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
 Work

Cooking

Dressing
Cleaning Pleasure
Bathing
Grooming

Shopping
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
Autoantibodies
Fc Portion (IgM) directed
against the Fc
Fragment of IgG
An Antibody to an
IgM Molecule
Antibody
Antigen Binding Their Role in RA
Groove is not understood
Rheumatoid Factor
Rheumatic Disease Non- Rheumatic Disease
• Sjogren’s syndrome • Normal Aging
• Rheumatoid Arthritis • Infection
• SLE – Hepatitis B & C
• MCTD – SBE
– Tb
• Myositis
– HIV
• Cryoglobulinemia • 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 PROGNOSIS
1. Patients who are RF +ve are more likely to
have aggressive disesase
4. NOT USEFUL to FOLLOW TITRES
1. Not predictive of flare
2. Not predictive of improvement
RADIOGRAPHIC
FINDINGS IN RA
Periarticular Osteopenia
Joint Space Narrowing
Erosions
Mal-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 Bang
90% 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
Severity of Arthritis
4
Type 1
3
Type 2
2 Type 3
1
0
0 0.5 1 2 3 4 6 8 16
Years

Type 1 = Self-limited—5% to 20%

Type 2 = Minimally progressive—5% to 20%
Type 3 = Progressive—60% to 90%

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
 Maintain
Induce Remission
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)
 TNF Receptor
How Does
TNF Exert Its
Effect?
Any Cell

Trans-Membrane
Bound TNF

Macrophage

Soluble TNF
 TNF Receptor
How Are the Effects
of TNF Naturally
Balanced?
Any Cell

Trans-Membrane
Bound TNF

Macrophage Soluble Receptor

Soluble TNF
Strategies for Monoclonal Antibody (Infliximab & Adalimumab)
Reducing
Effects of TNF

Trans-Membrane
Bound TNF

Macrophage

Soluble TNF
Infliximab (Remicade®) &
Adalimumab (Humira®)
• Chimeric (murine & human) monoclonal
antibody directed against TNF-α
Strategies for Soluble Receptor Decoy (Etanercept)
Reducing
Effects of TNF

Trans-Membrane
Bound TNF

Macrophage

Soluble TNF
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