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ELAR congress , Alexandria 2013. Treat to Target, Role of Orencia in Achieving the target. Prof. Hassan El-Shahaly Professor of Rheumatology and Rehabilitation Suez Canal University. Rheumatoid Arthritis Challenges. Complex, multifactorial pathogenesis - PowerPoint PPT Presentation
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Treat to Target, Role of Orencia in Achieving the target.
Prof. Hassan El-ShahalyProfessor of Rheumatology and Rehabilitation
Suez Canal University
ELAR congress, Alexandria 2013
Rheumatoid Arthritis Challenges
• Complex, multifactorial pathogenesis• Fluctuating clinical course; unpredictable
prognosis• Characterized by:
– Progressive joint destruction – Loss of physical function – Poor quality of life
CLASSIFICATION CRITERIA FOR RA
Rationale 1987 ACR
criteria
Elaborated in established RA
Considered as classification
criteria
Lack of sensitivity in early disease
Current trends in RA
Recognize the patients as soon
as possible
Treat the patients as soon as the
diagnosis is made
investigate new drugs/strategies at an early stage of the disease
ACR /EULAR classification criteria for RA
5
Early treatment reduces disability 5 years later
according to: Wiles NJ, et al. Arthritis Rheum 2001; 44: 1033 - 42* Odds ratio of HAQ ≥1
0.0
0.5
1.0
1.5
2.0
2.5
3.0
Degr
ee o
f Disa
bilit
y*af
ter 5
Year
s
<6 months(n = 60)
6-12 months(n = 47)
>12 months(n = 76)
0.9
2.4 2.3
Objectives
To recognise the disease at an early stage.
To develop a set of rules to be applied in newly patients with
undifferentiated synovitis
• Identify the subset at high risk of chronicity & erosion
• Be used as a basis for initiating disease modifying therapy
ACR /EULAR classification criteria for RA
Aletaha D, et al. Ann Rheum Dis 2010 ; 69:1580-8 ; Arthritis Rheum 2010;62:2569-81
2009 ACR / EULAR for the classification & diagnosis of rheumatoïd arthritis
Aletaha D, et al. Ann Rheum Dis 2010 ; 69:1580-8 ; Arthritis Rheum 2010;62:2569-81* van der Heidje D et al Ann Rheum Dis 2013 Feb 7
Joint involvement(0-5)1 large joint 0
2-10 large joints 1
1-3 small joints(large joints not counted) 2
4-10 small joints(large joints not counted) 3
> 10 joints(at Least one small joint) 5
Sérology (0-3)RF négative ET ACPA négative 0
RF low level (1 à 3 x ULN ) ORACPA low level (1 à 3 x ULN) 2
RF high level(> 3 x ULN) ORACPA high level (> 3 x ULN) 3
Symptoms duration (0-1)< 6 weeks 0
≥ 6 weeks 1
Acute Phase reactants (0-1)CRP normal AND ESR normal 0
CRP abnormal OR ESR abnormal 1
RA: score ≥ 6
≥1 1 swollen joint
Not best explained by another disease
Yes
No
yesNew criteria for RAFulfilled?
No RA
RA
Typical RA erosion on X-ray*
MANAGEMENT
Prevention / arrest of joint damage
Prevention / reversal of disability
Preventionof systemic co-morbidities:CV diseases,osteoporosis….
Sustained Remission
Management of patients with RA
Therapeutic objectives
Remission
RECOMMENDATION 1: Therapy with synthetic DMARDS should be started as soon as the diagnosis of RA is made
RECOMMENDATION 2: Treatment should be aimed at reaching a target of remission or low disease activity as soon as possible in every patient; as long as the target has not been reached, adjustment of the treatment should be done by frequent and strict monitoring.
RECOMMENDATION 3: Methotrexate should be part of the first treatment strategy in patients with active RA.
