Transcript Rheumatoid Arthritis (RA) - Asociacion Costarricense de Medicina

Rheumatoid Arthritis:
When to Start and when to Stop
anti-TNF Therapy
[¿Cuando iniciar o detener
la tx anti-TNF?]
Asociacion Costatarricense Medicina Interna
August 7, 2015
Arthur Weinstein, MD, FACP, FRCP, MACR
Professor of Medicine, Georgetown University
Rheumatology, MedStar Washington Hospital Center
Progression of RA
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Rheumatoid Arthritis (RA):
The Window of Treatment Opportunity
RA Sx Onset
4 Months
2 Years
10-20 Years
Bony Erosions
70%-80%
Long-term Disability
80%
Adapted from: Bykerk VP, Keystone EC. J Musculoskelet Med. 2004;21:133-146.
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Rate of Development of New Damage of Joints
Mean number of joints
3.0
Newly eroded
Newly narrowed
2.5
2.0
1.5
1.0
0.5
1
2
3
4
5
6
Follow-up in years
ulsmans
r thritis Rheum. 2000.
Window of Opportunity in RA:
Disease Modifying anti-rheumatic Drugs
(DMARDs)
DMARDs are associated with a decrease in
radiographic progression
Radiographic Score
(Disease Progression)
70
60
50
P<0.05 at
2 years
40
NO DMARD
DMARD
30
20
10
0
0
1
2
3
Years of Disease
4
5
Lard LR, et al. Am J Med. 2001;111:446-451; Weisman M. Ann Rheum Dis. 2002;61:287-289.
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DMARD Treatment:
The Earlier the Better
Delayed treatment (median treatment lag time, 123 days; n = 109)
Early treatment (median treatment lag time, 15 days; n = 97)
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Median Sharp Score
DMARDs = chloroquine or salazopyrine
12
10
8
6
4
*
2
0
0
6
*p < 0.05 vs delayed-treatment group.
Lard LR et al. Am J Med. 2001;111:446-451
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Time (months)
18
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Central Role of TNF in RA
TNF
osteoclasts
synoviocytes
chondrocytes
bone resorption
joint
inflammation
cartilage
degradation
bone erosion
pain/joint
inflammation
joint space
narrowing
TNF Antagonists
 5 currently approved agents (USA):
■ etanercept, adalimumab, infliximab, certolizumab pegol, golimumab
 Subcutaneous (etanercept, adalimumab, certolizumab pegol, golimumab)




and intravenous administration (infliximab)
Administration in combination with MTX is superior to monotherapy*
Time to onset: rapid (weeks)
Adverse events
■ infection - bacterial, TB, fungal, H. Zoster
■ malignancy - not higher rates than the background of lymphoma and
solid tumors in RA population
■ multiple sclerosis/demyelination, lupus-like syndrome, worsening CHF,
?Hep B reactivation syndrome (esp infliximab)
Monitoring
■ TB screening including PPD prior to therapy, Hep B screenig
■ Periodic CBC, LFTs
■ Infection
O'Dell JR. N Engl J Med. 2004;350:2591-2602.
Klareskog L, et al Lancet. 2004;363:675-681*; Breedveld F, et al. Arthritis Rheum. 2006;54:26-37*.
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ACR20 Response
Infliximab / Methotrexate Combination (ATTRACT)
p < 0.05 vs recommended dos e
Patients (%)
80
60
59† 59†
58*
50* 50* 52*
48
Methotrexate
Methotrexate
Methotrexate
Methotrexate
Methotrexate
+ placebo
+ infliximab 3 mg/kg q 8 wk
+ infliximab 3 mg/kg q 4 wk
+ infliximab 10 mg/kg q 8 wk
+ infliximab 10 mg/kg q 4 wk
48†
†
41† 40†
42†
42†
40
20
20
17
16
0
30 Weeks
*p < 0.001 vs control
†p < 0.05 vs control
54 Weeks
102 Weeks
Maini . Lancet. 1999.
Lipsky. Arthritis Rheum. 1999.
Lipsky. Arthritis Rheum. 2000.
ATTRACT STUDY GROUP
PERCENTAGE OF PATIENTS THAT REACHED ACR 50
35%
*
30%
*
25%
*
*
Placebo
3mg/4W
3mg/8W
10mg/4W
10mg/8W
20%
15%
10%
5%
0%
30 weeks
*
P<0.001
ATTRACT Trial
Mean Change in Total Modified Sharp Score at Week 102
12.6
Mean change from BL
12
10
8
6
4
*p < 0.001 vs placebo + MTX
2
1.0*
1.0*
1.1*
0
- 0.4*
Placebo
3 mg/kg
q 8 wk
3 mg/kg
q 4 wk
10 mg/kg
q 8 wk
10 mg/kg
q 4 wk
Lipsky. Arthritis Rheum. 2000.
Other biologics and small molecule for RA




