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Rheumatoid Arthritis
Joan M. Bathon, MDProfessor of Medicine
Director, Arthritis CenterJohns Hopkins Medical Institutions
2
Disclosures
• Research Support
Biogen-IDEC
Amgen
Bristol Myers Squibb
3
Objectives: Update in RA
•Diagnosis
•Treatment
•Mortality/Survival
4
5
Premature Mortality in Patients with RA
Non RA Women
Non RA Men
RA Women
RA Men
1.01.0
0.90.9
0.80.8
0.70.7
0.60.6
0.50.5
0.40.4
0.30.3
0.20.2
0.10.1
0.00.000 55 1010 1515 2020 2525
Years After Entry Into Study
Su
rviv
al P
rob
abil
ity
N = 886SMR = 3.08
SMR = standardized mortality ratio for patients with RA compared with non-RA controls.Wolfe F, et al. Arthritis Rheum. 1994;37:481-494.
Major Cause of Excess Deaths is
Cardiovascular Disease
6
Objectives: Update in RA
•Diagnosis
•Treatment
•Mortality/Survival
7
Antibodies toCyclic Citrullinated Peptides
(anti-CCP)
8
RA: Criteria for Classification (4 of 7)
1. Morning stiffness > 1 hour
2. Simultaneous arthritis of > 3 joints
3. Arthritis of hand joints
4. Symmetrical arthritis
5. Rheumatoid nodules
6. Serum rheumatoid factor
7. Typical radiographic changes in hands and wrists
9
Anti Cyclic Citrullinated Peptide Antibodies(Anti CCP)
• High Specificity for RA1,2
• High Positive Predictive Value for RA3
• Detectable earlier than Rheumatoid Factor (RF)4
• Found in up to 40% of patients who are RF negative especially early in disease5
• Predictive of erosive disease and joint damage6
• Highly associated with presence of HLA genetic polymorphisms that predispose to RA (“shared epitope”)
1. Schellekens GA et al. Arthritis Rheum 2000; 43: 155-63. 2. Lee DM Schur PH. Ann Rheum Dis 2003; 62: 870-4. 3. Jansen LMA et al. J Rheumatol 2002; 29: 2074-6. 4. Nielen MMJ et al. Arthritis Rheum 2004; 50: 380-6. 5. Vallbracht I, et al. Ann Rheum Dis 2004; 63: 1079-84. 5. van Gaalen FA et al. Ann Rheum Dis. 2005 Mar 30; [Epub ahead of print]
10
Anti-CCP and RF Antibodiesare Frequently Detected Before Clinical
Onset of Disease
Nielen MMJ et al. Arthritis Rheum 2004; 50: 380-6.
11
Anti-CCP Predicts Progression to RA
• How well can clinical parameters predict development of RA? (1 yr f/u)
ACR criteria plus CCP
OR 95% CI p-value
Morning stiffness >1 hour 2.1 (0.8–5.3) 0.108
Arthritis of three or more joints 5.0 (1.8–13.2) 0.001
Arthritis of wrist, MCP, PIP 1.2 (0.4–3.3) 0.762
Symmetric involvement of joints 6.1 (2.0–19.0) 0.002
Rheumatoid nodules 0.003 (0.0–∞) 0.795
Positive IgM rheumatoid factor 1.7 (0.5–5.6) 0.406
Erosions on radiographs 8.7 (2.4–31.2) 0.001
Positive anti-CCP2 antibody 38.6 (9.9–151.0) <0.001
ROC AUC 0.923
van Gaalen et al, Arthritis Rheum 2004;50:709–15
12
Anti-CCP as Prognostic Marker of Erosive disease in Early RA
• 145 patients with RA onset
• Followed for 5 years
• At baseline: 57% CCP1+/69% IgM RF+
• Radiographic progression monitored with Sharp score
Performance of CCP and RF in predicting joint damage
CCP1 Total 2.5 (1.2 to 5.0) 64%
Erosions 3.4 (1.6 to 7.2) 49%
Narrowing 1.8 (0.8 to 3.6) 56%
RF Total 0.7 (0.3 to 1.5) 47%
Erosions 1.2 (0.5 to 2.8) 27%
Narrowing 0.5 (0.2 to 1.1) 40%
Meyer O et al, Ann Rheum Dis 2003;62:120–6
13
Antibodies to Citrullinated Proteinsare Highly Specific for RA
L-arginine residue(+charged)
L-citrulline residue(neutral)
Peptidylargininedeiminase (PADI)
Ca2+
H
N
O
NH
NH2H2N+
H
N
O
NH
NH2O
14Vossenaar ER; BioEssays 25:1106–1118, 2003.
