Rheumatoid Arthritis: Definition

Progressive, systemic, inflammatory disorder

Unknown etiology
Characterized by

Symmetric synovitis

Joint erosions
Multisystem extra-articular manifestations

Epidemiology of Rheumatoid Arthritis

Approximately 1% of the total adult population is affected by RA 40% to 60% with advanced (functional class IV) RA will:

Survive 5 years or less following diagnosis

Die 10-15 years earlier than expected

Costs of Rheumatoid Arthritis versus Coronary Artery Disease

Costs per patient RA Direct costs* $3790 CAD $7929

Indirect costs
Total costs

$2735
$6525

$1051
$8980

*Estimated in 1.74 million patients with RA in 1994 dollars and 616,900 patients with CAD in 1995 dollars Estimated in 1.05 million patients with RA, ages 18-64, in 1994 dollars and 616,900 patients with CAD in 1995 dollars

Pathogenesis of Rheumatoid Arthritis

T cell

antigen

HLA class II molecule

Antigen presenting cell

Used with permission from Breedveld FC. J Rheumatol. 1998;25:3-7.

Pathogenesis of Rheumatoid Arthritis: Alternative Theories

Humoral immunity

70% to 80% of patients are positive for rheumatoid factor

Genetics

30% to 50% concordance rate for monozygotic twins

The Synovial Membrane

Normal synovial membrane, photomicrograph

Used with permission from the American College of Rheumatology.

Pathophysiology of Rheumatoid Arthritis

Synovitis, villous, gross (left) and photomicrograph (right)

Used with permission from the American College of Rheumatology.

Pathophysiology of Rheumatoid Arthritis: Late Destruction

Finger joint, bony ankylosis, photomicrograph

Used with permission from the American College of Rheumatology.

The Importance of Early Diagnosis

RA is progressive, not benign

Structural damage/disability occurs within first 2 to 3 years of disease

Slower progression of disease linked to early treatment

Diagnosis of Rheumatoid Arthritis: Baseline Evaluation

Patients subjective evaluation

Degree of joint pain

Duration of morning stiffness Presence/absence of fatigue Functional limitation(s)

Diagnosis of Rheumatoid Arthritis: Baseline Evaluation (cont.)

Physical examination

Actively inflamed joints

Mechanical joint problems including:

Loss of motion Crepitus

Instability
Malalignment and/or deformity

Diagnosis of Rheumatoid Arthritis: Laboratory Evaluations

Parameter
Rheumatoid factor

Timing
Baseline to establish diagnosis
Repeat 6-12 months following disease onset if negative

Complete blood count (CBC) Serum chemistries Liver function tests Urinalysis

Baseline to assess organ dysfunction due to co-morbidities Baseline Baseline Baseline

Synovial fluid analysis

Baseline to rule out other diseases

During disease flares to rule out septic arthritis

Acute Phase Reactants

C-Reactive protein

Correlates with disease activity and radiologic progression

One of the most responsive acute phase reactants Can be elevated in many non-RA related diseases

Erythrocyte sedimentation rate

Influenced by non-acute phase response factors Can be elevated in many non-RA related diseases

Correlation of ESR and CRP to Disease Progression Measured by Radiography

Category
High CRP* High ESR** High CRP Low ESR Low CRP High ESR Low CRP Low ESR
*

% Patients
31
37

% With 4 new erosions

85
47

14
18

33
0

>4mg/dL

**

>30 mm/h

<30 mm/h

<4mg/dL

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

ACR Criteria for Assessing Functional Status in Rheumatoid Arthritis

Classification
Class I

Specifications
Complete ability to perform usual daily activities (eg, self-care, vocational/avocational)
Ability to perform usual self-care and vocational activities; limited avocational activities Ability to perform usual self-care activities; limited vocational/avocational activities Limited ability to perform usual self-care/ vocational/avocational activities

Class II

Class III

Class IV

Risk Factors for Increased Morbidity and Mortality in RA

Social factors

Low socioeconomic status

Lack of formal education Psychosocial stress Low HAQ scores

Physical factors

Extra-articular manifestations Elevated CRP and ESR High titers of RF Erosions on x-ray Duration of disease

Goals of Therapy

Control disease activity

Alleviate pain
Maintain function for essential daily activities Maximize quality of life

Slow progression/rate of joint damage

Non-Pharmacological Management of Rheumatoid Arthritis

Rest

Exercise

Flexibility/stretching Muscle conditioning Cardiovascular/aerobic

Diet/weight control Physical/occupational therapy

NSAIDs: Mechanism of Action

Cyclooxygenase inhibition

COX-1
Constituent pathway pathway

COX-2
Inducible

(renal/GI homeostasis)

(inflammation)

NSAIDs: COX-2 Inhibitors

Improved GI tolerability

Reduced effects on renal blood flow

No effect on platelet function

Pros and Cons of NSAID Therapy

Pros

Cons

Effective control of inflammation and pain Effective reduction in swelling Improves mobility, flexibility, range of motion Improve quality of life

Does not affect disease progression GI toxicity common Renal complications (eg, irreversible renal insufficiency, papillary necrosis) Hepatic dysfunction

Relatively low-cost

CNS toxicity

Pros and Cons of Corticosteroid Therapy

Pros

Cons

Anti-inflammatory and immunosuppressive effects Can be used to bridge gap between initiation of DMARD therapy and onset of action Intra-articluar injections can be used for individual joint flares

Does not conclusively affect disease progression Tapering and discontinuation of use often unsuccessful Low doses result in skin thinning, ecchymoses, and Cushingoid appearance Significant cause of steroid-induced osteopenia

The New Treatment Paradigm

Orthopedic surgery

Higher dose steroids for flares or extraarticular disease

Occupational therapy

Intraarticular steroids

Physical therapy

Patient education
Weaver AL, 1998.