EULAR RECOMMENDATIONS FOR THE MANAGEMENT OF RA WITH SYNTHETIC AND BIOLOGICAL DMARDs
Smolen J. et al.Ann Rheum Dis 2010;-69:964-75Combe et al. Ann. Rheum. Dis. 2007; 66: 34-45
Turning recommendations into optimal treatment strategies
12
Early referral
Starting biologic agents
Treat to target
Short & long -term goals
Tight control usingcompositemeasures
Considerpoor
prognosticfactors
Early institution of DMARDs
Pre-determined treatment targets
Remission orLDAS
as soon as possible
Maximising HRQOL for the long-term
Shared decision between
doctorand
patient
Rheumatol-ogists
are primary carers
Newer RA Treatment Strategies
• Intensive management • Treat to Target
• Combination DMARD strategies
• Remission induction
Aggressive Strategies
• Monotherapy with frequent switches– Sawtooth (Fries)
• Classical step-up (pyramid)– MTX+SSZ+HO-Chl (O’Dell)– MTX+Leflunomide– Others
• Step-down– COBRA
Combination Step-Down Therapy: COBRA Trial
Boers M et al. Lancet. 1997;350:309-318.
Step-downtherapy
SSZ alone
Step-down (MTX + SSZ + Pred)
SSZ
MTX 7.5 mg/week
Weeks16 280
0.0
0.4
0.8
1.2
1.6
Prednisolone 7.5 mg/day
Prednisolone60 mg/day
SSZ 2000 mg/day
Pool
ed In
dex
Systematic literature review: from 1995 to 2008 Meta-analysis of 6 studies
Tight control and predefined strategy
Schipper LG et al Rheumatology 2010;49:2154-64
0 0,2 0,4 0,6 0,8 1,0 1,2 1,4 1,6 1,8 2,0-0,2-0,4
Tight controlwithout predefined protocol
Fransen, 2005
Fransen, 2003
Van Tuyl, 2008Tight controlwithout predefined protocol
Tight controlwith predefined protocol
Tight controlwith predefined protocol
Verstappen, 2007
Goekoop, 2009
Grigor, 2002
0,25 (IC95 : 0,03-0,46)
0,97 (IC95 : 0,64-1,3)
Mean difference in DAS28 change
Randomised effect model
Traditional DMARDs Are Effective but Do Not Maintain Long-term Response
Retention Rates of DMARDs
Cum
ulat
ive
Ret
entio
n R
ates
0 12 24 36 48 60 72 84 96 108 120
100908070605040302010
0
MethotrexateSulfasalazineChloroquineParenteral GoldOral GoldPenicillamineAzathioprineCyclosporineCombination
Legend:
Time (Months)
18
Taking steps to improve clinical outcome
Smolen J, et al. Ann Rheum Dis 2010;69:631–637.
Active RA
Main target
Alternative target
Adapt therapy according to
disease activity
Remission
Adapt therapy according to disease
activity
Low disease activity
Use a composite measure of disease
activity every 1–3 months
Adapt therapy if state is lost
Sustained remission
Adapt therapy if state is lost
Sustained low disease activity
Assess disease activity about every
3–4 months
Main long-term target
Alternative long-term
target
EULAR RECOMMENDATIONS
Phase I of EULAR RA Management Algorithm
19Smolen JS, et al. Ann Rheum Dis 2010;69:964–75
*The treatment target is clinical remission or, if remission is unlikely to be achieved, at least low disease activity
Phase II of EULAR RA Management Algorithm
20
*The treatment target is clinical remission or, if remission is unlikely to be achieved, at least low disease activity
Smolen JS, et al. Ann Rheum Dis 2010;69:964–75
Phase III of EULAR RA Management Algorithm
21Smolen JS, et al. Ann Rheum Dis 2010;69:964–75
*The treatment target is clinical remission or, if remission is unlikely to be achieved, at least low disease activity
Tracey D, et al. Pharmacology & Therapeutics 117 (2008) 244–279.