15
Citrullinated Substrates
• Keratin
• Filaggrin
• Fibrin and fibrinogen
• Vimentin
• Others ??
16
#1 Diagnosis: Summary
• Revision of criteria for diagnosis of RA is underway
• The presence of anti-CCP antibody will undoubtedly constitute a new diagnostic criterion
• Anti-CCP antibodies are also a prognostic factor for more severe disease
17
Objectives: Update in RA
•Diagnosis
•Treatment
•Mortality/Survival
18
Rheumatoid Arthritis:Expectations of Treatment
Reduce pain, stiffness and fatigue
Improve Quality of Life
Prevent joint destruction
Maintain full function
Reduce CV events
Prolong lifespan
19
RA: Treatment Strategies
Treat early
Treat “hard”
Treat with combination of agents
Treat with a targeted goal
20
#1 TREAT EARLY
• Rationale
– Delay in therapy is associated with more joint damage
– Active disease of long duration is less responsive to treatment than active disease of short duration
• Goals
– Prevent damage and disability
– Start DMARD within 6 wks of sx/dx
21
Ch
ang
e in
Med
ian
Ch
ang
e in
Med
ian
S
har
p S
core
Sh
arp
Sco
re
00
22
44
66
88
1010
1212
1414
00 66 1212 1818 2424
Time (months)Time (months)
*Patients were treated with *Patients were treated with chloroquinechloroquine or or salazopyrinesalazopyrine
Lard LR, et al. Lard LR, et al. Am J MedAm J Med. 2001;111:446-451. . 2001;111:446-451.
Treatment: The Earlier the BetterTreatment: The Earlier the Better
Delayed Treatment 1993-1995*Delayed Treatment 1993-1995*(median lag time to treatment = 123 days; n=109)(median lag time to treatment = 123 days; n=109)
Early Treatment 1996-1998* Early Treatment 1996-1998* (median lag time to treatment = 15 days; n=97)(median lag time to treatment = 15 days; n=97)
22
Disease Duration Predicts Response to Treatment in RA*
*Primary trial data analyzed from 14 randomized, controlled trials: (11) MTX, CyA + MTX, *Primary trial data analyzed from 14 randomized, controlled trials: (11) MTX, CyA + MTX, COBRA, and Prosorba COBRA, and Prosorba Anderson JJ, et al. Anderson JJ, et al. Arthritis Rheum.Arthritis Rheum. 2000;43:22-29 2000;43:22-29..
