Download Arthritis Rheum.

Biological Therapy for
Rheumatoid Arthritis
Michael Maricic, M.D.
Catalina Pointe Rheumatology
Rheumatoid arthritis
•
Is often an aggressive disease
•
May have potentially devastating consequences
•
Early, aggressive management can lead to
successful control and remission
Morbidity & Mortality
of Rheumatoid Arthritis
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Average life expectancy shortened by 5-15 years.
Twice as likely to have MI or CVA
Increased risk of infection
Risk of lymphoma 3 times greater than general
population
Brown SL, et al. Arthritis Rheum. 2002;46:3151–3158; Bjornadal L, et al. J Rheumatol. 2002;29:906–912;
Wolfe F, et al. J Rheumatol. 2003;30:36–40; Doran MF, et al. Arthritis Rheum. 2002;46:2287–2293;
Asten P, et al. J Rheumatol. 1999;26:1705–1714; Jones M, et al. Br J Rheumatol. 1996;35:738–745;
Baecklund E, et al. BMJ. 1998;317:180–181; Isomaki HA, et al. J Chronic Dis. 1978;31:691–696;
Solomon DH, et al. Circulation. 2003;107:1303–1307.
Disability in Rheumatoid Arthritis
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Average lifetime earnings loss = 50%
40%-85% of RA patients will be unable to work within
8-10 years of disease onset
Pathogenesis of Rheumatoid Arthritis
Current Treatment
Targets
Rheumatoid
Factors,
anti-CCP
B cell
Immune complexes
Complement
T cell
IFN- &
Neutrophil
Antigenpresenting
cells
B cell or
macrophage
Pannus
other
cytokines
Synoviocytes
Macrophage
Mast cell
TNF
Chondrocytes
IL-1
Osteoclast
Articular
cartilage
Production of collagenase and other
neutral proteases
Bone
Adapted from Arend WP, Dayer JM. Arthritis Rheum. 1990;33:305–15
Chronic Inflammation:
Imbalance Between Mediators
IL-10
TGF
IL-1Ra
IFN
IL-6
IL-8
IL-1
TNF
IL-4/IL-13
Functional Decline Begins Early in RA
Moderate loss
of function*
0
2
Severe loss
of function*
5
Years from Symptom Onset
* 50% rates of loss of function based on HAQ scores
Wolfe F, Cathey MA. J Rheumatol. 1991;18:1298-1306.
Very severe
loss of
function*
10
Cumulative Percentage of
Patients with Erosions
Most RA Patients Develop Bone
Erosions During First 2 Years of Disease
100
90
80
70
60
50
40
30
20
10
0
Hands
Feet
Hands or Feet
Hands and Feet
Baseline
1
2
3
4
5
Years of Follow-Up
Patients with RA < 1 year underwent annual radiologic assessment of hands and feet.
Hulsmans HM et al. Arthritis Rheum. 2000;43:1927-1940.
American College of Rheumatology
Diagnostic Criteria for RA
Must have at least 4 of the following 7 criteria:
-
Morning stiffness in joint for at least 1 hour.*
Arthritis in 3 or more joint areas (PIP, MCP, wrist, elbow, ankle, MTP)*
Arthritis of the hand (wrist, MCP, PIP)*
Symmetric arthritis*
Rheumatoid nodules
Rheumatoid factor
Radiographic changes
*Must be present at least 6 weeks
Anti-Cyclic Citrullinated Peptide Antibody
Specificity
Sensitivity
RF +
75%
60%
Anti-CCP +
96%
75%
Anti-CCP + RF +
99%
80%
* High titer anti-CCP may predict aggressive erosive disease.
Linn-Rasker SP, et al. Ann Rheum Dis 2006;65:366-71
Factors Suggesting Poor Prognosis
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>20 swollen joints
High RF titer
Elevated anti-CCPs
Elevated Sed Rate
Elevated CRP
Late implementation of
treatment
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Joint erosions
Presence of rheumatoid
nodules
Socioeconomic
characteristics
Smoking
Poor functional status
The Treatment of
Rheumatoid Arthritis
Therapeutic Window of Opportunity

Erosive changes occur early in disease

Even a brief delay of therapy can have a significant
impact on disease parameters years later

