1. Biological Therapy for Rheumatoid Arthritis
Michael Maricic, M.D.
Catalina Pointe Rheumatology

2. Rheumatoid arthritis Is often an aggressive disease
May have potentially devastating consequences
Early, aggressive management can lead to successful control and remission

3. 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.

4. 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

5. Pathogenesis of Rheumatoid Arthritis
Current Treatment
Targets
Rheumatoid
Factors, anti-CCP
Immune complexes
B cell
T cell
Antigen-
presenting
cells
B cell or
macrophage
Synoviocytes
Pannus
Articular
cartilage
Chondrocytes
Macrophage
HLA
-DR
Complement
other cytokines
IFN- &
Neutrophil
Mast cell
TNF
IL-1
Osteoclast
Production of collagenase and other
neutral proteases
Bone
Adapted from Arend WP, Dayer JM. Arthritis Rheum. 1990;33:305–15

6. Chronic Inflammation: Imbalance Between Mediators
IL-10
TGF
IL-1Ra
IFN
IL-6
IL-4/IL-13
IL-8
IL-1
TNF
In chronic inflammatory conditions we see an imbalance between mediators of the IR
Upregulation of both pro-inflammatory and anti-inflammatory cytokines
Pro-inflammatory cytokines overwhelming the anti-inflammatory cytokines
Resulting imbalance/tilt
Anti-inflammatory
Proinflammatory

7. Functional Decline Begins Early in RA
Very severe loss of function*
Moderate loss of function*
Severe loss of function*
Functional Decline Begins Early in RA
Patients with RA show rapid functional decline that begins early in the course of RA.
Using the HAQ Functional Disability Index, Wolfe and Cathey assessed functional disability in 1274 patients with RA who were followed longitudinally for up to 12 years.
The rate of functional loss increased sharply after the first clinic visit.
Half of the patients with RA showed moderate loss of function within 2 years.
Half of the patients showed severe loss of function within 6 years.
Half of the patients showed very severe loss of function within 10 years after the first clinic visit.
These data demonstrate that disability increases most rapidly during the early years of the disease; the decline in functional disability slows thereafter.
Wolfe F, Cathey MA. The assessment and prediction of functional disability in rheumatoid arthritis. J Rheumatol. 1991;18: Is there any more recent data? 5 10
Years from Symptom Onset
* 50% rates of loss of function based on HAQ scores
Wolfe F, Cathey MA. J Rheumatol. 1991;18:

8. 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:

9. 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

10. Anti-Cyclic Citrullinated Peptide Antibody
Specificity
Sensitivity
RF +
75%
60%
Anti-CCP +
96%
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

11. Factors Suggesting Poor Prognosis
>20 swollen joints
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
Which Factors Suggest Poor Prognosis?    
A number of clinical and laboratory variables have been related to disease activity/severity in patients with RA. Clinical factors that have been correlated with more aggressive or severe disease include duration of RA and number of swollen joints.1
The presence/severity of joint erosions and rheumatoid nodules is also a predictor of disease severity.1
Laboratory variables associated with more aggressive/severe RA include higher rheumatoid factor titer, the presence of anticyclic citrullinated peptides (anti-CCP), high levels of CRP, and elevated ESR.1-3
The presence of one or two shared epitope DRB1 alleles has also been associated with increased disease severity in patients with RA.4
Bukhari M, Lunt M, Harrison BJ, Scott DG, Symmons DP, Silman AJ. Rheumatoid factor is the major predictor of increasing severity of radiographic erosions in rheumatoid arthritis: results from the Norfolk Arthritis Register Study, a large inception cohort. Arthritis Rheum. 2002;46:
Kroot EJ, de Jong BA, van Leeuwen MA, et al. The prognostic value of anti-cyclic citrullinated peptide antibody in patients with recent-onset rheumatoid arthritis. Arthritis Rheum. 2000;43:
Mottonen T, Paimela L, Leirisalo-Repo M, Kautiainen H, Ilonen J, Hannonen P. Only high disease activity and positive rheumatoid factor indicate poor prognosis in patients with early rheumatoid arthritis treated with "sawtooth" strategy. Ann Rheum Dis. 1998;57:
Eberhardt K, Fex E, Johnson U, Wollheim FA. Associations of HLA-DRB and -DQB genes with two and five year outcome in rheumatoid arthritis. Ann Rheum Dis. 1996;55:34-39.