N=1435N=1435
Tender joint countTender joint countSwollen joint countSwollen joint count
ESRESR
Pro
po
rtio
n o
f P
atie
nts
Pro
po
rtio
n o
f P
atie
nts
Im
pro
vin
g 2
0%Im
pro
vin
g 2
0%
0-10-1 1-21-2 2-52-5 5-105-10 >10>10
0.80.8
0.70.7
0.60.6
0.50.5
0.40.4
0.30.3
Disease Duration (Years)Disease Duration (Years)
23
#2 TREAT HARD
•Maximally efficacious dose of disease modifying agent (DMARD) that is tolerated by the patient
•Rapid dose escalation of MTX (up to 20 mg over 8 wks)
24
8.3
1.3
PredictedPredicted ActualActual
Mean
ch
an
ge
Mean
ch
an
ge
9.5
1.3
8.7
0.8
0
2
4
6
8
10
PredictedPredictedActualActual PredictedPredictedActualActual
Etanercept and MTX Halt Radiographic Progression in Early RA
Etanercept 10 mgEtanercept 10 mgEtanercept 25 mgEtanercept 25 mg
MethotrexateMethotrexate
Bathon et al, NEJM 2000
25
#3 TREAT WITH COMBINATION OF AGENTS(when appropriate)
• Rationale
–Combination of agents is superior to monotherapy in every study reported in RA
–For signs/sx and retardation of joint damage
• Types of combinations
–Non-biologic + non-biologic DMARD
–Non-biologic + biologic DMARD
26
COBRA Trial
Long-term Structural BenefitsM
edia
n S
har
p S
core
Years of Follow-up
6060
00
1515
3030
4545
SSZ+MTX+steroids
SSZ alone
COBRA: Prednisolone (initially 60 mg/d, tapered in 6 weekly steps to 7.5 mg/d) plus COBRA: Prednisolone (initially 60 mg/d, tapered in 6 weekly steps to 7.5 mg/d) plus methotrexate 7.5 mg/wk x 40 wks plus sulfasalazine 2 g/d. SSZ: Sulfasalazine 2 g/d.methotrexate 7.5 mg/wk x 40 wks plus sulfasalazine 2 g/d. SSZ: Sulfasalazine 2 g/d.
LandewLandewéé RB, et al. RB, et al. Arthritis RheumArthritis Rheum. 2002;46:347-. 2002;46:347-356356..
11 22 33 4400 55
27
RA: Treatment Strategies
• #4 - Treat with a targeted goal*
– Remission of disease activity
– Or, at least low disease activity
*numerical goal, as in DM and HTN
28
Leflunomide
SSA
MTX 25 mg
MTX 15 mg
Group 1Sequential monotherapy
n=126
MTX + IFX
Gold
MTX + CsA + pred
AZA + pred
MTX + SSA + HCQ
MTX + SSA
MTX 25 mg
MTX 15 mg
Group 2Step-up combination
n=121
MTX + SSA + HCQ + pred
MTX + IFX
MTX + CsA + pred
Leflunomide
Gold
MTX + IFX
MTX + CsA + pred
MTX 25 mg + SSA + pred
MTX 7.5 mg/wk + SSA + pred 60→7.5 mg/day
Group 3Initial combination
n=133
Leflunomide
Gold
AZA + pred
SSA
MTX + IFX 10 mg/kg
MTX 25 mg + IFX 3 mg/kg
Group 4Initial IFX + MTX n=128
Leflunomide
MTX + CsA + pred
Gold
AZA + pred
BeST Trial
29
Mean HAQ
Mea
n H
AQ
0
0.4
0.8
1.2
1.6
0 3 6 9 12 15
18 21 24 27 30 33 36
Time (months)
**
Sequential monotherapy Step-up therapy
Initial combi with prednisone Initial combi with infliximab
% in remission (DAS <1.6)
% w
ith D
AS
<1.
6
0
25
50
75
100
0 3 6 9 12 15 18 21 24 27 30 33 36
Time (months)
44%
Van der Kooij SM, et al EULAR 2007, Barcelona, #OP0125
30
Radiographic progression 0–3 y Pts with xray progression at 3 y
P=0.001, groups 1+2 vs 3+4
Median 3.8 3.0 1.81.5Mean 9.5 6.6 3.93.3
% w
ith
pro
gre
ssio
n o
f S
HS 60
40
20
0
80
100
44 43
29 25
Sequentialmono
Step-upcombi
Combi withprednisone
Combi withinfliximab4.6
0 20 40 60 80 100
-20
0
20
40
60
80
SH
S S
ha
rp p
rog
res
sio
n
Sequential monotherapy
Step-up combination therapy
Initial combi with prednisone
Initial combi with infliximab
Van der Kooij SM, et al EULAR 2007, Barcelona, #OP0125
BeST Study
31
BeST Study: Conclusions
• Goal directed therapy resulted in
–excellent outcomes for signs and symptoms regardless of therapeutic agent(s) used.