Different Biologics for RA
23
APC
Down-regulation of T cell
Adapted from Kremer JM. J Clin Rheumatol. 2005;11:S55–S62.
CD28
T cell
CTLA-4 binding: down-regulation of T cell
Upstream T-cell Modulationwith ORENCIA® (abatacept)
CTLA-4
APC
CD28
MHC
APC
T-cell receptor
ORENCIA
ORENCIA inhibits T-cell activation by binding to CD80 and CD86. The relationship of these biologic response
markers to the mechanisms by which ORENCIA exerts its effects in rheumatoid arthritis (RA) is unknown.
T cell
Forest plot of risk ratios for clinical remission
• RR 1.74; 95% CI (1.54, 1.98)• no heterogeneity I2 0%; p = 0.496
Efficacy of initial MTX vs MTX + biological agent in Early RA
Kuriya B et al. Ann Rheum Dis online first april 26, 2010
Forest plot of risk ratios for radiographic remission
• RR 1.30; 95% CI (1.01, 1.68)• Significant heterogeneity I2 0%; p = 0.001
Efficacy of initial MTX vs MTX + biological agent in Early RA
Kuriya B et al. Ann Rheum Dis online first april 26, 2010
CLINICAL TRIALS FOR ABATACEPT
AGREE study design: patients with early RA and poor
prognostic factors*
1. Westhovens R, et al. Ann Rheum Dis 2009;68:1870–1877; 2. Bathon J et al. Ann Rheum Dis. 2011;70:1949–1956. 27
Inclusion criteria
• Early RA (≤2 years)• MTX-naïve • RF+ and/or anti-CCP2+ • ≥1 erosion
Co-primary endpoints• DAS28 (CRP) <2.6• Total Genant-modified Sharp score
Double-blind period1 Open-label period2
1:1 Randomisation
Screening
Abatacept + MTX**(n=256)
Placebo + MTX**
(n=253)
232
227
Abatacept + MTX
• DAS28 (CRP) • X-Ray progression• HAQ-DI
433
**MTX initiated at 7.5 mg/week at study entry, then increased to 15 mg at Week 4 and up to 20 mg at Week 8 until study completion; Dose reduction to 15 mg/week was permitted due to toxicity or intolerability; AGREE=Abatacept study to Gauge Remission and joint damage progression in MTX naïve patients with Early Erosive RA; CCP2+=cyclic citrullinated peptide positive.
Day 1 Year 1 Year 2
*Abatacept is not indicated in the EU for the treatment of early RA in MTX-naïve patients.
AGREE (MTX-naïve)
Significantly greater proportion of abatacept-treated patients achieved
DAS28 remission at Year 1*
Westhovens R, et al. Ann Rheum Dis 2009;68:1870–1877. 28
p<0.001
41.4%
23.3%
*Abatacept is not indicated in the EU for the treatment of early RA in MTX-naïve patients.Data are based on an ITT population, with patients who discontinued considered non-responders.
0
10
20
30
40
50
60
70
80
90
100
Prop
ortio
n of
pat
ient
s ac
hiev
ing
DA
S28
rem
issi
on (%
)
Abatacept + MTX (n=256)Placebo + MTX (n=253)
AGREE (MTX-naïve)
Abatacept provides sustained efficacy through 2 years in patients with early RA
(≤2 years)*
Bathon J, et al. Ann Rheum Dis. 2011;70:1949–1956. 29
Visit dayAbatacept plus MTX (n=232) MTX alone (n=227) MTX alone switched to abatacept plus MTX (n=227)
*Abatacept is not indicated in the EU for the treatment of early RA in MTX-naïve patients.Data are based on a modified ITT population, including patients who entered the open-label period and patients who discontinued considered non-responders.
