup , the between-group difference in the rate of radiologic progression was 3.7 points per year . The HAQ score did not change significantly over time . Independent baseline predictors of radiologic progression over time ( apart from treatment allocation ) were rheumatoid factor positivity , Sharp score , and DAS28 . CONCLUSION An initial 6-month cycle of intensive combination treatment that includes high-dose corticosteroids results in sustained suppression of the rate of radiologic progression in patients with early RA , independent of subsequent antirheumatic therapy 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 , patient education , joint protection and therapeutic exercise , pain management , and low-dose glucocorticoids are administered as needed , followed by DMARDs at 1 year for nonresponders . This is still the most common pattern of therapy because of delayed consultation and diagnosis ( 2830 ) . In the early DMARD strategy , conventional DMARDs ( such agents as leflunomide , sulfasalazine , hydroxychloroquine , or methotrexate ) are given within 12 weeks of symptom onset . Methotrexate is the current st and ard of care in U.S. rheumatology ( 30 ) and also has the most evidence for its effectiveness in very early RA ( 6 ) . The early biologic strategy involves very early use of biologics , defined as use of 3 sequential tumor necrosis factor inhibitors , in combination with methotrexate . In the first 2 strategies , patients initially receive conventional DMARDs ; those who do not respond to therapy with 3 conventional DMARDs , alone or in combination , then receive agents from the third strategy . We modified a published model ( 31 ) for this analysis . We tracked hypothetical patient cohorts through the model , one at a time , in 6-month cycles from symptom onset until death . The exact route a simulated patient takes through the model depends on the therapeutic strategy used and the patient 's disease characteristics ( type of disease progression , age , sex , education level , race , income , duration of disease , comorbid conditions , baseline and current Health Assessment Question naire [ HAQ ] Disability Index score , and type and number of previously received DMARDs ) . Figure 1 shows model pathways . Figure 1 . Model schematic . Patients can change disease state every 6 months , depending on the underlying disease type and the treatment strategy received . The time spent in a particular disease state determines the probability of transition and the ultimate outcome . DMARD = disease-modifying antirheumatic drug ;  HAQ = Health Assessment Question naire ; RA = rheumatoid arthritis . * See Appendix for discussion of this strategy . Appendix . Technical Appendix We assume that patients follow 1 of 3 disease courses : drug-free remission , a mild course with slow disease progression , or rapid disease progression . At presentation , we assume that a patient 's future course can not be predicted . The patients ' disease characteristics are representative of the U.S. population with RA ( 32 ) . The model synthesizes data from RCTs ( 33 ) ; the National Data Bank for Rheumatic Diseases ( NDB ) , a longitudinal data base of semi-annual , self-reported patient data ( 32 ) ; and other literature . Details on disease progression , treatment effect , estimates for QALYs , and costs are provided in the following sections . Table 1 ( 3445 ) describes input variables , and the Appendix details our methods . We used R project statistical software ( www.R-project.org ) for all decision analyses . Table 1 . Key Model Parameters and Assumptions Disease Progression We modeled the course of the disease by using functional disability and radiographic evidence of structural joint damage . Functional disability , measured by the HAQ ( 46 ) , is a primary outcome in most RA clinical studies . Structural joint damage can be assessed by several radiographic scoring methods . We used the percentage of the maximum score of each measure to include all sources of information ( 39 ) . We applied the rate of disease progression to each disease course pattern . Because these rates are often unknown over an extended period , we first assumed that all patients present with a HAQ score of 1 and no radiographic damage . We then used the literature as a guide for the mean progression rates in each disease course . Finally , we calibrated the overall progression for all disease courses . We calibrated the HAQ with data from the NDB that show increases during early disease to an annual HAQ score progression of around 0.03 in patients with established disease , similar to previous estimates ( 47 ) . We assumed that radiographic damage increased linearly over time and calibrated it with rates of approximately 2 % per year ( 48 ) . We computed the relationship between radiographic damage and HAQ score . Estimates indicate that a 1percentage point change in radiographic progression is equivalent to a 0.04 change in HAQ score ( 38 ) . However , the effect of radiographic progression on functional disability in early phases of disease is only OBJECTIVE To evaluate societal costs and quality -adjusted life years ( QALYs ) of treatment strategies for patients with recent-onset active rheumatoid arthritis ( RA ) . METHODS Patients ( n = 508 ) were r and omly allocated to 1 of 4 treatment strategy groups : sequential monotherapy , step-up combination therapy , initial combination therapy with prednisone , or initial combination therapy with infliximab . For 2 years , patients reported cost and utility measures . RESULTS Average QALYs ( ideally 2.00 ) for groups 1 - 4 were 1.29 , 1.31 , 1.32 , and 1.41 , respectively , for the British EuroQol ( P < or= 0.05 for group 4 versus groups 1 - 3 ) ; 1.41 , 1.43 , 1.44 , and 1.52 , respectively , for the Dutch EuroQol ( P < or= 0.05 for group 4 versus groups 1 - 3 ) ; and 1.38 , 1.38 , 1.39 , and 1.44 , respectively , for the Short Form 6D ( P < or= 0.05 for group 4 versus groups 1 - 3 ) . The Time Trade-Off showed no significant differences . In the primary analysis , using the friction cost method to value productivity , the cost-utility ratio for group 4 against the next best alternative was estimated at euro 130,000 ( 95 % confidence interval euro 27,000 , euro 3,000,000 ) per QALY . Using the human capital method , the value of sustained productivity in group 4 largely compensated for the extra medication costs . CONCLUSION Initial combination therapy with infliximab for patients with recent-onset active RA result ed in significantly better quality of life than other strategies . Using the friction cost method , costs to achieve this improvement are generally considered too high , and initial combination therapy with prednisone should be preferred . However , depending on the extent to which productivity is valued , infliximab costs could be largely compensated for by savings on productivity . Since patterns of infliximab use had not yet stabilized after 2 years , longer followup may change the economic conclusions
The total cost of RA is substantial , particularly in patients with high levels of disability .
There are considerable differences in cost between countries , driven in part by differences in the use of biologic therapies .
Economic evaluations are needed to assess the extra cost of using these treatments and the benefits obtained , to ensure appropriate allocation of limited health care re sources .