18th Congress of the
European Association of Hospital Pharmacists (EAHP)
Paris, 14 March 2013
Value-based Decision Making in Rheumatic Disease
What does it mean for What does it mean for What does it mean for What does it mean for Pharmacists? Pharmacists? Pharmacists? Pharmacists?
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Pr. Robert LaunoisREES France
28, Rue d’Assas
75016, PARIS
Value-based Decision Making in Rheumatic Disease
Disclosure • Financial interests: None
• Durable or permanent links
• Expert comittees : Alcon, Alliance-Médica, Aventis, Bayer Diagnotics,Bristol Myers Squibb Company, Eli-Lilly, Pierre Fabre Médicaments, Glaxo-SmithKline, IMS Squibb Company, Eli-Lilly, Pierre Fabre Médicaments, Glaxo-SmithKline, IMS Health, Innothera, MSD, Lundbeck, Medpass International, Pfizer, Roche, Servier, Abbott, Celgene, Les Entreprises du Médicament (LEEM)
• Occasional interventions : Bayer Diagnotics,Bristol Myers Squibb Company, Eli-Lilly, Pierre Fabre Médicaments, Glaxo-SmithKline, MSD, Lundbeck, Pfizer, Roche, Servier, Abbott, Celgene, Les Entreprises du Médicament (LEEM)
• Study sponsored by Pfizer
• “Mixed treatment comparison, cost-effectiveness analysis and budget impact model in the treatment of rheumatoid arthritis after failure of conventional DMARD
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in the treatment of rheumatoid arthritis after failure of conventional DMARD therapy. A comprehensive Bayesian decision analytical modelling” (To be published)
• Participation in the protocol design, the statistical analysis and finalization of the manuscript
• In collaboration with academic researchers Pr MC Boissier MD
Robert Launois
OutlineOutlineOutlineOutline
• Background & Objectives
• The Buyer Case
• Methods
• Results
• Discussion
3Robert Launois
Background
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• Health care professionals are encouraged to consider the value, i.e the balance between costs and benefits in their decisions.
ValueValueValueValue----based Decision Making: based Decision Making: based Decision Making: based Decision Making: What Does it Mean?What Does it Mean?What Does it Mean?What Does it Mean?
balance between costs and benefits in their decisions.
• Value-based decision-making should not be confused with:
– Value-based purchasing : P4P programs linking payments to specific performance measures.
– Value-based benefit design : heath plans structuring cost sharing to encourage the use of the most effective services.
– Value based pricing : payers using the Incremental Cost Effectiveness Ratio (ICER), not as a value criterion in itself, but as a price
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Health And Ethics Policies Of The AMA House Of DelegatesH-155.960 Strategies to Address Rising Health Care Costs
Ratio (ICER), not as a value criterion in itself, but as a price negotiation tool to be compared to a socially acceptable price.
• The aim of the value-based decision-making approach is to improve the processes by which health-related decisions are made.
Robert Launois
What Does it Mean For Pharmacists?What Does it Mean For Pharmacists?What Does it Mean For Pharmacists?What Does it Mean For Pharmacists?
• It encourages pharmacists to achieve better value for healthcare spending.
• Value can be defined as the best balance between benefits and costs.
• Better value can be defined as improved clinical outcomes, quality of life and patient satisfaction per euro spent.
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• The goal is not to reduce appropriate utilisation but to find the most valuable use of services : « the bang for the buck »
Robert Launois
Aim of the PresentationAim of the PresentationAim of the PresentationAim of the Presentation
The aimof my presentation is to answerthe question asked:The aimof my presentation is to answerthe question asked:
« What does value-based decision making mean for pharmacists? »
by illustratinghow to balance the comparative effectiveness,
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by illustratinghow to balance the comparative effectiveness, safety and efficiency of TNF inhibitors in rheumatoid arthritis in 2nd and 3rd line of treatment.
Robert Launois
The Buyer CaseThe Buyer CaseHow should pharmacist recommend one out of five TNF α inhibitors in the 2nd and 3rd line of
treatment for rheumatoid arthritis?
