John R'P' Tesser, MD, FACP, FACR

1
John R.P. Tesser, MD, FACP, FACR Practicing
Rheumatologist Arizona Arthritis Rheumatology
Associates, P.C. Paradise Valley, AZ
2
Learning Objectives

• Identify 3 early warning signs of rheumatoid
  arthritis (RA)
• Describe the epidemiology and systemic
  complications of RA and integrate the treatment
  of comorbidities into a patients overall
  treatment plan
• Describe how control of signs and symptoms and
  radiographic progression are both important in
  the treatment of RA
• List 2 adverse events associated with each
  disease-modifying antirheumatic drug (DMARD)
• Describe current and evolving treatment options
  for RA, and be alert to monitoring and side
  effects related to these therapies

3
Rheumatoid Arthritis (RA)

• A systemic disease in which immune system
  mistakenly attacks body tissues, causing chronic
  inflammation of the joints, tissue, and other
  organs1-3
• Ongoing features include1-3
• Chronic destructive synovitis
• Chronic joint destruction
• Functional disability in untreated patients
• Etiology of RA is unknown, although RA may be
  linked to genetic factors and environmental
  influences4

• Helmick CG, et al. Arthritis Rheum.
  20085815-25.
• Kavanaugh A. Rheum Dis Clin North Am.
  20063245-56.
• Verstappen SMM, et al. Ann Rheum Dis.
  2007661443-1449.
• Kountz DS, et al. J Fam Pract. 200756(10 suppl
  A)59a-73a.

4
Cytokine Signaling Pathways Involved in
Inflammatory Arthritis
Rheumatoid factor and other autoantibodies
Interleukin-4 Interleukin-10
Interleukin-4 Interleukin-6 Interleukin-10
Th2
Th0
Plasma cell
Macrophage
Interferon-? Interleukin-12
Interferon-?
B cell
CD4 T cell
CD11
OPGL
CD69
TNF-a, interleukin-1, interleukin-6
Synovium
CD11
CD69
Chondrocyte
Osteoclast
Fibroblast

• Production of metalloproteinases and other
  effector molecules
• Migration of polymorphonuclear cells

EROSION OF BONE AND CARTILAGE
Adapted from Choy EHS, et al. N Engl J Med.
2001344907-916.
5
The Impact of Rheumatoid Arthritis

• Affects 1.3 million adults in the United States1
• Left untreated, 20 to 30 of RA patients become
  permanently unable to work within 3 years of
  diagnosis2
• Life expectancy may be substantially reduced2
• Early diagnosis and appropriate therapy can stave
  off joint damage and reduce comorbidities2

Patients presenting with arthritis of more than 1
joint should be referred to and seen by a
rheumatologist, ideally within 6 weeks after the
onset of symptoms3 - European League Against
Rheumatism (EULAR)
recommendations for the management of early
arthritis

• Helmick CG, et al. Arthritis Rheum.
  20085815-25.
• Harris ED, et al, eds. Kelleys Textbook of
  Rheumatology. 7th ed. Philadelphia, PA
  Elsevier/Saunders 2005.
• Combe B, et al. Ann Rheum Dis. 20076634-45.

6
Triangle of Treatment
Patient

• Modify lifestyle as recommended by clinicians
• Adhere to medication regimen and monitor for side
  effects, infections
• Report joint counts
• Report symptoms
• Understand RA is a lifelong disease

Lifelong care and consultation
Lifelong care and consultation
Rheumatologist
PCP
Lifelong care and consultation

• Confirm diagnosis of RA
• Obtain baseline studies, tests
• Initiate aggressive treatment with DMARDs
• Devise strategy for safe and efficacious
  implementation of biologic therapies
• Laboratory and comorbidity monitoring

• Recognize early warning signs and symptoms
• Diagnose RA and refer to rheumatologist
• Understand risks and benefits of current
  treatment options
• Laboratory and comorbidity monitoring
• Monitor patient throughout disease process

Kountz DS, et al. J Fam Pract. 200756(10 suppl
A)59a-73a.
Expert opinion
7
Mortality Gap Between RA Patients and General
Population
Observed mortality rates in RA patients (N 822)
vs Minnesota white population over last
4-5 decades1

• Gonzalez A, et al. Arthritis Rheum.
  2007563583-3587.
• American College of Rheumatology Web site.
  http//www.rheumatology.org/public/factsheets/.
  Accessed March 5, 2008.