0102030405060708090
100
0 29 85 141 197 253 309 365 449 553 617 729
Year 1Abatacept added to MTX alone group
Prop
ortio
n of
pat
ient
s ac
hiev
ing
DA
S28-
CR
P re
mis
sion
(%, 9
5% C
I)
46.1%
26.9%
44.5%
55.2%
AGREE (MTX-naïve)
Early referral
0.840.65
1.75
1.48
Baseline Year 1 Year 2
Mea
n ch
ange
from
base
line
in S
harp
tota
l sco
re
∆=0.25 Yr 1–2
∆=0.18 Yr 1–2
∆=0.66 BL-Yr 1p<0.001 for ∆Yr 1–2 vs ∆ BL–Yr 1
Patients with X-rays at all timepoints (n=207)
1.0
Adding abatacept to MTX slows the rate of radiographic progression*
Bathon J, et al. Ann Rheum Dis. 2011;70:1949–1956. 30
0.0
2.0
Visit dayAbatacept plus MTX MTX alone MTX alone switched to abatacept plus MTX
*Abatacept is not indicated in the EU for the treatment of early RA in MTX-naïve patients.Data are as-observed for patients treated in the open-label period.
Abatacept added to MTX alone group
AGREE (MTX-naïve)
Abatacept leads to sustained HAQ normalisation (≤0.5) over 2 years in half of treated patients*
Bathon J, et al. Ann Rheum Dis. 2011;70:1949–1956. 31
Abatacept + MTX (n=232)MTX alone (n=227)MTX alone switched to abatacept + MTX (n=227)
*Abatacept is not indicated in the EU for the treatment of early RA in MTX-naïve patients.Data are as-observed for all patients who entered the open-label extension.
0
10
20
30
40
50
60
70
80
90
100
Year 1
Prop
ortio
n of
pat
ient
s ac
hiev
ing
HA
Q n
orm
alis
atio
n (%
)
Year 2
AGREE (MTX-naïve)
32
Efficacy and Safety of Abatacept or Infliximab Versus Placebo
ATTEST Trial
A Phase III, Multicenter, Randomized, Double-blind, Placebo-controlled Trial on the efficacy and safety of abatacept or Infliximab
versus placebo in Patients with Rheumatoid Arthritis and an Inadequate Response to Methotrexate•
Primary Objective
–To study the efficacy of Abatacept in reduction of disease activity in comparison to placebo as measured by disease activity score (DAS) 28 (ESR) at 6 months (day 197)
–Determine ACR 20, 50, and ACR 70 response rates for subjects treated with placebo, abatacept, or infliximab at 6 months and 12 months
Schiff M, et al. Ann Rheum Dis 2008;67:1096–103
ATTEST
the primary endpoint was not designed to be a head-to-head comparison between Abatacept and infliximab.
Abatacept + MTX and infliximab + MTX ACR20 response rates are similar at Month 3
34
ACR 50AbataceptACR 50Infliximab
ACR 20AbataceptACR 20Infliximab
ACR 70AbataceptACR 70Infliximab
80
Visit day0
10203040506070
1 29 57 85 113141169197225253281309337365
ACR
resp
onse
rat
e (%
)ATTEST
The onset of action of infliximab was generally more rapid than abatacept however, by day 85, ACR 20 responses are similar
Schiff M, et al. Ann Rheum Dis 2008;67:1096–103
Further improvement from Month 6 to 12 was observed with abatacept + MTX in ACR 20 response
The onset of action of infliximab was generally more rapid than abatacept up to Day 85 By Day 365, ACR 20 responses were higher with abatacept than with infliximab (ACR 20:
72.4 vs 55.8%, difference of 16.7 [95% CI: 5.5, 27.8])
35
ATTEST
ACR 50AbataceptACR 50Infliximab
ACR 20AbataceptACR 20Infliximab
ACR 70AbataceptACR 70Infliximab
80
Visit day0
10203040506070
1 29 57 85 113141169197225253281309337365
ACR
resp
onse
rat
e (%
)ATTEST
Schiff M, et al. Ann Rheum Dis 2008;67:1096–103