Early DMARD treatment appears to reset the rate of
progression for years to come
O’Dell JR. Arthritis Rheum. 2002;46:283-285.
Van der Heijde DM. Br J Rheum. 1995;34 (suppl 2):74-78.
Treatment: The Earlier the Better
Delayed Treatment
Early Treatment
(median treatment lag time = 123 days; n = 109)
(median treatment lag time = 15 days; n = 97)
Change in Sharp Scores
12
10
8
6
4
2
0
0
6
12
18
Months
Patients were treated with chloroquine or azathioprine
Lard LR, et al. Am J Med. 2001;111:446–451.
24
Traditional DMARD’s
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Methotrexate (Rheumatrex)
Hydroxychloroquine
(Plaquenil)
Sulfasalazine (Azulfidine)
D-penicillamine
Leflunomide (Arava)
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Azathioprine (Imuran)
Gold (Solganol,
Ridaura)
Cyclosporine (Neoral)
Minocycline (Minocin)*
*Not FDA approved for RA
Conventional DMARD
Safety Considerations
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Hematologic
Host Defense
Hepatic
Gastro-intestinal
Malignancy &
Lymphoma
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Reproductive
Pulmonary
Allergic
Cutaneous
Renal
Ocular
Problems with Old Approach
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Damage can occur early.
Risk of morbidity and mortality potentially
increases when disease is poorly controlled.
Toxicity
References: 1. Mulherin D, et al. Br J Rheumatol. 1996;35:1263-1268. 2. McGonagle D, et al. Arthritis Rheum. 1999;42:
1706-1711. 3. Gabriel SE, et al. Arthritis Rheum. 2003;48:54-58. 4. Anderson JJ, et al. Arthritis Rheum. 2000;43:22-29.
Evolving RA Treatment Paradigm
Current Approach
Initial
treatment:
traditional
DMARDs
Evolving Paradigm
• Early aggressive
treatment
• Biologics
• Combination therapy
Biologic DMARD’s – Genetically Engineered
Targeted Molecules Similar or Identical to
Naturally Occurring Molecules