8
RA An Inherently Aggressive, Systemic Disorder

• Patients with RA are1-3
• Twice as likely to have a myocardial infarction
• 70 more likely to have a stroke
• 70 more likely to develop an infection
• More likely to have an increased risk of
  non-Hodgkin lymphoma
• More likely to develop osteoporosis
• More likely to have their life spans reduced

• Maradit-Kremers H, et al. Arthritis Rheum.
  200552402-411.
• Turesson C, et al. Curr Opin Rheumatol.
  200719190-196.
• Gonzalez A, et al. Ann Rheum Dis. 20086764-69.

9
Extra-articular Disease Is Associated with CV
Events
Extra-articular RA manifestations include
nodules, pericarditis, Feltys syndrome,
vasculitis, serositis, pulmonary
disease, ocular manifestations
Survival free of CVD ()
Follow-up (years)
Turesson C, et al. Ann Rheum Dis. 20076670-75.
ExRA extra-articular rheumatoid arthritis
10
Coexisting Diseases Play Pivotal Role in
Determining RA Outcome
Chronic, debilitating, autoimmune nature of RA
affects almost all organ systems1

• Most deaths in RA are caused by comorbidities1
• Deaths could be attributed to disease process, or
  effects of pharmacotherapies1
• 58 of patients with RA have 1 comorbidity, and
  25 have 2 comorbidities2

• Blom M. Best Pract Res Clin Rheumatol.
  20072143-57.
• Hyrich K, et al. Ann Rheum Dis. 200665895-898.

11
Strategies to Manage CVD in RA
Patients

• Strategies must focus on controlling both
  traditional CV factors and unique issues related
  to RA1
• Combination of anti-TNF-a therapies and
  methotrexate may reduce risk of acute myocardial
  infarction2-5
• In long-term outcome study of 19,580 patients
  with RA, anti-TNF use associated with reduced
  risk of mortality (hazard ratio 0.69), as was
  methotrexate (hazard ratio 0.84)2
• Atherosclerosis in RA may be mediated through
  conventional CV risk factors, disease activity,
  corticosteroid use, and unfavorable body
  composition6,7

• Gonzalez A, et al. Ann Rheum Dis. 20086764-69.
• Michaud K, Wolfe F. 2005 ACR/ARHP Annual
  Scientific Meeting November 12-17 San Diego,
  CA. Poster 296.
• Dixon WG, et al. Arthritis Rheum.
  2006542368-2376.
• Nurmohamed MT, et al. Drugs. 2002621599-1609.
• Singh G, et al. EULAR 2007 meeting.
  http//www.eular.org/. Abstract OP0106.
• Warrington KJ, et al. Arthritis Res Ther.
  20057R984-R991.
• del Rincón I, et al. Arthritis Rheum.
  2001442737-2745.

TNF tumor necrosis factor
12
Smoking Associated with Disease Incidence and
Severity in RA
100 patients with early RA studied over 2-year
span
Current smokers
Former smokers
Never smokers
P 0.04
P 0.03
P 0.02
30
30
P lt 0.001
25
25
P 0.13
20
P 1.0
20
P 0.08
P 0.02
SJC score (mean)
TJC score (mean)
15
15
10
10
5
5
0
0
Entry
6 months
24 months
6 months
24 months
Entry
Despite treatment, smokers still had higher
disease activity and more radiographic joint
damage (independent of age, sex, education level,
alcohol, or duration of follow-up)
P values derived from one-way ANOVA and denote
difference in disease activity between the groups
at each evaluation
Manfredsdottir VF, et al. Rheumatology.
200645734-740.
13
Global RA Management Goals

• Prevent or control joint damage
• Prevent loss of function
• Decrease pain
• Treat comorbidities along with RA
• Improve functional status

The ideal objective disease remission
Tutuncu Z, et al. Rheum Dis Clin North Am.
20073357-70.
14
Progression of RA
Inflammation and subsequent radiographic
progression are dominant contributors to
disability in RA patients
Disability
Inflammation
Joint damage
Severity (arbitrary units)
0
5
10
15
20
25
30
Years of disease

• Effect of joint destruction dominates disability
  late in disease
• Inflammatory joint symptoms determine disability
  early in disease

Adapted from Kirwan JR. J Rheumatol.
200128881-886.
15
Early Intervention The Key to Optimal Treatment
Autoimmune and genetic factors

