Therapeutic Revolution in Therapeutic Revolution in Rheumatoid ArthritisRheumatoid Arthritis

Brian J. Keroack, MD

Rheumatology Associates

Portland, Maine

Rheumatoid ArthritisRheumatoid Arthritis

Morning stiffness>1 hour

Usually symmetric Parameters of

systemic inflammation >6 weeks duration 70% +RF

Rheumatoid ArthritisRheumatoid Arthritis

Accepted Prevalence: 1-1.5% (classic seropositive)

200,000 new cases annually

19.9 billion/year spent on RA. 9.5 billion dollars/million patients. This exceeds cost/patient in diabetes and cardiovascular disease.

Rheumatoid Arthritis affects Survival:

Impact of RAImpact of RA

Premature mortality Increased morbidity Significant impact on quality of life

– Pain with associated functional disability– Fatigue

73% of patients 42% with severe fatigue

– Depression

Economic impact– Work dysfunction– Earnings loss of approximately 50%

Clinically Detectable Damage Occurs Early in RA

MRI-detectable erosions are present within 4 months of symptom onset1

Most patients (up to 93%) with RA of < 2 years’ duration show radiographic damage2

Disease progression is more rapid during the first year than during the second and third years3

Cartilage in RA: Target or Cartilage in RA: Target or Bystander? Bystander?

Early: – Cytokines (IL-1, TNF- ): Macrophages– Catabolic Effects on Chondrocytes – Proteoglycan Depletion– Weakens ability to rebound from a load

Next:– Induction of Metalloproteinases—Stromolysin,

Collagenase Last:

– Phagocytosis of Cartilage by Pannus

TNF- is a pivotal cytokinein the pathogenesis of RA

Mediates pathologic inflammation

Mediates joint destruction

Mediates systemic, extra-articular symptoms of inflammation

Regulates levels of adhesion molecules responsible for leukocyte migration

Parameters of Inflammation Parameters of Inflammation

Approach to the Treatment of Approach to the Treatment of RARA

Try to figure out ‘what type’ of Rheumatoid Arthritis the patient has

This is not a uniform disease– Young, Sero-positive patient vs. Older Sero-

negative patient.– Abrupt vs gradual onset– Response to 10-15 mg prednisone (‘Lourdes’

response)

Mild DMARDS vs Immunosuprssives

Approach to the Treatment of RA: Early Approach to the Treatment of RA: Early

ImmunosupressionImmunosupression Antiproliferative agents

– More aggressive doses of methotrexate– Leflunomide

Biologics– Infliximab/ Etanercept/Humira (TNF-)– Kineret (IL-1ra)– Orencia (abatacept)

Rituxan (B-cell depletion)– MRA (IL-6 receptor)– Small Modular Immunopharmaceutical (SIMP)

Combination therapy—sooner than ever before

Weinblatt StudyWeinblatt Study

MethotrexateMethotrexate Multiple Trials Support Use DMARD of Choice (but there are challengers) Long Term Efficacy/Compliance Radiographic Data Relatively Rapid Onset of Action (4-8 weeks) Dosage 7.5-25mg/week (above 20 mg inject) I still try Methotrexate in Most RA patients before

moving on to Newer DMARDS—but I move faster to Biologics in partial responders (2-3 months) —patience is NOT a virtue here.

I would never give you a drug worse than your disease

EtanerceptEtanerceptActivatedActivated

macrophagemacrophageTargetTarget

cellcell

SignalSignalsTNFR

sTNFR

TNFTNF

TNFRTNFR

EtanerceptEtanercept

TNF Inhibition: EtanerceptTNF Inhibition: EtanerceptTNF Inhibition: EtanerceptTNF Inhibition: Etanercept

MethotrexateMethotrexateEtanerceptEtanercept

25 mg25 mg

Patients with Patients with

baseline baseline erosionserosions

86%86%(25/29)(25/29)

96%96%(24/25)(24/25)

52%52%(98/188)(98/188)

72%72% (130/181)(130/181)

57%57%(123/217)(123/217)

75%75%(154/206)(154/206)

All All patientspatients

PP < 0.001 < 0.001

Patients With No New Erosions Patients With No New Erosions at 1 Yearat 1 Year

PP < 0.001 < 0.001

PP = 0.159 = 0.159Patients with Patients with no baseline no baseline erosionserosionsFinck B. Arthritis Rheum. 1999.

