Transcript Grisanti.RD.LBP - Rheumatology Information

Diagnostic and Treatment
Innovations in Rheumatology
Name of Speaker
Credentials
Date
Site
1
Program Outline

What is rheumatoid arthritis?

The importance of early diagnosis

The critical role of the primary care provider
2
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
3
Common Types of Arthritis
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Inflammatory arthritis
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Degenerative diseases
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Infectious arthritis
4
Types of Inflammatory Arthritis
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Rheumatoid arthritis
Seronegative
spondyloarthropathies
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Psoriatic arthritis
Ankylosing spondylitis
Reactive arthritis
Enteropathic arthritis
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Systemic lupus erythematosus
Sarcoidosis
Infectious/Post infectious
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Lyme Disease
Post viral (Parvovirus, Echo,
Coxsackie, Hepatitis)
Post streptococcal
Crystalline induced arthropathies
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Gouty arthritis (uric acid)
Pseudogout (calcium
pyrophosphate)
5
What is Rheumatoid Arthritis?

Rheumatoid Arthritis:
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Is a chronic progressive systemic autoimmune disease
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Affects primarily joints and tendons
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Leads to cartilage and bone destruction

Because of the systemic nature of this disease, involvement
of internal organs is common
6
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
7
Characteristics of Rheumatoid Arthritis

RA affects young people
 Peak age of onset: 20-45 years
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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
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Life expectancy reduced by 5-15 years
8
Undifferentiated Arthritis

What happens to ~1700 patients with undifferentiated
arthritis (eg, those with recent onset inflammatory
arthritis who do not fulfill ACR criteria for RA?) within 2
years of developing arthritis…
~40% go into long
lasting spontaneous
remission
~17–32% progress and
can be classified as
rheumatoid arthritis
Van Dongen H, et al. EULAR, Amsterdam 2006, #OP0001
~28–43% remain
undifferentiated
9
The Pathogenesis of RA
Why should a normal healthy immune system
suddenly begin to destroy healthy joints?
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The answer is not known
Appears to be some genetic predisposition in
many instances
Popular theories implicate an external stimulus,
most likely a virus
10
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
11
Chronic Inflammation:
Imbalance Between Mediators
IL-10
TGF
IL-1Ra
IFN
IL-6
IL-4/IL-13
IL-8
IL-1
TNF
12
Impact of Rheumatoid Arthritis
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80% complain of fatigue
40% meet criteria for clinical depression
Chronic pain is common
Disability is common
Negative impact on family
Pollard LC, 2006 Rheumatology (on line advance access, Huyser BA et al Arthritis Rheum 1998; 41: 2230-7, Rupp I et al Arthritis
Rheum 2004 51(4): 578-85, Fifield J et al Arthriitis Rheum 1998;41(1851-7), Wolfe F et al J Rheum 2004;31: 2115-20
13
Morbidity & Mortality
of Rheumatoid Arthritis
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Average life expectancy shortened by 5-15 years.
Twice as likely to have myocardial infarction
Increased risk of stroke
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.
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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
15
Functional Decline Begins Early in RA
Moderate loss
of function*
0
2
Severe loss
of function*
5
Very severe
loss of
function*
10
Years from Symptom Onset
* 50% rates of loss of function based on HAQ scores
Wolfe F, Cathey MA. J Rheumatol. 1991;18:1298-1306.
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Clinical Manifestations of RA
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Musculoskeletal manifestations
Systemic manifestations
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Fatigue
Fever
Depression
Weight loss
Extra-articular manifestations
17
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
18
Late Clinical Manifestations of RA
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Joint destruction and deformity
“Ulnar Drift” of MCP’s
Rheumatoid nodules
Extra-articular manifestations
19
Clinical Spectrum of RA
Images courtesy of J. Cush, 2002.
20
Swan Neck Deformities
21
Metatarsal Head Protrusion
Do the squeeze test
22
X-Rays
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May be normal early
Radiographic features of RA become more
evident with advancing disease
Earliest findings on x-ray: soft-tissue swelling
and peri-articular osteopenia
May not be as sensitive as MRI or ultrasound
23
24
25
Extra-Articular Manifestations of RA
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Rheumatoid Nodules
Vascular:
 Vasculitis
 Raynaud’s
Pulmonary:
 Fibrosis
 Caplan’s lung
 Pleural effusion
Cardiac:
 Carditis
 Pericarditis
 ASHD
Neurologic:
 Peripheral neuropathy
 Cerebrovascular
 Carpal tunnel
 Cervical cord compression
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Hematologic:
 Anemia of chronic disease
 Thrombocytosis
 Lymphadenopathy
Felty’s Syndrome:
 Granulocytopenia
 Splenomegaly
Ophthamologic:
 Episcleritis, keratoconjunctivitis
 Sjogren’s
Myopathy
Xerostomia
Cutaneous
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Ulceration, thinning
Amyloid (Renal, G.I., Lung)
26
ExtraSkeletal
Manifestations
Of
Rheumatoid
Arthritis
27
Nodulosis: Elbow
28
Rheumatoid Nodules of Lung
29
Laboratory Findings
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Rheumatoid Factor
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May be negative early
Becomes positive in 80% of patients
Positive rheumatoid factor seen in up to 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
30
Rheumatoid Factor: Not Unique
to Rheumatoid Arthritis
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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)
31
Anti-Cyclic Citrullinated Peptide Antibody
Specificity and Sensitivity
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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
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RA Is a Progressive Disease
Severity
Inflammation
Disability
Radiographs
0
5
10
15
20
25
30
Duration of Disease (years)
Graph: Adapted from Kirwan JR. J Rheumatol. 2001;28:881-886.
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Factors Suggesting Poor Prognosis
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Longer disease duration
Late implementation of
treatment
>20 swollen joints
Joint erosions
High RF titer
Elevated anti-CCPs
Elevated Sed Rates
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Elevated CRP
Presence of rheumatoid
nodules
Socioeconomic
characteristics
Smoking
Poor functional status
Shared epitope HLA-Dr4
34
Differentiating RA
From Other Diseases
35
Osteoarthritis
Bouchard’s
Nodes
Heberden’s
Nodes
©ACR
36
Psoriatic Arthritis
©ACR
37
Tophaceous Gout
©ACR
38
The Treatment of
Rheumatoid Arthritis
39
Goals of Therapy
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Prevent joint damage, disability and premature
death
Improve quality of life
Relieve symptoms, including fatigue, pain,
swelling, and stiffness
Achieve clinical remission
40
Therapeutic Window of Opportunity
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Erosive changes occur early in disease
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Even a brief delay of therapy can have a significant
impact on disease parameters years later
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Early DMARD treatment that suppresses
inflammation 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.
41
Erosions May Develop Very Early
in Disease Course
 Radiographic
erosions may
develop before arthritis is
clinically apparent
 25%
of RA patients have
erosions at their first visit
.
Reference: 1. van der Horst-Bruinsma IE, et al. Br J Rheumatol. 1998;37:1084-1088
Radiograph courtesy of C. Michael Franklin, M.D., Willow Grove, Pa.
42
Radiographic End Point: Sharp Score
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Measures erosions and joint-space
narrowing separately
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Erosions scored in areas
marked with a dot (left)
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Joint-space narrowing (JSN)
scored in areas marked with
lines (right)
Van der Heijde modification
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Eliminated 2 hand sites for
erosions and 2 hand sites for
JSN
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Added joints on the feet
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Maximum erosion scores=
160 (hands) and 120 (feet)
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Maximum JSN scores=
120 (hands) and 48 (feet)
Van der Heijde, DM. Bailliere’s Clin Rheumatol. 1996;10:435-453.
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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
24
Months
Patients were treated with chloroquine or azathioprine
Lard LR, et al. Am J Med. 2001;111:446–451.
44
Treatment Options in RA
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Non pharmacologic approaches: rest, exercise, PT
Medications
 NSAID’s
 Disease modifying anti-rheumatic drugs (DMARD’s)
 Biologic Agents
 Corticosteroids
Surgery
45
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
46
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
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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
48
Problems with Old Approach
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Symptom control does not mean disease
control.1
Damage can occur early.2
Risk of mortality potentially increases when
disease is poorly controlled.3,4
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.
49
Evolving RA Treatment Paradigm
Current Approach
Initial
treatment:
traditional
DMARDs
Add traditional
DMARD
(Combination
Therapy)
Evolving Paradigm
• Early aggressive
treatment
• Biologics
• Combination therapy
Chronic Inflammation:
Imbalance Between Mediators
IL-10
TGF
IL-1Ra
IFN
IL-6
IL-4/IL-13
IL-8
IL-1
TNF
51
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

