Clinical features and research opportunities in rheumatoid arthritis Clinical Immunology March 26, 2013 HARVARD MEDICAL SCHOOL.

Clinical features and research opportunities in rheumatoid arthritis

Clinical Immunology

March 26, 2013

HARVARDMEDICAL SCHOOL

Overview

• Clinical characteristics and pathophysiology

• Differential diagnosis

• Exam and laboratory studies

• Treatment strategy

• Research opportunities

Overview






Inflammed synovium

Rheumatoid Synovium

Normal Synovium

Lining

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






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 manifestationsNote: Older patients need more careful history and physical exam-labs often confusing

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

Overview






• 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

Physical exam of joint

• Swelling is confined to the area of the joint capsule

• Synovial thickening feels like a firm sponge

Proximal InterPhalangeal joint

PIP

MetaCarpal Phalangeal joint

MCP

• Rheumatoid Arthritis



• 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





• SLE, Vasculitis

• PMR-GCA

Markers of inflammationESR and CRP

Auto-antibodiesRF and CCP

X-rays hands/feeterosions





• SLE, Vasculitis

• PMR-GCA

joint aspirationPresence of crystals

bloodUric acid

X-rayserosions





• SLE, Vasculitis

• PMR-GCA

autoantibodiesANAANCA

bloodCH50

urineurinalysis

X-rayslack of erosions

• Cell count and differential

• Crystals

• Gram stain and culture

non-inflammatory <1500mildly inflammatory 1500-3500inflammatory >3500possible infection >50,000

Joint fluid analysis

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 OAgout

Patterns of radiographic changes

RApsoriasis

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

OA gout CPPD

A. Soft-tissue swelling, osteopenia, no erosions

B. Thinning of cortex with minimal joint space narrowing

C. Marginal erosion with joint space narrowing

How fast is joint damage progressing?

ACR Clinical Slide Collection, 1997.

Progression of RA erosions

A B C

Overview






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

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

• 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

Treatment principles

General strategy of treatment escalation in RA patients

abatacept(Orencia)

Overview






Cost is increasing, productivity is decreasing

Scannell et al Nat Rev Drug Discovery (2012)

We need new drugs to treat RA and other

complex traits!

Major driver of cost is failure in clinical trials…

target Medicinal chemistry trials

…and most drugs fail due to lack of efficacy or toxicity

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



We determine dose-response in clinical trials, after many

years and millions of dollars


We aspire to determine dose-response at the time

of 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

Human genetics is a unique tool for target validation

Dose-response curves derived from human genetics

44

The history and success of GWAS – illuminating for common phenotypes

2007

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

http://www.genome.gov/GWAStudies


2008



2009




2010




2011




2012




Similarly, great success in unraveling genetics of RA

Plenge et al NEJM 2007

15

10

5

0

Chromosomal position

GWAS 1,522 RA cases, 1,850 controls

No. GWAS hits = 3

Total No. risk loci = 5*

(* includes replication beyond GWAS)


Raychaudhuri et al Nat Gen 2008

15

10

5

0



No. GWAS hits = 4

Total No. risk loci = 6


15

10

5

0


Stahl et al Nat Gen 2010


No. GWAS hits = 9

Total No. risk loci = 25

From 1 to 100

Yukinori Okada et al unpublished

15

10

5

0



No. GWAS hits = 56

Total No. risk loci = ~100

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

(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




likely infrequent







likely infrequent




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

2

3

1

1. Allelic series of LOF mutations alter PCSK9

2. Lowers LDL cholesterol3. Protects against CAD4. No obvious “ADE”

phenotypes

Allelic series in PCSK9: no obvious “adverse events”

2

3

4

1. Allelic series of LOF mutations alter PCSK9

2. Lowers LDL cholesterol3. Protects against CAD4. No obvious “ADE”

phenotypes

Monoclonal antibodies to PCSK9: dramatically lower LDL levels




likely infrequent




Polygenic architecture but discrete biological pathways

Rossin et al (2011) PLoS Genetics

CD40-CD40L pathway

1. CD40 is expressed on surface of B lymphocytes

2. Pathway is upregulated in inflammed synovial tissue of RA patients

3. CD40 mutations lead to human immunodeficiency

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

luciferase

FDA-approved drugs, other

Identified two “known” and two “novel” compounds

luciferase

• 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

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

• 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

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+• anticipate progressive course

• Treatment• Initial treatment with prednisone, NSAIDs• Start MTX weekly• Education on pregnancy, alcohol, risks,

benefits• ROM, conditioning, and strengthening

exercises

Case #2 (continued)

*

~1/3 of patients will respond adequately

• 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

• 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

Case #3 (continued)

*

~1/3 of patients will respond adequately

Clinical features and research opportunities in rheumatoid arthritis Clinical Immunology March 26, 2013 HARVARD MEDICAL SCHOOL.

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