De-Escalation of Therapy in Rheumatoid Arthritis Patients A First World ChallengeVivian P. Bykerk MDDirector of Inflammatory Arthritis CenterHospital for Special Surgery

ACR 2018

Disclosures and Conflicts of Interest

Consultant/Advisor: Amgen, Abbvie, BMS, Gilead, Pfizer, Sanofi/Genzyme, Regeneron, UCBClinical / Investigator Initiated Research: Amgen,, Abbvie, BMS, Pfizer, Roche, UCB, Sanofi, Lilly Boehringer IngelheimSpeaker: EULAR, ACR, UCBSpouse: an employee of Brainstorm Therapeutics

Research Grants: PCORI, NIH/NIAMS, CIHRData Safety Monitoring Boards: Astellas Pharmaceuticals, KAI for NIH

Author on studies involving tapering or withdrawal of therapyDevelopment of a Patient Reported Flare MeasureCIHR funded to study treatment withdrawal

ObjectivesStrategies to de-escalate (reduce or withdraw) csDMARDs or biologic DMARD

Risk of flare (increased disease activity) of RA after therapy de-escalation

Potential clinical benefits and adverse effects

Potential economic benefits of therapy de-escalation of RA

Definitions & Acronyms• De-escalation (tapering OR discontinuing, OR both in a staged

algorithm)• Success or Failure – worsening of synovitis as a result of de-

escalation• RA flare: defined by clinician measure (i.e. DAS28)• Drug free remission (DFR) or Drug reduced remission (DRR)• Stable clinical sustained remission (susREM)- DAS28≤2.6 or

DAS≤ 1.6 for 2 or 3 sequential visits• Low disease activity (LDA) – DAS28 defined < 3.2

Definitions & Acronyms

• De-escalation (tapering OR discontinuing, OR both in a staged algorithm)

• Success or Failure – worsening of synovitis as a result of de-escalation, RA Flare

• RA flare: in studies has been defined by clinician measure (i.e. DAS28)

• Drug free remission (DFR) or Drug reduced remission (DRR)• Sustained remission (susREM)- 2 or 3 sequential visits where

DAS28≤2.6 or DAS≤ 1.6 in remission• Low disease activity (LDA) – DAS28 defined < 3.2

28+ Studies of De-escalation, 6 SLR or Meta-analyses

• Singh JA. Tapering Janus kinase inhibitors in rheumatoid arthritis with low disease activity or remission: reality or dream? Singh JA, Ann Rheum Dis. 2018 Oct

• Henaux S, et al. Risk of losing remission, low disease activity or radiographic progression in case of bDMARD discontinuation or tapering in rheumatoid arthritis: systematic analysis of the literature and meta-analysis. Ann Rheum Dis 2018;77:515–522

• Edwards CJ , Fautrel B , Schulze-Koops H , et al. Dosing down with biologic therapies: a systematic review and clinicians' perspective. Rheumatology 2017

• Lau CS , Gibofsky A , Damjanov N , et al. Down-titration of biologics for the treatment of rheumatoid arthritis: a systematic literature review. Rheumatol Int 2017

• Schett G , Emery P , Tanaka Y , et al . Tapering biologic and conventional DMARD therapy in rheumatoid arthritis: current evidence and future directions. Ann Rheum Dis 2016

• van Herwaarden N et al, Down-titration and discontinuation strategies of tumor necrosis factor-blocking agents for rheumatoid arthritis in patients with low disease activity. Cochrane Database Syst Rev. 2014 Sep 29; (9):CD010455. Epub 2014 Sep 29.

Increase in Real World DataDouble Blind RCTs

– Phase III/IV Trials

– Established RA, if LDA randomized to de-escalate

– Early RA: Induction regimen 6 – 12 months – if LDA (or REM) randomized de-escalation

– Shorter 6-12 month FU

Pragmatic Studies

– Generalizable : few restrictions, allow co-therapy, unblinded

– Unblinded RCT: in registries if REM/LDA taper or stop

– Staged de-escalation: aim for drug free remission

– Open single arm study: Mandated Observation

– Goal directed/Algorithm based de-escalation study

2012-2018…Europe

2012-2014

Should Tx De-Escalation of bDMARDs be Recommended or Mandated?

