Download here - Plengegen

Clinical features and research
opportunities in rheumatoid arthritis
Clinical Immunology
March 26, 2013
HARVARD
MEDICAL SCHOOL
Overview
• Clinical characteristics and
pathophysiology
• Differential diagnosis
• Exam and laboratory studies
• Treatment strategy
• Research opportunities
Overview
• Clinical characteristics and
pathophysiology
• Differential diagnosis
• Exam and laboratory studies
• Treatment strategy
• Research opportunities
Inflammed synovium
Normal
Synovium
Rheumatoid
Synovium
Sublining
The 1-2-3 of Rheumatoid Arthritis
Lee, Kiener and Brenner, Synoviocytes 2004
Understanding pathogenesis
Klareskog et al Lancet 2009
Clinical characteristics
•
•
•
•
Systemic chronic inflammatory disease
Mainly affects synovial joints
Variable expression
Extra-articular manifestations (e.g., nodules, ILD, ocular)
•
•
•
•
Prevalence ~1%
Worldwide distribution
Female: Male ratio 3:1
Peak age of onset 30 – 50 years (median in 40’s)
ACR Criteria for Diagnosis
• Four or more of the following criteria must be
present:
•
•
•
•
Morning stiffness >1 hour
Arthritis of >3 joint areas
Arthritis of hand joints (MCPs, PIPs, wrists)
Symmetric swelling (arthritis)
• Serum rheumatoid factor
• Rheumatoid nodules
• Radiographic changes
First four criteria must be
present for 6 weeks or
more
Overview
• Clinical characteristics and
pathophysiology
• Differential diagnosis
• Exam and laboratory studies
• Treatment strategy
• Research opportunities
Differential Diagnosis
• Rheumatoid Arthritis
• Psoriatic Arthritis
• Inflammatory bowel
disease
• Ankylosing spondylitis
• Crystal – Gout,
Pseudogout
• SLE, Vasculitis
• PMR-GCA
• Any “immune complex”
illness
• Paraneoplastic syndrome
• Viral – Parvovirus,
HepBSAg, HCV, Rubella
• Bacterial – Lyme, GC,
chlamydia
• Osteoarthritis, bursitis,
tendonitis
Conceptual organization
• Inflammatory vs. non-inflammatory
– synovitis vs structural
• Articular vs. non-articular
• Systemic vs. regional
• Polyarticular vs. monarticular
• Extra-articular manifestations
Note: Older patients
need more careful
history and physical
exam-labs often
confusing
Pertinent historical features
• Duration
– acute vs chronic
– gradual vs abrupt onset
DIP
PIP
• Pattern
– symmetrical vs asymetrical MCP
– large vs small joints
– morning stiffness
– effect of activity
• Joint distribution
– DIP vs PIP/MCP
Overview
• Clinical characteristics and
pathophysiology
• Differential diagnosis
• Exam and laboratory studies
• Treatment strategy
• Research opportunities
Physical exam of joint
•
Tenderness
• synovitis = tender joint
• mechanical or periarticular
lesions (bursitis and
tendonitis) = tenderness
often localized
•
Swelling
• bony vs. soft tissue swelling
•
Pattern
• proximal vs. distal
• asymetric vs. symmetric
• DIP and nail changes
Proximal InterPhalangeal joint
• Swelling is
confined to the
area of the joint
capsule
PIP
• Synovial
thickening feels
like a firm
sponge
MetaCarpal Phalangeal joint
MCP
Laboratory values based on
DiffDx
• Rheumatoid Arthritis
• Psoriatic Arthritis
• Inflammatory bowel
disease
• Ankylosing spondylitis
• Crystal – Gout,
Pseudogout
• SLE, Vasculitis
• PMR-GCA
• Any “immune complex”
illness
• Paraneoplastic syndrome
• Viral – Parvovirus,
HepBSAg, HCV, Rubella
• Bacterial – Lyme, GC,
chlamydia
• Osteoarthritis, bursitis,
tendonitis
Laboratory values based on
DiffDx
• Rheumatoid Arthritis
Markers of inflammation
ESR and CRP
• Psoriatic Arthritis
• Inflammatory bowel
disease
• Ankylosing spondylitis
• Crystal – Gout,
Pseudogout
• SLE, Vasculitis
• PMR-GCA
Auto-antibodies
RF and CCP
X-rays hands/feet
erosions
Laboratory values based on
DiffDx
• Rheumatoid Arthritis
• Psoriatic Arthritis
• Inflammatory bowel
disease
• Ankylosing spondylitis