Abatacept (Orencia) – recombinant CTLA4-Ig (co-stimulatory blockade)
Rituximab (Rituxan) – Bell-cell depletion (anti-CD20)
Tocilizumab (Actemra) – IL-6 receptor antagonist
Anakinra (Kineret) – recombinant IL-1 receptor
 Tofacitinib (XELJANZ, Jakvinus) – oral JAK inhibitor (JAK 3, JAK 1)
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Poor Prognostic Factors in RA
 Early age at onset
 Polyarticular disease (increasing number of joints)
 Systemic extra-articular disease (nodules, vasculitis,
eye disease, interstitial lung disease)
 High-titer RF positive
 Anti-CCP antibody positive
 Persistent disease activity (high ESR, CRP, disease
activity scores)
 HLA-DRB1 “shared epitope” positive
(strongest known genetic risk factor for RA)
Lindqvist E, et al. Ann Rheum Dis. 2005;64:196-201; Erhardt CC, et al. Ann Rheum Dis. 1989;48:7-13; Wolfe F, et al. Arthritis Rheum.
2003;48:1530-1542.
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Standard Treatment in Early RA (< 6 months)
Singh et al. Arthritis Rheum 2012
DISEASE
ACTIVITY
LOW
MOD
HIGH
POOR
PROGNOSIS
DMARD
MONOTHERAPY
MTX
LEF
SSZ/HCQ
COMBO DMARD (2/3)
DMARD + ANTI-TNF
Inadequate response to MTX
Smolen JS et al. Ann Rheum Dis 2013
sub-optimal MTX response (3 months)
combination
DMARDs
other
DMARD?
biologics
monotherapy
combination
therapy
anti-TNF switching
change biologic
Optimizing Treatment Response
Target low disease activity/remission
Weinblatt ME et al: Arthritis Rheum 2008; Dervieux T et al: Rheumatology 2010
O’Dell JR et al: NEJM 2013; Scott et al : BMJ 2015
O’Dell JR et al: Arthritis Rheum 2013; Villeneuve E, Haroui B: Int J Adv Rheumatol 2006
De Punder YMR et al: Rheumatology 2012
Saevarsdottir S et al. Arthritis Rheum 2011
 Optimizing MTX response (monotherapy or combination
therapy)
■ Dose – can increase to 20-25 mg/week
■ Route – SC, IM
■ ? Role of MTX polyglutamate levels (whole blood MTX levels)
■ 30% achieve low disease activity/remission with MTX alone
 Use combination DMARDs or MTX plus anti-TNF early (step up)
■ another 30-40% achieve low disease activity/remission
 Stop smoking
 Switch anti-TNFs or to other biologics as needed
■ dose increase not effective with anti-TNFs
 Monitor disease activity – clinical, ultrasound, biomarkers –
CRP, Vectra (MBDA score) - TREAT TO TARGET (LDA/REM)
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What about corticosteroids?
Wassenberg S et al: Arthritis Rheum 2005; Smolen JS et al. Ann Rheum Dis 2013
 Low dose prednisone/prednisolone (<7.5mg/day)
reduces inflammation and radiographic progression
 EULAR recommendation – consider at start
 High doses should not be used
 IM methylprednisolone can be used for flares, bridge
therapy
 Concern regarding long term side effects - glucose
intolerance, osteoporosis, infections, H Zoster, CV risk
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Stopping biologics (anti-TNFs)
Why Stop?




