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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.

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Biological therapy for rheumatoid arthritis l.jpg

Biological Therapy for Rheumatoid Arthritis

Michael Maricic, M.D.

Catalina Pointe Rheumatology


Rheumatoid arthritis l.jpg
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 l.jpg
Morbidity & Mortality of Rheumatoid Arthritis

  • 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 l.jpg
Disability in Rheumatoid Arthritis

  • 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 l.jpg

Rheumatoid

Factors, anti-CCP

Immune complexes

B cell

T cell

IFN- &

HLA

Neutrophil

-DR

other cytokines

Antigen-

presenting

cells

Macrophage

Mast cell

B cell or

macrophage

Synoviocytes

Chondrocytes

TNF

IL-1

Pannus

Articular

cartilage

Production of collagenase and other

neutral proteases

Pathogenesis of Rheumatoid Arthritis

Current Treatment

Targets

Complement

Osteoclast

Bone

Adapted from Arend WP, Dayer JM. Arthritis Rheum. 1990;33:305–15


Chronic inflammation imbalance between mediators l.jpg
Chronic Inflammation: Imbalance Between Mediators

IL-10

TGF

IL-1Ra

IFN

IL-4/IL-13

IL-6

IL-8

IL-1

TNF

Anti-inflammatory

Proinflammatory


Functional decline begins early in ra l.jpg
Functional Decline Begins Early in RA

Very severe loss of function*

Moderate loss of function*

Severe loss of function*

10

0 2

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.


Most ra patients develop bone erosions during first 2 years of disease l.jpg
Most RA Patients Develop Bone Erosions During First 2 Years of Disease

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 l.jpg
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 l.jpg
Anti-Cyclic Citrullinated Peptide Antibody Diagnostic Criteria for RA

* 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 l.jpg

>20 swollen joints Diagnostic Criteria for RA

High RF titer

Elevated anti-CCPs

Elevated Sed Rate

Elevated CRP

Late implementation of treatment

Joint erosions

Presence of rheumatoid nodules

Socioeconomic characteristics

Smoking

Poor functional status

Factors Suggesting Poor Prognosis


The treatment of rheumatoid arthritis l.jpg

The Treatment of Rheumatoid Arthritis Diagnostic Criteria for RA


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Therapeutic Window of Opportunity Diagnostic Criteria for RA

  • 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 l.jpg
Treatment: The Earlier the Better Diagnostic Criteria for RA

Delayed Treatment (median treatment lag time = 123 days; n = 109)

Early Treatment (median treatment lag time = 15 days; n = 97)

Patients were treated with chloroquine or azathioprine

Lard LR, et al. Am J Med. 2001;111:446–451.


Traditional dmard s l.jpg

Methotrexate (Rheumatrex) Diagnostic Criteria for RA

Hydroxychloroquine (Plaquenil)

Sulfasalazine (Azulfidine)

D-penicillamine

Leflunomide (Arava)

Azathioprine (Imuran)

Gold (Solganol, Ridaura)

Cyclosporine (Neoral)

Minocycline (Minocin)*

*Not FDA approved for RA

Traditional DMARD’s


Conventional dmard safety considerations l.jpg

Hematologic Diagnostic Criteria for RA

Host Defense

Hepatic

Gastro-intestinal

Malignancy & Lymphoma

Reproductive

Pulmonary

Allergic

Cutaneous

Renal

Ocular

Conventional DMARD Safety Considerations


Problems with old approach l.jpg
Problems with Old Approach Diagnostic Criteria for RA

  • 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 l.jpg

Initial Diagnostic Criteria for RA

treatment:

traditional DMARDs

Evolving RA Treatment Paradigm

Evolving Paradigm

Current Approach

  • Early aggressive treatment

  • Biologics

  • Combination therapy


Slide19 l.jpg
Biologic DMARD’s – Genetically Engineered Diagnostic Criteria for RATargeted Molecules Similar or Identical to Naturally Occurring Molecules

  • TNFα antagonists:

    • Adalimumab (Humira)

    • Etanercept (Enbrel)

    • Infliximab (Remicade)

  • Interleukin-1 antagonist

    • Anakinra (Kineret)

  • Suppress T-Cell activation

    • Abatacept (Orencia)

  • Anti B-Cell monoclonal antibody

    • Rituximab (Rituxan)


Characteristics of biologics l.jpg
Characteristics of Biologics Diagnostic Criteria for RA


Anti tnf monotherapy improves clinical signs symptoms l.jpg
Anti-TNF Diagnostic Criteria for RAMonotherapy Improves Clinical Signs & Symptoms

Placebo (n = 30)

59*

Etanercept 25 mg (n = 78)

40*

% of Patients

15*

11

5

1

ACR20

ACR50

ACR70

* p  0.001.

Moreland LW et al. Ann Intern Med. 1999;130:478-486.