• Crystal – Gout,
Pseudogout
joint aspiration
Presence of crystals
blood
Uric acid
X-rays
erosions
• SLE, Vasculitis
• PMR-GCA
Laboratory values based on
DiffDx
• Rheumatoid Arthritis
• Psoriatic Arthritis
• Inflammatory bowel
disease
• Ankylosing spondylitis
• Crystal – Gout,
Pseudogout
autoantibodies
ANA
ANCA
blood
CH50
urine
urinalysis
• SLE, Vasculitis
• PMR-GCA
X-rays
lack of erosions
Joint fluid analysis
• Cell count and differential
non-inflammatory <1500
mildly inflammatory 1500-3500
inflammatory
>3500
possible infection
>50,000
• Crystals
• Gram stain and culture
Clinical utility of x-rays
• X-rays show only bone, not cartilage or
synovium
• Lesions must correlate w/ clinical picture
• Erosive pattern (or lack) useful in diff. diagnosis
• Early inflammatory lesions often non-specific
• X-ray changes take months to occur
– avascular necrosis not visible for 6 wks
– spondylitis not evident for 2 – 10 yrs
• Valuable for plotting the clinical course in terms
of structural changes
Patterns of radiographic
changes
RA
gout
OA
Patterns of radiographic
changes
psoriasis
RA
OA
gout
CPPD
http://www.gentili.net/Hand/summary.htm
Progression of RA erosions
How fast is joint damage progressing?
A. Soft-tissue swelling,
osteopenia, no
erosions
A
B
C
B. Thinning of cortex
with minimal joint
space narrowing
C. Marginal erosion with
joint space narrowing
ACR Clinical Slide Collection, 1997.
Overview
• Clinical characteristics and
pathophysiology
• Differential diagnosis
• Exam and laboratory studies
• Treatment strategy
• Research opportunities
Typical Course
• Damage occurs early in most patients
•
•
2 yrs: 50% show joint space narrowing or
erosions
10 yrs: 50% of young working patients are
disabled
• Death comes early
•
•
Multiple causes (especially cardiovascular)
Women lose Pincus,
10 yrs,
men lose 4 yrs
et al. Rheum Dis Clin North Am. 1993;19:123–151.
Treatment principles
• Determine spectrum of disease
• Use the safest treatment plan that
matches the aggressiveness of the
disease
• Monitor treatment for adverse effects
• Monitor disease activity, revise Rx as
General strategy of treatment
escalation in RA patients
abatacept
(Orencia)
Overview
• Clinical characteristics and
pathophysiology
• Differential diagnosis
• Exam and laboratory studies
• Treatment strategy
• Research opportunities
Cost is increasing,
productivity is decreasing
We need new drugs to
treat RA and other
complex traits!
Scannell et al Nat Rev Drug Discovery (2012)
Major driver of cost is failure in
clinical trials…
…and most drugs
fail due to lack of
efficacy or toxicity
in humans
target
Medicinal chemistry
trials
“Target validation” is key to avoid
failure from efficacy/safety
Current models are
ineffective at
choosing targets
that are safe and
effective in humans
target
Medicinal chemistry
trials
target
Medicinal chemistry
trials
We determine dose-response
in clinical trials, after many
years and millions of dollars
target
Medicinal chemistry
We aspire to determine
dose-response at the time
of target validation
trials
Human genetics is a unique tool
for target validation
• Nature’s perturbation of many drug
targets in the human genome
• Links physiological state in humans (e.g.,
disease risk) to a target perturbation
• Indicates gain- or loss-of-function
• Provides allelic series for range of effect
on perturbing a potential drug target
Dose-response curves derived from
human genetics
The history and success of GWAS –
illuminating for common phenotypes
2007
Cumulative genomewide-significant SNPs
500
Somatic
Biomarkers
Pharmacogenetics
Physical/other
Psychiatric
400
2007
300
200
100
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
Chromosome
Psychiatric
Autoimmune
Cancer
Cardio/cerebrovascular