Guidelines and Older Meta-Analyses

ACR / EULAR guidelines:

• Taper bDMARDs in stable treated RA patients in sustained clinical remission (with caution)

• Based on data (2011-2014) from randomized controlled trials

• Data from Pragmatic trials published in past 3 years

Need Real World Evidence

• Strategies for de-escalation

• Order of de-escalation

• Predict who can taper/stop cs/bDMARDs

• Who is at risk of not regaining disease control

• Potential benefits vs. harms

• Risk of damage progression

• Risk of job loss

• Will patients benefit economically?

Each time consider de-escalation assess chance of success and risk

• Would you actively taper therapy in patients who are in:– Stable Low disease activity (LDA)?– Stable clinical sustained Remission (susREM)?– Deep/Prolonged susREM, confirmed by imaging?

• Would you taper if the chance of success was:– 25-30%– 45-50%– 75-80%

• Would you taper or stop if you knew your patient would flare by – 6 months– 1 year– 2 years

Data from Meta-Analyses

and Specific Recent Trials

P

Low Disease Activity

Schema of Drug De-escalation Studies

Sustained Remission

30% of dose 50% of dose

50% of dose

Population of RAPatients

Stop

Stop

Stop bDMARD

or all

Run in Study

RCT of bDMARD vs

PBO

Registry, Cohort, Practice

Flare

Flare

Current therapy – csDMARD (MTX) ± Steroids ± bDMARD

3 mos 6 mos 9 mos 2 years1 year

Continue / Maintain Current Therapy

Slightly > Radiographic Progression if Stop CZP

Weinblatt M et al. A&R, Oct 2017

Complete Study Duration

Baseline to End of Year 2

Withdrawal and Retreatment

Phase (Year 2 Only)

C-EARLY: Study – RCT Continue, Taper, or Withdraw Certolizumab after 1 Year of therapy in Early RA Patients

Patients stopping CZP lost LDA vs. those who continued

Methotrexate 25 mg continued in all

Flare Rate from Meta-analysis of 25 RCTs or Observational Studies De-escalation

Flare Rates:csDMARDs - 4 studies

• 8% at 24 weeks

• 63% at 4 months after de-escalation

TNFi - 15 studies

• 0.26 (95% CI 0.17-0.39) (de-escalation)

• 0.49 (95% CI 0.27-0.73)(stopping)

Tocilizumab 3 studies

• 41% by 6 months

• 55-87% at 1 year

Abatacept 3 studies

• 34-41% at 1 year

• 72% at 6 months

Kuiper TM et al. J Rheumatol. Nov 2015

2 x Risk of Losing Remission and LDA if Stop bDMARDs for 1 year vs. continuing, with risk for further damage

(A) RR (95% CI)=1.97 (1.43 to 2.73), P<0.0001) of losing remission after bDMARD discontinuation vs. bDMARD continuation

(B) RR (95% CI)=2.24 (1.52 to 3.30) of losing LDA after bDMARD discontinuation

(C) Structural progression after stopping 10% progression

Risk = Risk Ratio (95% CI) Henaux S,, et al. Ann Rheum Dis 2018;77:515–522.

A. RR (95% CI)=1.23 (1.06 to 1.42), P=0.006) of losing remission

B. RR (95% CI)=1.02 (0.85 to 1.23), P=0.81) of losing LDA after bDMARD tapering – i.e. no risk

C. RR (95% CI)=1.09 (0.94 to 1.26), P=0.26) showing no damage from tapering a bDMARD

If Taper bDMARDs for 1 year vs. continuing - lose REM but not LDA, with no additional damage

PICOD:Patients with early or established RA treated with Biologic DMARDs (bDMARDs) in LDA or REM Intervention: Extend interval or/then withdraw bDMARD Control: Continue bDMARDOutcome: Flare (increase in DAS28 of 1.2)Design: RCT (blinded) or Pragmatic

Despite differences in PICOD flare with treatment reduction typically 10-25%, and with treatment cessation is 60-75%

Modified from Henaux S, Ruyssen-Witrand A, Cantagrel A, et al. Ann Rheum Dis 2018;77:515–522.