• Function begins to decline within months, and
  these changes may quickly become irreversible

Activation of RA is multifactorial

• Immunologic events in RA can occur years before
  disease

Environmental stimuli

• Presence of rheumatoid factor
• Presence of anticyclic citrullinated peptide
  antibodies
• Increases in C-reactive protein

• Spontaneous, drug-free remission is rare

• As measured by the Health Assessment Questionnaire

• Defined as a low disease activity state that if
  sustained is neither damaging nor disabling

Quinn MA, et al. Rheum Dis Clin North Am.
200531575-589.
16
Catching the Warning Signs
Refer to a rheumatologist if the patient shows
these symptoms

• 3 swollen joints
• Positive squeeze test
• Morning stiffness 30 minutes

What should you ask the patient?
Squeeze test indicates pain across second to
fifth metacarpals (MCP), metatarsals (MTP)

• What hurts when you get out of bed?

• How long does it take to feel as limber as you
  are going to feel for the day?

• When is your pain the worst (morning or night)?

• Do you smoke?

• Do any members of your family have RA?

• Can you perform daily activities (turn faucet
  handles, hold toothbrush, dress/bathe
  independently)?

• What are the things you cannot do because of your
  symptoms?

Kountz DS, et al. J Fam Pract. 200756(10 suppl
A)59a-73a.
17
Diagnosis Challenges and Initial Management for
PCP

• Order laboratory tests1
• Complete blood count
• Rheumatoid factor
• Anticyclic citrullinated peptide antibody
• C-reactive protein (CRP)
• Erythrocyte sedimentation rate (ESR)
• Order imaging studies1
• X-rays
• When preliminary diagnosis is made, treatment
  begins1
• NSAIDs for pain relief
• Glucocorticoids to suppress inflammation
• Monitor patient for adverse events
• Advise patient on exercise, lifestyle
• If there is any evidence of inflammatory
  arthritis, refer to rheumatologist lt 3 months
  after initial diagnosis2

Joints involved in 80 of RA cases
Joints involved in 50-80 of RA cases
1. Kountz D, et al. J Fam Pract. 200756(10 suppl
A)59a-73a. 2. Cush JJ. J Rheumatol.
200734(suppl 80)1-7.
NSAID nonsteroidal anti-inflammatory drug
18
Criteria for Rheumatoid Arthritis
A patient has RA if he/she has satisfied at
least 4 of these 7 criteria criteria 1 through 4
must have been present for at least 6 weeks
Arnett FC, et al. ARA 1987 revised criteria for
the classification of rheumatoid arthritis.
Arthritis Rheum. 198831315-324.
http//www.rheumatology.org/publications/classific
ation/ra/ra.asp. Accessed March 31, 2008.
19
American College of Rheumatology Guidelines for
the Management of RA

• INITIATE THERAPY
• Patient education
• Start DMARDs within 3 months
• Consider NSAID therapy
• Consider local or low-dose systemic steroids
• Physical/occupational therapy

• PATIENT PRESENTATION
• Establish diagnosis of RA early
• Document baseline disease activity and damage
• Estimate prognosis

PCPs
Adequate response, decreased disease activity
Periodically assess disease activity
Rheumatologists
Inadequate response (ongoing disease activity
after 3 months maximal therapy)

• CHANGE OR ADD DMARDs
• If patient is methotrexate naive, options
  include
• Methotrexate, other monotherapy, combination
  therapy
• If patient has suboptimal methotrexate response,
  options include
• Combination therapy, other monotherapy, biologics
  (either as monotherapy or combination therapy)

American College of Rheumatology Subcommittee on
Rheumatoid Arthritis Guidelines. Arthritis Rheum.
200246328-346.
20
Therapy Decisions Based on Clinical Measurement
Provide Improved Outcomes
TICORA study a single-blind, 18-month controlled
trial with 110 patients with RA lt 5 years
randomized to either intensive management with
protocol-based escalation of DMARDs or routine
care
Routine group (n 55)
Routine group (n 50)
Intensive group (n 53)
Intensive group (n 55)
100
91
8.5
9
P lt 0.0001
80
8
71
P 0.02
65
64
7
60
6
Increase in median TSS from baseline
Percent of patients
4.5
5
40
4
3
18
16
20
2
1
0
0
ACR70
Remission
ACR20
Grigor C, et al. Lancet. 2004364263-269.
TSS total Sharp score
21
Delaying DMARD Therapy Adversely Affects
Treatment Outcome
Beneficial effect of early DMARD treatment on the
radiologic progression of joint damage is still
present at 2 years1
14
Patients receiving early DMARD treatment (n 97)
(median treatment lag time 15 days)
P lt 0.05 compared with the delayed treatment
group
12
10
8
Change in median Sharp score
6
Patients receiving delayed DMARD treatment (n
109) (median treatment lag time 123 days)

