Rheumatoid Arthritis

1
Rheumatoid Arthritis

• Joan M. Bathon, MD
• Professor of Medicine
• Director, Arthritis Center
• Johns Hopkins Medical Institutions

2
Disclosures

• Research Support
• Biogen-IDEC
• Amgen
• Bristol Myers Squibb

3
Objectives Update in RA

• Diagnosis
• Treatment
• Mortality/Survival

4
(No Transcript)
5
Premature Mortality in Patients with RA
Major Cause of Excess Deaths is Cardiovascular
Disease
SMR standardized mortality ratio for patients
with RA compared with non-RA controls. Wolfe F,
et al. Arthritis Rheum. 199437481-494.
6
Objectives Update in RA

• Diagnosis
• Treatment
• Mortality/Survival

7
Antibodies toCyclic Citrullinated Peptides
(anti-CCP)
8
RA Criteria for Classification (4 of 7)

• Morning stiffness gt 1 hour
• Simultaneous arthritis of gt 3 joints
• Arthritis of hand joints
• Symmetrical arthritis
• 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
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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)

van Gaalen et al, Arthritis Rheum 20045070915
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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

Meyer O et al, Ann Rheum Dis 2003621206
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Antibodies to Citrullinated Proteinsare Highly
Specific for RA
H
H
O
O
N
N
Peptidylargininedeiminase (PADI) Ca2
NH
NH
H2N
O
NH2
NH2
L-arginine residue (charged)
L-citrulline residue(neutral)
14
Vossenaar ER BioEssays 2511061118, 2003.
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Citrullinated Substrates

• Keratin
• Filaggrin
• Fibrin and fibrinogen
• Vimentin
• Others ??

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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 ArthritisExpectations 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

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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
Treatment The Earlier the Better
Delayed Treatment 1993-1995(median lag time to
treatment 123 days n109) Early Treatment
1996-1998 (median lag time to treatment 15
days n97)
14
12
10
Change in Median Sharp Score
8
6
4
2
0
0
6
12
18
24
Time (months)
Patients were treated with chloroquine or
salazopyrine Lard LR, et al. Am J Med.
2001111446-451.
22
Disease Duration Predicts Response to Treatment
in RA
0.8
Tender joint count
Swollen joint count
0.7
ESR
0.6
Proportion of Patients Improving 20
0.5
0.4
N1435
0.3
0-1
1-2
2-5
5-10
gt10
Disease Duration (Years)
Primary trial data analyzed from 14 randomized,
controlled trials (11) MTX, CyA MTX, COBRA,
and Prosorba


Anderson JJ, et al.
Arthritis Rheum. 20004322-29.
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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
Etanercept and MTX Halt Radiographic Progression
in Early RA
Etanercept 25 mg
Etanercept 10 mg
Methotrexate
9.5
10
8.3
8
6
Mean change
4
2
1.3
1.3
0
Predicted
Actual
Predicted
Actual
Predicted
Actual
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 Benefits
60
SSZ alone
45
Median Sharp Score
SSZMTX steroids
30
15
0
Years of Follow-up
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. Landewé RB, et al.
Arthritis Rheum. 200246347-356.
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
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BeST Trial
29
Van der Kooij SM, et al EULAR 2007, Barcelona,
OP0125
30
BeST Study
Radiographic progression 03 y
Van der Kooij SM, et al EULAR 2007, Barcelona,
OP0125
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

32
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 Hodgkins 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
Major Cause of Excess Deaths is Cardiovascular
Disease
SMR standardized mortality ratio for patients
with RA compared with non-RA controls. Wolfe F,
et al. Arthritis Rheum. 199437481-494.
41
Top Three Causes of Death in RA

• Cardiovascular
• Pulmonary
• Infection

42
New Mortality/Survival DataEquivocal 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
200552402-422.
46
Reduced Survival in RA Patients with Acute
Coronary Syndrome
Douglas, Ann Rheum Dis 200665348353.
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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. 199437481 2Doran
et al. Arthr Rheum. 200246625 3Van Doorrnum
et al. Arthr Rheum. 200246862.
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. 2001442737
2Solomon D, et al. Circulation. 20031071303.
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. 2003301403
2Paolisso G, et al. Metabolism. 199140902 3Lee
YH, et al. Clin Rheum. 200019324 4Heldenberg
D, et al. Clin Rheum. 19832387 5del Rincon I,
et al. Arthr Rheum. 2001442737 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 RA
Hydroxychloroquine Protects Against Incident
Diabetes in RA
Wasko et al. JAMA 2007 298 187.
54
Methotrexate Effect on Mortality Rates is
Inconsistent
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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
TNF inhibition and Insulin Resistance 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

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
TNF Inhibition and Lipids 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 patients pre-disease lipid profile
• Similar effects seen with effective non-biologic
  DMARDs4,5

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 62 842 3Tam 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 lt 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 2005321213
65
Jacobbson Reduction of events with TNF
inhibitor but not statistically significant
age and sex adjusted rates
66
Solomon et al - 2006

• Methods
• Nested case-control (110)
• 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
543790 cyclosporine, azathioprine, leflunomide
67
Solomon et al.
Adjusted RR MI/CVA
68
Suissa et al - 2006

• Methods
• Nested case control study (110 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 55531
69
Suissa et al.
Adjusted RR Acute MI
2
1
0.5
0.3
Other DMARDs 513
Biologics 366
LEF 200
MTX 757
No DMARD 4361
416
60
6
42
34
70
Singh et al (abstract), 2007

• Methods
• Nested case control study (14 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.
72
Dixon et al - 2007

• Methods
• Prospective national cohort study
• Population
• National register
• No. on anti-TNF8659 nonbiologic DMARDs2170
• 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
10
6
4
Incidence Rate Ratio (95 CI)
2
1.44
1.0
0.6
DMARD
0.4
Anti-TNF
0.2
17
63
0.1
Adjusted for age, gender, disease severity,
BMI, smoking, co-morbidity and baseline drug use
Dixon et al. Arth Rheum 2007
74
BSRBR
10
Anti-TNF Treated Only
6
4
Non-responders (Referent)
Responders
Incidence Rate Ratio (95 CI)
2
1.0
0.6
0.4
0.36
0.2
0.1
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
Bio v MTX
8
Bio/MTX v MTX
Bio/Oth v MTX
TNF v DMARDs
4
TNF v No Dmards
2
1
0.5
0.25
0.06
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 3036 2Nicola
2005 AR 52412
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
Wolfe F et al, Am J Med 2004 Adjusted for
propensity score
81
Bernatsky - 2006

• Methods
• Nested case control study (110 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 44677
82
Bernatsky et al
Adjusted RR Hosp. CHF
2.00
1.00
0.50
0.25
Anti-TNF
Other DMARDS
MTX
No DMARD
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
JOHNS HOPKINS
arthritis
center
center
httpwww.hopkins-arthritis.org
86
RA Unanswered Questions

• What is the cause?
• Who will get it?
• How to cure it?
• How to prevent it?

87
JOHNS HOPKINS
arthritis
center
center
httpwww.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
Effect of TNF Inhibitors on Mortality Risk
Expressed as standardized mortality ratios,
hazard ratios, IRR
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. 20024R12
2Dessein PH, et al. J Rheum. 200431867 3Vis
M, et al. J Rheum. 200532252 4Park Y-B, et
al. Am J Med. 2002113188 5Gonzalez-Juanatey
C, et al. Arthritis Care Res. 200451447
6Hurlimann D, et al. Circulation. 20021062184