Simple analgesic

Treatment of Rheumatoid Arthritis: DMARDs

Agent
Azathioprine Cyclosporin Gold, oral Gold, parenteral Hydroxychloroquine Leflunomide Methotrexate D-Penicillamine Sulfasalazine

Recommended Dose
1.0-2.5 mg/kg/d 2.5-4.0 mg/kg/d 6-9 mg/d

25-50 mg every 2-4 weeks following initial weekly titration doses 200-400 mg/d 100 mg x 3 days loading; 20 mg/q.d. 7.5-20 mg/wk 125-750 mg/d 0.5-3.0 g/d

*Physicians Desk Reference, 1998. Recommended doses are not necessarily those utilized in clinical practice.

Advantages of DMARDs

Slow disease progression

Improve functional disability

Decrease pain Interfere with inflammatory processes

Retard development of joint erosions

Selection of an Initial DMARD

Agent
Azathioprine

Time to benefit
2-3 months

Potential toxicity
Moderate

Toxicities to monitor
Myelosuppression, hepatotoxicity, lymphoproliferative Renal, hyperuricemia Myelosuppression, rash, proteinuria, gastrointestinal Myelosuppression, rash proteinuria Macular damage Hepatotoxicity, gastrointestinal Hepatotoxicity, pulmonary, myelosuppression Myelosuppression, proteinuria Myelosuppression, gastrointestinal

Cyclosporin Gold, oral

4-8 weeks 4-6 months

High Low Moderate Low Low Moderate High Low

Gold, parenteral
Hydroxychloroquine Leflunomide

3-6 months
2-4 months 4-8 weeks

Methotrexate
D-Penicillamine

1-3 months
3-6 months 1-3 months

Sulfasalazine

Selection of an Initial DMARD: Sulfasalazine

Pros

Cons

Clinical effectiveness demonstrated in short-term use Mild level of toxicity

Effective for mild-to-moderate RA Contraindicated in patients with sulfa intolerance or G6PD deficiency Toxicities: myelosuppression, gastrointestinal, CNS Rate of AEs dose-dependent

CBC every 2-4 weeks for 3 months, then every 12 weeks

Selection of an Initial DMARD: Azathioprine

Pros

Cons

Effective in refractory RA

High risk for severe leukopenia and/or thrombocytopenia Other toxicities: hepatotoxicity, may increase cancer risk, high risk for opportunistic infections, macrocytic anemia, severe bone marrow depression Requires monitoring every 1-2 weeks with dosage change, every 1-3 months thereafter

Selection of an Initial DMARD: Methotrexate

Pros

Cons

Long-term clinical experience

Favorable rate of continuation of therapy Proven efficacy in moderate to severe RA

Laboratory monitoring every 4-8 weeks

Toxicities: hepatotoxicity, myelosuppression, pulmonary

Combination DMARD Therapy

Combination DMARD regimen

Does not increase toxicity levels

Long-term outcome more favorable Superior efficacy to single-DMARD regimen

Possible combinations

Methotrexate/sulfasalazine/hydroxychloroquine Cyclosporine/methotrexate Leflunomide/methotrexate

Unmet Needs in RA Therapy

Existing agents are lacking in the following three areas:

Maintaining an acceptable safety profile Controlling disease activity in a large proportion of patients Limiting disease flares despite discontinuation

Leflunomide/A77 1726
O O NH C C C O N

NH C

F3C

H3C
Leflunomide

F3C

CH3
A77 1726 Active Metabolite

OH

Leflunomide/A77 1726 Primary Mechanism of Action

DHODH Dihydroorotate Orotate Salvage pathway

Leflunomide
Extracellular pyrimidines

Glutamine + HCO 3 + Aspartate

UMP

Pyrimidine nucleotides

DNA/RNA synthesis; glycosylation

Pharmacology of Leflunomide: Plasma Concentrations of A77 1726

0.30 2.0

Unbound concentration (g/ml)

0.25 0.20 0.15 0.10 0.5 0.05 0.00 0 10 20 30 40 50 Equilibrium concentration (g/ml) % Unbound 60 0.0 1.0

Unbound concentration

% Unbound

1.5

Selection of an Initial DMARD: Leflunomide

Pros

Cons

Early onset of action (~ 4 weeks)

Stabilized benefit for long-term use Selectively targets autoimmune lymphocytes to reduce untoward AEs

Lack of clinical experience

Toxicities: hepatotoxicity, gastrointestinal

Safety and Efficacy of Varying Doses of Leflunomide vs. Placebo

Six-month trial of 402 patients with active RA

Patients randomized to placebo, 5 mg, 10 mg, or 25 mg leflunomide

Eligibility based on ACR criteria, demonstrating at least 3 of the following:

8 tender joins 8 swollen joints Morning stiffness lasting 45 minutes or longer ESR 40 mm/hr

Safety and Efficacy of Varying Doses of Leflunomide vs. Placebo (cont.)