• Radiological outcomes better with
–early combination than delayed combination.
• Goal of treatment should be remission or, at least, low disease activity
Specific Therapeutic Agents for RA
33
Landmark Developments: Therapeutic
• Corticosteroids - 1940s
• Methotrexate - 1980s
• Anti-TNF therapy – 1998
34
RA TREATMENT: 2008
• Methotrexate - most commonly used first DMARD
–High benefit to risk ratio
• If response to MTX monotherapy inadequate, add second agent
–Oral agents: hydroxychloroquine, sulfasalazine
–Anti-TNF therapy
• If combination of MTX + TNF inhibitor inadequate, substitute TNF inhibitor for newer biologic
35
TNF Inhibitors: Excellent Efficacy and Comparable for All Three
• Improve signs and symptoms (joint pain and swelling)
• Improve laboratory parameters (ESR and CRP)
• Slow or prevent radiographic progression (erosions and joint space narrowing)
• Effective in early and late disease
• Do they reduce mortality?
36
TNF Inhibitors: Safety Issues
• Infectious
–opportunistic and ?common bacteria?
• Malignancy: non Hodgkin’s lymphoma ?
• Congestive heart failure
• Demyelinating disease
37
Options for TNF Failures
• 50% of pts have only mild-mod response
• Switch TNF inhibitor (while continuing MTX) ???
– Data are muddy but worth considering
• New biologics:
– Inhibitor of T cell costimulation: abatacept
– B cell depleting mAb: rituximab
• On the horizon: tocilizumab (anti-IL6)
38
Does Treatment of RA…..
• Prolong lifespan?
• Reduce cardiovascular events?
• Reduce cardiovascular risk factors?
39
Objectives: Update in RA
•Diagnosis
•Treatment
•Mortality/Survival
40
Premature Mortality in Patients with RA
Non RA Women
Non RA Men
RA Women
RA Men
1.01.0
0.90.9
0.80.8
0.70.7
0.60.6
0.50.5
0.40.4
0.30.3
0.20.2
0.10.1
0.00.000 55 1010 1515 2020 2525
Years After Entry Into Study
Su
rviv
al P
rob
abil
ity
N = 886SMR = 3.08
SMR = standardized mortality ratio for patients with RA compared with non-RA controls.Wolfe F, et al. Arthritis Rheum. 1994;37:481-494.
Major Cause of Excess Deaths is
Cardiovascular Disease
41
Top Three Causes of Death in RA
•Cardiovascular
•Pulmonary
• Infection
42
New Mortality/Survival Data:Equivocal Results
• Observational Studies of RA vs nonRA
– Mayo Clinic: no change in mortality rates.
In fact, gap is widening beteween RA and nonRA
– European studies of early inflammatory arthritis
Some show improvement, some not
• Observational Studies of DMARDs within RA populations
– Also equivocal
• Explanations ??
– Short time frame
– Methodological issues
43
Top Three Causes of Death in RA
•Cardiovascular
•Pulmonary
• Infection
44
RA is associated with higher rates of:
Overall mortality
CV associated mortality
CV associated morbidity
CV risk factors
Do DMARDs reduce these complications?
45
Atypical CV Presentation in RA Patients
Maradit-Kremers H, Arthritis Rheum 2005;52:402-422.
46
Douglas, Ann Rheum Dis 2006;65:348–353.
Reduced Survival in RA Patients with Acute Coronary Syndrome
47
RA: Mortality
• Standardized Mortality Ratio (SMR) is 1.28-3.0 compared to non-RA controls1-3
• Lifespan of RA patients is decreased by 5-10 years compared to non-RA controls
• CV disease is the largest contributor to excess deaths
1Wolfe, et al. Arthr Rheum. 1994;37:481; 2Doran et al. Arthr Rheum. 2002;46:625; 3Van Doorrnum et al. Arthr Rheum. 2002;46:862.
