Rheumatoid Arthritis

Acknowledgements

• Dr. Andrew Thompson, rheumatologist at SJHC and developer of the UWO rheumatology medical school program

Objectives

• Gain a basic understanding of Rheumatoid Arthritis

• Understand the presentation of Rheumatoid Arthritis (Inflammatory Arthritis)

• Understand the current treatment paradigm and medications used

Case Presentation

• 43 yo woman, has been healthy apart from:– C-Section for– Mild depression

• Her current medications are– Sertraline 100 mg per day (depression)– Naproxen 500 mg twice a day (recent joint

pain)

Case Presentation

• 4 months ago developed pain in the left knee with some mild swelling. – The episode lasted a few days and then went

away.

Case Presentation

• About a week later the right knee began to swell and become sore

• Then both wrists began to swell and become sore. She also noticed some soreness in her feet.

• About two weeks later her hands started to stiffen up and she couldn’t get her rings on.

Case Presentation

• She feels stiff when she wakes up in the morning and this stiffness lasts for at least 3 hours

• She has no energy and has missed the last week of work

• Her sleep is difficult because she is uncomfortable

• She isn’t running because it “hurts too much”

Differential Diagnosis

INFLAMMATORY POLYARTHRITIS

1. Infection

2. Rheumatoid Arthritis

3. Seronegative Arthritis (Psoriatic)

4. Connective Tissue Disease (SLE etc)

5. Associated with another Systemic Disease

Who gets RA?

• ANYONE CAN GET RA– From babies to the very old

• Common Age to Start: 20’s to 50’s

• Sex: Females more common than males 3:1

How does RA start?

• RA usually starts off slowly (insidious) over weeks to months and progresses (70%)

• It can come on overnight (acute) but this is rare (10%)

• It can come on over a few weeks (subacute – 20%)

• Palindromic Presentation– RACECAR, RADAR, MOM, DAD

How does RA start?

• Initially, most patients notice stiffness of the joints which seems more pronounced in the morning

• Some fatigue

• Some pain

What Joints are affected?

• RA usually begins as an oligoarticular process (<5 joints) and progresses to polyarticular involvmement

• Has a predilection for the small joints of the hands and feet!

Small Joints of the Hand

What Joints are affected?

How are the Joints Affected

• Joints are usually– Swollen– Warm

–NOT RED (might be a bit purple)

NO REDNESS!

Morning Stiffness

• Prominent Feature

• Greater than 60 minutes of morning stiffness (Patients minimize)

• Some patients have difficulty answering the question because they are stiff all day

• “How long does it take until you are the best you are going to be?”

Morning Stiffness

• Inflammatory fluid increases in and around the joint

• As patients get moving the fluid gets resorbed

• Stiffness can occur after rest “gelling”

Constitutional Features

• Fever – Unusual• Weight Loss – Can be seen with severe

polyarticular disease (again not common)• Anorexia – Unusual• Fatigue – VERY COMMON• Sleep Disturbance – VERY COMMON

– Musculoskeletal Reasons– Neurologic Reasons – Carpal Tunnel– Psychological Reasons – Worry about illness,

finances, job, family etc.

Functional Status

• In the Rheumatology Clinic we use a Health Assessment Questionnaire (HAQ)– Dressing, Bathing, Grooming– Cooking, Cleaning, Shopping– Mobility – Walking and Standing– Working– Social Activities & Sports

• Rank the Functional Status (IMPORTANT)– Mild, Moderate, or Severe

Pleasure

Work

Cooking

Cleaning

Shopping

Dressing

Bathing

Grooming

Rheumatoid Arthritis is …

1. Usually insidious in onset

2. Adds joints over time

3. Has a predilection for the small joints of the hands and feet

4. Joints become warm and swollen but not red

5. Morning stiffness is greater than 1 hour

6. Patients are often tired and don’t sleep properly

7. Can result in significant disability very quickly

Doesn’t just affect the joints

EXTRA-ARTICULAR

MANIFESTATIONS

Xerophthalmia (Dry Eyes)

Xerostomia (Dry Mouth)

