Transcript RA=rheumatoid arthritis - The American Society of Clinical

Diagnostic and Treatment
Innovations in Rheumatology
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
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Objectives
After this educational activity, participants will be able to:
• Describe the pathophysiology of rheumatoid arthritis
• Describe the differential diagnosis and the spectrum of clinical presentations of
rheumatoid arthritis, and an improved ability to utilize applicable diagnostic tools in
their daily practice
• Describe the most current and innovative treatment approaches for rheumatoid
arthritis.
• Demonstrate that they are able to apply their increased understanding of the
diagnosis and management of inflammatory arthritis through the successful
completion of case reports.
Program Outline

What is rheumatoid arthritis?

The importance of early diagnosis

The critical role of the primary care provider
Key Learning Points
•
Rheumatoid arthritis:
•
Is often an aggressive disease
•
May have potentially devastating consequences
•
Early, aggressive management can lead to
successful control and remission
Common Types of Arthritis

Inflammatory arthritis

Degenerative diseases

Infectious arthritis
Types of Inflammatory Arthritis


Rheumatoid arthritis
Seronegative
spondyloarthropathies


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

Psoriatic arthritis
Ankylosing spondylitis
Reactive arthritis
Enteropathic arthritis
Crystalline induced arthropathies


Gouty arthritis (uric acid)
Pseudogout (calcium
pyrophosphate)

Connective Tissue Diseases






Systemic lupus erythematosus
Polymyositis/dermatomyositis
Systemic sclerosis
Sjogren syndrome
Sarcoidosis
Infectious/Post infectious
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


Lyme Disease
Hepatitis C
Post viral (Parvovirus, Echo,
Coxsackie)
Post streptococcal
What is Rheumatoid Arthritis?

Rheumatoid Arthritis:

Is a chronic progressive systemic autoimmune disease

Affects primarily joints

Leads to cartilage and bone destruction

Systemic disease: internal organ involvement common
American College of Rheumatology
Diagnostic Criteria for RA
Must have at least 4 of the following 7 criteria:
6.
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
7.
Radiographic changes
1.
2.
3.
4.
5.
*Must be present at least 6 weeks
Characteristics of Rheumatoid Arthritis

Affects young people
 Peak age of onset: 20-45 years

Affects approximately 1% of the population
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Affects 3 million Americans
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2-3 times more common in women
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Loss of physical function and quality of life

Life expectancy reduced
The Pathogenesis of RA
Why should a normal healthy immune system
suddenly begin to destroy healthy joints?



Answer not known
Genetic predisposition in many instances
Popular theories: environmental stimulus,
hypothesis most likely viral; unproved
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
Morbidity & Mortality
of Rheumatoid Arthritis





Average life expectancy shortened by 5-15 years
Myocardial infarction: twice as likely
Risk of stroke: increased
Risk of infection: increased
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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Disease progression in first 2 years determines long
term disability
Average work day loss/year = 30
Average lifetime earnings loss = 50%
40%-85% of RA patients will be unable to work within
8-10 years of disease onset
1 Allaire, SH et al. The costs of RA. PharmacoEconomics. 1994;6:513-522. 2. Wolfe, F et al. The prevalence and meaning of fatigue in RA. J Rheum 1996;23:1407-1417.
3 Verhoeven AC et al. Combination therapy in RA. Br J Rheum 1998; 37:612-619. 4. Lard LR et al. Early vs delayed treatment in RA. Am J Med 2001; 111:446-451.
5. Goldbach-Mansky R et al. New concepts in the treatment of RA. Annu Rev Med 2003; 54: 197-216. 6. Kirwan JR. J Rheumatol. 2001;28:881-886.
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
Clinical Manifestations of RA

Musculoskeletal manifestations

Systemic manifestations

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
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Fatigue
Fever
Depression
Weight loss
Extra-articular manifestations
Early Clinical Manifestations of RA
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Symmetric soft tissue swelling of joints
Prolonged morning stiffness common
Hand, wrist, foot involvement common
Fatigue
Late Clinical Manifestations of RA

