1. Rheumatology: Back to Basics: 2010
James Gillray
“The Gout”
1799

2. Immune Mechanisms of Disease
Type I: Anaphylactic IgE eg. asthma
Type II: Cytotoxic eg. AIHA
Type III: Immune Complex eg. SLE
Type IV: Cell-mediated/Delayed Hypersensitivity: T-cells
eg. Contact dermatitis

3. GENETICS
ENVIRONMENT
Infections...
AUTOIMMUNITY

4. HLA: Disease Associations
HLA B27 (MHC Class I)
- Ankylosing Spondylitis Reiter’s/reactive arthritis
- Psoriatic arthritis
- IBD arthropathy
HLA DR4, DR1 (MHC Class II) - RA
HLA DR3 (MHC Class II)
- SLE, Sjogren’s, Type I DM…

5. We love our antibodies...

6. Rheumatoid Factor Rheumatoid Arthritis: - sensitivity = 70%
Anti-antibodies (Fc domain of IgG)
Rheumatoid Arthritis:
- sensitivity = 70%
- poor prognosis
- extra-articular features
Non-specific:
- other rheumatic diseases eg. Sjogren’s
- chronic inflammatory diseases
- chronic infections – SBE, Hep C
% over age 65

7. Antinuclear Antibodies
Sensitivity for SLE 90%+
Specificity low
- other autoimmune diseases
- family members
- drugs
- ...

8. Shmerling R. N Engl J Med 2003;349:1499-1500
Antinuclear Antibody (ANA) Test Results in a Hypothetical Population. Although the ANA may be present before the development of SLE, current estimates of disease incidence and test sensitivity and specificity suggest that most positive results are of uncertain (or no) clinical significance.
Shmerling R. N Engl J Med 2003;349:

9. Anti-centromere Antibodies: Limited Systemic Sclerosis (CREST)

10. Other Autoantibodies Anti-DNA (native, double-stranded)
- SLE- sensitivity 60-70%
- specificity ~ 100%
- correlate with disease activity
Anti-SSA, SSB (Ro, La)
- Sjogren’s, SLE
- congenital complete heart block

11. Anti-DNA (double stranded)
Sensitivity for SLE: ~60%
Specificity: ~ 100%
Levels: may correlate with;
- disease activity
- hypocomplementemia
- renal disease

12. Antibodies to Ro/SSA 30-35% of patients with Lupus Associated with:
- Sjogren’s syndrome
- photosensitive rashes “subacute cutaneous lupus”
- Neonatal lupus
- transient rashes
- congenital complete heart block

13. Adult: Subacute Newborn: Cutaneous Lupus Neonatal Lupus
Antibodies to Ro/SSA
Adult: Subacute Newborn:
Cutaneous Lupus Neonatal Lupus

14. Antiphospholipid Antibodies
Anticardiolipin antibodies
Lupus anticoagulant
Associations:
- thrombosis
- recurrent pregnancy losses
SLE, other CTD’s, primary

15. Anti-Neutrophil Cytoplasmic Antibodies (ANCA)
Patients with suspected vasculitis:
- Wegener’s
- pulmonary/renal
- RPGN
Cytoplasmic
Perinuclear

16. Anti-Neutrophil Cytoplasmic Antibodies (ANCA)
Patients with suspected vasculitis
- pulmonary/renal syndromes
cANCA: Wegener’s Granulomatosus:
- 80% sensitive and specific
- specificity is for PR-3
pANCA: less specific

17. Wegener’s: cANCA (PR-3)
Medium + small vessels
Granulomatous
Upper +/- lower respiratory
Renal

18. Specific Diseases…

19. Osteoarthritis (OA) The most common type of arthritis
Disease of cartilage (cf. RA)
Characterized by:
- Cartilage degradation, loss
- hypertrophic bone formation
(osteophytes...

20. Primary (idiopathic) OA
Peripheral Joints:
- hands - DIP, PIP (cf. RA)
- 1st C-MC
- feet - 1st MTP
- large weight-bearing joints hips, knees
Spine - apophyseal joints
- intervertebral discs

21. OA: Heberden’s (DIP) Bouchard’s (PIP) Nodes

22. Osteoarthritis: X-ray 1st C-MC Joint
Joint space narrowing
Subchondral sclerosis
Osteophytes

23. Rheumatoid Arthritis Prevalence 1:100
small joint, symmetric polyarthritis
+ AM stiffness
chronic (>6weeks)
Path = synovial inflammation
Extra-articular features

24. DIPs 
(spared)
PIPs 
MCPs 

25. Rheumatoid Arthritis Deformities Nodules Periarticular osteopenia
Marginal erosions

26. RA: Extra-articular Features
Skin - sc nodules, vasculitis...
Eyes - sicca, scleritis, episcleritis
Lungs - pleurisy/effusion
- interstitial fibrosis
- nodules
Cardiac - pericarditis, nodules
Hematologic - anemia, Felty’s (neutropenia…)
Neurologic - peripheral neuropathy...

