1. Rheumatoid Arthritis

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

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

4. 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)

5. 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.

6. 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.

8. 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”

9. Differential Diagnosis
INFLAMMATORY POLYARTHRITIS
Infection
Rheumatoid Arthritis
Seronegative Arthritis (Psoriatic)
Connective Tissue Disease (SLE etc)
Associated with another Systemic Disease

10. Who gets RA? ANYONE CAN GET RA Common Age to Start: 20’s to 50’s
From babies to the very old
Common Age to Start: 20’s to 50’s
Sex: Females more common than males 3:1

11. 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

12. How does RA start?
Initially, most patients notice stiffness of the joints which seems more pronounced in the morning
Some fatigue
Some pain

13. 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!

14. Small Joints of the Hand

15. What Joints are affected?

16. How are the Joints Affected
Joints are usually
Swollen
Warm
NOT RED (might be a bit purple)

17. NO REDNESS!

18. 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?”

19. Morning Stiffness Inflammatory fluid increases in and around the joint
As patients get moving the fluid gets resorbed
Stiffness can occur after rest “gelling”

20. 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.

21. 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

22. Pleasure
Work
Cooking
Cleaning
Shopping
Dressing
Bathing
Grooming

23. 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 don’t sleep properly
Can result in significant disability very quickly

24. Doesn’t just affect the joints
EXTRA-ARTICULAR
MANIFESTATIONS

25. Xerophthalmia (Dry Eyes)

26. Xerostomia (Dry Mouth)

27. Raynaud’s Phenomenon

28. Carpal Tunnel Syndrome

29. Pleural Effusion

30. Rheumatoid Nodules

31. Rheumatoid Nodules

32. Rheumatoid Vasculitis

33. Extra-Articular Manifestations
Sicca Features: Xerostomia & Xerophthalmia
Raynaud’s Phenomenon
Neuropathy: Carpal Tunnel Syndrome
Rheumatoid Nodules
Pleural Effusions
Rheumatoid Vasculitis

34. INVESTIGATING A PATIENT WITH SUSPECTED RA
Tests, Tests, Tests
INVESTIGATING A PATIENT WITH SUSPECTED RA

35. 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.

36. 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)

37. TO MAKE SURE MEDS WILL BE SAFE
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

38. ANTIBODIES
Rheumatoid Factor
Anti-Nuclear Antibody

39. 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

40. Non- Rheumatic Disease
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

41. 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

42. 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

43. RADIOGRAPHIC
FINDINGS IN RA

44. Periarticular Osteopenia Joint Space Narrowing Erosions Mal-Alignment

46. SYNOVIAL
FINDINGS IN RA

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

48. Rheumatoid Synovium

49. PRINCIPLES OF TREATMENT

50. 90% of the joints involved in RA are affected within the first year
The Big Bang
90% of the joints involved in RA are affected within the first year
SO TREAT IT EARLY

51. Disability in Early RA Inflammation Fatigue Potentially Reversible
Swollen
Stiff
Sore
Warm
Fatigue
Potentially Reversible

52. 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!

53. 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?

54. Clinical Course of RA Type 1 = Self-limited—5% to 20%
Severity of Arthritis
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. 7

55. 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

56. Why is Early Treatment Important?
EARLY Treatment has Long-Term Beneficial Effects
WINDOW OF OPPORTUNITY
Delay of 4 months can have long-term effects

57. Disability in Late RA (Too Late)
Damage
Bones
Cartilage
Ligaments and other structures
Fatigue
Not Reversible

58. Induce Remission
Maintain Remission

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

60. DMARDs Methotrexate Sulfasalazine Hydroxychloroquine (Plaquenil)
Leflunomide (Arava)
Gold
Azathioprine (Imuran)

61. 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

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

63. Common DMARD Combinations
Triple Therapy
Methotrexate, Sulfasalazine, Hydroxychloroquine
Double Therapy
Methotrexate & Leflunomide
Methotrexate & Sulfasalazine
Methotrexate & Hydroxychloroquine
Methotrexate & Gold
Sulfasalazine & Plaquenil

64. 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

65. Case Study
Change DMARDs – Add leflunomide
Biologic Therapy

66. BIOLOGIC THERAPY

67. 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)

68. How Does TNF Exert Its Effect?
TNF Receptor
How Does TNF Exert Its Effect?
Any Cell
Trans-Membrane Bound TNF
Macrophage
Soluble TNF

69. Destructive effects of TNF
TNF triggers multiple destructive effects in RA. In part, it stimulates osteoclasts to resorb bone, ultimately resulting in bone erosions visible on x-ray.1 TNF also induces the proliferation of synoviocytes, which in turn produces inflammation due to the release of inflammatory mediators.2,3 As depicted here, inflammation not only causes pain and swelling but also has been shown to precede joint damage.2,4 Chondrocytes are a third target of TNF activation, producing collegenase that degrades cartilage and eventually causes joint space narrowing.1,5
In addition to these effects, TNF plays an early role in the inflammatory process by stimulating activation of T cells by foreign antigens.2,3 TNF also induces expression of adhesion molecules, thereby promoting the migration of macrophages and lymphocytes into the synovium.5
References: 1. Goronzy JJ, Weyand CM. Rheumatoid arthritis: epidemiology, pathology, and pathogenesis. In: Klippel JH, ed. Primer on the Rheumatic Diseases. 11th ed. Atlanta, Ga: Arthritis Foundation; 1997: Carpenter AB. Immunology and inflammation. In: Wegener ST, ed. Clinical Care in the Rheumatic Diseases. Atlanta, Ga: American College of Rheumatology; 1996: Albani S, Carson DA. Etiology and pathogenesis of rheumatoid arthritis. In: Koopman WJ, ed. Arthritis and Allied Conditions: A Textbook of Rheumatology. Vol 1. 13th ed. Baltimore, Md: Williams & Wilkins; 1997: McGonagle D, Conaghan PG, O'Connor P, et al. The relationship between synovitis and bone changes in early untreated rheumatoid arthritis: a controlled magnetic resonance imaging study. Arthritis Rheum. 1999;42: Rosenberg AE. Skeletal system and soft tissue tumors. In: Cotran RS, ed. Robbins Pathologic Basis of Disease. 5th ed. Philadelphia, Pa: W.B. Saunders Company; 1994:

70. How Are the Effects of TNF Naturally Balanced?
TNF Receptor
How Are the Effects of TNF Naturally Balanced?
Any Cell
Trans-Membrane Bound TNF
Macrophage
Soluble Receptor
Soluble TNF

71. Strategies for Reducing Effects of TNF
Monoclonal Antibody (Infliximab & Adalimumab)
Trans-Membrane Bound TNF
Macrophage
Soluble TNF

72. Infliximab (Remicade®) & Adalimumab (Humira®)
Chimeric (murine & human) monoclonal antibody directed against TNF-α

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

74. Etanercept (Enbrel®)
2 soluble p75receptors attached to the Fc portion of the IgG molecule

75. Biologics Monoclonal Antibodies to TNF Soluble Receptor Decoy for 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®)

76. Infection Common (Bacterial) Side Effects Opportunistic (Tb, Histo)
Demyelinating Disorders
Malignancy
Worsening CHF
Blood Counts

77. 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

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