12. The Treatment of Rheumatoid Arthritis

13. 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
The Therapeutic Window of Opportunity
Recent research has confirmed that early, aggressive treatment with disease-modifying antirheumatic drugs (DMARDs) is critical for optimizing long-term results in patients with rheumatoid arthritis.1
Among the findings leading to this conclusion are those showing that approximately 75% RA patients show evidence of joint erosions during the first 2 years of their disease. The rate of progression, expressed as newly eroded joints or increased radiographic damage, is highest during the early years of the disease.2
Others studies have shown that even a brief delay (as little as 8 to 9 months) in starting DMARD therapy can have a significant impact on disease parameters many years later.
Research suggests that:2
Early and aggressive DMARD therapy suppresses the inflammatory response can reset the rate of radiographic progression.
Reliance on the traditional “pyramid approach” to therapy, which involved the initial prescription of aspirin and NSAIDs and then individual DMARDs is no longer recognized as effective. Moreover, combination therapy is not necessarily more toxic than monotherapy.
O’Dell JR. Treating rheumatoid arthritis early: A window of opportunity? Arthritis Rheum. 2002;46:
Van der Heijde DM. Joint erosions and patients with early rheumatoid arthritis. Br J Rheum. 1995;34 (suppl 2):74-78.
O’Dell JR. Arthritis Rheum. 2002;46:
Van der Heijde DM. Br J Rheum. 1995;34 (suppl 2):74-78.

14. Treatment: The Earlier the Better
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.

15. Traditional DMARD’s Methotrexate (Rheumatrex)
Hydroxychloroquine (Plaquenil)
Sulfasalazine (Azulfidine)
D-penicillamine
Leflunomide (Arava)
Azathioprine (Imuran)
Gold (Solganol, Ridaura)
Cyclosporine (Neoral)
Minocycline (Minocin)*
*Not FDA approved for RA

16. Conventional DMARD Safety Considerations
Hematologic
Host Defense
Hepatic
Gastro-intestinal
Malignancy & Lymphoma
Reproductive
Pulmonary
Allergic
Cutaneous
Renal
Ocular

17. Problems with Old Approach
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: McGonagle D, et al. Arthritis Rheum. 1999;42: Gabriel SE, et al. Arthritis Rheum. 2003;48: Anderson JJ, et al. Arthritis Rheum. 2000;43:22-29.

18. Evolving RA Treatment Paradigm
Current Approach
Evolving Paradigm
Initial
treatment:
traditional DMARDs
Early aggressive treatment
Biologics
Combination therapy

19. Biologic DMARD’s – Genetically Engineered Targeted 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)

20. Characteristics of Biologics
Etanercept
Enbrel
Infliximab
Remicade
Adalimumab
Humira
Anakinra
Kineret
Abatacept
Orencia
Rituximab
Rituxan
Target
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
Dosing
Once Biweekly-weekly
Once every 4-8 weeks
Once every 1-2 weeks
Once Daily
Once Monthly
Twice every 6-12 months
Route
Sub-Cut
I.V.

21. Anti-TNF Monotherapy Improves Clinical Signs & Symptoms
Placebo (n = 30)
59*
Etanercept 25 mg (n = 78)
40*
% of Patients
Biologic DMARD Monotherapy Improves Clinical Signs & Symptoms
Results from the phase II study of etanercept monotherapy (25 mg injected subcutaneously twice per week) in 234 patients with active RA who had inadequate responses to DMARDs indicated significant and sustained efficacy over 6 months.
At 6 months, 59% of the 25-mg etanercept group and 11% of the placebo group achieved an ACR20 response (p < 0.001); 40% and 5%, respectively, achieved an ACR50 response (p < 0.001); and 15% and 1%, respectively, achieved an ACR70 response (p = 0.001). The respective mean percentage reductions in the number of tender and swollen joints at 6 months were 56% and 47% in the 25-mg etanercept group and 6% and 7% in the placebo group (p < 0.05).
Moreland LW, Schiff MH, Baumgartner SW, et al. Etanercept therapy in rheumatoid arthritis. A randomized, controlled trial. Ann Intern Med. 1999;130:
15* 11 5 1
ACR20
ACR50
ACR70
* p 
Moreland LW et al. Ann Intern Med. 1999;130:

22. Better Outcomes in Patients Receiving Combination Therapy of MTX & Anti TNFα
ACR50 Response
Mean Change TSS
Mean Change in
Total Sharp Score
Patients (%)
MTX
Adalimumab
MTX + Adalimumab
Breedveld FC Arthritis Rheum 2006; 54(1): 26-37

23. Half of Patients on Anti TNFα+MTX Achieve Clinical Remission by DAS28<2.6: 2-year Data43 23 21 49 25 10 20 30 40 50 60
Adalimumab
+ MTX
MTX
Week 52
Week 104
% of Patients *
*p<0.001 vs adalimumab alone and MTX alone
Breedveld FC Arthritis Rheum 2006; 54(1): 26-37

24. Anti TNF + MTX Combination Slows Radiographic Progression
4.8 1
0.6
1.3
1.6
0.2
12.6
1.1
-0.3
-0.5
-0.7 7
-0.4 -2 2 4 6 8 10 12 14
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
Biologic DMARDs + MTX Combination Slows Radiographic Progression
In patients with active RA despite MTX therapy, treatment with infliximab in iv doses of 3 or 10 mg/kg every 4 or 8 weeks (q4w, q8w) in combination with oral MTX resulted in significant suppression of radiographic progression compared with treatment with MTX alone.
From 0 to 30 weeks, radiographic evidence of joint damage, as reflected by Sharp scores, increased in the group given MTX plus placebo, but not in the groups treated with infliximab plus MTX (mean change in radiographic score, 4.8 for MTX plus placebo versus 1 to –0.5 for all infliximab treatment regimens plus MTX, p < 0.001).1
From 0 to 54 weeks, Sharp scores increased to 7.0 in patients on MTX plus placebo, but varied between 1.6 for the 3-mg/kg q4w group to -0.7 for the 10-mg/kg q4w group.2
For the period from 0 to 102 weeks, Sharp scores increased to 12.6 for the MTX plus placebo group compared with a score of 1.1 for the 10-mg/kg q8w group and -0.4 for the 10-mg/kg q4w group.3
Radiographic evidence of progression of joint damage was absent in infliximab-treated patients whether or not they had a clinical response.
1. Maini R, St Clair EW, Breedveld F, et al. Infliximab (chimeric anti-tumour necrosis factor  monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. ATTRACT Study Group. Lancet. 1999;354:
2. Lipsky PE, van der Heijde DM, St Clair EW, et al. Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. N Engl J Med. 2000;343:
3. Lipsky P, van der Heijde D, St Clair W, et al. 102-wk clinical & radiologic results from the ATTRACT: a 2 year, randomized, controlled, phase 3 trial of infliximab (Remicade) in pts with active RA despite MTX. Arthritis Rheum. 2000;43(suppl):S269. Abstract.
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: ; Lipsky PE et al. N Engl J Med. 2000;343:

25. 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
Key Point:
The combination of etanercept + MTX has been found to be effective in patients with disease duration of several years; however, it is also effective in patients with early disease (duration ≤3 years). These data support early treatment for RA, although it’s never too late to begin an aggressive disease-modifying regimen.1
Even for patients with early disease, the combination of etanercept + MTX was significantly more effective than MTX alone in reducing the progression of joint damage.1
Reference: 1. Data on file, Wyeth Pharmaceuticals Inc., Philadelphia, Pa.
(n=72)
(n=76)
(n=74)
(n=206)
(n=202)
(n=212)
*p<0.05 vs. MTX
†p<0.05 vs. etanercept
Bathon et al NEJM 2000;343(1):