4
2
0
0
6
12
18
24
Months
Early cohort received chloroquine or
sulfasalazine Delayed cohort received initial
treatment with analgesics, then were
treated with chloroquine or sulfasalazine Sharp
score score measuring lower median radiologic
damage theoretical maximum score is 4222

• Lard LR, et al. Am J Med. 2001111446-451.
• Aletaha D, et al. Rheum Dis Clin North Am.
  2006329-44.

22
Aggressive Early Treatment Improves Outcomes
COBRA
Multicenter, double-blind, randomized trial
comparing the combination of sulfasalazine (2000
mg/day), methotrexate (7.5 mg/week), and
prednisolone (60 mg/day, tapered in 6 weekly
steps to 7.5 mg/day) with sulfasalazine alone1
5-year follow-up to determine if COBRA benefits
are sustainable2
1.6
50
SSZ alone
MTX SSZ prednisolone
1.2
40
Step-down (n 76)
30
Sulfasalazine (n 79)
Pooled index
0.8
Total Sharp score
20
60 mg/d
N 148
10
0.4
Step-down therapy
Prednisolone 7.5 mg/d
Methotrexate 7.5 mg/wk
0
1
2
3
4
5
Sulfasalazine 2000 mg/d
0.0
Years
16
28
40
56
0
Weeks

• Boers M, et al. Lancet. 1997350309-318.
• Landewé RBM, et al. Arthritis Rheum.
  200246347-356.

COBRA Combinatietherapie Bij Reumatoide Artritis
23
Treatment of RA May Be Influenced by Age of
Patient

• Data for 5864 Medicare beneficiaries with RA who
  participated in a pharmaceutical benefit
  program in Pennsylvania

Aged 65-74 (n 2002)
Aged 75-84 (n 2815)
Aged gt 85 (n 1047)
P for trend lt 0.001
Percent of population
Drug Combination
Schmajuk G, et al. Arthritis Rheum.
200757928-934.
24
The Clinical Spectrum of RA
Early PIP swelling
Active with some deformity
Late-stage deformities
Images courtesy of J. Cush, 2005.
25
Disease Activity Measures
Measurement
Factors

• 20 improvement in tender joint count, swollen
  joint count, 20 improvement in 60 of other core
  set items
• Adopted as the primary outcome measure in RA
  clinical trials
• Can be expanded to include more substantial
  improvement (eg, ACR50, ACR70)

ACR20

• Combined index to measure disease activity in RA
  patients
• Score derived by assessment of number of swollen
  and tender joints, patient global assessment, and
  measurement of ESR or C-reactive protein

Disease Activity Score (DAS) (DAS28 or DAS44)
Simplified Disease Activity Index (SDAI)

• Employs a linear sum of variables based on ACR
  and EULAR core sets

• Developed as a modification of SDAI, sparing
  C-reactive protein (thus eliminating time waiting
  for lab results)

Clinical Disease Activity Index (CDAI)

• Assesses discomfort, drug side effects, costs,
  mortality, ability to perform activities of daily
  living

Health Assessment Questionnaire (HAQ)
Aletaha D, et al. Rheum Dis Clin North Am.
2006329-44.
26
Clinical Measurements
Cush JJ. Arthritis Rheum. 200552(9 suppl)S686.
Sesin CA, et al. Semin Arthritis Rheum.
200535185-196. Mäkinen H, et al. Clin Exp
Rheumatol. 200624(6 suppl 43)S22-S28.
27
Clinical Measurement Tools to Guide Treatment
Decisions
Low Disease Activity
Moderate Disease Activity
High Disease Activity
Remission