Raynaud’s Phenomenon

Carpal Tunnel Syndrome

Pleural Effusion

Rheumatoid Nodules

Rheumatoid Nodules

Rheumatoid Vasculitis

Extra-Articular Manifestations

• Sicca Features: Xerostomia & Xerophthalmia

• Raynaud’s Phenomenon

• Neuropathy: Carpal Tunnel Syndrome

• Rheumatoid Nodules

• Pleural Effusions

• Rheumatoid Vasculitis

Tests, Tests, Tests

INVESTIGATING A PATIENT WITH

SUSPECTED RA

CASE SUMMARY

• Has a 4 month history of an inflammatory polyarthritis

• Nothing else on history or physical examination to suggest an associated connective tissue disorder or seronegative spondyloarthropathy.

INFLAMMATION

• Complete Blood Count (CBC)– Hemoglobin: May be anemic (normocytic)– WBC: Should be normal– Platelets: May be normal to elevated

• Erythrocyte Sedimentation Rate (ESR)

• C-Reactive Protein (CRP)

ORGAN FUNCTION

TO MAKE SURE MEDS WILL BE SAFE

• Renal Function– Creatinine + Urinalysis

• Liver Enzymes– AST, ALT, ALP, ALB– Hepatitis B & C Testing

• Consider baseline Chest X-Ray

ANTIBODIES

• Rheumatoid Factor

• Anti-Nuclear Antibody

Rheumatoid Factor

IgG Molecule

Fc Portion

Antigen Binding Groove

IgM Molecule

Autoantibodies (IgM) directed against the Fc Fragment of IgG

An Antibody to an Antibody

Their Role in RA is not understood

Rheumatoid Factor

Rheumatic Disease• Sjogren’s syndrome• Rheumatoid Arthritis• SLE• MCTD• Myositis• Cryoglobulinemia

Non- Rheumatic Disease• Normal Aging• Infection

– Hepatitis B & C

– SBE

– Tb

– HIV

• Sarcoidosis• Idiopathic Pulmonary

Fibrosis

Rheumatoid Factor (RF)

• Question: What Percentage of New Onset RA will have a positive RF?

• Answer: 30-50%

• Question: What Percentage of Established RA will have a positive RF?

• Answer: 70-85%

NOT USEFUL FOR DIAGNOSIS OF RA

Pearls about RF in RA

1. Asymptomatic people with a positive RF are unlikely to go on to develop RA

2. The higher the value the greater the likelihood of rheumatic disease

3. USEFUL for PROGNOSIS1. Patients who are RF +ve are more likely to

have aggressive disesase

4. NOT USEFUL to FOLLOW TITRES 1. Not predictive of flare2. Not predictive of improvement

RADIOGRAPHIC

FINDINGS IN RA

Periarticular OsteopeniaJoint Space Narrowing

ErosionsMal-Alignment

SYNOVIAL

FINDINGS IN RA

Rheumatoid Synovium

• A non-suppurative (no pus) inflammatory infiltrate in the synovium

• Due to the aggregation of lymphocytes and plasma cells

Rheumatoid Synovium

PRINCIPLES OF TREATMENT

The Big Bang90% of the joints involved in RA are

affected within the first year

SO TREAT IT EARLY

Disability in Early RA

• Inflammation– Swollen– Stiff– Sore– Warm

• Fatigue

• Potentially Reversible

Disability in RA

• Most of the disability in RA is a result of the INITIAL burden of disease

• People get disabled because of:– Inadequate control– Lack of response– Compliance

• GOAL: control the disease early on!

A Fire in the Joints

If there’s a fire in the kitchen do you wait until it spreads to the living room or do you try and put it out?

Clinical Course of RA

Type 1 = Self-limited—5% to 20%Type 2 = Minimally progressive—5% to 20%Type 3 = Progressive—60% to 90%

0

1

2

3

4

0 0.5 1 2 3 4 6 8 16

Type 1Type 2Type 3

Years

Sev

erity

of

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hriti

s

Pincus. Rheum Dis Clin North Am. 1995;21:619.

Why is Early Treatment Important?

• Joint Damage Occurs EARLY– 93% of patients with less than 2 years of

disease have radiographic abnormalities– Rate of radiographic progression is higher in

the first 2 years of disease

• Disability Occurs EARLY– 50% out of work at 10 years

• Increased MORTALITY– With severe disease

Why is Early Treatment Important?