26. Rituximab: Mechanism of Action
Rituximab initiates complement-mediated B-cell lysis
Rituximab initiates cell-mediated cytotoxicity via macrophages and natural killer (NK) cells
Rituximab induces apoptosis caspase-3,-9
Macrophage
Complement
cascade
B cell
B cell
Comments:
This slide summarises the mechanism of action of Rituximab. References:
Clynes RA, Towers TL, Presta LG, Ravetch JV. Inhibitory Fc receptors modulate in vivo cytoxicity against tumour targets. Nat Med. 2000;6:443–446.
Reff ME, Carner K, Chambers KS, Chinn PC, Leonard JE et al. Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD20. Blood. 1994;83:435–445.
B-cell lysis
CD20
Rituximab
Apoptosis
Clynes RA et al. Nat Med. 2000;6: ; Reff ME et al. Blood. 1994;83:

27. B Cell Depleting Therapy in RA Patients Refractory to Anti TNFα Therapy: ACR Responses at 6 Months60 51 50 40
p <
% Patients 30 27
p < 18 20 12
Analysis of the primary efficacy parameter showed that a significantly higher proportion of patients achieved an ACR20 response at week 24 following treatment with rituximab in combination with MTX than with MTX monotherapy (51% vs. 18%, p < ).
For secondary efficacy parameters, the proportion of patients achieving ACR50 and ACR70 responses at week 24 were also statistically significantly higher for rituximab + MTX patients than for those who received placebo + MTX (ACR50: 27% vs. 5%, p < , ACR70: 12% vs. 1%, p < ). 10 5 1
ACR20
ACR50
ACR70
Placebo (N=201)
Rituximab (N=298)
Cohen S, et al. Arthritis and Rheumatism 2006:54(9):

28. B Cell Depleting Therapy in RA Patients Refractory to Anti 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
0.5
0.4
0.2
Changes in radiographic endpoints at week 24 for observed cases showed a trend toward improvement in rituximab-treated patients.
Changes from baseline in the joint narrowing scores were statistically reduced in patients receiving rituximab compared with those receiving placebo (p=0.0156).
60% of the placebo patients had no new erosions, compared to 66% of Rituximab patients. This difference was not statistically significant (p = ).
Total Genant-Modified
Joint Space
Erosion Score
Sharp Score
Narrowing Score
Placebo (N=177)
Rituximab (N=268)
*Statistically significant Placebo and 30 rituximab patients were missing x-rays at week 24
Cohen S, et al. Arthritis and Rheumatism 2006:54(9):

29. Abatacept 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:

30. CTLA4lg (Abatacept) Effectively Blocks CD28 Dependent Costimulatory Signals
Antigen Presenting Cell
T Lymphocyte
TCR
MHC II
Signal 1
CD80
CD28
Signal 2
CD86
Clonal Proliferation
Cytokine Production IL-2
IL-4
IL-5
TNF-
Full Activation
Antigen specific
Costimulation
CTLA4lg

31. 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:

32. Safety Considerations with Biologic DMARD’s
Serious Infections
Opportunistic infections (TB)
Malignancies/lymphoma
Demyelination
Hematologic abnormalities
Administration reactions
Congestive heart failure
Hepatic
Autoantibodies and drug induced lupus
Vaccination

33. Biologics: Relative Contraindications
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)

34. ACR Algorithm for Management of RA
Diagnosis
Establish early diagnosis of RA
Document baseline disease activity and damage
Estimate prognosis of patient
Subjective criteria
Physical exam
Laboratory tests
Radiography
Initiate therapy
Patient education
Start disease-modifying agent within 3 months
Consider NSAID and/or local or low-dose steroids
Physical/occupational therapy
DMARDs
Biologics
Periodically assess disease activity
ACR Subcommittee on RA Guidelines. Arthritis Rheum. 2002;46:

35. ACR Algorithm for Management of RA
Periodically assess disease activity
Adequate response with
disease activity
Inadequate response
(ongoing disease activity)
Change or add disease-modifying drugs
Methotrexate naive
Methotrexate
Other
monotherapy
Suboptimal methotrexate response
Combination
therapy
Biologics
ACR Subcommittee on RA Guidelines. Arthritis Rheum. 2002;46:

36. 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.

37. Conclusion Rheumatoid Arthritis is a serious disease
Early diagnosis is key to good outcomes
Advent of new therapies have major impact in altering disease progression