48
RA: Clinical CV Events
• Adjusted incidence rate for CV events is 2-4 fold higher in RA patients compared to non-RA controls 1, 2
– Myocardial infarctions (MI)
– strokes (CVA)
1del Rincon I, et al. Arthr Rheum. 2001;44:2737; 2Solomon D, et al. Circulation. 2003;107:1303.
49
Statement of the Problem
• Morbidity and mortality due to cardiovascular (CV) disease are higher in RA populations than in controls.
• Hypothesis: Accelerated CV disease in RA populations is due to chronic inflammation.
• Implication: Aggressive treatment of inflammation in RA patients should lower morbidity and mortality associated with CV disease.
50
Potential Mechanisms for Increased Risk of CVD in RA
• Increased prevalence of conventional risk factors?
• Increased thrombotic tendency
• Drug toxicity
– Steroids, COX-2, MTX, anti-TNF
• De-conditioning
• Inflammation = independent, additive risk factor
51
Are CV Risk Factors More Prevalent in RA Patients?
• Not by clinical definitions (HTN, DM, hypercholesterolemia, obesity, etc)
• But, yes, alternate definitions:
– Increased prevalence of insulin resistance1,2
– Pro-atherogenic lipid profiles3,4
– Increased BMI5 and percentage of body fat6
– Increased prevalence of metabolic syndrome
• TNF-mediated? Correlate with ESR, CRP
1Dessein PH, et al. J Rheum. 2003;30:1403; 2Paolisso G, et al. Metabolism. 1991;40:902; 3Lee YH, et al. Clin Rheum. 2000;19:324; 4Heldenberg D, et al. Clin Rheum. 1983;2:387; 5del Rincon I, et al. Arthr Rheum. 2001;44:2737; 6Giles JT, et al. 2005 ACR annual meeting, San Diego, CA.
52
Do non-biologic DMARDs ---
Reduce CV risk factors?
Reduce CV events?
Reduce CV mortality?
Sparse Data
53
Cardiovascular Disease in RAHydroxychloroquine Protects Against Hydroxychloroquine Protects Against
Incident Diabetes in RAIncident Diabetes in RA
Wasko et al. JAMA 2007; 298: 187.
54
Study Number of
Patients
Mortality Rate
Kraus et al 2000
271 ↓
Landewe 2000 623 ↑
Choi et al 2002 1240 ↓
Methotrexate: Effect on MortalityRates is Inconsistent
55
Do biologic inhibitors ---
Reduce CV risk factors?
Reduce subclinical CV disease?
Reduce CV events?
Reduce CV mortality?
56
Do biologic (anti-TNF) inhibitors ---
Reduce CV risk factors?
Reduce subclinical CV disease?
Reduce CV events?
Reduce CV mortality?
57
Cardiovascular Disease in RA
• Results Conflicting…
• 2 studies with improvement in HOMA with infliximab1,2
• 1 study with no change in hyperinsulinemic euglycemic clamp with adalimumab3
• Non-RA– little effect of TNF inhibition on insulin sensitivity4
TNF inhibition and TNF inhibition and Insulin Resistance in RAInsulin Resistance in RA
1 Kiortsis et al. Ann Rheum Dis 2005; 64: 765.2 Tam et al. Clin Rheumatol 2007; 26: 1495.3 Rosenvinge et al. Scand J Rheumatol 2007; 36: 91.4 Bernstein et al. Arch Intern Med 2006; 166: 902.
58
Cardiovascular Disease in RA
• Results also conflicting
• General themes:
– HDL-C increases1,2,3
– LDL-C increases1,2,3
– Atherogenic index decreases or stays the same1,2,3
– Triglycerides go up in some studies3
• May represent patient’s pre-disease lipid profile
• Similar effects seen with effective non-biologic DMARDs4,5
TNF Inhibition and Lipids in RATNF Inhibition and Lipids in RA
1Popa et al. Ann Rheum Dis 2005; 64: 303. 4Park et al. Am J Med 2002; 113: 188.2Vis et al. J Rheumatol 2005; 32: 252. 5Boers et al. Ann Rheum Dis 2003; 62: 8423Tam et al. Clin Rheumatol 2006; 26: 1495.
