Therapeutic Revolution in
Rheumatoid Arthritis
Brian J. Keroack, MD
Rheumatology Associates
Portland, Maine
Rheumatoid Arthritis

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Morning stiffness>1
hour
Usually symmetric
Parameters of
systemic inflammation
>6 weeks duration
70% +RF
Rheumatoid Arthritis
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


Accepted Prevalence: 11.5% (classic seropositive)
200,000 new cases
annually
19.9 billion/year spent on
RA. 9.5 billion
dollars/million patients.
This exceeds cost/patient
in diabetes and
cardiovascular disease.
Rheumatoid Arthritis
affects Survival:
Impact of RA

Premature mortality

Increased morbidity

Significant impact on quality of life
– Pain with associated functional disability
– Fatigue


73% of patients
42% with severe fatigue
– Depression

Economic impact
– Work dysfunction
– Earnings loss of approximately 50%

Clinically Detectable Damage Occurs Early
in RA
 MRI-detectable erosions are present within
4 months of symptom onset1

Most patients (up to 93%) with RA of < 2
years’ duration show radiographic damage2

Disease progression is more rapid during
the first year than during the second and
third years3
Cartilage in RA: Target or
Bystander?

Early:
–
–
–
–

Cytokines (IL-1, TNF-a ): Macrophages
Catabolic Effects on Chondrocytes
Proteoglycan Depletion
Weakens ability to rebound from a load
Next:
– Induction of Metalloproteinases—Stromolysin,
Collagenase

Last:
– Phagocytosis of Cartilage by Pannus
TNF-a is a pivotal cytokine
in the pathogenesis of RA

Mediates pathologic
inflammation

Mediates joint destruction

Mediates systemic,
extra-articular symptoms
of inflammation

Regulates levels of
adhesion molecules
responsible for leukocyte
migration
Parameters of Inflammation
Approach to the Treatment of
RA
Try to figure out ‘what type’ of Rheumatoid
Arthritis the patient has
 This is not a uniform disease

– Young, Sero-positive patient vs. Older Sero-
negative patient.
– Abrupt vs gradual onset
– Response to 10-15 mg prednisone (‘Lourdes’
response)

Mild DMARDS vs Immunosuprssives
Approach to the Treatment of RA: Early

Immunosupression
Antiproliferative agents
– More aggressive doses of methotrexate
– Leflunomide

Biologics
– Infliximab/ Etanercept/Humira (TNF-a)
– Kineret (IL-1ra)
– Orencia (abatacept)
Rituxan (B-cell depletion)
– MRA (IL-6 receptor)
– Small Modular Immunopharmaceutical (SIMP)

Combination therapy—sooner than ever before
Weinblatt Study
Methotrexate

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Multiple Trials Support Use
DMARD of Choice (but there are challengers)
Long Term Efficacy/Compliance
Radiographic Data
Relatively Rapid Onset of Action (4-8 weeks)
Dosage 7.5-25mg/week (above 20 mg inject)
I still try Methotrexate in Most RA patients before
moving on to Newer DMARDS—but I move
faster to Biologics in partial responders (2-3
months) —patience is NOT a virtue here.
 I would never give you a drug worse than your
disease
TNF Inhibition: Etanercept
Etanercept
Activated
macrophage
Target
cell
Signal
TNF
Etanercept
Patients With No New Erosions
at 1 Year
All
patients
Patients with
baseline
erosions
Patients with no
baseline erosions
Finck B. Arthritis Rheum. 1999.
Etanercept
25 mg
Methotrexate
75%
(154/206)
57%
(123/217)
P < 0.001
72%
52%
P < 0.001
(130/181)
(98/188)
96%
86%
(24/25)
(25/29)
P = 0.159
Antibody Neutralization of TNFa
Infliximab in Active RA Despite MTX
ATTRACT
Improvement in Swollen Joints
MTX Control
3 mg/kg q 8 wks
10 mg/kg q 8 wks
MTX Control
3 mg/kg q 4 wks
10 mg/kg q 4 wks
ATTRACT
Infliximab in Active RA Despite MTX
Improvement in Tender Joints
MTX Control
3 mg/kg q 8 wks
10 mg/kg q 8 wks
MTX Control
3 mg/kg q 4 wks
10 mg/kg q 4 wks
ATTRACT
Infliximab in Active RA Despite MTX
Median C-reactive Protein (mg/dL)
PREMIER
2-Year Results of Selected
Clinical Responses
Percentage of Patients
70
HUMIRA + MTX
(n=268)
HUMIRA
(n=274)
60
*
*
39
36
*
34
33
30 30
30
21
20
55
53
50
40
*
MTX
(n=257) *
19 19
29
19 19
15
10
0
TJC=0
SJC=0
HAQ=0
*P<0.05 for HUMIRA + MTX vs MTX alone and HUMIRA alone
†Normal CRP was defined as ≤0.5 mg/dL
Emery P, et al. Presented at: EULAR; June 8-11, 2005; Vienna, Austria.
Data on file, Abbott Laboratories.
Morning Normal CRP†
Stiffness=0
So What is the Catch?

Cost = $17,000-25,000/year
 Injections or infusions
 Profound immunosupression
– Careful who you put on the drug (Diabetes,
COPD, Renal failure, etc)
– When patients present with infection, they have
more subtle complaints—fewer ‘systemic’
symptoms occur
– Low threshold for antibiotics as most serious
infections are ‘typical’
– Can you educate the patient?
The Other Biologics

Orencia: Approved by FDA 2/2006—Role
unclear—does work in TNF failures
 Rituxan: 2 doses can produce a protracted
period of remission in refractory RA—
Infusion reactions (1-2%)
Orencia—CTLA4-Ig
Rituxan
Bridge to the 21st Century

Early aggressive therapy especially in young seropositive
patients—DMARDS within 3 months of diagnosis. Best
chance for remission
 Methotrexate first—But in partial responders rapidly move
to TNF-a blockers. The data suggest the they should be
ADDED to Methotrexate.
 Biologics to induce early remissions for those with
erosions at diagnosis.
 Try more than one TNF-a blocker (70% respond to a
switch)
 Orencia/Rituxan in TNF-a Failures
 ?Low dose prednisone (5-10 mg) combined with
osteoporosis protection—Many need it for symptoms
 NSAIDS/COX-2 as bridge therapy in mild Rheumatoid
Arthritis (essentially worthless)
Future?
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MRA ?—IL-6 receptor antibody (+/- data to date and
multiple problems—LFT’s, GI bleeding?) probably not a
‘player’
SIMP’s: these are single chain polypeptides with greater
tissue penetration—high affinity --??greater efficacy
We are in the ‘infancy’ of immune ‘manipulation’