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 • 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 g n ni Li 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, Hep. BSAg, 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 Inter. Phalangeal joint • Swelling is confined to the area of the joint capsule PIP • Synovial thickening feels like a firm sponge

Meta. Carpal Phalangeal joint MCP

Laboratory values based on Diff. Dx • Rheumatoid Arthritis • Psoriatic Arthritis • Inflammatory bowel disease • Ankylosing spondylitis • Crystal – Gout, Pseudogout • SLE, Vasculitis • PMR-GCA • Any “immune complex” illness • Paraneoplastic syndrome • Viral – Parvovirus, Hep. BSAg, HCV, Rubella • Bacterial – Lyme, GC, chlamydia • Osteoarthritis, bursitis, tendonitis

Laboratory values based on Diff. Dx • 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 Diff. Dx • 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 Diff. Dx • Rheumatoid Arthritis • Psoriatic Arthritis • Inflammatory bowel disease • Ankylosing spondylitis • Crystal – Gout, Pseudogout autoantibodies ANA ANCA blood CH 50 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 10 yrs, men lose 4 yrs Pincus, 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 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 Data: www. genome. gov/GWAStudies - slide from Sara Pulit and Paul de Bakker

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 phenotypes 2010 Data: www. genome. gov/GWAStudies - slide from Sara Pulit and Paul de Bakker

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 phenotypes 2012 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 PCSK 9: loss-of-fxn, protective for CAD 1 3 2 1. Allelic series of LOF mutations alter PCSK 9 2. Lowers LDL cholesterol 3. Protects against CAD 4. No obvious “ADE” phenotypes

Allelic series in PCSK 9: no obvious “adverse events” 4 3 2 1. Allelic series of LOF mutations alter PCSK 9 2. Lowers LDL cholesterol 3. Protects against CAD 4. No obvious “ADE” phenotypes

Monoclonal antibodies to PCSK 9: 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 CD 40 -CD 40 L pathway 1. CD 40 is expressed on surface of B lymphocytes 1. Pathway is upregulated in inflammed synovial tissue of RA patients 1. CD 40 mutations lead to human immunodeficiency Rossin et al (2011) PLo. S Genetics

Cell-based phenotype screens to find inhibitors of CD 40 signaling “target” is a pathway, rather than a specific molecule Gang Li et al in press PLo. S 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 • • • 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 • • 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+ 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 • • 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+ 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