59
Do biologic (anti-TNF) inhibitors ---
Reduce CV risk factors?
Reduce subclinical CV disease?
Reduce CV events?
Reduce CV mortality?
60
Does Anti-TNF TherapyReduce Subclinical CV Disease?
• Endothelial dysfunction*
–Transient improvement, not sustained
• Coronary artery calcium
–No prospective data
• Carotid intima-medial thickness (IMT) or plaque
–No prospective data*Gonzalez-Juanatey et al, Arthritis Rheum 2004; Cardillo et al Clin Pahrmacol Ther 2006; Bilsborough et al, Rheumatol Int 2006
61
Do biologic (anti-TNF) inhibitors ---
Reduce CV risk factors?
Reduce subclinical CV disease?
Reduce CV events?
Reduce CV mortality?
62
Does Anti-TNF Therapy ReduceClinical CV Events
• Best Design: Intervention Trial
– CV events are relatively infrequent. Therefore,
Large number of patients must be studied
Long period of treatment required
– What comparator group?
Placebo unethical
Non-biologic DMARD ??
63
Anti-TNF Therapy and Clinical CV Events
• Observational Studies
– Types:
Prospective cohort study
Nested case-control studies
– Data Bases
RA registries
» Frequently lack information on CV risk factors
Administrative (claims) data bases
» Usually lack information on RA characteristics (severity)
– These unmeasured factors may confound the results → → overestimate or underestimate the effect of treatment
64
Jacobbson et al - 2005
• Methods
– Prospective cohort study
– Subjects (RA pts < 80 y.o.):
National register of RA pts on TNF inhibitors, n= 531
Community based RA pts on non-biol DMARDs, n = 543
– Exposure period to drugs: 5-8 yrs?
– Primary outcome: First CV event
– Statistical adjustments: disease severity, COPD, DM, prednisone, smoking. Other CV risk data unknown.
Jacobbson L et al, J Rheum 2005;32:1213
65
Jacobbson – Reduction of events with TNF inhibitor but not statistically significant
Treatment No. of events Incidence rate per 1000 patient-
years*
Relative Risk
(95% CI)
No TNF inhibitor 85 35.4 1.0 (referent)
TNF inhibitor 13 14 0.62
(0.34-1.12)
p=0.111
*age and sex adjusted rates
66
Solomon et al - 2006• Methods
– Nested case-control (1:10)
– Subjects: 3,501 Medicare RA patients on DMARDs (mean age 80 yo)
– Primary Outcome: MI or CVA
Prior CV events not excluded
– Exposure period: 90 days prior to event
– Comparison to MTX
– Statistical adjustments: prior CV events, comorbidity, CV meds. Not available: RA disease activity/severity, important CV risk factors (smoking, BMI, ASA use, Framingham risk score).
Solomon DH et al, Arthritis Rheum 2006; 54:3790*cyclosporine, azathioprine, leflunomide
67
Noncytotoxic892
Cytotoxic208
SteroidsOnly1266
BiologicOther228
BiologicMTX117
Biologic149
MTX1180
4
2
1
0.50.3
84 12 8 20 148 26 69
Solomon et al.Adjusted RR – MI/CVA
68
Suissa et al - 2006
• Methods
– Nested case control study (1:10 match)
107, 908 RA patients in PharMetrics database
– Primary Outcome: Acute MIs (first)
– Exposure to drug(s): 12 mos prior to event
– Comparison to no DMARD
– Statistical adjustments: prior non-MI CV disease, comorbidity (HTN, DM, hypercholesteremia), CV drugs. Not available: RA activity/severity, smoking, BMI
Suissa S et al, Arthritis Rheum 2006; 55:531
69
Other DMARDs513
Biologics366
LEF200
MTX757
No DMARD4361
2
1
0.50.3
416 60 6 42 34
Suissa et al.Adjusted RR – Acute MI
70
Singh et al (abstract), 2007
• Methods
– Nested case control study (1:4 match)
California Medicaid Population (MediCal)
– Population: 19, 233 RA patients taking
MTX = 13,383; other nonbiologic DMARDs = 14,95; TNF inhibitors = 4,943
– Primary Outcome: Acute MI
– Comparison to MTX monotherapy
– Exposure to drug: filling of a prescription 60 days prior to event
– Statistical adjustments: 38 potentially confounding factors (including smoking, lipids). ??No data on RA disease activity/severity??