Infectious
Neurological
Other somatic
Cell levels
Lipid levels
Protein levels
Vit/min levels
Other biomarkers
Drug response
Physical/other
44
Data: www.genome.gov/GWAStudies - slide from Sara Pulit and Paul de Bakker
The history and success of GWAS –
illuminating for common phenotypes
2008
Cumulative genomewide-significant SNPs
500
Somatic
Biomarkers
Pharmacogenetics
Physical/other
Psychiatric
400
2008
300
200
100
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
Chromosome
Psychiatric
Autoimmune
Cancer
Cardio/cerebrovascular
Infectious
Neurological
Other somatic
Cell levels
Lipid levels
Protein levels
Vit/min levels
Other biomarkers
Drug response
Physical/other
Data: www.genome.gov/GWAStudies - slide from Sara Pulit and Paul de Bakker
The history and success of GWAS –
illuminating for common phenotypes
2009
Cumulative genomewide-significant SNPs
500
Somatic
Biomarkers
Pharmacogenetics
Physical/other
Psychiatric
400
2009
300
200
100
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
Chromosome
Psychiatric
Autoimmune
Cancer
Cardio/cerebrovascular
Infectious
Neurological
Other somatic
Cell levels
Lipid levels
Protein levels
Vit/min levels
Other biomarkers
Drug response
Physical/other
Data: www.genome.gov/GWAStudies - slide from Sara Pulit and Paul de Bakker
The history and success of GWAS –
illuminating for common phenotypes
2010
Cumulative genomewide-significant SNPs
500
Somatic
Biomarkers
Pharmacogenetics
Physical/other
Psychiatric
400
2010
300
200
100
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
Chromosome
Psychiatric
Autoimmune
Cancer
Cardio/cerebrovascular
Infectious
Neurological
Other somatic
Cell levels
Lipid levels
Protein levels
Vit/min levels
Other biomarkers
Drug response
Physical/other
Data: www.genome.gov/GWAStudies - slide from Sara Pulit and Paul de Bakker
The history and success of GWAS –
illuminating for common phenotypes
2011
Cumulative genomewide-significant SNPs
500
Somatic
Biomarkers
Pharmacogenetics
Physical/other
Psychiatric
400
2011
300
200
100
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
Chromosome
Psychiatric
Autoimmune
Cancer
Cardio/cerebrovascular
Infectious
Neurological
Other somatic
Cell levels
Lipid levels
Protein levels
Vit/min levels
Other biomarkers
Drug response
Physical/other
Data: www.genome.gov/GWAStudies - slide from Sara Pulit and Paul de Bakker
The history and success of GWAS –
illuminating for common phenotypes
2012
Cumulative genomewide-significant SNPs
500
Somatic
Biomarkers
Pharmacogenetics
Physical/other
Psychiatric
400
2012
300
200
100
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
Chromosome
Psychiatric
Autoimmune
Cancer
Cardio/cerebrovascular
Infectious
Neurological
Other somatic
Cell levels
Lipid levels
Protein levels
Vit/min levels
Other biomarkers
Drug response
Physical/other
Data: www.genome.gov/GWAStudies - slide from Sara Pulit and Paul de Bakker
Similarly, great success in
unraveling genetics of RA
15
GWAS 1,522 RA cases, 1,850 controls
No. GWAS hits = 3
Total No. risk loci = 5*
(* includes replication beyond GWAS)
10
5
0
Chromosomal position
Plenge et al NEJM 2007
Similarly, great success in
unraveling genetics of RA
15
GWAS 3,393 RA cases, 12,462 controls
No. GWAS hits = 4
Total No. risk loci = 6
10
5
0
Chromosomal position
Raychaudhuri et al Nat Gen 2008
Similarly, great success in
unraveling genetics of RA
15
GWAS 5,539 RA cases, 20,169 controls
No. GWAS hits = 9
Total No. risk loci = 25
10
5
0
Chromosomal position
Stahl et al Nat Gen 2010
From 1 to 100
15
GWAS 19,234 RA cases, 61,565 controls
No. GWAS hits = 56
Total No. risk loci = ~100
10
5
0
Chromosomal position
Yukinori Okada et al unpublished
Given the wealth of GWAS and
other genetic data…how should it
be used for drug discovery?