SDAI gt22
lt 3.6
DAS 2.4
gt 5.5
N/A

2.9-10
CDAI 2.8
gt 22
11-22

3.4-11
SDAI 3.3
12-26
gt 26
Aletaha D, et al. Clin Exp Rheumatol.
200523(suppl 39)S100-S108. Cush JJ. Arthritis
Rheum. 200552(9 suppl)S686.
28
Radiographic Damage Occurs Early
(c) 1972-2004 American College of Rheumatology
Clinical Slide Collection. Used with permission.
29
Audience Discussion

• Which of these statements is true?
• RA damage can occur within weeks
• Life expectancy may be substantially reduced in
  RA patients
• Remission is possible with early diagnosis and
  early referral to a rheumatologist
• Cardiovascular disease is a serious comorbidity
  associated with RA
• All of the above

30
Treatment Options for RA
31
Pharmacologic Options for RA
Three Main Classes of Pharmacologic Therapy for
Treating RA
DMARDs

• Nonbiologics (first line)
• Target immune cells, usually by an unknown
  mechanism
• Examples include hydroxychloroquine,
  sulfasalazine, methotrexate, leflunomide, gold

• Biologics (second line)
• Target specific parts of inflammatory cascade
• Examples include infliximab, etanercept,
  adalimumab, anakinra, abatacept, rituximab

Adjunctive (PCP may initiate)
Low-dose Corticosteroids
NSAIDs

Kountz D, et al. J Fam Pract. 200756(10 suppl
A)59a-73a.
32
Corticosteroid Use in RA

• No agreement on
• Efficacy, safety, and adverse effects of low-dose
  corticosteroids1-4
• Definition of low-dose corticosteroids5
• Low-dose corticosteroids (less than 7.5 mg per
  day) may provide initial relief to RA patients,
  but relief may mask disease progression
• Corticosteroids slow radiographic progression
  (Sharp scores) in early disease6
• However, not to the degree of traditional DMARDs
  and/or biologics
• Clinicians must weigh the benefits
  corticosteroids provide versus the risk of
  treatment complications

• Pisu M, et al. Rheumatology. 200544781-788.
• Da Silva JAP, et al. Ann Rheum Dis.
  200665285-293.
• Saag KG. Arthritis Care Res. 200145468-471.
• Conn DL. Arthritis Care Res. 200145462-467.
• Pincus T, et al. Ann Intern Med. 200213676-78.
• Jacobs JW, et al. Arthritis Rheum.
  2006541422-1428.
• Expert opinion

33
Disease-Modifying Anti-rheumatic Drug (DMARD)
Therapy

• All RA patients are candidates for DMARD therapy
• Used as initial therapy
• Often used in combination to maximize efficacy
• Selection of DMARD therapy is based on
• Individual patient
• Efficacy
• Convenience of administration
• Monitoring
• Time until expected benefit
• Frequency and severity of adverse events
• Costs
• Insurance coverage

American College of Rheumatology Subcommittee
on Rheumatoid Arthritis Guidelines. Arthritis
Rheum. 200246328-346.
34
2008 ACR Recommendations for Using Nonbiologic
DMARDs in RA Patients
Disease duration lt 6 months
Low
Moderate or high
Disease activity?
Features of poor prognosis?
Features of poor prognosis?
With
Without
Without
With
LEF MTX MTXHCQ
LEF MTX SSZ
MTXSSZ MTXSSZHCQ
HCQ MIN
SSZ
LEF leflunomide MTX methotrexate SSZ
sulfasalazine HCQ hydroxychloroquine MIN
minocycline
Saag KG, et al. Arthritis Rheum. 200859762-784.
35
2008 ACR Recommendations for Using Biologic
DMARDs in RA Patients
Disease Duration lt 6 months
Low or Moderate lt 6 months
High for lt 3 months
Disease activity?
Without
Features of poor prognosis?
High for 3-6 months
(See previous slide)
With
(See previous slide)
Anti-TNF-a and MTX
Cost or insurance coverage limits?
Yes
No
Saag KG, et al. Arthritis Rheum. 200859762-784.
36
Traditional Nonbiologic DMARDs
Bykerk VP, et al. J Musculoskelet Med.
200421133-146. ODell JR. N Engl J Med.
20043502591-2602. Bingham CO, et al. J Fam
Pract. 200759(suppl 10)S1-S8.
37
Biologic DMARDs
AntiTNF-a Therapies

• These medications are most effective when used in
  combination with methotrexate
• Prior to initiation of therapy, perform tests for
  HIV, PPD, hepatitis B and C, as well as
  appropriate immunizations