Rituximab (Rituxan)
52
Efficacy of Biologic Agents
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Clinical efficacy of combination therapy equal
and often superior to DMARDs.
Mechanism of action identified-targeted.
Rapid onset of action.
Well tolerated: improved risk/benefit ratio.
Sustained response in many patients:
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prevention of structural damage
control of symptoms
prevention of disability
53
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.
54
MEASURING DISEASE ACTIVITY

Subjective—pain, morning stiffness, fatigue, limitation of
function, PGAs

Physical exam—tender joint count, swollen joint

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
55
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
year 2
MTX
Adalimumab
MTX + Adalimumab
Breedveld FC Arthritis Rheum 2006; 54(1): 26-37
56
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.
57
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
58
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
MTX
*p<0.001 vs adalimumab alone and MTX alone
Breedveld FC Arthritis Rheum 2006; 54(1): 26-37
59
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)
60
Post-hoc Subset Analysis: Combination Inhibits
Erosion Despite Lack of Clinical Improvement
MTX + placebo
MTX + Infliximab 3 mg/kg
MTX + Infliximab 6 mg/kg
Change in vdH-S score
5
4.36
4.11
4
3.48
3.28
3
*
2
1
*
1.68
0.9
*
*
*
1†
0.11 0.08
0.04
0
2.2
*
-0.05
-1
ACR20
Responders
ACR20
Nonresponders
DAS
Responders
DAS
Nonresponders
Patients treated with infliximab + MTX showed less radiographic
progression vs patients on MTX alone at week 54 regardless of lack
of clinical improvement (ACR20; DAS28)
*P<0.01,†P=0.01.
Smolen J et al; Arthritis and Rheumatism;2006 54(3),702-710
61
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)
62
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
63
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
6 Mos
12 Mos
ACR 70
1. Kremer et al. Annals of Internal Medicine: 2006; 144:865-876
64
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.
65
Safety Considerations
 Morbidity
and mortality of RA
 Safety of conventional DMARDs
 Safety of biologics
66
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
67
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)
68
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.
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Common Misperceptions About RA






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
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Keys to Improving Outcomes and Slowing
Disease Progression

Early diagnosis



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
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What can the Primary Care Provider do?




Be mindful of the 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
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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 +
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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
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