Singh G et al, EULAR and ACR 2007
71
Singh – 80% reduction in risk with MTX + TNF inhibitor. Increased risk with steroids.
Treatment Adjusted RR (95% CIs)MTX mono 1.0 (referent)
TNF inhib + MTX 0.20 (0.05-0.88)
TNF inhib mono 1.17 (0.50-2.75)
TNF inhib + other DMARD 1.78 (0.60-5.27)
Other DMARDs without MTX 0.88 (0.60-1.31)
Combination of DMARDs + MTX
0.93 (0.54-1.62)
Corticosteroids 1.37 (1.07-1.75)
72
Dixon et al - 2007
• Methods
– Prospective national cohort study
– Population
National register
No. on anti-TNF=8659; nonbiologic DMARDs=2170
–Primary outcome: first MI
– Exposure: ever exposed
– Comparison to nonbiologic DMARDs
– Statistical adjustments: RA disease activity/severity, BMI, smoking, co-morbidity, CV drugs. Data on other CV risk factors not available.
Dixon et al, Arthritis Rheum 2007
73
BSRBR
1.0
2
Inci
den
ce R
ate
Rat
io*
(95%
CI)
0.1
0.4
0.2
DMARD0.6
10
6
4
Anti-TNF
* Adjusted for age, gender, disease severity, BMI, smoking, co-morbidity and baseline drug use
1.44
Dixon et al. Arth Rheum 2007
17 63
74
BSRBR
1.0
2
0.1
0.4
0.2
0.6
10
6
4
RespondersNon-responders
(Referent)
0.36
Anti-TNF Treated Only
Inci
den
ce R
ate
Rat
io*
(95%
CI)
* Adjusted for age, gender, disease severity, BMI, smoking, co-morbidity and baseline drug use
Dixon et al. Arth Rheum 2007
75
Risk of CV Events
8
4
2
1
0.5
0.25
0.06
Bio v MTX
Bio/MTX v MTX
Bio/Oth v MTX
TNF v DMARDs
TNF v No Dmards
Solomon 2006
MI/CVA
Jacobssen 2005
All CVD
Dixon 2007
MI
Singh 2007
MI
Suissa 2006
MI
76
Limitations
• Different outcomes (predominantly MI)
• Different lengths of exposure to drugs
• Inadequate information on many confounding CV risk factors
• Inadequate information on RA characteristics in most studies
– Confounding by indication (channelling bias)
• Different populations
• Different comparator groups (no DMARD, MTX, all nonbiol)
• Variable exclusion of prior CV events
77
Heart Failure (HF) in RA
• Prevalence of symptomatic HF increased in RA vs nonRA
– Adjusted RR 1.43 (Wolfe et al)1
– Hazard ratio 1.87 (Rochester Minn)2
Even after adjusting for ischemic CHD
• In animal studies, overexpression of TNF in the heart leads spontaneously to inflammatory myocarditis, CHF and death
– Anti-inflammatory agents may reduce risk for CHF
1 Wolfe et al. J Rheum 2003; 30:36; 2Nicola 2005; A&R 52:412
78
Anti-TNF Therapy in Non-RAPatients with CHF
• Non RA patients with moderate to severe CHF
–Etanercept, no effect
–Infliximab, increased hospitalizations/mortality
79
Anti-TNF Therapy in Non-RAPatients with CHF
• Non RA patients with moderate to severe CHF
–Etanercept, no effect
–Infliximab, increased hospitalizations/mortality
80
Wolfe 2004 – Decrease in prevalent but not incident CHF in patients treated with TNF inhibitors
No anti-TNF
N=7,339
Anti-TNF
N=5,832
Prevalent 3.8% 3.1%
Adjusted difference*
Referent -1.2 (-1.2, -0.5) %
Incident 0.4% (n=12) 0.4% (n=12)
Adjusted difference*
Referent -0.1 (-0.1, 0.0) %
Wolfe F et al, Am J Med 2004*Adjusted for propensity score
81
Bernatsky - 2006
• Methods
– Nested case control study (1:10 match)
41,885 RA patients in administrative database
– Primary Outcome: hospitalization for CHF
Prior CHF excluded
– Exposure to drug(s): ??ever exposed??