Bykerk VP, et al. J Musculoskelet Med.
200421133-146. ODell JR. N Engl J Med.
20043502591-2602. Bingham CO, et al. J Fam
Pract. 200759(suppl 10)S1-S8.
Expert opinion
38
Other Biologic DMARDs
Bykerk VP, et al. J Musculoskelet Med.
200421133-146. ODell JR. N Engl J Med.
20043502591-2602. Bingham CO, et al. J Fam
Pract. 200759(suppl 10)S1-S8. Visentini M, et
al. Clin Immunol. 200712530-33.
IL interleukin
39
Regular Monitoring of Patients Taking DMARDs Is
Required

• Smolen JS, et al. Lancet. 1999353259-266.
• FDA Web site. www.fda.gov/cder/drug/advisory/ritux
  imab.htm. Accessed March 5, 2008.
• Physicians Desk Reference. Montvale, NJ Thomson
  PDR 2007.

• Bykerk VP, et al. J Musculoskelet Med.
  200421133-146.
• ODell JR. N Engl J Med. 20043502591-2602.
• Bingham CO, et al. J Fam Pract. 200759S1-S8.
• Shergy WJ, et al. Am J Med. 198885771-774.

40
Regular Monitoring of Patients
Taking DMARDs Is Required (cont.)
5. Physicians Desk Reference. Montvale, NJ
Thomson PDR 2007. 6. US Food and Drug
Administration Web site. www.fda.gov/cder/drug/ear
ly_comm/TNF_blockers.htm. Accessed June 13, 2008

• Bykerk VP, et al. J Musculoskelet Med.
  200421133-146.
• ODell JR. N Engl J Med. 20043502591-2602.
• Bingham III CO, et al. J Fam Pract.
  200759S1-S8.
• US Food and Drug Administration Web site.
  www.fda.gov/cder/drug/advisory/rituximab.htm.
  Accessed June 13, 2008.

41
Mechanism of Action in Biologics
Hypothesized (auto) antigen triggering event
Genetic predisposition
Dendritic cell (antigen-presenting cell)
(Costimulation)
Biologic DMARD abatacept
T cell (CD4)
Biologic DMARD rituximab
B cell
Traditional DMARD methotrexate,
leflunomide sulfasalazine
Macrophage
Biologic DMARD anakinra, infliximab, etanercept,
adalimumab
Rheumatoid factor and other antibodies
Cytokines IL-1 TNF IL-6
Osteoclast activity
Metallopro-teinases
CARTILAGE/BONE
Kountz DS, et al. J Fam Pract. 200756(10 suppl
A)59a-73a.
42
Methotrexate Monotherapy Versus Combination
Therapy with Biologics and
Methotrexate in Early RA
Newly instituted methotrexate therapy and
methotrexate plus TNF-inhibitor therapy from
12-month clinical trials of infliximab (ASPIRE, N
1049),1,2 adalimumab (PREMIER, N 799),1,3 and
etanercept (COMET, N 542)4
Methotrexate monotherapy
TNF-inhibitor methotrexate
Patient response ()
Patient response ()
ACR20
ACR70

• Smolen JS, et al. Lancet. 20073701861-1874.
• St. Clair EW, et al. Arthritis Rheum.
  2004503432-3443.
• Breedveld FC, et al. Arthritis Rheum.
  20065426-37.

• Emery P, et al. ACR 2007 meeting.
  http//www.rheumatology.org. Abstract L17.

43
TEMPO Trial Etanercept Used in Combination with
Methotrexate
52-week, double-blind clinical trial in which
patients with active RA were randomized to
receive etanercept 25 mg twice weekly,
methotrexate 20 mg weekly, or
combination therapy
P 0.0091 (combo vs MTX) P 0.0151 (combo vs
ETN)
P lt 0.0001 (combo vs MTX) P lt 0.0001 (combo vs
ETN)
Methotrexate (n 228)
Etanercept (n 223)
Mean percent of responders
Methotrexate etanercept (n 231)
Klareskog L, et al. Lancet. 2004363675-681.
44
ASPIRE Trial Infliximab Used in Combination with
Methotrexate
Patients (N 1004) were randomly assigned to 3
treatment groups methotrexate placebo,
methotrexate infliximab 3 mg/kg,
and methotrexate infliximab 6 mg/kg
P 0.028
P lt 0.001
Methotrexate placebo


