Rheumatoid Arthritis Joan M. Bathon, MD Professor of Medicine Director, Arthritis Center Johns...

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