Clinical features and research opportunities in rheumatoid arthritis
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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.

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Clinical features and research opportunities in rheumatoid arthritis

Clinical features and research opportunities in rheumatoid arthritis

Clinical Immunology

March 26, 2013

HARVARD

MEDICAL SCHOOL


Overview

Overview

  • Clinical characteristics and pathophysiology

  • Differential diagnosis

  • Exam and laboratory studies

  • Treatment strategy

  • Research opportunities


Overview1

Overview

  • Clinical characteristics and pathophysiology

  • Differential diagnosis

  • Exam and laboratory studies

  • Treatment strategy

  • Research opportunities


Inflammed synovium

Inflammed synovium


Rheumatoid synovium

Rheumatoid Synovium

Normal Synovium

Lining

Sublining


The 1 2 3 of rheumatoid arthritis

The 1-2-3 of Rheumatoid Arthritis

Lee, Kiener and Brenner, Synoviocytes 2004


Understanding pathogenesis

Understanding pathogenesis

Klareskog et al Lancet 2009


Clinical characteristics

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

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


Overview2

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

Differential Diagnosis


Conceptual organization

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

Pertinent historical features

  • Duration

    • acute vs chronic

    • gradual vs abrupt onset

  • Pattern

    • symmetrical vs asymetrical

    • large vs small joints

    • morning stiffness

    • effect of activity

  • Joint distribution

    • DIP vs PIP/MCP

DIP

PIP

MCP


Overview3

Overview

  • Clinical characteristics and pathophysiology

  • Differential diagnosis

  • Exam and laboratory studies

  • Treatment strategy

  • Research opportunities


Physical exam of joint

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


P roximal i nter p halangeal joint

Proximal InterPhalangeal joint

  • Swelling is confined to the area of the joint capsule

  • Synovial thickening feels like a firm sponge

PIP


M eta c arpal p halangeal joint

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


Laboratory values based on diffdx1

Rheumatoid Arthritis

Psoriatic Arthritis

Inflammatory bowel disease

Ankylosing spondylitis

Crystal – Gout, Pseudogout

SLE, Vasculitis

PMR-GCA

Laboratory values based on DiffDx

  • Markers of inflammation

    • ESR and CRP

  • Auto-antibodies

    • RF and CCP

  • X-rays hands/feet

    • erosions


Laboratory values based on diffdx2

Rheumatoid Arthritis

Psoriatic Arthritis

Inflammatory bowel disease

Ankylosing spondylitis

Crystal – Gout, Pseudogout

SLE, Vasculitis

PMR-GCA

Laboratory values based on DiffDx

  • joint aspiration

    • Presence of crystals

  • blood

    • Uric acid

  • X-rays

    • erosions


Laboratory values based on diffdx3

Rheumatoid Arthritis

Psoriatic Arthritis

Inflammatory bowel disease

Ankylosing spondylitis

Crystal – Gout, Pseudogout

SLE, Vasculitis

PMR-GCA

Laboratory values based on DiffDx

  • autoantibodies

    • ANA

    • ANCA

  • blood

    • CH50

  • urine

    • urinalysis

  • X-rays

    • lack of erosions


Clinical features and research opportunities in rheumatoid arthritis

Joint fluid analysis

  • Cell count and differential

  • Crystals

  • Gram stain and culture

non-inflammatory <1500

mildly inflammatory 1500-3500

inflammatory >3500

possible infection >50,000


Clinical features and research opportunities in rheumatoid arthritis

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


Clinical features and research opportunities in rheumatoid arthritis

Patterns of radiographic changes

RA

OA

gout


Clinical features and research opportunities in rheumatoid arthritis

Patterns of radiographic changes

psoriasis

RA

OA

gout

CPPD

http://www.gentili.net/Hand/summary.htm


Clinical features and research opportunities in rheumatoid arthritis

Progression of RA erosions

How fast is joint damage progressing?

  • Soft-tissue swelling, osteopenia, no erosions

  • Thinning of cortex with minimal joint space narrowing

    C.Marginal erosion with joint space narrowing

A

B

C

ACR Clinical Slide Collection, 1997.


Overview4

Overview

  • Clinical characteristics and pathophysiology

  • Differential diagnosis

  • Exam and laboratory studies

  • Treatment strategy

  • Research opportunities


Typical course

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 10 yrs, men lose 4 yrs

Pincus, et al. Rheum Dis Clin North Am. 1993;19:123–151.


Treatment principles

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 needed


General strategy of treatment escalation in ra patients

General strategy of treatment escalation in RA patients


Clinical features and research opportunities in rheumatoid arthritis

abatacept

(Orencia)


Overview5

Overview

  • Clinical characteristics and pathophysiology

  • Differential diagnosis

  • Exam and laboratory studies

  • Treatment strategy

  • Research opportunities


Clinical features and research opportunities in rheumatoid arthritis

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)


And most drugs fail due to lack of efficacy or toxicity in humans

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


Current models are ineffective at choosing targets that are safe and effective in humans

“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


Clinical features and research opportunities in rheumatoid arthritis

target

Medicinal chemistry

trials

We determine dose-response in clinical trials, after many years and millions of dollars