Logistics, questions and concerns when tapering or stopping DMARDs

Logistical Issues• Order of treatment taper • What has patient already tried?

• In low adherent patient how much more tapering should occur?

• If patient known to have flares, should they taper?

• How to “prescribe” tapering? Step down or all at once?

• Impact on prior authorization

Risks

• What is the “cost” to health, work/productivity of a treatment reduced flare

• If flare occurs, will disease control be regained to the same level?

• Risk for more damage, CVD, infection• If steroids started for flares, can

patients stop them?

• Will there be loss of efficacy over time from the bDMARD (do antidrug antibodies develop?)

• Cost savings

• Will the cost savings come back to care of RA patients?

• What risks are reduced by tapering and or stopping bDMARDs?

• E.g. infection

Benefits

Pragmatic Studies

Studies in settings more typical of usual care

IMPROVED – A 5 Year “Pragmatic” Goal Driven Study of De-escalation in very early RA to achieve Drug Free Remission (DFR)

ARD 2014

IMPROVED Treatment Flow Chart 2 Year – If Reached Remission, 1/3 Achieved DFR

Baseline: Enrolled 610

12 Months: 576 continued

24 Months 533 continued

At 4 Groups Patients Split 3 Groups

a) Early DAS REM (n=387)

b) Group 1 – Randomized to Triple Tx (n=83)

c) Group 2 – Randomized to Adalimumab & MTX (n=78)

• Out of Protocol (followed in parallel)(n=50)

Pragmatic Study – Observational, Patients Stratified by Initial ResponseFollowed every 4 months - treatment escalated or de-escalated Goal- to achieve sustained drug free remission (DAS<1.6), maintain susREM

5 Year Outcomes for Drug Free Remission (DFR)

•More UA (37%) vs. RA (23%) achieved DFR at some time over 5 years

• RF-/ACPA-: more DFR but not more remission

• 4% achieved persistent DFR - all 4 years

Mixed population: 20% (131) Undifferentiated Arthritis (UA)479 had RA

IMPROVED 5 Year Outcomes Function and Damage Progression

• 32% of RA and 21% of UA - damage progression

• 37%/39% - damage progression in Arms 1 & 2

• More damage in early REM/DFR patients and less with TNFi Tx

IMPROVED is a Pragmatic Goal Driven Study Informed Patient and Provider Concerns About Strategy and Tapering

• Achieving periods of DFR desirable, but may come with a cost of damage

• No clear safety advantages for achieving DFR

• Cost savings are low

• RA patients less likely to achieve early REM vs. UA patients if treated with initial Prednisone + MTX monotherapy as an induction therapy?

Surprise Study – Withdrawal of Tocilizumab

Kaneko Y, Ann Rheum Dis. Oct 2018

233 RA patients, 3 years RA, 80% RF+, MTX-IR Year 1:Tocilizumab (TCZ) added or patients switch to TCZ only102 patients sustained REM (DAS28 1.6), stopped TCZ

bDMARD tapering less successful in patients not on methotrexate

Survival of remaining in remission

Phase IV Open Label Withdrawal Study

Not all patients regain their prior disease activity controlMaintaining LDA ≠ Regaining Remission

Patients are not free of damage progression

Kaneko Y, Ann Rheum Dis. Oct 2018

• Retreatment with tocilizumab led to remission in more than 80% of patients.

• Prior clinical control was not regained in 10-20% of patients

Trend for more clinically significant radiographic damage in TCZ monotherapy

Phase IV Open Label Withdrawal Study

Risks of Flare if Taper and or Stop bDMARD therapy in settings of usual care?