Joint destruction and deformity

“Ulnar Drift” of MCP’s

Rheumatoid nodules

Extra-articular manifestations
Clinical Spectrum of RA
Images courtesy of J. Cush, 2002.
Clinical Spectrum of RA
Images courtesy of J. Cush, 2002.
Swan Neck Deformities
Metatarsal Head Protrusion
Do the squeeze test
Early Referral Algorithm for
Newly Diagnosed RA
Rapid evaluation advised with clinical suspicion of RA,
which may be supported by the presence of any of the following:
• 3 swollen joints
• MTP/MCP involvement
– Positive squeeze test
• Morning stiffness 30 minutes
Emery P et al. Ann Rheum. Dis. 2002:61:290-297
X-Rays



Early on: may be normal
Advancing disease: radiographic features more
evident
Earliest findings:



soft-tissue swelling
peri-articular osteopenia
May not be as sensitive as MRI or ultrasound
ExtraSkeletal
Manifestations
Of
Rheumatoid
Arthritis
Nodulosis: Elbow
Rheumatoid Nodules of Lung
Laboratory Findings

Rheumatoid Factor
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
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Early on: May be negative
Eventually positive in 80% of patients
Positive rheumatoid factor: 8% of the general population
Anti-cyclic citrullinated peptide antibody (CCP)
ANA: present in approximately 40% of RA patients
Erythrocyte sedimentation rate
C-reactive protein
Anemia of chronic disease, thrombocytosis,
leukocytosis
Rheumatoid Factor: Not Unique
to Rheumatoid Arthritis
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
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
Aging
Other connective tissue diseases (Sjogrens,
SLE, dermatomyositis, etc)
Chronic infections (endocarditis, hepatitis, etc.)
Granulomatous diseases (Wegener’s, Crohn’s,
sarcoidosis)
Anti-Cyclic Citrullinated Peptide Antibody
Specificity and Sensitivity



Early RA (< 2 years)
Anti-CCP 79% sensitivity
Clinically Confirmed RA
Anti-CCP 81% sensitivity
Sero-negative RA
Anti-CCP 40% sensitivity
Specificity
Sensitivity
RF +
75%
60%
Anti-CCP +
96%
75%
Anti-CCP +
RF +
99%
80%
* High titer anti-CCP may predict aggressive erosive disease
* Rarely anti-CCP reported in SLE, scleroderma, JRA
Linn-Rasker SP, et al. Ann Rheum Dis 2006;65:366-71
Anti-Cyclic Citrullinated Peptide Antibody
Specificity and Sensitivity

Positive CCP antibody: almost always
means RA

If not: almost certainly a closely related
auto immune connective tissue disease
RA Is a Progressive Disease
Severity
Inflammation
Disability
Radiographs
0
5
10
15
20
25
Duration of Disease (years)
Graph: Adapted from Kirwan JR. J Rheumatol. 2001;28:881-886.
30
CV Risk in Newly Diagnosed RA
Patients
80


Study of patients with RA and
conventional cardiac risk
factors
Given identical cardiac risk
factors, patients with RA have
a higher likelihood of having
MI than non-RA patients
10-yr absolute CVD risk in 60-yr-old
female
RA
60
40
Non RA
20

Important to control both
inflammatory disease and
conventional risk factors
DM, diabetes mellitus; DYS, dyslipidaemia;
HTN, hypertension; OBE, obesity; SMO, smoker
1 Kremers HM, et al. 71st ACR, Boston 2007 #2185
0
Without
risk
factor
SMO
SMO
HTN
SMO
HTN
DM
SMO
HTN
DM
DYS
SMO
HTN
DM
DYS
OBE
SMO
HTN
DM
DYS
Low
BMI
Early Treatment Reduces the Cardiovascular
Risk in Newly Diagnosed RA Patients
Objective: Study sub-clinical atherosclerosis in early RA

Methods: prospective cohort of 40 early RA patients tx with MTX and
prednisone compared with 45 non-RA patients for cardiac risk parameters
and carotid IMT by B-mode US after one year of treatment