P 0.001
P lt 0.002 vs methotrexate placebo group
Infliximab 3 mg/kg methotrexate

Infliximab 6 mg/kg methotrexate

Percent of patients in response at week 54



ASPIRE Active-Controlled Study of Patients
Receiving Infliximab for the Treatment of
Rheumatoid Arthritis of Early Onset
St. Clair EW, et al. Arthritis Rheum.
2004503432-3443.
45
PREMIER Trial Adalimumab Used in Combination
with Methotrexate
2-year, multicenter, double-blind, active
comparator-controlled study of 799 RA patients
with active disease of lt 3 years duration who
had never been treated with methotrexate
ACR20


ACR50

ACR70
Percent of patients in response at Year 2
ACR90
P lt 0.001 vs. adalimumab alone and P 0.002
vs. methotrexate alone P lt 0.001 vs. adalimumab
alone and versus methotrexate alone
Breedveld FC, et al. Arthritis Rheum.
20065426-37.
46
Mortality in RA Patients Treated with AntiTNF-a
Therapies
Age- and sex-adjusted survival curves for
patients treated versus those not treated with
antiTNF-a therapies, stratified by median Health
Assessment Questionnaire (HAQ) score
Low HAQ, treated with antiTNF-a
Low HAQ, not treated with antiTNF-a
High HAQ, treated with antiTNF-a
High HAQ, not treated with antiTNF-a
Median HAQ for men 1.13 Median HAQ for
women 1.50
Jacobsson LTH, et al. Ann Rheum Dis.
200766670-675.
47
Rates of Serious Infections DMARDs Versus
AntiTNF-a Medications
National prospective observational study of 7664
antiTNF-a treated and 1354 DMARD-treated
patients with severe RA
Adjusted for age, sex, disease severity,
comorbidity, extra-articular manifestations,
steroid use, and smoking
Dixon WG, et al. Arthritis Rheum.
2006542368-2376.
48
Reasons for Switching AntiTNF-a
Therapies

• Primary lack of efficacy
• Patient has no meaningful clinical benefit
• Secondary loss of efficacy
• Patient symptoms worsen after initial good
  response
• Partial response
• Patient has a measurable response, yet more is
  desired
• Side effect
• Patient has a good response but discontinues
  therapy due to adverse effects

van Vollenhoven RF. Ann Rheum Dis.
200766849-851.
49
Discontinuation of AntiTNF-a Agents/DMARDs in RA

• 1-year follow-up observational study from 5
  Norwegian rheumatology clinics
• Patients started DMARD therapy and followed for 1
  year
• AntiTNF-a monotherapy (n 194)
• Methotrexate monotherapy (MTX) (n 856)
• AntiTNF-a MTX (n 319)
• MTX other DMARDs (n 262)
• Leflunomide (LEF) (n 304)
• Crude 1-year survival for
  antiTNF-a MTX was superior to
  antiTNF-a monotherapy, MTX other DMARDs, and
  leflunomide

1-year survival of DMARD regimens in patients
with RA (crude estimates)
1.0
0.8
0.6
Cumulative survival
0.4
0.2
0.0
200
300
400
100
0
Days
AntiTNF-a
AntiTNF-a MTX
MTX other DMARD
MTX
LEF
Heiberg M, et al. ACR 2005 meeting.
http//www.rheumatology.org. Abstract 268.
50
Abatacept ATTAIN Study

• 6-month, randomized, double-blind,
  placebo-controlled study of patients with severe
  RA (N 391) who had inadequate response to
  antiTNF-a therapy who were receiving a
  background DMARD to assess safety and efficacy of
  abatacept or placebo in combination with at least
  1 other DMARD

Genovese MC, et al. N Engl J Med.
20053531114-1123.
51
REFLEX Trial Evaluating the Efficacy of Rituximab
Multicenter, randomized, double-blind,
placebo-controlled, phase III trial evaluating
primary efficacy and safety of rituximab at 24
weeks
Percent of patients
P lt 0.0001
Response
Cohen SB, et al. Arthritis Rheum.
2006542793-2806.
52
Novel Agents in Development
53
Emerging Therapies for RA
Therapies listed are not approved by FDA at
current time
54
RAPID 2 Study Certolizumab

