Rheumatoid Arthritis * * * * 7 * * * * * * * * * * * * * *

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Rheumatoid Arthritis
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Acknowledgements

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

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Objectives

• Gain a basic understanding of Rheumatoid
  Arthritis
• Understand the presentation of Rheumatoid
  Arthritis (Inflammatory Arthritis)
• Understand the current treatment paradigm and
  medications used

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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)

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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.

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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 couldnt get her rings on.

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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 isnt running because it hurts too much

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Differential Diagnosis

• INFLAMMATORY POLYARTHRITIS
• Infection
• Rheumatoid Arthritis
• Seronegative Arthritis (Psoriatic)
• Connective Tissue Disease (SLE etc)
• Associated with another Systemic Disease

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Who gets RA?

• ANYONE CAN GET RA
• From babies to the very old
• Common Age to Start 20s to 50s
• Sex Females more common than males 31

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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

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How does RA start?

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

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What Joints are affected?

• RA usually begins as an oligoarticular process
  (lt5 joints) and progresses to polyarticular
  involvmement
• Has a predilection for the small joints of the
  hands and feet!

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Small Joints of the Hand
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What Joints are affected?
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How are the Joints Affected

• Joints are usually
• Swollen
• Warm
• NOT RED (might be a bit purple)

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NO REDNESS!
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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?

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Morning Stiffness

• Inflammatory fluid increases in and around the
  joint
• As patients get moving the fluid gets resorbed
• Stiffness can occur after rest gelling

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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.

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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

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Rheumatoid Arthritis is

• Usually insidious in onset
• Adds joints over time
• Has a predilection for the small joints of the
  hands and feet
• Joints become warm and swollen but not red
• Morning stiffness is greater than 1 hour
• Patients are often tired and dont sleep properly
• Can result in significant disability very quickly

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Doesnt just affect the joints

• EXTRA-ARTICULAR
• MANIFESTATIONS

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Xerophthalmia (Dry Eyes)
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Xerostomia (Dry Mouth)
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Raynauds Phenomenon
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Carpal Tunnel Syndrome
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Pleural Effusion
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Rheumatoid Nodules
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Rheumatoid Nodules
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Rheumatoid Vasculitis
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Extra-Articular Manifestations

• Sicca Features Xerostomia Xerophthalmia
• Raynauds Phenomenon
• Neuropathy Carpal Tunnel Syndrome
• Rheumatoid Nodules
• Pleural Effusions
• Rheumatoid Vasculitis

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Tests, Tests, Tests

• INVESTIGATING A PATIENT WITH SUSPECTED RA

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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.

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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)

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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

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ANTIBODIES

• Rheumatoid Factor
• Anti-Nuclear Antibody

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Rheumatoid Factor
IgG Molecule Fc Portion
Autoantibodies (IgM) directed against the Fc
Fragment of IgG An Antibody to an Antibody Their
Role in RA is not understood
IgM Molecule
Antigen Binding Groove
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Rheumatoid Factor

• Non- Rheumatic Disease
• Normal Aging
• Infection
• Hepatitis B C
• SBE
• Tb
• HIV
• Sarcoidosis
• Idiopathic Pulmonary Fibrosis

• Rheumatic Disease
• Sjogrens syndrome
• Rheumatoid Arthritis
• SLE
• MCTD
• Myositis
• Cryoglobulinemia

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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

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Pearls about RF in RA

• Asymptomatic people with a positive RF are
  unlikely to go on to develop RA
• The higher the value the greater the likelihood
  of rheumatic disease
• USEFUL for PROGNOSIS
• Patients who are RF ve are more likely to have
  aggressive disesase
• NOT USEFUL to FOLLOW TITRES
• Not predictive of flare
• Not predictive of improvement

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• RADIOGRAPHIC
• FINDINGS IN RA

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Periarticular OsteopeniaJoint Space
NarrowingErosionsMal-Alignment
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• SYNOVIAL
• FINDINGS IN RA

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Rheumatoid Synovium

• A non-suppurative (no pus) inflammatory
  infiltrate in the synovium
• Due to the aggregation of lymphocytes and plasma
  cells

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Rheumatoid Synovium
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PRINCIPLES OF TREATMENT
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The Big Bang
90 of the joints involved in RA are affected
within the first year SO TREAT IT EARLY
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Disability in Early RA

• Inflammation
• Swollen
• Stiff
• Sore
• Warm
• Fatigue
• Potentially Reversible

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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!

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A Fire in the Joints
If theres a fire in the kitchen do you wait
until it spreads to the living room or do you try
and put it out?
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Clinical Course of RA
Severity of Arthritis
Years
Type 1 Self-limited5 to 20 Type 2
Minimally progressive5 to 20Type 3
Progressive60 to 90
Pincus. Rheum Dis Clin North Am. 199521619.
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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

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Why is Early Treatment Important?

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

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Disability in Late RA (Too Late)

• Damage
• Bones
• Cartilage
• Ligaments and other structures
• Fatigue
• Not Reversible

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Induce Remission
Maintain Remission
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DMARDs

• Disease Modifying Anti-Rheumatic Drugs
• Reduce swelling inflammation
• Improve pain
• Improve function
• Have been shown to reduce radiographic
  progression (erosions)

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DMARDs

• Methotrexate
• Sulfasalazine
• Hydroxychloroquine (Plaquenil)
• Leflunomide (Arava)
• Gold
• Azathioprine (Imuran)

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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

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Combination therapy (using 2 to 3) DMARDs at a
time works better than using a single DMARD
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Common DMARD Combinations

• Triple Therapy
• Methotrexate, Sulfasalazine, Hydroxychloroquine
• Double Therapy
• Methotrexate Leflunomide
• Methotrexate Sulfasalazine
• Methotrexate Hydroxychloroquine
• Methotrexate Gold
• Sulfasalazine Plaquenil

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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

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Case Study

• Change DMARDs Add leflunomide
• Biologic Therapy

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BIOLOGIC THERAPY
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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)

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TNF Receptor
How Does TNF Exert Its Effect?
Any Cell
Trans-Membrane Bound TNF
Soluble TNF
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TNF Receptor
How Are the Effects of TNF Naturally Balanced?
Any Cell
Trans-Membrane Bound TNF
Soluble Receptor
Soluble TNF
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Strategies for Reducing Effects of TNF
Monoclonal Antibody (Infliximab Adalimumab)
Trans-Membrane Bound TNF
Macrophage
Soluble TNF
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Infliximab (Remicade) Adalimumab (Humira)

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

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Strategies for Reducing Effects of TNF
Soluble Receptor Decoy (Etanercept)
Trans-Membrane Bound TNF
Macrophage
Soluble TNF
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Etanercept (Enbrel)

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

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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)

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Side Effects

• Infection
• Common (Bacterial)
• Opportunistic (Tb, Histo)
• Demyelinating Disorders
• Malignancy
• Worsening CHF
• Blood Counts

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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

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SUMMARY

• Rheumatoid Arthritis is a chronic potentially
  debilitating illness
• Early treatment can have a PROFOUND effect on
  this disease
• Treatment is multidisciplinary