36
ACR Responses at 6 Months
ITT population; D/C =Non responders *p<0.001; †p<0.05 and ‡p<0.01; Χ square test; p-values represent active drug versus placebo
The study was conducted in RA patients with inadequate response to MTX and was not designed to demonstrate non-inferiority or superiority of ORENCIA vs infliximab
ATTEST
ACR20 ACR50 ACR700.0
10.0
20.0
30.0
40.0
50.0
60.0
70.0
80.0
59.4
37.0
24.2
41.8
20
9.1
Infliximab + MTX (n=165) Placebo + MTX (n=110)
Pat
ient
s (%
)
‡
‡
‡
ACR20 ACR50 ACR700
10
20
30
40
50
60
70
80
66.7
40.4
20.5
41.8
20
9.1
Abatacept + MTX (n=156) Placebo + MTX (n=110)
Patie
nts
(%)
†
*
*
Schiff M, et al. Ann Rheum Dis 2008;67:1096–103
37
ACR responses at 12 monthsATTEST
ITT population; D/c =Non responders The study was conducted in RA patients with inadequate response to MTX and was not designed to demonstrate non-inferiority or superiority of ORENCIA vs infliximab
ACR20 ACR50 ACR700
1020304050607080 72.4
45.5
26.3
55.8
36.4
20.6
Abatacept + MTX (n=156) Infliximab + MTX (n=165)
Perc
enta
ge o
f pat
ient
s
Schiff M, et al. Ann Rheum Dis 2008;67:1096–103
Abatacept+MTX Delivered Sustained Improvements in ACR Responses Over 2 Years
38
0 3 6 9 12 15 18 21 24
Visit (month)
Infliximab patients switched to abatacept
ACR
Resp
onde
rs (%
)
Open label LTE periodDB period
89% (83,94)*
69% (61,77)*
55% (46,64)*
43 (35,52)*
24% (16,31)*
31% (23,39)*
87% (80,93)*84% (78,91)*
71% (63,79)*
61 (52,70)*
41% (32,50)*45% (36,54)*
Data are for patients who entered the open-label period, and had data available at the considered time point (as-observed analysis)
Treatment groups represent treatment received during the double-blind period
*95% confidence intervals
Schiff M and Bessette L Clin Rheum 2010 ; 29: 583-519 9
Abatacept+MTX
Infliximab 3mg/kg + MTX to abatacept
ATTEST-LTE
ABATACEPTSHORT & LONG -TERM EFFICACY
40
Abatacept provides similar short-term efficacy at 6 months compared with other biologic agents
• Placebo-adjusted analysis, based on ACR50 responses
• Mixed populations included:– MTX-IR– DMARD-IR– Anti-TNF-IR
• All biologic agents showed significantly greater efficacy compared with placebo, except anakinra
Singh JA, et al. Cochrane Database Syst Rev 2009;4:CD007848.
Favours Placebo Favours Biologic
Abatacept
Adalimumab
Anakinra
Etanercept
Infliximab
Rituximab
GLIMMIX: Odds Ratio (95% CI)
0.1 1.0 10
COCHRANE META-ANALYSIS
Studies included only approved dosages.
Abatacept short-term efficacy is similar to other biologic agents in real life
Yazici Y, et al. Arthritis Rheum 2011; 63(Suppl 10):S873. Abstract 2233.
Cum
ulati
ve in
cide
nce
of ti
me
to R
APID
≥3.6
re
spon
se*
(%)
Month
0
20
40
60
80
0 6 12 302418
Abatacept
EtanerceptAdalimumab
Infliximab
0 1 2 6543
*Adjusted for age and duration of disease.Prospective patient data from the Arthritis Registry Monitoring Database in patients receiving abatacept (n=114), etanercept (n=148), infliximab (n=38) and adalimumab (n=85).3,574 encounters were reviewed for this analysis. A total of 385 treatment courses were determined. 272 of the 385 courses represent the only biologic medication used by an individual; 40 individuals used two biologic medications at different times, while 11 had used three biologics.