Result(s):
CCA-IMT:
Common carotid
Artery intimamedia
thickness
CCA - IMT in mm

1
0.82
0.63
0.57
0
Baseline
12 Months
eRA

0.57
Non RA
Conclusion(s): Atherogenic lipid profile and subclinical
atherosclerosis are features of early RA, which improved after
therapy. Improvement in CCA-IMT .82mm to 0.63mm; p<.01-similar
to non RA population.
Georgiadis et al. ACR 2007 Abstract 1005
RR vs MTX Monotherapy
Combination TNF-Inhibitor-MTX Therapy is Superior to
MTX Monotherapy in Reducing the Risk of Acute MI in
Patients with RA
2
1.78
p<0.03
1.10
0.88
1
0.93
0.20
0
Anti-TNF/MTX
DMARD
Anti-TNF
DMARD/MTX
Anti-TNF/DMARD
Conclusion(s):

Combined TNF-inhibitor and MTX therapy was associated with an 80% reduced risk
of acute MI compared to MTX monotherapy in RA pts. “Such dramatic effect
enhances the therapeutic gains of TNFinhibitor therapy in patients with RA and
should be seriously considered, particularly in high-risk patients.”
Singh et al. ACR 2007 Abstract 1339
Differentiating RA
From Other Diseases
Osteoarthritis
Bouchard’s
Nodes
Heberden’s
Nodes
©ACR
Psoriatic Arthritis
©ACR
Tophaceous Gout
©ACR
The Treatment of
Rheumatoid Arthritis
Therapeutic Window of Opportunity

Erosive changes occur early in disease

Brief delay of therapy: significant impact years later

Early DMARD treatment that suppresses
inflammation: resets 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.
Evolving Approaches in Treating RA
1980s
 Emphasis on treating
symptoms of the disease
 Less treatment in early stages
 NSAIDs considered least toxic
 In US, MTX and
corticosteroids considered
most toxic
Experimental drugs
and procedures
Immunosuppressants, gold-based
drugs, and antibiotics
Nonsteroidal anti-inflammatory drugs
(NSAIDs) and analgesics
Self-management: education, rest, exercise
Evolving Approaches in Treating RA
1990s to Present

Emphasis on treating
symptoms, limiting joint
destruction

Earlier use of DMARDs in
higher doses

MTX and SSZ considered
first-choice DMARDs

Combination therapy
Early diagnosis
Early treatment
DMARDs and Biologics
Preserve
function
and
quality of life
2008 and On
 Even earlier use of
biologic monotherapy
or biologic with MTX
Remission
ACR Treatment Algorithm
Rheumatologist
Initial
Establish diagnosis of RA early
Multiple DMARD failure
Initiate therapy
Periodically assess disease activity
Adequate response
Inadequate response
Change/add DMARDs
MTX-naïve
Combination
MTX
Other
monotherapy
Suboptimal MTX response
Other
Combination
Biologics
monotherapy
Monotherapy Combination
Multiple DMARD failure
RA=rheumatoid arthritis; MTX=methotrexate;
DMARDs=disease-modifying antirheumatic drugs.
Adapted from ACR Subcommittee on Rheumatoid Arthritis Guidelines. Arthritis Rheum. 2002;46:328-346.
Treatment Options in RA



Non pharmacologic approaches: rest, exercise, PT
Medications
 NSAIDs
 Disease modifying anti-rheumatic drugs (DMARDs)
 Biologic Agents
 Corticosteroids
Surgery
Disease Modifying Anti-Rheumatic Drugs
(DMARDs)




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Generally slower acting
Reduce signs and symptoms of
inflammation
Slow or retard rate of joint damage
Oral or by injection
Non-targeted
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
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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Symptom control does not mean disease
control1
Damage can occur early2
Risks of morbidity and mortality increase when
disease is poorly controlled3,4
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
Add traditional
DMARD
(Combination
Therapy)
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