Clinical features and research opportunities in rheumatoid arthritis

target

Medicinal chemistry

trials

We aspire to determine dose-response at the time of target validation


Human genetics is a unique tool for target validation

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

The history and success of GWAS – illuminating for common phenotypes

2007

Data: www.genome.gov/GWAStudies - slide from Sara Pulit and Paul de Bakker


The history and success of gwas illuminating for common phenotypes1

The history and success of GWAS – illuminating for common phenotypes

2008

Data: www.genome.gov/GWAStudies - slide from Sara Pulit and Paul de Bakker


The history and success of gwas illuminating for common phenotypes2

The history and success of GWAS – illuminating for common phenotypes

2009

Data: www.genome.gov/GWAStudies - slide from Sara Pulit and Paul de Bakker


The history and success of gwas illuminating for common phenotypes3

The history and success of GWAS – illuminating for common phenotypes

2010

Data: www.genome.gov/GWAStudies - slide from Sara Pulit and Paul de Bakker


The history and success of gwas illuminating for common phenotypes4

The history and success of GWAS – illuminating for common phenotypes

2011

Data: www.genome.gov/GWAStudies - slide from Sara Pulit and Paul de Bakker


The history and success of gwas illuminating for common phenotypes5

The history and success of GWAS – illuminating for common phenotypes

2012

Data: www.genome.gov/GWAStudies - slide from Sara Pulit and Paul de Bakker


Similarly great success in unraveling genetics of ra

Similarly, great success in unraveling genetics of RA

GWAS 1,522 RA cases, 1,850 controls

No. GWAS hits = 3

Total No. risk loci = 5*

(* includes replication beyond GWAS)

15

10

5

0

Chromosomal position

Plenge et al NEJM 2007


Similarly great success in unraveling genetics of ra1

Similarly, great success in unraveling genetics of RA

GWAS 3,393 RA cases, 12,462 controls

No. GWAS hits = 4

Total No. risk loci = 6

15

10

5

0

Chromosomal position

Raychaudhuri et al Nat Gen 2008


Similarly great success in unraveling genetics of ra2

Similarly, great success in unraveling genetics of RA

GWAS 5,539 RA cases, 20,169 controls

No. GWAS hits = 9

Total No. risk loci = 25

15

10

5

0

Chromosomal position

Stahl et al Nat Gen 2010


F rom 1 to 100

From 1 to 100

GWAS 19,234 RA cases, 61,565 controls

No. GWAS hits = 56

Total No. risk loci = ~100

15

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

Given the wealth of GWAS and other genetic data…how should it be used for drug discovery?


Three potential solutions

Three potential solutions

(1) “look-up” method – simpleand suggestive but undisciplined

(2) “Allelic series” method – powerful but likely infrequent

(3) “pathway” method – powerful and comprehensive but target ID difficult


Three potential solutions1

Three potential solutions

(1) “look-up” method – simpleand suggestive but undisciplined

(2) “Allelic series” method – powerful but likely infrequent

(3) “pathway” method – powerful and comprehensive but target ID difficult


Three potential solutions2

Three potential solutions

(1) “look-up” method – simpleand 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

Allelic series in PCSK9: loss-of-fxn, protective for CAD

1

3

Allelic series of LOF mutations alter PCSK9

Lowers LDL cholesterol

Protects against CAD

No obvious “ADE” phenotypes

2


Allelic series in pcsk9 no obvious adverse events

Allelic series in PCSK9: no obvious “adverse events”

4

3

Allelic series of LOF mutations alter PCSK9

Lowers LDL cholesterol

Protects against CAD

No obvious “ADE” phenotypes

2


Monoclonal antibodies to pcsk9 dramatically lower ldl levels

Monoclonal antibodies to PCSK9: dramatically lower LDL levels


Three potential solutions3

Three potential solutions

(1) “look-up” method – simpleand 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

Polygenic architecture but discrete biological pathways

CD40-CD40L pathway

CD40 is expressed on surface of B lymphocytes

Pathway is upregulated in inflammed synovial tissue of RA patients

CD40 mutations lead to human immunodeficiency

Rossin et al (2011) PLoS Genetics


Clinical features and research opportunities in rheumatoid arthritis

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


Clinical features and research opportunities in rheumatoid arthritis

Using this HTS assay, test >2000 chemical compounds

FDA-approved drugs, other

luciferase


Clinical features and research opportunities in rheumatoid arthritis

Identified two “known” and two “novel” compounds

luciferase


Case 1

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

*

Case #1 (continued)

  • Assessment

    • current activity: mild

    • no sign of damage after 5 years

    • anticipate minimally progressive course

  • Treatment

    • NSAIDs prn

    • safer, less potent drugs (SSZ or HCQ) daily

    • education

    • ROM, conditioning, and strengthening exercises


Case 2

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

Case #2 (continued)

Early erosion at the tip of the ulnar styloid


Case 2 continued1

*

Case #2 (continued)

  • Assessment

    • current activity: moderate with more joint involvement

    • early radiographic damage with CCP+

    • anticipate progressive course

  • Treatment

    • Initial treatment with prednisone, NSAIDs

    • Start MTX weekly

    • Education on pregnancy, alcohol, risks, benefits

    • ROM, conditioning, and strengthening exercises

~1/3 of patients will respond adequately


Case 3

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

*

Case #3 (continued)

  • Assessment

    • current activity: severe, poorly controlled on MTX

    • Clear destruction with CCP+

    • progressive course

  • Treatment

    • continue prednisone, NSAIDs, MTX

    • Add anti-TNF therapy

    • Education on risks of infection

    • ROM, conditioning, and strengthening exercises

~1/3 of patients will respond adequately


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