Antibody Neutralization of TNFAntibody Neutralization of TNF

Infliximab in Active RA Despite MTXInfliximab in Active RA Despite MTXATTRACTATTRACT

Improvement in Swollen JointsImprovement in Swollen Joints

MTX Control

3 mg/kg q 8 wks

10 mg/kg q 8 wks

MTX Control

3 mg/kg q 4 wks

10 mg/kg q 4 wks

Infliximab in Active RA Despite MTXInfliximab in Active RA Despite MTXATTRACTATTRACT

Improvement in Tender JointsImprovement in Tender Joints

MTX Control

3 mg/kg q 8 wks

10 mg/kg q 8 wks

MTX Control

3 mg/kg q 4 wks

10 mg/kg q 4 wks

Infliximab in Active RA Despite MTXInfliximab in Active RA Despite MTXATTRACTATTRACT

Median C-reactive Protein (mg/dL)Median C-reactive Protein (mg/dL)

3639

33

53 55

1519 19

3034

2119 19

30 29

0

10

20

30

40

50

60

70HUMIRA + MTX HUMIRA MTX

*P<0.05 for HUMIRA + MTX vs MTX alone and HUMIRA alone†Normal CRP was defined as ≤0.5 mg/dL

**

*

*

Pe

rce

nta

ge

of

Pa

tie

nts

*

TJC=0 SJC=0 HAQ=0 MorningStiffness=0

Normal CRP†

PREMIER 2-Year Results of Selected 2-Year Results of Selected

Clinical ResponsesClinical Responses

Emery P, et al. Presented at: EULAR; June 8-11, 2005; Vienna, Austria. Data on file, Abbott Laboratories.

(n=268) (n=257) (n=274)

So What is the Catch?So What is the Catch? Cost = $17,000-25,000/year Injections or infusions Profound immunosupression

– Careful who you put on the drug (Diabetes, COPD, Renal failure, etc)

– When patients present with infection, they have more subtle complaints—fewer ‘systemic’ symptoms occur

– Low threshold for antibiotics as most serious infections are ‘typical’

– Can you educate the patient?

The Other BiologicsThe Other Biologics

Orencia: Approved by FDA 2/2006—Role unclear—does work in TNF failures

Rituxan: 2 doses can produce a protracted period of remission in refractory RA—Infusion reactions (1-2%)

Orencia—CTLA4-IgOrencia—CTLA4-Ig

RituxanRituxan

Bridge to the 21Bridge to the 21st st CenturyCentury Early aggressive therapy especially in young seropositive

patients—DMARDS within 3 months of diagnosis. Best chance for remission

Methotrexate first—But in partial responders rapidly move to TNF- blockers. The data suggest the they should be ADDED to Methotrexate.

Biologics to induce early remissions for those with erosions at diagnosis.

Try more than one TNF- blocker (70% respond to a switch)

Orencia/Rituxan in TNF-Failures ?Low dose prednisone (5-10 mg) combined with

osteoporosis protection—Many need it for symptoms NSAIDS/COX-2 as bridge therapy in mild Rheumatoid

Arthritis (essentially worthless)

Future?Future?

MRA ?—IL-6 receptor antibody (+/- data to date and multiple problems—LFT’s, GI bleeding?) probably not a ‘player’

SIMP’s: these are single chain polypeptides with greater tissue penetration—high affinity --??greater efficacy

We are in the ‘infancy’ of immune ‘manipulation’