Remission is achievable (?20-30%) with DMARD + antiTNF agents and low disease activity is attained in the
majority – but is it lasting off drug?
Short and long term side effects of anti-TNF agents –
skin, infection, opportunistic infection, granulomatous
inflammation
Cost of anti-TNF agents
Patient preference – these are injectables, infusions
Stopping anti-TNFs
Uncontrolled Studies
Van den Broek et al. ARD 2011: BeSt study. Active early RA (<
2years) –IFX + MTX. 104 pts DAS<2.4 (mean 1.3) for >6 mos – IFX
d/c . 50/104 (48%) flared in 3-6mos. Successfully reintroduced
in 84%
Tanaka et al. A&R 2012 (abstract): HONOR Study: 51 pts on ADA +
MTX - DAS 28-ESR< 2.6 > 6 mos, ADA d/c followed for 12 mos.
Mean disease dur’n 7.1yrs - 27/42 (64%) flared. Deeper remission
(DAS<1.9) and shorter disease duration correlated with
remission maintenance
Stopping Anti-TNFs
Recent Controlled Trials
Smolen JS et al . Lancet 2013; Smolen JS et al . Lancet 2014; Emery P et al. NEJM 2014
PRESERVE Trial: Patients with active RA (mean disease duration
app 7yrs) put
on MTX + ETA (50mg/wk). Those with LDA for 3-9mos randomized (blinded) to:
MTX + placebo (ETA stopped); MTX + ETA 25mg; MTX + ETA 50mg
LDA maintained @ 36 wks? 43% vs
79% vs
83%
OPTIMA TRIAL: Patients with active RA (< 1 yr) in RCT for ADA +MTX. Those
achieving LDA randomized to ADA withdrawal or not.
LDA maintained @ app 52 weeks? 54% vs 70%
PRIZE TRIAL: ETA + MTX similar to PRESERVE but early RA (< 1 yr) to 3 gps:
placebo (no MTX or ETA); MTX + placebo (no ETA); MTX + ETA 25mg
LDA/REM maintained @ 39 wks? 23% vs
40% vs
63%
Stopping anti- TNFs
Is it possible – yes …….Flare Rate: 30-65%
Predictors of sustained remission (clinical):
“deep remission” (DAS28<1.9), low HAQ, prolonged duration of
remission, short duration RA (early RA)
Predictors of flare (imaging):
MSKUS Power Doppler (PD) (Saleem et al. Ann Rheum Dis 2012,
Foltz et al. A&R 2012)
If PD present flare OR 4-6
Stopping Anti-TNF Agents in Rheumatoid
Arthritis (STARA) Trial






Double-blind
Placebo-controlled (2:1 placebo:drug)
Stopping trial – 48 weeks (8 week run in, 52 week FU)
Patients taking infliximab, adalimumab or etanercept
Taking traditional DMARD
NIAMS/Extramural site collaboration- academic and
priivate practice sites
Flare Rate and Predictors of Flare
STARA Trial
1.
2.
3.
Baseline depth of remission (DAS 28, SDAI<3.3,
ACR/EULAR) and other clinical data, smoking
Baseline imaging (ultrasound, MRI)
Baseline flow cytometry, genetics (shared epitope) and
gene expression profiles, cytokine profiles
“CAN A CLINICAL/ IMAGING/LABORATORY
PROFILE PREDICT WHICH PATIENTS WILL
FLARE AND WHICH WILL NOT?”
RA:
It’s Not Just the Joints!!
CVD
10 Years Earlier
 Osteoporosis
2X  Rate
Malignancy
Joint
Destruction
Disability
Pain
6-9X  Serious
Infection Rate
 Pulmonary
Disease
 GI
Bleeding
Deane K. J Musculoskel Med. 2006;23:S24-S31.
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What has Modern RA Therapy Accomplished?
A GREAT DEAL
 Chronic deforming/ destructive RA greatly reduced
and delayed
 Quality of life greatly improved
 Secondary amyloidosis almost gone
 Rheumatoid vasculitis (high mortality) now very rare
 CV fatality rate has decreased – RA with LDA
GRACIAS
Meek IL et al. BMC Musculoskeletal Disorders 2014
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