Three potential solutions
(1) “look-up” method – simple and
suggestive but undisciplined
(2) “Allelic series” method – powerful but
likely infrequent
(3) “pathway” method – powerful and
comprehensive but target ID difficult
Three potential solutions
(1) “look-up” method – simple and
suggestive but undisciplined
(2) “Allelic series” method – powerful but
likely infrequent
(3) “pathway” method – powerful and
comprehensive but target ID difficult
Three potential solutions
(1) “look-up” method – simple and
suggestive but undisciplined
(2) “Allelic series” method – powerful but
likely infrequent
(3) “pathway” method – powerful and
comprehensive but target ID difficult
Allelic series in PCSK9:
loss-of-fxn, protective for CAD
1
3
2
1. Allelic series of LOF
mutations alter PCSK9
2. Lowers LDL cholesterol
3. Protects against CAD
4. No obvious “ADE”
phenotypes
Allelic series in PCSK9:
no obvious “adverse events”
4
3
2
1. Allelic series of LOF
mutations alter PCSK9
2. Lowers LDL cholesterol
3. Protects against CAD
4. No obvious “ADE”
phenotypes
Monoclonal antibodies to PCSK9:
dramatically lower LDL levels
Three potential solutions
(1) “look-up” method – simple and
suggestive but undisciplined
(2) “Allelic series” method – powerful but
likely infrequent
(3) “pathway” method – powerful and
comprehensive but target ID difficult
Polygenic architecture but discrete
biological pathways
CD40-CD40L pathway
1. CD40 is expressed on
surface of B lymphocytes
1. Pathway is upregulated in
inflammed synovial tissue
of RA patients
1. CD40 mutations lead to
human immunodeficiency
Rossin et al (2011) PLoS Genetics
Cell-based phenotype screens to
find inhibitors of CD40 signaling
“target” is a
pathway, rather
than a specific
molecule
Gang Li et al in press PLoS Genetics
Using this HTS assay, test >2000
chemical compounds
FDAapproved
drugs, other
luciferase
Identified two “known” and two
“novel” compounds
luciferase
Case #1
•
•
•
•
34-year-old woman
5-year history of RA
Morning stiffness = 30 minutes
Exam
– Synovitis: 1+ swelling of MCP, PIP, wrist, and MTP
joints
– Normal joint alignment
• Labs
– ESR and CRP normal
– RF positive (CCP negative)
• No erosions seen on x-rays
Case #1 (continued)
• Assessment
•
•
•
4
Type 1
Type 2
Type 3
3
2
current activity: mild
1
no sign of damage after 5 years 00 0.5 1
anticipate minimally progressive course
2
3
4
*
6
• Treatment
•
•
•
•
NSAIDs prn
safer, less potent drugs (SSZ or HCQ) daily
education
ROM, conditioning, and strengthening exercises
8 16
Case #2
•
•
•
•
34-year-old woman
1-year history of RA
Morning stiffness = 90 minutes
Exam
– Synovitis: 2+ of MCP, PIP, wrist, knee, and MTP
joints
– Normal joint alignment
• Labs
– ESR and CRP elevated
– RF positive and CCP positive
• Small erosions seen on x-rays
Case #2 (continued)
Early erosion at the tip of the ulnar styloid
Case #2 (continued)
• Assessment
•
•
•
current activity: moderate with more joint involvement
early radiographic damage with CCP+
4
3
anticipate progressive course
*
2
1
• Treatment
0
0 0.5 1
2
3
4
•
Initial treatment with prednisone, NSAIDs
Start MTX weekly
Education on pregnancy, alcohol, risks, benefits
•
ROM, conditioning, and strengthening exercises
•
•
6
8 16
~1/3 of patients will
respond adequately
Typ
Typ
Typ
Case #3
•
•
•
•
34-year-old woman
2-year history of RA
Morning stiffness = 3 hours
Exam
– Synovitis: 3+ swelling of MCP, PIP, wrist, and MTP
joints
– Ulnar deviation, decreased ROM wrists
– nodules on elbows
• Labs
– ESR and CRP elevated
– RF positive and CCP positive
• prednisone (10 mg QD) + MTX (25 mg Qweek)
Case #3 (continued)
• Assessment
•
•
•
current activity: severe, poorly controlled on MTX
Clear destruction with CCP+
4
3
progressive course
2
1
0
• Treatment
0 0.5 1
2
3
4
•
continue prednisone, NSAIDs, MTX
Add anti-TNF therapy
Education on risks of infection
•
ROM, conditioning, and strengthening exercises
•
•
*
6
8 16
~1/3 of patients will
respond adequately
Typ
Typ
Typ