Conaghan P, et al. Ann Rheum Dis 2011;70(Suppl 3):151
Abatacept leads to reductions in synovitis and structural damage by Month 4 – MRI data
Synovitis Osteitis Erosion
Adju
sted
mea
n ch
ange
(9
5% co
nfide
nce
inte
rval
)
-1.9
-0.3
0.5
-2.0
-1.0
0.0
1.0
-3.0
2.0
3.0
0.4
1.51.0
Abatacept + MTX (n=25)Placebo + MTX (n=23)
MRI (OMERACT RAMRIS) scores from baseline to Month 4 in MTX-IR patients treated with abatacept + MTX or placebo: synovitis of the wrist; osteitis and erosion scores of wrist and hand.
Improvements with abatacept seen via sonographic monitoring
Personal communication, Walter Grassi. 43
16 Months
• M.E. 51 year old man with RA• Disease duration: 3 years• Rheumatoid factor: positive• Anti-CCP Ab: positive• DAS28: 6.9• Finger pain: VAS 6
16 months later:• DAS28: 2.4• Finger pain: VAS 0
Conclusion: Excellent responder
LONG TERM GOAL ACHIEVEMENTBY ABATACEPT
An increasing proportion of abatacept patients show sustained LDAS or DAS28 remission over 7 years
Westhovens R, et al. Ann Rheum Dis 2009;68(Suppl3):577. Poster SAT0108. 45
Res
pond
ers
(%)
Year0 0.5
0
302010
4050
7060
80
10090
1 2 3 4 5 6 7
48.2% (37.4, 58.9) n/N=40/83
25.3% (15.9, 34.7) n/N=21/83
69.7% (54.0, 85.4) n/N=23/33
51.5% (34.5, 68.6)n/N=17/33
Response (95% CI)
Remission
LDAS
DAS28 CRP-defined remission = DAS28 <2.6; LDAS=DAS28 (CRP) ≤3.2.Data are based on all patients originally randomised to 10 mg/kg abatacept who entered the LTE, with data available at the visit of interest (as-observed analysis). Mean disease duration was 9.9 (10.1) years.
Double-blindphase Open-label LTE phase
Abatacept has demonstrated increasing reductions in rate of structural damage progression through Year 5
Schiff M, et al. Rheumatology 2011;50:437–449; Orencia SmPC November 2011; Data on file;Genant HK, et al. Ann Rheum Dis 2008;67(Suppl 2):193.
*Mean change in TS from year to year.Data are for those patients who entered the open-label period, and had evaluable radiographs available at the appropriate time points.Treatment groups represent treatment received in the double-blind period.TS=Total Score
AIM (MTX-IR)
Mea
n ch
ange
from
bas
elin
e in
Gena
nt-m
odifi
ed sh
arp
scor
es (T
S)
0 1 2 3 4 50
0.5
1
1.5
2
2.5
3
3.5
4
Abatacept + MTX Placebo + MTX Placebo + MTX switched to abatacept + MTXYear
Year 1
*0.80
*0.26*0.34
*0.37
*0.41*1.48
*0.29
*0.43
*0.68
*0.74
46
Sustained improvement in physical function with abatacept over 5 years (HAQ-DI response)
Schiff M and Bessette L. Clin Rheum 2010;29:583–591.
100
50
40
30
90
80
70
60
0 0.5 1.0 3.5 5.03.02.52.01.5 4.0 4.5
20
0
74.2%(69.0, 79.4)
71.8%(67.2, 76.4)
Double-blindphase Open-label LTE phase
Data are based on all patients originally randomised to abatacept who entered the long-term extension, with data available at the visit of interest (as-observed analysis).HAQ-DI response ≥ 0.3.