Better outcomes in patients receiving combination therapy of mtx anti tnf l.jpg

MTX Diagnostic Criteria for RA

Adalimumab

MTX + Adalimumab

Better Outcomes in Patients Receiving Combination Therapy of MTX & Anti TNFα

ACR50 Response

Mean Change TSS

Mean Change in

Total Sharp Score

Patients (%)

Breedveld FC Arthritis Rheum 2006; 54(1): 26-37


Half of patients on anti tnf mtx achieve clinical remission by das28 2 6 2 year data l.jpg

60 Diagnostic Criteria for RA

Week 52

*

Week 104

49

50

*

43

40

% of Patients

30

25

25

23

21

20

10

0

Adalimumab

+ MTX

Adalimumab

MTX

Half of Patients on Anti TNFα+MTX Achieve Clinical Remission by DAS28<2.6: 2-year Data

*p<0.001 vs adalimumab alone and MTX alone

Breedveld FC Arthritis Rheum 2006; 54(1): 26-37


Anti tnf mtx combination slows radiographic progression l.jpg

14 Diagnostic Criteria for RA

12.6

12

10

8

7

6

4.8

4

1.6

2

1.3

1.1

1

1

1

0.6

-0.5

0.2

-0.4

-0.3

-0.7

0

-2

Anti TNF + MTX Combination Slows Radiographic Progression

N = 428

30 Weeks

54 Weeks

102 Weeks

Mean Change in

Total Sharp Score

p < 0.001

p < 0.001

p < 0.001

p < 0.001

Placebo

+ MTX

Infliximab + MTX

3 mg/kg 3 mg/kg 10 mg/kg 10 mg/kg q8w q4w q8w 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 l.jpg

(n=72) Diagnostic Criteria for RA

(n=76)

(n=74)

(n=206)

(n=202)

(n=212)

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

All Patients

*p<0.05 vs. MTX

†p<0.05 vs. etanercept

Bathon et al NEJM 2000;343(1):1586-1593


Rituximab mechanism of action l.jpg

Rituximab initiates complement-mediated Diagnostic Criteria for RAB-cell lysis

Rituximab initiates cell-mediated cytotoxicity via macrophages and natural killer (NK) cells

Rituximab induces apoptosis caspase-3,-9

Rituximab: Mechanism of Action

Macrophage

Complement

cascade

B cell

B cell

B-cell lysis

Apoptosis

CD20

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 tnf therapy acr responses at 6 months l.jpg
B Cell Depleting Therapy in RA Patients Refractory to Diagnostic Criteria for RAAnti TNFα Therapy: ACR Responses at 6 Months

p < 0.0001

60

51

50

40

p < 0.0001

% Patients

27

30

p < 0.0001

18

20

12

10

5

1

0

ACR20

ACR50

ACR70

Placebo (N=201)

Rituximab (N=298)

Cohen S, et al. Arthritis and Rheumatism 2006:54(9):2793-2806


Slide28 l.jpg
B Cell Depleting Therapy in RA Patients Refractory to Diagnostic Criteria for RAAnti TNFα Therapy: Radiographic Endpoints at 6 Months

p=0.1693

1.5

1.2

p=0.2358

1

Mean Change

0.8

p=0.0156*

0.6

0.5

0.4

0.5

0.2

0

Total Genant-Modified

Joint Space

Erosion Score

Sharp Score

Narrowing Score

Placebo (N=177)

Rituximab (N=268)

*Statistically significant 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 l.jpg
Abatacept for RA Diagnostic Criteria for RA

  • Abatacept

    • 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 l.jpg

Clonal Diagnostic Criteria for RAProliferation

Signal 2

CytokineProduction IL-2

IL-4

IL-5

TNF-

Costimulation

Signal 1

CD80

CD28

CD86

CD28

Full Activation

CTLA4lg

MHC II

TCR

Antigen specific

CTLA4lg (Abatacept) Effectively Blocks CD28 Dependent Costimulatory Signals

Antigen Presenting Cell

T Lymphocyte


Slide31 l.jpg
Inhibition of T-Cell Activation by Co-Stimulatory Pathway Blockade in RA Patients With Inadequate MTX Response

ACR Response

Placebo + MTX

Abatacept + MTX

ACR 20

ACR 50

ACR 70

1. Kremer et al. Annals of Internal Medicine: 2006; 144:865-876


Safety considerations with biologic dmard s l.jpg

Serious Infections Blockade in RA Patients With Inadequate MTX Response

Opportunistic infections (TB)

Malignancies/lymphoma

Demyelination

Hematologic abnormalities

Administration reactions

Congestive heart failure

Hepatic

Autoantibodies and drug induced lupus

Vaccination

Safety Considerations with Biologic DMARD’s


Slide33 l.jpg

Biologics: Relative Contraindications Blockade in RA Patients With Inadequate MTX Response

  • Active Hepatitis B Infection

  • Multiple sclerosis, optic neuritis

  • Active serious infections

  • Chronic or recurrent infections

  • Current neoplasia

  • History of TB or positive PPD (untreated)

  • Congestive heart failure (Class III or IV)


Treatment summary l.jpg
Treatment Summary Blockade in RA Patients With Inadequate MTX Response

  • 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 l.jpg
Conclusion Blockade in RA Patients With Inadequate MTX Response

  • Rheumatoid Arthritis is a serious disease

  • Early diagnosis is key to good outcomes

  • Advent of new therapies have major impact in altering disease progression


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