– Comparison to no DMARD
– Statistical adjustments: comorbidity, prior CV disease, HTN, DM, hypercholesterolemia. Not available: RA disease activity/severity, smoking, BMI.
Bernatsky S et al, Rheumatology 2005; 44:677
82Anti-TNFOther DMARDSMTXNo DMARD
2.00
1.00
0.50
0.25
Adjusted RR Hosp. CHF
Bernatsky et al
Bernatsky et al. Rheumatology 2005
83
SUMMARY: ANTI-TNF THERAPY AND CV MORBIDITY IN RA
Treatment of RA is associated with…..
• Transient improvement in some CV risk factors
– Insulin resistance, endothelial dysfunction
– Effect on lipids is more complex
• Effect on CV events (MIs, CVAs) inconclusive
– Limitations of study designs and available data
• Effect on CHF inconclusive
– Possible reduction but need to reconcile with data in non-RA pts with CHF
Can an intervention study be done with clinical CV events as outcome?
84
Conclusions
• Great advances in the treatment of RA
–Specific agents
–Treatment strategies (especially tight control)
• Although not definitively proven yet, seems likely that these agents and strategies will result in
–Less CV morbidity and mortality
–Reduced overall mortality
85
centerarthritisarthritis
center
JOHNS HOPKINS
http:www.hopkins-arthritis.org
86
RA: Unanswered Questions
• What is the cause?
• Who will get it?
• How to cure it?
• How to prevent it?
87
centerarthritisarthritis
center
JOHNS HOPKINS
http:www.hopkins-arthritis.org
88
When to use combination of MTX + TNF inhibitor as initial therapy?
• Consider if patient has high number of risk factors for poor outcome:
–Very high titer RF and/or anti-CCP
–Strong family history, suggesting SE
–Radiographic erosions at baseline
–Very high inflammatory markers
89
Inhibitors of TNF-
• Soluble TNF Receptor
– Etanercept
• Anti-TNF Monoclonal Antibodies
– Infliximab
– Adalimumab
• In development
– Golimumab (monoclonal antibody)
– Certolizumab (pegylated-TNF receptor)
– Dominant negative TNF
90
MichaudJacobsson
Carmona
Greenberg
Solomon
Suissa
Dixon
0
0.5
1
1.5
2
2.5
Expressed as standardized mortality ratios, hazard ratios, IRR
Effect of TNF Inhibitors on Mortality Risk
Jacobsson L, et al EULAR 2007, Barcelona, #SP0045
91
Treatment of RA patients with a TNF inhibitor (temporarily, partially) improves
CV risk factors
Insulin resistance1,2
Dyslipidemia3,4
Endothelial dysfunction5,6
1Dessein PH, et al. Arthritis Res. 2002;4:R12; 2Dessein PH, et al. J Rheum. 2004;31:867; 3Vis M, et al. J Rheum. 2005;32:252; 4Park Y-B, et al. Am J Med. 2002;113:188; 5Gonzalez-Juanatey C, et al. Arthritis Care Res. 2004;51:447; 6Hurlimann D, et al. Circulation. 2002;106:2184