27. Scleritis

28. RA: Nodules

29. RA: Factors Associated with Poor Prognosis
Rheumatoid factor positivity
HLA-DR4 haplotype
Degree of disease activity at onset …
 Early aggressive therapy

30. RA: Treatment Symptomatic - rest, education - splints, orthotics
- ASA, NSAID’s, Coxibs
Disease Modifying Anti-Rheumatic Drugs (DMARDs)

31. RA: Common DMARD’s Methotrexate Hydroxychloroquine Sulfasalazine
New Biologics...

32. RA: New Therapies - Biologics
anti-TNF
soluble TNF receptor
Concerns: - cost
- parenteral
- risk of infections, TB

33. Systemic Lupus Erythematosus
Affects 1: individuals
African American blacks > Asian > Caucasian
Females : Males = 9:1
Any age - usually young females in their reproductive years

34. Lupus: Criteria Malar rash Hematology: Photosensitivity anti-WBC
Discoid rash
Mucosal ulcers
Arthritis
Serositis “Pleurisy”
Renal
CNS
Hematology:
anti-WBC
anti-platelet
anti-rbc
Immunologic:
anti-DNA
anti-phospholipid
anti-Sm
Antinuclear antibodies

35. SLE: Organs Affected Joints: 80-90% Skin: 70%, often photosensitive
Serositis: 50%
Kidneys: 25-50%
CNS: 15%

36. Discoid Lupus Plaques Photosensitive Often head & neck Scarring
10% develop SLE

37. Lupus: Treatment Sunscreens, sunprotection Anti-inflammatory drugs
Anti-malarial drugs
Steroids
Immunosuppressants
Mycophenolate mofetil

38. Systemic Sclerosis (Scleroderma): Skin thickening, tightening

39. Scleroderma - small blood vessels = SPASM, ischemia +
Disorder of:
- small blood vessels = SPASM, ischemia +
- overproduction of connective tissue
(collagen) = FIBROSIS

40. Scleroderma: Types Systemic - Diffuse
- Limited (CREST) anti-centromere
Localized - morphea
- linear scleroderma

41. Raynaud’s phenomenon Cold, stress 3 phases: white blue  red
8-10% of normals
90% - scleroderma
Consider ANA when screening (SLE, CREST)

42. Scleroderma Lungs - fibrosis - Pulmonary hypertension GI - GERD...
Renal - malignant hypertension
- microangiopathic anemia - renal failure
- ACEI !!!!!!!!!!!!!!!!!!!

43. Limited Scleroderma (CREST)
Calcinosis
Telangiectasias

44. Acute Monoarthritis (in absence of trauma)
Infection
Crystal (gout, pseudogout)
Spondyloarthropathy

45. Synovial Fluid Testing
Cell count, differential
WBC: = non-inflammatory
,000 = inflammatory
>75,000 = septic
Gram stain, C&S
Crystals

46. Question 1: What did Ramses II have, besides riches and fame?

47. Answer: Ankylosing Spondylitis

48. Spondyloarthropathies
Axial and/or peripheral joints
HLA-B27
Path = enthesopathy
Inflammatory back pain
Extra-articular:
- uveitis etc.
RF negative
Ankylosing Spondylitis
Reiter’s/reactive arthritis
Psoriatic arthritis
Inflammatory Bowel Disease

49. Enthesitis Erosion Calcaneal Spur
Reiter’s - erosion at Achilles insertion into calcaneus and extra bone at site of plantar fasciitis
Calcaneal Spur

50. Achilles tendinitis

51. Inflammatory low back pain?
Insidious onset
Worse with rest
Better with activity
Morning stiffness
Family history
Bilateral Sacroiliitis

53. HLA-B27: Disease Associations
Ankylosing Spondylitis >90%
Reiter’s syndrome/ reactive 80%
Inflammatory bowel disease 50%
Psoriatic Arthritis
- with spondylitis 50%
- with peripheral arthritis 15%
Caucasians 8%
Inuit %

54. Reactive Arthritis: Concept
A sterile inflammatory arthritis
- triggered by an infection
- at a distant site (GI or GU)
- in a genetically susceptible host
An inflammatory reaction to a persistent organism or antigen(s)

55. Bacteria that Trigger Reactive Arthritis
Post-venereal: Chlamydia trachomatis
Post-dysenteric:
Salmonella
Shigella flexneri
Yersinia enterocolitica
Campylobacter
Clostridium difficile

56. HLA-B27: Reactive Arthritis
Campylobacter

57. Spondyloarthropathies: Extra-articular features
Skin: Psoriasis, E. nodosum, pyoderma gangrenosum...
Eyes: iritis, conjunctivitis
Lungs: apical pulmonary fibrosis
Cardiac: aortic insufficiency, conduction abnormalities
Neurologic: cauda equina...