Brahe CH et al. Rheumatology July 2018

ADOPT StudyData from DANBIO Registry

bDMARD Tapering is a mandated by Danish National Healthcare System in patients in Clinically Stable Remission

Study Of Patients Mandated to Taper From DANBIO RegistryPatients • 11 years of RA on bDMARD, followed in DANBIO

Registry• In remission for 2.2 (1.4–3.2) years (DAS28-CRP

1.8)• 80% on csDMARDs (72% on MTX)• On bDMARD (median 4 (3–7) years):

• 86% on 3 TNFi (31% ADA, 28% ETA, 27% IFX )• 14% other

• All baseline MRI (combined inflammation-and damage score)

Intervention:• Taper bDMARD by 33% at week 16• Taper again to 50% by week 32

Primary clinical outcome: • % tapered or stopped bDMARD at 2

years (no flare)Secondary outcomes: •% regained DAS28 REM by 2 years•% of patients with radiographic progression from baseline to 2 years•Predictors of unsuccessful taper

Flare definition:DAS28-CRP ⩾ 2.6 andΔDAS28-CRP ⩾0.6 and ⩽1.2 from baseline

Brahe CH et al. Rheumatology July 2018

The ADOPT bDMARD tapering algorithmBiological DMARD Standard dose Two-thirds of standard dose Half standard dose

Infliximab (IV) 3mg/kg every 8 weeks 2mg/kg every 8 weeks 1.5mg/kg every 8 weeks

Etanercept (SC) 50mg once weekly or

25mg twice weekly

50mg every 10 days

25mg every 5 days

50mg every other week or

25mg once weekly

Adalimumab (SC) 40mg every other week 40mg every 3 weeks 40mg every 4 weeks

Golimumab (SC) 50mg every 4 weeks 50mg every 6 weeks 50mg every 8 weeks

Certolizumab (SC) 200mg every other week or

400mg every 4 weeks

200mg every 3 weeks or 400mg every 6

weeks

200mg every 4 weeks or

400mg every 8 weeks

Tocilizumab (IV) 8mg/kg every 4 weeks 5.3mg/kg every 4 weeks 4mg/kg every 4 weeks

Abatacept (IV) 500mg (body weight<60kg) or

750mg (body weight 60-100kg)

or

1000mg (body weight >100kg)

every 4 weeks

500mg (body weight<60kg) or

750mg (body weight 60-100kg) or

1000mg (body weight >100kg) every 6

weeks

500mg (body weight<60kg)

or

750mg (body weight 60-

100kg) or

1000mg (body weight

>100kg) every 8 weeks

Brahe CH et al. Rheumatology July 2018

• 88% of flared in 1st year , 39% failed over 2 years

• 5 switch DMARDs

• 59 needed parenteral steroid (95% “flare” patients)

• 21 (15%) patients were not in remission at 2 years

• 18% radiographic damage progression

• 9% significant damage progression

Observational Study of Mandated De-EscalationDANBIO Registry Patients

Predictors of success:• Male• Only 1 bDMARD• MRI inflammation & Damage

Scores Low • RF negative

Brahe CH et al. Rheumatology July 2018

Some real world data suggest tapering not as successful as expected

Patients will need extra care

Using a concentration-based tapering strategy to guide tapering while

preventing flares

l’Ami MJ, Krieckaert CLM, Nurmohamed MT, et al. Ann Rheum Dis 2018;77:484–487

ROC-curve analysis: EULAR non and

moderate vs. good response. Mieke F Pouw et al. Ann Rheum Dis 2015;74:513-518

• A cut-off value of 5 ug/mL previously found as optimal to distinguish between EULAR non-/moderate responders vs. good responders

• AUC of 0.695 (95% CI 0.626 to 0.764, p<0.0001)

• Specificity of 43% and sensitivity of 91%

5 ug/mL is Dose of Adalimumab Needed for a Good EULAR Response (Prior Work)

As Tx intervals prolonged adalimumab concentrations remain within “therapeutic

range” without worsening of DAS28

Concentration drop < 5 μg/mL in 7 patients (1/7 flared)

Prolonged IntervalN=26

Continue TherapyN=23

Baseline 10.6±2.5 μg/mL 10.4 ± 2.4 μg/mL

28 weeks 6.6±2.0 μg/m 9.3 ± 3.0 μg/mL

49 of 233 patients had high enough concentrationsto justify tapering guided by adalimumab levelWere all patients adhering to adalimumab or MTX?