TNFα antagonists:
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Interleukin-1 antagonist
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Anakinra (Kineret)
Suppress T-Cell activation
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Adalimumab (Humira)
Etanercept (Enbrel)
Infliximab (Remicade)
Abatacept (Orencia)
Anti B-Cell monoclonal antibody
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Rituximab (Rituxan)
Characteristics of Biologics
Etanercept
Enbrel
Infliximab
Remicade
Adalimumab
Humira
Anakinra
Kineret
Abatacept
Orencia
Rituximab
Rituxan
Target
TNF
TNF
TNF
IL-1
Receptor
T-Cell
Activation
B-Cell
Half Life
3-5 Days
8-10 Days
10-20 Days
4-6 Hrs
13-16
Days
19 Days
Construct
Human
Chimeric
Human
Human
Human
Chimeric
Dosing
Once
Biweeklyweekly
Once every
4-8 weeks
Once every
1-2 weeks
Once
Daily
Once
Monthly
Twice
every 6-12
months
Route
Sub-Cut
I.V.
Sub-Cut
Sub-Cut
I.V.
I.V.
Anti-TNF Monotherapy Improves Clinical
Signs & Symptoms
70
Placebo (n = 30)
Etanercept 25 mg (n = 78)
59*
60
50
40*
40
30
20
15*
11
5
10
1
0
ACR20
* p  0.001.
ACR50
ACR70
Moreland LW et al. Ann Intern Med. 1999;130:478-486.
Better Outcomes in Patients Receiving
Combination Therapy of MTX & Anti TNFα
70
60
50
40
30
20
10
0
Mean Change TSS
61
46
42
59
43
37
Mean Change in
Total Sharp Score
Patients (%)
ACR50 Response
12
10.4
10
8
6
4
2
5.7
5.5
3
1.3
1.9
0
year 1
year 2
year 1
MTX
Adalimumab
MTX + Adalimumab
Breedveld FC Arthritis Rheum 2006; 54(1): 26-37
year 2
Half of Patients on Anti TNFα+MTX Achieve
Clinical Remission by DAS28<2.6: 2-year Data
60
% of Patients
50
Week 52
Week 104
49*
43*
40
30
23
25
25
21
20
10
0
Adalimumab
+ MTX
Adalimumab
*p<0.001 vs adalimumab alone and MTX alone
Breedveld FC Arthritis Rheum 2006; 54(1): 26-37
MTX
Anti TNF + MTX Combination Slows
Radiographic Progression
14
N = 428
12.6
30 Weeks
10
54 Weeks
Mean Change in
Total Sharp Score
12
102 Weeks
8
6
7
4.8
4
2
p < 0.001
p < 0.001
1.3
1.6
1
1
0.6
p < 0.001
p < 0.001
1.1
1
-0.5 0.2
-0.3 -0.7 -0.4
0
-2
Placebo
+ MTX
Infliximab + MTX
3 mg/kg
q8w
3 mg/kg
q4w
10 mg/kg
q8w
10 mg/kg
q4w
p values are versus placebo + MTX.
Maini R et al. Lancet. 1999;354:1932-1939; Lipsky PE et al. N Engl J Med. 2000;343:1594-1602
Patients Treated Early Will Respond:
Change in Total Sharp Score at 2 Years
Mean Change in Total Sharp Score From Baseline
Disease Duration  3 Years
8
All Patients
8
7.0
7
7
6
6
5
5
4
4
2.8
3
3.3
3
2
2
1
0.4
1.1*
1
0
0
-1
-1
Methotrexate
Etanercept
Etanercept +
Methotrexate
Methotrexate
(n=72)
(n=76)
(n=74)
(n=206)
*p<0.05 vs. MTX
†p<0.05 vs. etanercept
Bathon et al NEJM 2000;343(1):1586-1593
Etanercept
(n=202)
-0.6*†
Etanercept +
Methotrexate
(n=212)
Rituximab: Mechanism of Action
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Rituximab initiates
complement-mediated
B-cell lysis
Rituximab initiates cellmediated cytotoxicity
via macrophages and
natural killer (NK) cells
Rituximab induces
apoptosis caspase-3,-9
CD20
Macrophage
B cell
Complement
cascade
B cell
B-cell lysis
Apoptosis
Rituximab
Clynes RA et al. Nat Med. 2000;6:373-374; Reff ME et al. Blood. 1994;83:435-445.
B Cell Depleting Therapy in RA Patients Refractory to
Anti TNFα Therapy: ACR Responses at 6 Months
60
p < 0.0001
51
% Patients
50
40
p < 0.0001
30
27
20
p < 0.0001
18
12
10
5
1
0
ACR20
ACR50
Placebo (N=201)
Cohen S, et al. Arthritis and Rheumatism 2006:54(9):2793-2806
ACR70
Rituximab (N=298)
B Cell Depleting Therapy in RA Patients Refractory to
Anti TNFα Therapy: Radiographic Endpoints at 6 Months
Mean Change
1.5
p=0.1693
1.2
p=0.2358
1
0.6
0.5
p=0.0156*
0.8
0.5
0.4
0.2
0
Total Genant-Modified
Sharp Score
Joint Space
Narrowing Score
Placebo (N=177)
*Statistically significant
Erosion Score
Rituximab (N=268)
24 Placebo and 30 rituximab patients were missing x-rays at week 24
Cohen S, et al. Arthritis and Rheumatism 2006:54(9):2793-2806
Abatacept for RA
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Abatacept
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Fusion protein
First in the new class of “costimulation blockers” for
treatment of RA
Prevents T-cell activation via binding CD80 and
CD86 on antigen-presenting cells
Kremer JM et al. N Engl J Med. 2003;349:1907-1915.
CTLA4lg (Abatacept) Effectively Blocks
CD28 Dependent Costimulatory Signals
Antigen Presenting Cell
T Lymphocyte
Costimulation
CD80
CD28
CD86
CD28
Clonal
Proliferation
Full Activation
CTLA4lg
MHC II
TCR
Antigen specific
Cytokine
Production
IL-2
IL-4
IL-5
TNF-
Inhibition of T-Cell Activation by CoStimulatory Pathway Blockade in RA Patients
With Inadequate MTX Response
100
ACR Response
90
80
68
70
Patients (%)
Placebo + MTX
73
Abatacept + MTX
60
48
50
40
40
40
40
29
30
17
20
20
18
10
7
6
0
6 Mos
12 Mos
ACR 20
6 Mos
12 Mos
ACR 50
1. Kremer et al. Annals of Internal Medicine: 2006; 144:865-876
6 Mos
12 Mos
ACR 70
Safety Considerations with Biologic
DMARD’s
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Serious Infections
Opportunistic infections
(TB)
Malignancies/lymphoma
Demyelination
Hematologic abnormalities
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Administration reactions
Congestive heart failure
Hepatic
Autoantibodies and drug
induced lupus
Vaccination
Biologics: Relative Contraindications
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Active Hepatitis B Infection
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Multiple sclerosis, optic neuritis
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Active serious infections
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Chronic or recurrent infections
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Current neoplasia
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History of TB or positive PPD (untreated)
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Congestive heart failure (Class III or IV)
Treatment Summary
Early appropriately aggressive intervention in
patients with inflammatory arthritis: critical to best
possible outcome.
The combination of a biologic plus MTX is
frequently more effective than either agent alone.
Conclusion
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Rheumatoid Arthritis is a serious
disease
Early diagnosis is key to good
outcomes
Advent of new therapies have major
impact in altering disease progression