• Certolizumab a pegylated, fab' fragment of a
  humanized anti-TNF-a monoclonal antibody1
• Adding pegylation adds half-life to molecule and
  eliminates chimeric Fc portion, which may
  increase duration and may decrease adverse
  events2
• RAPID 2 study Phase III, multicenter,
  double-blind, placebo-controlled, parallel-group
  study to investigate efficacy and tolerability of
  liquid formulation of certolizumab at 2 different
  doses as an add-on therapy to methotrexate2
• Low incidence of injection-site pain2

ACR20 at 24 weeks2
Certolizumab 200 mg (n 246) Q 4 weeks
Certolizumab 400 mg (n 246) Q 4 weeks
Placebo (n 127)
- Certolizumab 200 mg, 400 mg, and
placebo all administered with methotrexate
Percent of patients who achieved ACR20 response
Not approved by FDA at current time

• Rose-John S, et al. Curr Opin Invest Drugs.
  20034588-592.
• Mease P, et al. ACR 2007 meeting.
  http//www.rheumatology.org. Abstract 941.

55
Efficacy of Golimumab

• Golimumab, a new fully human monoclonal antibody,
  now in development for subcutaneous and
  intravenous administration
• Phase II, randomized, double-blind,
  placebo-controlled, 52-week, dose-ranging trial
  (N 172 adults with RA 3 months duration
  refractory to methotrexate monotherapy)

ACR20

ACR50
P lt 0.05 vs placebo
ACR70

Percent of patients achieving ACR response at 16
weeks






Not approved by FDA at current time
Kay J, et al. Arthritis Rheum. 200858964-975.
56
Efficacy of Tocilizumab
Double-blind, randomized, controlled trial of
intravenous infusions of tocilizumab (MRA), a
humanized antiinterleukin-6 (IL-6) receptor
antibody, in RA patients who experienced
incomplete response to methotrexate (MTX) (N
359)
P lt 0.05
ACR20
ACR50


ACR70
Percent of patients
Not approved by FDA at current time
Maini RN, et al. Arthritis Rheum.
2006542817-2829.
57
Triangle of Treatment
Patient

• Modify lifestyle as recommended by clinicians
• Adhere to medication regimen and monitor for side
  effects, infections
• Report joint counts
• Report symptoms
• Understand RA is a lifelong disease

Lifelong care and consultation
Lifelong care and consultation
Rheumatologist
PCP
Lifelong care and consultation

• Confirm diagnosis of RA
• Obtain baseline studies, tests
• Initiate aggressive treatment with DMARDs
• Devise strategy for safe and efficacious
  implementation of biologic therapies
• Laboratory and comorbidity monitoring

• Recognize early warning signs and symptoms
• Diagnose RA and refer to rheumatologist
• Understand risks and benefits of current
  treatment options
• Laboratory and comorbidity monitoring
• Monitor patient throughout disease process

Kountz DS, et al. J Fam Pract. 200756(10 suppl
A)59a-73a.
Expert opinion
58
ACR Position Statement on Rheumatologists
Treating RA Patients

• The role of rheumatologists is primarily to
  diagnose and treat and educate individuals with
  RA
• However
• RA patients may not see rheumatologist without
  PCP referral
• Once the patient is seen by the rheumatologist,
  follow-up visits may be restricted, or the
  ability to treat concomitant related problems is
  curtailed
• Responsibilities of rheumatologist after making
  or confirming diagnosis of RA

- Working with PCPs or other physicians on
treatment of new medical problems unrelated to RA
- Treating or consulting with PCPs on any disease
flares or complications
- Making major decisions for managing disease
- Directing diagnostic studies in the most
appropriate and cost-effective manner
- Assessing musculoskeletal complaints early in
their course
- Educating patient
ACR Position Statement, approved August 2007.
http//www.rheumatology.org/publications/position/
. Accessed March 3, 2008.
59
Clinical Pearls

• Early, aggressive combination treatment affords
  RA patients the best chance of limiting joint
  damage, preventing further radiographic
  progression of disease, and improving quality of
  life
• Recognizing warning signs of RA enables PCPs to
  diagnose the disease early and refer patients to
  rheumatologists
• Close coordination between PCPs and
  rheumatologists in monitoring toxicities and
  comorbidities is essential to managing RA
  patients
• There is a disconnect between controlling signs
  and symptoms and controlling radiographic
  progression clinicians need to control both
• Therapy decisions based on clinical measurements
  are superior to decisions based solely on
  clinician judgment

60
Audience Question Answer Session