Resp
onde
rs (%
)
Year
AIM (MTX-IR)
1. Vander Cruyssen B, et al. Arthritis Res Ther 2006;8:R112; 2. Moreland LW, et al. J Rheum 2006;33:854–861; 3. Weinblatt M, et al. Ann Rheum Dis 2006;65:753–759; 4. Data on file; 5. Hetland ML, et al. Arthitis Rheum 2010;62:22–32.
Subjects remaining at the end of 4 years of LTE
n/N %
Infliximab1 295/511 62%
Etanercept2 429/581 74%
Adalimumab3 147/262 56%
Abatacept4*(IM101102)
394/539 73%
Abatacept has a retention rate that is comparable with or higher than the anti-TNF agents
• Retention may be considered as a surrogate marker of long-term efficacy for biologic agents5
*Summation of the original abatacept plus placebo treatment groups who entered LTE.Data from literature search on the long-term efficacy results from open-label extension studies of anti-TNFs (in MTX-naïve and MTX-IR patients).
48
LT- RCT
Abatacept: Safety Issues
Acute infusion reactions• 9.8% vs 6.7% placebo, mild-moderate
Malignancy & Infection outcomes• 4134 Abatacept-treated patients compared with
41,529 DMARD treated patients in 5 cohorts• No increased rates of malignancy, infection over
6 years.aSibilia J, Westhovens R. Safety of T-cell costimulation modulation with abatacept in patients with rheumatoid
arthritis. Clin Exp Rheumatol 2007;25 (5Suppl46):S46-56. bSimon TA et al. Malignancies In RA Abatacept clinical development program. ARD 2008.
RA Safety Population
Cumulative (Double-Blind and Open-Label)
Open-Label, UncontrolledN = 2,339
N = 2,688
PlaceboAbatacept
N = 1,955(204)
Double-Blind, Controlled(Biologic Background)
N = 989(134)
BLA/4M
Overview of Patients with Adverse EventsDouble-Blind, Controlled Study Periods
AEs
SAEs
Discontinuation due to AEs
Deaths
AbataceptN = 1955
1736 (88.8)
266 (13.6)
107 (5.5)
10 (0.5)
PlaceboN = 989
840 (84.9)
122 (12.3)
39 (3.9)
6 (0.6)
Number (%) of Patients
Total Patients with Infections
Upper Respiratory Tract Infection
Nasopharyngitis
Sinusitis
Urinary Tract Infection
Influenza
Bronchitis
1051 (53.8)
248 (12.7)
225 (11.5)
125 (6.4)
113 (5.8)
111 (5.7)
101 (5.2)
478 (48.3)
119 (12.0)
90 (9.1)
68 (6.9)
45 (4.6)
52 (5.3)
45 (4.6)
Most Common Infections (≥ 5%) Double-Blind, Controlled Study Periods
Preferred TermAbataceptN = 1955
PlaceboN = 989
Number (%) of Patients
Total Patients with Serious Infections
Pneumonia
Cellulitis
Urinary Tract Infection
Bronchitis
Diverticulitis
Pyelonephritis Acute
Sepsis
Serious Infections (≥ 0.2%) Double-Blind, Controlled Study Periods
58 (3.0)
9 (0.5)
5 (0.3)
4 (0.2)
4 (0.2)
3 (0.2)
3 (0.2)
1 (<0.1)
19 (1.9)
5 (0.5)
2 (0.2)
1 (0.1)
0
0
0
3 (0.3)
Preferred TermAbataceptN = 1955
PlaceboN = 989
Number (%) of Patients
Relative Risk to general population: 1.9 [1.7 – 2.1] Best predictors:
RA severity / disease activity Age Corticosteroid therapy Comorbid diseases: CVD, CHF, CRF, DM, lung disease Previous infection Joint surgery
Contributory role of DMARDs not clearly defined Moreland et al. J Rheum 2001;28:1238-44.