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Launois, R., Le Moine, JG., Huynh MT., Boissier, MC. (To be Published) “Mixed treatment comparison, cost-effectiveness analysis and budget impact model in the treatment of rheumatoid arthritis after failure of conventional DMARD therapy. A comprehensive Bayesian decision analytical modelling”
Robert Launois
Methods
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• Patients with an inadequate response to MTX are treated with one of the following
Alternative Treatment StrategiesAlternative Treatment StrategiesAlternative Treatment StrategiesAlternative Treatment Strategies
MTX are treated with one of the following biotherapies:
• adalimumab (ADA), Humira®• etanercept (ETA), Enbrel®• infliximab (INF), Remicade®• certolizumab pegol (CZP), Cimzia
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infliximab (INF), Remicade• certolizumab pegol (CZP), Cimzia®• tocilizumab (TCZ), Roctemra®
Robert Launois
Target PopulationTarget PopulationTarget PopulationTarget Population
Median value presented
According to expert knowledge†Prevalence estimate: 130,000-240,000 patients
18% failed treatment with MTX
Median value presented(45-60% lower & upper bounds estimates
treated with MTX)L1 : Méthotrexate (MTX)
L2 :TNF α inhibitors + MTX
15,000 patients
84,000 patients(60 000-144 000)
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33% experience an inadequate response to TNF α inhibitors
L3 : TNF α inhibitors + MTX
15,000 patients
5,000 patients
† : Guillemin & Saraux, 2001Robert Launois
Turning Evidence Into ActionTurning Evidence Into ActionTurning Evidence Into ActionTurning Evidence Into Action
• Management of the disease is first defined in benefits and harm: will the intervention help or hurt? and harm: will the intervention help or hurt?
• The systematic review is the main instrument for comparing « alternative methods to treat a clinical condition »
• But a second dimension has to be considered : how does the efficiency of a treatment compare with other
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the efficiency of a treatment compare with other alternatives?
Robert Launois
• 2 databases were interrogated between 1999 and 2011.
Systematic ReviewSystematic ReviewSystematic ReviewSystematic Review
Iden
tific
atio
n Articles from Embase n=637
Articles from Medline n=1356
Articles selected for title review, after elimination on duplicates
n=1286
Articles from other bases
n=7
• There were 2,000 initial hits.
• 714 duplicates identified and eliminated, resulting in 1,300 (approx.)articles for screening, based on title and abstract.
• This resulted in 59 eligible
Scr
een
ing
n=1286
Articles selected for abstracts review n=101
Excluded : n= 1185- Treatment- Design- Small samples- No comparator- Economics- Juvenile population- Inadequate subgroup- Outcomes (other than efficacy, safety)- Editorial
Excluded : n= 42- Non randomized trial- Systematic review
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• This resulted in 59 eligible articles for full reading.
• Finally, 24 articles were retained for the meta-analysis.
Elig
ibili
tyIn
clud
ed
Excluded : n= 35- 24 weeks ± 10 weeks- Methotrexate naive- Inadequate comparators- Patients after failure of TNF alpha inhibitors- Adaptative trials
Articles selected for entire article reviewn=59
Articles included in MTCn=24
PRISMA Template, 2009Robert Launois
Bayesian Network Meta AnalysisBayesian Network Meta AnalysisBayesian Network Meta AnalysisBayesian Network Meta Analysis
• 24 trials were included: involving 8,000 (approx.)patients who had an inadequate response to MTX.
• The Network Meta-analysis included 11 protocols, of which 10 were direct comparisons.
• Two studies were excluded to reduce heterogeneity among trials: one on etanercept (ETA)
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trials: one on etanercept (ETA) and one on adalimumab (ADA).
• 22 studies were effectively used in the meta analysis.
Robert Launois
ValueValueValueValue----based Decision Makingbased Decision Makingbased Decision Makingbased Decision Making
• A Markov model was developed to implement:
– A cost-effectiveness analysis
– A budget impact analysis– A budget impact analysis
• Both simulations were programmed using Winbugs Software
• The criteria from the American College of Rheumatology (ACR 50†) was used as the effectiveness
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Rheumatology (ACR 50†) was used as the effectiveness end-point at week 24 ± 2.