59. Reiter’s Syndrome

60. Gout
Acute monoarthritis
- lasts days
- recurrent attacks
Uncontrolled hyperuricemia
 tophi
 polyarthritis

61. Gout: uric acid crystals
Needle-shaped
Strong negative bireringence
Phagocytosed by PMN’s

62. Gout: Treatment Asymptomatic hyperuricemia  none
Acute attack - NSAID’s
- colchicine
- steroid’s
Indications to lower uric acid - allopurinol
- renal stones
- frequent attacks
- tophi

63. Pseudogout - CPPD Acute monoarthritis Knees, wrists Chondrocalcinosis
Pyrophosphate crystals:
- rhomboid
- weak positive birefringence

64. Vasculitis: Classification
Small Vessel Hypersensitivity
Medium Vessel:
- necrotizing = Polyarteritis nodosa
- Kawasaki’s
Large Vessel:
- Giant Cell (Temporal) arteritis
- Takayasu’s (Aortic Arch Syndrome)

65. Vasculitis: Classification NB! can have overlap...
1. Large Vessel Vasculitis
2. Medium Vessel Vasculitis
3. Small Vessel Vasculitis

66. Large Vessel Vasculitis
- Giant Cell Arteritis
- Takayasu’s (Aortic Arch Syndrome)

67. Medium Vessel Vasculitis
- Polyarteritis nodosa (PAN)
- Kawasaki Disease
- Primary CNS Vasculitis

68. Small Vessel Vasculitis
- ANCA Associated: - Wegener Granulomatosis
- Churg-Strauss Syndrome
- Microscopic Polyangiitis (MPA)
- Henoch-Schönlein Purpura (HSP)
- Vasculitis with connective tissue diseases
- Vasculitis/essential mixed cryoglobulinemia (Hep C)
- Hypersensitivity vasculitis (leukocytoclastic)
- Vasculitis with viral infections (Hep B, C, HIV, CMV, parvo-B19)

69. Small Vessel Vasculitis
Palpable purpura
Most common vasculitis
Leukocytoclastic vasculitis
Ag (eg. Infection, drug)
+ Ab  immune complex
Rule out other organ involvement (kidney, lung…)

70. Wegener’s Granulomatosis
Small + medium vessels
Granulomatous
Upper +/- lower respiratory (ulcers, sinuses...)
Renal

71. Anti-Neutrophil Cytoplasmic Antibodies (ANCA)
Patients with suspected vasculitis:
Pulmonary - renal:
- Wegener
- ...
Cytoplasmic
Perinuclear

72. ANCA Immunofluorescence Solid Phase Assays (ELISA…) :
cytoplasmic - cANCA
perinuclear – pANCA
Solid Phase Assays (ELISA…) :
pANCA = anti-MPO (myeloperoxidase)
cANCA = anti-PR3 (proteinase 3)

73. cANCA (anti-PR3)
Highly sensitive, specific for Wegener’s granulomatosis
Specificity: 95%

74. Giant Cell Arteritis (GCA)
Age >50 years - mean = 70 years
Symptoms related to arteries:
- headache, scalp tenderness
- visual loss
- jaw claudication

75. Giant Cell (Temporal) Arteritis

76. Giant Cell (Temporal) Arteritis
Diagnosis:
- CBC - anemia of chronic disease
- ESR - markedly elevated, often >100
- Biopsy temporal artery
Treatment: URGENT! (prevent visual loss)
- steroids - prednisone 60mg daily...

77. Fibromyalgia Tender Points (18)

78. Fibromyalgia Prevalence 3% widespread pain, tender points
sleep disturbance
Absence of inflammatory markers…
Exclusion of other systemic disorders
Treatment: - education
- exercise
- low dose tricyclic
- New = pregabalin, duloxetine

79. NSAIDs, Coxibs

80. Toxicity: ASA and NSAIDs
GI: ulcers, bleeding
CVS: hypertension, increased risk MI, stroke
Renal: Na retention, edema, renal failure
CNS
platelet effects
contraindicated ASA hypersensitivity
avoid if possible - pregnancy and lactation

81. Cox-2 “specific” Inhibitors (coxibs)
improved GI safety
no effect on platelets
efficacious in RA, OA, pain
?? Increased risk MI, stroke
renal effects like other NSAID’s
 caution! - elderly hypertension
- cardiac disease
- renal disease