0 -5 -10 -15 Change from -20 baseline -25 -30 -35 -40
S wollen Tender S wollen Tender joint score joint s core joint count joint count Placebo (n= 102) 5 mg/day (n= 95) 10 mg/day (n= 100) 25 mg/day (n= 101)

Parameters

Safety of Leflunomide: Adverse Events

Placebo 5 mg (n=102) Leflunomide (n=95) Gastrointestinal* Rash/allergic reaction Reversible alopecia Weight loss 3 5 1 2 15 6 1 2

10 mg Leflunomide (n=101) 10 4 1 4

25 mg Leflunomide (n=104) 12 8 7 4

*Includes anorexia, abdominal pain, diarrhea, nausea w/wo vomiting, gastritis, gastroenteritis

Efficacy of Leflunomide Compared with Placebo and Methotrexate in Early and Late RA*
2 1 0 -1 -2 -3 -4 -5 -6 -7 -8 -9

Total joint count Swollen joint count

Physician assessment
Patient assessment *Early RA = 2 years; late RA= >2 years

Methotrexate Early RA (n=73)

Methotrexate Late RA (n=107)

Placebo Early RA (n=39)

Onset of Action and Duration of Response of Leflunomide vs. Methotrexate or Placebo

35 30 25 20 15 10 5 0 Mean AUC* * Time to initial response Time to sustained response Duration of sustained response Leflunomide Methotrexate Placebo * *

* P 0.0001 vs placebo.

* * AUC = area under the curve, weeks of ACR response; duration measured in weeks

Efficacy of Leflunomide, Placebo, and Methotrexate Based on ACR Responder Index

60 * 50 40 30 20 10 0 ACR success* * ACR responders * * Leflunomide Placebo Methotrexate *

*P 0.0001 vs placebo. **ACR success is defined as a patient who completed 12 months treatment and is classified as an ACR responder at endpoint; ACR responder is defined as a patient who shows 20% improvement in disease progression.

X-ray Analysis of Active RA Treated with Leflunomide, Placebo, or Methotrexate

Leflunomide Placebo Methotrexate (n=131) (n=83) (n=138) Baseline total score Estimated yearly progression Change at endpoint Change in JSN subscore Change in erosion subscore 23.1 3.3 0.5* 0.3 0.2 25.4 3.7 2.2 1.3 0.9 22.8 3.5 0.9** 0.4*** 0.5

*P 0.0007 leflunomide vs placebo; **P 0.0187 methotrexate vs placebo; P 0.0323 leflunomide vs placebo; P 0.0002 leflunomide vs placebo; ***P 0.0031 methotrexate vs placebo. JSN = joint space narrowing

Functional Activities and Health Related Quality of Life Parameters in Active RA

0.1 0 -0.1 -0.2 -0.3 -0.4 -0.5 MHAQ HAQ-DI Leflunomide Placebo Methotrexate
* * * *

* P 0.0001 vs placebo; P 0.01 leflunomide vs methotrexate. Negative values indicate improvement. MHAQ= Modified Health Assessment Questionnaire; HAQ-DI= Health Assessment Questionnaire (disability index).

Functional Activities and Health Related Quality of Life Parameters in Active RA (cont.)
10 8 6 4 2 0 -2 -4 -6 -8

Leflunomide (n= 166)

* * **

Placebo (n= 101) Methotrexate (n= 169)

PET

SF-36

Work productivity

*P 0.0001 leflunomide vs placebo; P 0.01 leflunomide vs methotrexate; P 0.001 leflunomide vs methotrexate; **P 0.01 leflunomide vs placebo. Negative values for PET indicate improvement; positive values for SF-36 and work productivity indicate improvement. PET=Problem Elicitation Technique (weighted top 5 scores); SF-36=Medical Outcomes Survey Short Form 36 (physical component).

Therapies in Development: TNF Inhibitors

Agent
TNF- p75 soluble receptor TNF- monoclonal antibody

Comment
75% improvement in ACR-20 criteria Over 60% improvement in swollen joint counts and CRP levels

Therapies in Development: Interleukins

Agent
IL-1ra

Comment
Improvement noted when higher doses are added to daily initiation therapy Anti-inflammatory cytokines

IL-10 and IL-11

Conclusions

DMARDs should be initiated early in active RA

DMARDs may be limited by their toxicity profiles

Leflunomide as a DMARD:

Effect on primary and secondary outcome measures is superior to placebo Efficacy and tolerability is comparable or superior to other DMARDs