†ACR 50 : ACR 50% improvement incorporates 50% of tender (nombre de synovites) and swollen joints (nombre d’articulations douloureuses) and 3 of the 5 remaining core outcome measures : Pain – (VAS), Patients global assessment -(VAS), Physicians global assessment –(VAS), Function - Health Assessment Questionnaire (HAQ), and biologic Inflammation: CRP or ESR (VSb ou Créatinines).
Robert Launois
• There are 5 health states in the 2nd line and 5 in the 3rd line of treatment.
• There are 2 additionalhealthstates: one
The Engine: A 12 HealthThe Engine: A 12 HealthThe Engine: A 12 HealthThe Engine: A 12 Health----State Markov Model State Markov Model State Markov Model State Markov Model
DeathDEAD
L2:ADA + MTXEntry: Prevalence
15,000 patients GO L2:CZP + MTX
• There are 2 additionalhealthstates: one for yearly prevalent cases and anotherfor death.
• Following the clinical pathway: the patient either stays in the 2nd treatmentline or moves to the 3rd after failure, infection or dropout.
• The fundamentalidea: eachpatient who
L2:ETA + MTX
L2:TCZ + MTXSuccess
L2:INF + MTX No infectionGO
Failure Infection L3:ADA + MT X
L2:ADA + MTX FollowupL3:CZP + MTX
L2:CZP + MTX DropoutL3:ETA + MTX
MTX failure M L2:ETA + MTXL3:TCZ + MTX
L2:TCZ + MTXL3:INF + MTX
L2:INF + MTX
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• The fundamentalidea: eachpatient whoexits on the right-hand side of the treatment line either
– (a) re-enters the next cycle on the same 2nd
line treatment or – (b) switches to the 3rd line after failure.
DeathL3:ADA + MTX DEAD
L3:CZP + MTX
L3:ETA + MTX
L3:TCZ + MTX
L3:INF + MTX
Exit: DEAD
Robert Launois
Data sourcesData sourcesData sourcesData sources
Epidemiological dataSource: French Transparency Commission
Target population size (L2 + L3) 13,500 - 34,000 patients†
Resource utilisation Ad hoc observational studies
Treatment acquisition costs (per patient for 6 months)
Calculated from: Market Authorization (MA) dosages, Source: Ameli.fr drug database
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Source: Ameli.fr drug database
Treatment administration costsExtracted from: French National Health Insurance nomenclatures*
† : Guillemin & Saraux, 2001 ; * : CCAM v32, NABM, v22, DRG v11c, NGAP
Robert Launois
Results
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Lessons from the Meta AnalysisLessons from the Meta AnalysisLessons from the Meta AnalysisLessons from the Meta Analysis
• Results reported for the treatmentcombinations are measured in terms of log OR, therefore with respect to zero.
• The line crossing at zero represents equalefficacy/safetywith respect to MTX or INF + MTX vs DMARD
GOL + MTX vs DMARD
ETA + MTX vs DMARD
CZP + MTX vs DMARD
ADA + MTX vs DMARD
EF
FIC
AC
Y :
AC
R 5
0
efficacy/safetywith respect to MTX or placebo
• The relative rates of response are on the right-side and the rates of detrimental side-effectson the left-side.
• ACR 50 response rates for all biotherapies were significantly higher than for the MTX treatment or placebo(circled in red)
• None of the biotherapies could be ADA + MTX vs DMARD
TCZ + MTX vs DMARD
INF + MTX vs DMARD
ETA + MTX vs DMARD
GOL + MTX vs DMARD
CZP + MTX vs DMARD
ADA + MTX vs DMARD
TCZ + MTX vs DMARD
INF + MTX vs DMARD
SA
FE
TY
: In
fect
ion
sE
FF
ICA
CY
:
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• None of the biotherapies could be distinguished from each other because the confidence intervals overlapped.
• No significant difference was found between treatments for infection rates
-4 -3 -2 -1 0 1 2 3
TCZ + MTX vs DMARD
INF + MTX vs DMARD
GOL + MTX vs DMARD
ETA + MTX vs DMARD
CZP + MTX vs DMARD
SA
FE
TY
: D
rop
ou
ts
• Dropout rates were lower for CZP, ETA, and TCZ compared to DMARDs.