Value of in depth profiling of auto-antibodies in predicting drug free remission?

Might RA be more modifiable if treated when auto-antibodies specificities are still expanding and switching in isotypes resulting in more drug reduced / drug free remission?

• A broad baseline autoantibody profile is associated with a better early treatment response

• Indicates break in tolerance to several autoantigens

• Extensive isotype switching, suggests more active humoral autoimmunity

• A window when immune progression is more suppressible by medication

BUT:

• Autoantibody status not associated with long-term sustained drug free remission

• Value of antibody profiling antibody diminishes over time

De Moel E, et al. Arthritis Res Ther. 2018 Feb

Patient Perspective

Themes from Qualitative Studies

Patients indicate conflicting views

• My RA flares now and then• I can’t risk loosing my job• Concerns about adverse effects in future• Intrude on life (taking a bDMARD on vacation• Family doesn’t want me to risk this• Tried to stop before and flared badly• If I reduce, I need to be sure I can reach my

rheumatologist• You can’t be serious that this is about cost. We

are talking about my health here!

• Disease activity (flares)

• Threat: participation/function

• Future adverse effects

• Burden of bDMARD use

• Pre-contemplation

• Social influences – family discourages it

• Past experience (stop and flare)

• Logistical issues – MD access

• Put patient priority over cost

Verhoef LM et al. Rheumatology June 2018

Mental health, fatigue and function scores taken prior to TNFi tapering are associated with increased risk of disease flare

• Exploratory analysis from OPTTIRA trial RCT (open label)• 97 randomised to taper TNFi (by 33% or 66%)• 41 flared (DAS28 increase of 0.6 and 1 joint)• Baseline predictors of flare: Higher DAS28, SF-36 MH• Baseline HAQ, FACIT-F not significant predictors in

adjusted model

Bechman K et al. RMD Open

OPTTIRA

RCT Open Label – Post Hoc Analysis

PREDICTORS OF TAPERING OR WITHDRAWAL FAILURE?

Up to 80% could taper if remain on bDMARDs

Systematic Review by Schett – No consistent pattern in loss of remission despite study design: 50-90% stayed in remission

23 studies – between 2011 – 2016PatientsEarly RA – 10 / Established RA 187 in LDA , 15 in REM 15 susREM or susLDA x 6 monthsSample size

<100 - 15 studies100-200 – 7 studies>200 – 5 studies

InterventionDe-escalation Strategy:17 Stop /7 Taper / 4 Taper then StopControl: 10 studies control armOutcome: % remission over time of FUFollow Up: 6-12 months in 24 studiesDesign11 Uncontrolled, 9 Sub-analysis 8 RCT; Schett G et al. Ann Rheum Dis 2016

Predictors of successful tapering and maintaining remission after tapering of bDMARD or csDMARD• Presence of deep remission state (DAS28 ≤2.2) prior to

tapering • Shorter duration (early RA)• Longer period of sustained remission• More rapid initial response to DMARDs • Absence of serum markers of inflammation• ACPA negativity • BUT synovitis detected by ultrasound predicted failure of

successful tapering of biologics in 3 studiesSchett G et al. ARD 2016

The chance of relapse may depend on how remission is defined

Schett G et al. ARD 2016

Composite of Imaging, Serology and Clinical Status may best predict successful de-escalation