Predictors and Risk of Infection in Rheumatoid Arthritis
TuberculosisCumulative Study Periods
• 2 cases of presumed tuberculosis with abatacept– Tuberculous Infection (Double-Blind):
• Presented with cervical lymphadenitis; diagnosis based on histology
– Pulmonary Tuberculosis Suspected (Open-Label)
• Presented with dry cough, fever, diaphoresis and crepitus; diagnosis based on clinical presentation and chest radiograph
• 1 case of presumed tuberculosis with placebo– Tuberculosis - Suspect (Double-Blind):
• Unknown presentation; no definitive diagnosis
Malignancy
Continued use of abatacept does not increase the risk of malignancy over time
Hochberg M, et al. Arthritis Rheum 2010;62(10Suppl):S164–5. Abstract 390. 57
Integrated safety summary
NMSC=non-melanoma skin cancer; Data over a 7-year period; Data lock December 2009. 12,132 p–y of exposure (N=4,149).
Clinical trial experience
Short term Short term(2,331 p–y)
Long term(9,752 p–y)
Cumulative(12,132 p–y)
Placebo Abatacept Abatacept Abatacept
Malignancies, incidence rate (95% CI)
Malignancies (excluding NMSC)
0.59 (0.19–1.37)
0.69 (0.39–1.11)
0.74 (0.58–0.93)
0.73 (0.58–0.89)
Lymphoma – 0.04 (0.00–0.24)
0.08 (0.04–0.16)
0.07 (0.03–0.14)
Total solid organ (combined)
0.59 (0.19–1.37)
0.60 (0.33–1.01)
0.60 (0.45–0.77)
0.59(0.46–0.75)
Lung cancer – 0.21 (0.07–0.50)
0.13 (0.07–0.23)
0.15 (0.09–0.23)
NMSC 0.82 (0.33–1.70)
0.82 (0.49–1.28)
0.74 (0.58–0.93)
0.73 (0.58–0.90)
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Malignancies: Double-Blind studies
MalignantAbatacept: 29
(1.5%)Placebo: 11
(1.1%%)Non-Melanoma
Skin CAAbatacept: 15
(0.8%)Placebo: 6
(0.5%)
Solid Organ CAAbatacept: 13
(0.7%)Placebo: 5
(0.5%)
HematologicAbatacept: 2
(0.1%)Placebo: 0
Immunogenicity was low in the abatacept clinical trial program
• Overall incidence of anti-abatacept antibody responses was 4.8% (187/3,985) in patients treated for up to 8 years with abatacept
• In patients assessed for antibodies at least 42 days after discontinuation of abatacept, incidence of immunogenicity was 5.5% (103/1,888)1
– There was no apparent correlation of antibody development to clinical response or adverse event based on this limited dataset of patients with antibodies1
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BIOLOGICS AND PREGNANCYDrug #
casesDevelopmental
toxicity - animalsFetal problems – Humans Drug Discontinuation?
ETA 51 - Preterm , VACTERLVert,anal, CVS, tracheobr
fistula, renal, & Limb
At missed period, (+) pregnancy test
INF 81 - TOF, intestinal malrotation At missed period, (+) pregnancy test
ADA 13 - Preterm, limb reduction, Tracheobronchomalacia
At missed period, (+) pregnancy test
RIT 10 B cell depletion (2nd/3rd tri)
Lymphopenia (1st tri) 12 mos pre-pregnancy
ABAT 0 +/None (?) unknown 10 wks pre-pregnancy
Ostensen M, Forger F. Management of RA medications in pregnant patients. Nat Rev Rheumatol 2009;5:382-90. UptoDate 2009
*1 case each - CZP, ANA, 0 - GOL and ABA; no animal and human/fetal toxicity reported; drug discontinuation recommended for GOL, CZP, ANA
ConclusionsAbatacept in RA:• Is efficacious in achieving remission in early RA• Is efficacious in short and long term treatment• Has a high retention rate • Is a safe and reliable drug
Recommended