Robert Launois
Efficiency FrontierEfficiency FrontierEfficiency FrontierEfficiency Frontier
• The Efficiency Frontier was constructed from 3,000 simulations based on:
• Average annual cost per patient (cost criterion) and,
Cost-Effectiveness Plane of the First Line anti-TNF Treatment after Failure of a Antibody Treatment
3400
0Cand,
• Average annual rate of maintenance on treatment (efficacy endpoint).
• The frontier was defined by the linear combination of ADA and ETA.
• CZP, INF and TCZ combinations are strongly dominated (i.e. more costly for the same effectiveness).
2200
028
000
INF(Dominated)
TCZ(Dominated)
1170
012
000
CZP ETAAve
rage
ann
uel C
ost i
n €
, C
//
Ave
rag
eAn
nu
alC
ost
(€)
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• The positive gradient of the frontier means that remission rate for ETA is greater than that of ADA.
• A longer remission is obtained at an additional cost of 1,715€ p.y.
Dominated: more cost and less effectiveAverage annuel rate of maintenance under treatment, E
0.10 0.15 0.20 0.25 0.301140
011
700
ADA
CZP ETA
(Dominated)
1715 €/ Maintenance under treatment 3000 iterations
Ave
rage
ann
uel C
ost i
n A
vera
ge
Robert Launois
Cost Effectiveness PlaneCost Effectiveness PlaneCost Effectiveness PlaneCost Effectiveness Plane
• The value of the societal willingness to pay (WTP) is represented by a line whose slope increases with the amountof money society is willing to allocate 40
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Incremental Quadrant Plot The First Line : Etanercept vs. Certolizumab
of money society is willing to allocate• 3000 simulations of the differences
between average cost and effectivenessper patient were implemented.
• The Incremental Net Health Benefit(INHB) of an intervention compared to another is equal to the differencebetween:
– the additionalhealthbenefit∆E valued
-200
00
2000
4000
Incr
emen
tal a
vera
ge
annu
al c
ost i
n € ∆
C
CZP
ETA dominated(16%)
ETA dominating(37%)
3000 itérations
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– the additionalhealthbenefit∆E valuedon the basis of the social WTP and,
– the amount of the additional expenditureto be incurred in order to fund the project∆C
• INHB = WTP * ∆E-∆C .
-1.0 -0.5 0.0 0.5 1.0-4
000
-200
0
p: Probability to be efficient for a given value of WTPIncremental average annual rate of maintenance under treatment, ∆E
Incr
emen
tal a
vera
ge
annu
al c
ost i
n
WTP : Willingness To Pay
WTP(€) : p
150 € : 0.49 5.000 € : 0.6410.000 € : 0.69
Robert Launois
Acceptability FrontierAcceptability FrontierAcceptability FrontierAcceptability Frontier
• When several treatments are mutually exclusive; the acceptability frontier, should be
Acceptability Frontier The First Line
1 ADA INFacceptability frontier, should be used instead of the Cost Effectiveness Acceptality Curve (CEAC)†
• The acceptability frontier envelopes the totality of the Net Health Benefit curves.
Pro
bab
ility
cos
t-effe
ctiv
e
0.2
0.4
0.6
0.8
1
Adalimumab Etanercept
ADACZPETA
INFTCZEfficient Frontier
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• INF, TCZ and CZP being located below the acceptability frontier are dominated and should therefore be considered as inefficient above a WTP of 1,715 € p.y. 3000 iterations
Willingness to pay( € )
0 € 10000 € 25000 € 40000 € 55000 €0
1715 €
† Briggs, 2002 Medical Desicion Making22: 290-308
Robert Launois
Budget Impact ModelBudget Impact ModelBudget Impact ModelBudget Impact Model
• Average annual costs per patient were estimated assuming a 10% reduction in the market share of eternacept (ETA) in the next 5 years.