• EARLY Treatment has Long-Term Beneficial Effects– WINDOW OF OPPORTUNITY– Delay of 4 months can have long-term effects

Disability in Late RA (Too Late) • Damage

– Bones– Cartilage– Ligaments and

other structures

• Fatigue

• Not Reversible

Induce RemissionMaintain Remission

DMARDs

• Disease Modifying Anti-Rheumatic Drugs

• Reduce swelling & inflammation

• Improve pain

• Improve function

• Have been shown to reduce radiographic progression (erosions)

DMARDs

• Methotrexate

• Sulfasalazine

• Hydroxychloroquine (Plaquenil)

• Leflunomide (Arava)

• Gold

• Azathioprine (Imuran)

Combining DMARDs

• DMARDs all work slightly differently• Never truly know how a patient will respond to

an individual DMARD• Most clinicians now agree that combinations of

DMARDs are more effective than single agents• This is now supported by some research

Combination therapy (using 2 to 3) DMARDs at a time works better than

using a single DMARD

Common DMARD Combinations

• Triple Therapy– Methotrexate, Sulfasalazine, Hydroxychloroquine

• Double Therapy– Methotrexate & Leflunomide– Methotrexate & Sulfasalazine– Methotrexate & Hydroxychloroquine– Methotrexate & Gold– Sulfasalazine & Plaquenil

Case Study

• Began therapy with Methotrexate, Sulfasalazine, & Plaquenil

• Initially responded well and took them for 4 months

• On a friends “advice”, stopped all DMARDs in favour of “natural” therapy

• “Natural” therapy was a dismal failure• Triple therapy re-instituted – difficulty obtaining

adequate control

Case Study

• Change DMARDs – Add leflunomide

• Biologic Therapy

BIOLOGIC THERAPY

Tumour Necrosis Factor (TNF)

• TNF is a potent inflammatory cytokine• TNF is produced mainly by macrophages and

monocytes• TNF is a major contributor to the inflammatory

and destructive changes that occur in RA• Blockade of TNF results in a reduction in a

number of other pro-inflammatory cytokines (IL-1, IL-6, & IL-8)

Macrophage

Any Cell

Trans-Membrane Bound TNF

TNF Receptor

Soluble TNF

How Does TNF Exert Its Effect?

Any Cell

Trans-Membrane Bound TNF

TNF Receptor

Soluble TNF

How Are the Effects of TNF Naturally Balanced?

Soluble ReceptorMacrophage

Trans-Membrane Bound TNF

Soluble TNF

Strategies for Reducing Effects of TNF

Macrophage

Monoclonal Antibody (Infliximab & Adalimumab)

Infliximab (Remicade®) & Adalimumab (Humira®)

• Chimeric (murine & human) monoclonal antibody directed against TNF-α

Trans-Membrane Bound TNF

Soluble TNF

Strategies for Reducing Effects of TNF

Macrophage

Soluble Receptor Decoy (Etanercept)

Etanercept (Enbrel®)

• 2 soluble p75receptors attached to the Fc portion of the IgG molecule

Biologics

• Monoclonal Antibodies to TNF– Infliximab (Remicade®)– Adalimumab (Humira®)

• Soluble Receptor Decoy for TNF– Etanercept (Enbrel®)

• Receptor Antagonist to IL-1– Anakinra (Kineret®) (rarely used)

• Monoclonal Antibody to prevent T-Cell Signaling– Abatacept (Orencia®)

• Monoclonal Antibody to CD-20– Rituximab (Rituxan®)

Side Effects

• Infection–Common (Bacterial)–Opportunistic (Tb, Histo)

• Demyelinating Disorders• Malignancy• Worsening CHF• Blood Counts

Do they work?• Resounding YES!

• Outcome measured by ACR20– 20% reduction in swollen & tender joints– Plus 20% reduction in at least 3 of the

following:• Patient VAS pain• Physician global VAS• Patient global VAS• HAQ• ESR or CRP

SUMMARY

• Rheumatoid Arthritis is a chronic potentially debilitating illness

• Early treatment can have a PROFOUND effect on this disease

• Treatment is multidisciplinary