Schett G et al. ARD 2016

Role of Ultrasound in Predicting Successful Tapering

• Prediction of relapse after discontinuation of biologic agents by ultrasonographic assessment in patients with RA in clinical remission shows high predictive values of total gray-scale and power doppler scores that represent residual synovial inflammation before discontinuation. Iwamoto T, et al . Arthritis Care Res 2014

• Power Doppler ultrasound-detected synovitis in RA patients who failed to taper biologic therapy. Naredo E. Rheumatology 2015

• Tapering and discontinuation of TNF-α blockers without disease relapse Used ultrasonography as a tool to identify RA patients with rheumatoid arthritis in clinical and histological remission to decide who should taper and discontinue bDMARDs. Alivernini S, et al. Arthritis Res Ther. 2016

3 studies using Ultrasound as a predictor of successful tapering of bDMARD

If patient attests to remission does ultrasound confirm this? • 43 RA patients - answered yes to “Are you feeling free of

symptoms, just like before your RA symptoms started?”

• Clinical exam and US of 24 joints and 26 Tendons

• 73% in clinical remission (DAS28, CRP)

• High rates of tenosynovitis (PD+) in ankles and feet,

• 10% US findings in upper extremities

Vlad et al. Med Ultrason. 2018 Aug 30;20(3):328-334Open Label Pilot Study

If active synovitis is a predictor of failure to taper more needs to be known about predictive role of US in successful tapering (maintaining sustained remission)

Economic Considerations• Assessed cost-effectiveness of maintaining full dose vs. tapered bDMARD (30% or

50% of full dose) • Measured number of Quality-Adjusted Life Years (QALYs) that are lost relative to

cost savings • Cost effectiveness ratio: cost of an intervention / QALY (0-1 or 0-5)• Incremental cost effectiveness ratio• Decision Analysis: decision analyses:

– cost-effectiveness analysis– cost-benefit analysis– budget impact analysis

• Impact of providers/provider groups, and patients in terms of similar or divergent preferences

STRASS Study: >50,000 EUROs saved per QALY Lost

• Economic analysis from the STRASS study• 140 patients randomized to increase interval to

adalimumab and etanercept vs. maintain usual dosing• Fewer QALY’s in the tapering vs. maintenance arm

DRESS Study• Dose REduction Strategy of Subcutaneous TNF inhibitors RCT,

open label, trial: RA LDA patients reduce or maintain therapy

• Measured total healthcare costs measured and Quality adjusted life years (QALYs) were based on EQ5D utility scores

• Used Decremental cost-effectiveness analyses and Incremental net monetary benefit (iNMB) used for cost-effectiveness

• N=180; 121 to dose optimization; 59 to control

• Mean cost saving in tapering arm −€12 280 per pt/ 18mos

• 84% of QALY loss was 0.02 “considerable cost savings while no relevant loss of quality of life”

Keveit et al. ARD Jan 2016

Summary

Patients with RA in stable sustained remission can achieve drug reduced remission (DRR) and drug free remission (DFR)

Imperative that sustained remission is preserved to optimize low symptoms , participation / function and survival

If initial strategy influences success of early remission and then withdrawal need strategies to “choose” well Early “inadequate response” predicts failure to achieve these goal

Novel (more costly upfront) treatments, may be necessary for some to effectively to achieve prolonged DRR and even DFR

Potential Logistical challenges of bDMARD de-escalation in practice

• Worsening in terms of symptoms and impacts may occur between scheduled clinical encounters

• Worsening may not occur for many months or even 1-2 years –patient may not have a scheduled follow up visit

• Monitoring people during and after de-escalation

• Travel distance and time, Season

• Impact authorization of bDMARDs and forced switches

Withdrawing therapy has economic advantages but have the correct economic analysis been fully assessed?

• Has quality of life been adequately assessed?

• Does EQ5D capture events & consequences of treatment lowering such as high impact flares in RA?

Reduced medication can reduce burden from side effects and risk, and increase quality of life

Personalized strategies of integrated induction followed by de-escalation will likely be the key to cost

effective improved care

Thank you