Average annual cost per patient and per treatment in 1st line
Average annual cost per patient and per treatment in 2nd line
• Two distinct groups with significantly different overall annual average expenditures (per patient, per year) were identified :
Group Components A. A. C. in €
I ADA, CZP & ETA 12,000-13,000
2000
03
5000
26663
32290
Ave
rage
ann
ual c
ost i
n €
//
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I ADA, CZP & ETA 12,000-13,000
II INF & TCZ 26,000-33,000
Treatment
110
001
5000
ADA CZP ETA INF TCZ
12781
13186 13062
Ave
rage
ann
ual c
ost i
n • Differences are simply explained by the
fact that INF & TCZ are administered intravenously at the hospital.
Robert Launois
An overly restrictive policy based solely on
DiscussionDiscussionDiscussionDiscussion
An overly restrictive policy based solely on the daily cost of drug acquisition may conceal the cost saving that the therapeutic intervention could have on the overall cost of the healthcare system.
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of the healthcare system.
Robert Launois
References for Eligible Articles in the MAReferences for Eligible Articles in the MAReferences for Eligible Articles in the MAReferences for Eligible Articles in the MA1 Furst, D. E., M. H. Schiff, et al. (2003). "Adalimumab, a Fully Human Anti-Tumor Necrosis Factor-(alpha) Monoclonal Antibody, and Concomitant Standard Antirheumatic Therapy for the Treatment ofRheumatoid Arthritis: Results of STAR (Safety Trial of Adalimumab in Rheumatoid Arthritis)." Journal of Rheumatology30(12): 2563-2571.2 Keystone et al (2004) Radiographic, Clinical, and functinal Outcomes of treatment with adalimumab (a human anti-Tumor Necrosis Factor Monoclonal Antibody) in patients with active rheumatoid arthritisreceiving concomitant Methotrexate therapy : Arth & Rheu 50(5): 1400-14113 Kim, H. Y., S. K. Lee, et al. (2007). "A randomized, double-blind, placebo-controlled, phase III study of the human anti-tumor necrosis factor antibody adalimumab administered as subcutaneous injections inKorean rheumatoid arthritis patients treated with methotrexate." APLAR Journal of Rheumatology 10(1): 9-16.4 Weinblatt ME, Keystone EC, Furst DE, Moreland LW, Weisman MH, Birbara CA, et al. "Adalimumab, a fully human antitumor necrosis factor _ monoclonal antibody, for the treatment of rheumatoidarthritis in patients taking concomitant methotrexate: the ARMADA trial". Arthritis Rheum 2003;48:35-45.5 Keystone, E., D. Van Der Heijde, et al. (2008). "Certolizumab pegol plus methotrexate is significantly more effectivethan placebo plus methotrexate in active rheumatoid arthritis: Findings of a fifty-two-week,phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group study." Arthritis and Rheumatism 58(11): 3319-3329.6 Smolen,J., R. B. Landewe,et al. (2009). "Efficacy andsafetyof certolizumabpegolplusmethotrexatein activerheumatoidarthritis: theRAPID 2 study. A randomisedcontrolledtrial." Ann RheumDis 68(6):6 Smolen,J., R. B. Landewe,et al. (2009). "Efficacy andsafetyof certolizumabpegolplusmethotrexatein activerheumatoidarthritis: theRAPID 2 study. A randomisedcontrolledtrial." Ann RheumDis 68(6):797-804.7 Combe, B., C. Codreanu, et al. (2009). "Efficacy, safety and patient-reported outcomes of combination etanercept andsulfasalazine versus etanercept alone in patients with rheumatoid arthritis: a double-blindrandomised 2-year study." Ann Rheum Dis 68(7): 1146-1152.8 Klareskog, L., D. Van Der Heijde, et al. (2004). "Therapeutic effect of the combination of etanercept and methotrexatecompared with each treatment alone in patients with rheumatoid arthritis: Double-blindrandomised controlled trial." Lancet 363(9410): 675-681.9 Weinblatt ME, Kremer JM, Bankhurst AD et al. "A trial of etanercept, a recombinant tumor necrosis factor receptor:Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate". N Engl JMed 1999;340:253-9.10 Kay, J., E. L. Matteson, et al. (2008). "Golimumab in patients with active rheumatoid