Anakinra (Kineret)
Modulate T cell-antigen presenting cell interactions


Adalimumab (Humira)
Etanercept (Enbrel)
Infliximab (Remicade)
Abatacept (Orencia)
Anti B-Cell monoclonal antibody

Rituximab (Rituxan)
Efficacy of Biologic Agents

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
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Combination therapy efficacy: equal or
superior to DMARDs
Targeted Mechanism of action identified
Rapid onset of action
Well tolerated: improved risk/benefit ratio
Sustained response in many patients:



prevention of structural damage
control of symptoms
prevention of disability
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 Q
I.V.
Sub Q
Sub Q
I.V.
I.V.
MEASURING DISEASE ACTIVITY

Subjective—pain, morning stiffness, fatigue, limitation of
function, PGAs

Physical exam—swollen and tender joint count

Lab evaluation—RF, anti-CCP, ESR, CRP

Imaging—X-ray (Sharp Score), US, MRI

Disease Activity and Outcome Scoring: ACR 20,50,70, DAS,
HAQ, Global Arthritis Score (GAS) C-DAI, S-DAI, RAPID
Better Outcomes in Patients Receiving
Combination Therapy of MTX & Anti TNFα
Patients (%)
ACR50 Response
61
46
42
Patients (%)
70
60
50
40
30
20
10
0
Mean Change TSS
59
43
37
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
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.
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
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
Inhibition of T-Cell Activation by Co-Stimulatory 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
Inhibition of T-Cell Activation by Co-Stimulatory Pathway
Blockade in RA Patients: Radiographic Outcomes
2.5
2.3
2
Placebo + MTX
*
1.5
1.2
Abatacept + MTX
1
*P<0.05 vs placebo
0.5
Change From Baseline
0
40
Abatacept
1
P=0.012
for Total Score
X-Ray
Progression
30
Placebo at 1 Year
P=0.029 for Erosion Score
20
10
0
10
1.
2.
P=0.009 for JSN Score
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Cumulative Probability2
Kremer, et al Annals of Internal Medicine: 2006; 144:865-876
Genant H, et al. Presented at: EULAR Annual Meeting; June 8-11, 2005; Vienna, Austria. Abstract OP0001.
Figure courtesy of H. Genant, MD.
Safety Considerations
 Morbidity
and mortality of RA
 Safety of conventional DMARDs
 Safety of biologics
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
Is Cancer More Aggressive on TNF-I?
Mortality rate comparison in RA pts
after cancer diagnosis between
those treated and not treated with
TNF-Is

Swedish database (inpatient,
outpatient and early RA registries)
TNF naïve (n=61,585) and the
Swedish Biologic Registry
(n=6296) (1998–2005)
Conclusion
 Preliminary results: no major
difference in cancer survival
between RA pts treated and not
treated with TNF-antagonists
Raaschou, P et al. 71st ACR, Boston 2007 #1344
All sites
Mortality

Anti-TNF
No anti-TNF
RR=0.8 (95% CI 0.5-1.2)
Days
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)
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
RA: Misperceptions






Controlling symptoms = controlling the disease
Early treatment should be conservative, eg, NSAIDs,
COX-2 inhibitors
Positive rheumatoid factor (RF) = RA
RA is a disease of (postmenopausal) women and elderly
people
RA is inevitably progressive, regardless of therapy
RA does not affect mortality rate
Keys to Improving Outcomes and Slowing
Disease Progression

Early diagnosis-learn about the Anti-CCP test
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

Irreversible joint destruction often begins within the first
year after RA onset
>70% of patients exhibit radiographic disease progression
after only 2 years
Joint damage strongly correlates with disability over the
course of RA
What can the Primary Care Provider do?




Be mindful: serious nature of RA
Remember early intervention is important
Keep up to date on new developments
Be an advocate for your patients


Early referral to specialist
Pick up the phone if necessary
Warning Signs




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Morning stiffness 1 hour
Joint pain lasting 3 months
Symmetrical, bilateral painful and/or
swollen joints
3 swollen joints
MCP/MTP involvement
Positive squeeze test
RF+
CCP +
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