arthritis despite treatment with methotrexate: a randomized, double-blind, placebo-controlled, dose-ranging study."Arthritis Rheum 58(4): 964-975.11 Keystone, E. C., M. C. Genovese, et al. (2009). "Golimumab, a human antibody to tumour necrosis factor {alpha} given bymonthly subcutaneous injections, in active rheumatoid arthritis despitemethotrexate therapy: the GO-FORWARD Study." Ann Rheum Dis68(6): 789-796.12 Kremer, J., C. Ritchlin, et al. (2010). "Golimumab, a new human anti-tumor necrosis factor alpha antibody, administered intravenously in patients with active rheumatoid arthritis: Forty-eight-week efficacyand safety results of a phase III randomized, double-blind,placebo-controlled study." Arthritis Rheum 62(4): 917-928.13 Maini et al. (1999) " Infliximab (chimeric anti-tumour necrosis factor & monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate : a randomised phase IIItrial". Lancet 354: 1932-3914 Schiff, M., M. Keiserman, et al. (2008). "Efficacy and safety of abatacept or infliximab vs placebo in ATTEST: a phase III, multi-centre, randomised, double-blind, placebo-controlled study in patients withrheumatoid arthritis and an inadequate response to methotrexate." Ann Rheum Dis 67(8): 1096-1103.15 Westhovens, R., D. Yocum, et al. (2006). "The safety of infliximab, combined with background treatments, among patients with rheumatoid arthritis and various comorbidities: alarge, randomized, placebo-controlledtrial." Arthritis Rheum54(4): 1075-1086.
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controlledtrial." Arthritis Rheum54(4): 1075-1086.16 Zhang, F. C., Y. Hou, et al. (2006). "Infliximab versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: A preliminary study from China." APLAR Journal of Rheumatology 9(2):127-130.17 Genovese, M. C., J. D. McKay, et al. (2008). "Interleukin-6 receptor inhibition with tocilizumab reduces disease activity in rheumatoid arthritis with inadequate response to disease-modifying antirheumaticdrugs: the tocilizumab in combination with traditional disease-modifying antirheumatic drug therapy study." Arthritis Rheum 58(10): 2968-2980.18 Maini, R. N., P. C. Taylor, et al. (2006). "Double-blind randomized controlled clinical trial of the interleukin-6 receptor antagonist, tocilizumab, in European patients withrheumatoid arthritis who had anincomplete response to methotrexate." Arthritis Rheum 54(9): 2817-2829.19 Smolen, J. S., A. Beaulieu, et al. (2008). "Effect of interleukin-6 receptor inhibition with tocilizumab in patientswith rheumatoid arthritis (OPTION study): a double-blind,placebo-controlled, randomisedtrial." Lancet 371(9617): 987-997.20 Miyasaka N. Clinical investigation in highly disease-affected rheumatoid arthritis patients in Japan with adalimumab applying standard and general evaluation: the CHANGE study. Mod Rheumatol.2008;18(3):252-262.21 van de Putte LB, Atkins C, Malaise M, et al. Efficacy and safety of adalimumab as monotherapy in patients with rheumatoid arthritis for whom previous disease modifying antirheumatic drug treatment hasfailed. Ann Rheum Dis. May 2004;63(5):508-516.22 Moreland LW, Schiff MH, Baumgartner SW, et al. Etanercepttherapy in rheumatoid arthritis. A randomized, controlledtrial. Ann Intern Med. Mar 16 1999;130(6):478-486.23 Nishimoto N, Hashimoto J, Miyasaka N, et al. Study of active controlled monotherapy used for rheumatoid arthritis, anIL-6 inhibitor (SAMURAI): evidence of clinical and radiographic benefit from an x rayreader-blinded randomised controlled trial of tocilizumab. Ann Rheum Dis. Sep 2007;66(9):1162-1167.24 Nishimoto N, Miyasaka N, Yamamoto K, et al. Study of activecontrolled tocilizumab monotherapy for rheumatoid arthritis patients with an inadequate response to methotrexate (SATORI): significantreduction in disease activity and serum vascular endothelial growth factor by IL-6 receptor inhibition therapy. Mod Rheumatol. 2009;19(1):12-19.
Thank you !
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