Rheumatoid Arthritis

1. Rheumatoid Arthritis

2. Sponsored
Medical Lecture Notes – All Subjects
USMLE Exam (America) – Practice

3.  Rheumatoid Arthritis
 Diagnostic Criteria
 Pathophysiology
 Therapeutic Approach
 Disease Severity and Course

4. Joint Pain
 most common symptom
 Pain (arthralgia) vs. Inflammation (arthritis)
 Inflammation:
 heat, redness, pain, swelling, loss of function
 inflammatory arthritis (RA, SLE) vs. pain syndrome
(fibromyalgia)

5. Number of Joints Affected
 Monoarticular
 Crystal-induced
 Infection
 Reactive Arthritis
 Hemarthrosis
 OA: joint effusions
 Autoimmune disease
 Psoriasis, IBD, AS,
Behçet's
 Oligo/Polyarticular
 Monoarticular causes
 RA
 SLE
 Viral infection
 B19
 Acute Serum Sickness
 Untreated Crystal-induced
 Vasculidities

6. Inflammatory vs. Non-Inflammatory
 Inflammatory: i.e. RA
 Generalized AM
stiffness
 > 30 min
 Resolves with
movement
 Classic signs of
inflammation
 Non-Inflammatory:
i.e. Osteoarthritis
 Localized AM stiffness
 < 30 min

8. Arthrocentesis
 Confirm diagnoses
 Differentiate between inflammatory & noninflammatory
 Therapeutic/Adjunct to Antibiotics
 Labs:
 cell count w/diff
 crystal analysis
 Gram stain & Culture
 WBC >2000/µL indicates inflammatory arthritis
 Arthroscopy
 Evaluate ligamentous & cartilaginous integrity
 Biopsy
 Infectioun: aspirate thick or loculated fluid

9. RA
 Systemic inflammatory autoimmune disorder
 ~1% of population
 Onset: 52 years
 40-70 years of age
 <60 - 3-5:1 female predominance

10. Genetics
 Increased incidence among Pima &
Chippewa Native American tribes (5%)
 Genetic & Environmental
 HLA-DRB1*0401 & HLA-DRB1*0404
 Increased risk
 Increased joint damage
 Increased joint surgery

11. Immunology
 Macrophages:
 Produce cytokines
 Cytokines (TNF-α) cause
systemic features
 Release chemokines  recruit
PMNs into synovial
fluid/membrane
 TNF-α & IL-1:
 Proliferation of T cells
 Activation of B cells
 Initiates proinflammatory/joint-
damaging processes
 TH-1 cells:
 Mediate disease processes
 Activate B cells
 B cells:
 Release cytokines
 Plasma cells that produce Ab
 Osteoclasts:
 Bone erosion
 Juxta-articular & Systemic
osteoporosis

12. Pathophysiology
 Swelling of Synovial lining
 Angiogenesis
 Rapid division/growth of cells = Pannus
 Synovial thickening/hyperplasia
 Inflammatory vascularized tissue
 Generation of Metalloproteinases
 Cytokine release
 Infiltration of leukocytes
 Change in cell-surface adhesion molecules & cytokines
 Destruction of bone & cartilage

13. Bottom Line
 Proliferation
 Destruction of joints
 Disability

14. Disease Trigger
 Subclinical vs. Viral trigger
 Lab manifestations up to 10 yrs before clinical
 RF & anti-CCP (anti–cyclic citrullinated peptide) Ab
 Increased CRP subclinical inflammatory disease
 Activities of Daily Livings(ADLs):
 > 50% of pts stop working w/i 5-10 years of disease onset
 ~ 80% disabled to some degree > 20 years
 Life expectancy: decreased by 3-18 years

15. Clinical Presentation
 Gradual onset
 Stiffness & Swelling
 Intermittent or Migratory involvement
 Extraarticular manifestations
 Myalgia, fatigue, low-grade fever, wt loss,
depression

16. Stiffness & Swelling
 Pain with pressure to joint
 Pain with movement of joint
 Swelling due to hypertrophy
 Effusion
 Heat
 Redness

17. Physical Exam
 Decreased grip strength
 Boxing glove edema
 Carpal tunnel
 Ulnar deviation
 Boutonniere/Swan neck deformities
 Extensor tendon rupture

18. Extraarticular Involvement
 Anemia
 Rheumatoid nodules
 Pleuropericarditis
 Neuropathy
 Episcleritis, Scleritis
 Splenomegaly
 Sjogren’s
 Vasculitis

19. Differential
 Seronegative polyarthritis
 Psoriatic arthritis
 Crystal-induced
 Tophaceous gout
 Pseudogout
 Erosive inflammatory OA
 Reiter’s
 Enteropathic arthritis
 SLE
 Paraneoplastic syndrome

20. Diagnostic Criteria
 Symmetric peripheral polyarthritis
 AM Stiffness >1 hour
 Rheumatoid nodules
 Laboratory features
 Radiographic bone erosions

21. Symmetric Peripheral Polyarthritis
 3 or more Joints for >6 weeks
 Small Joints
 Hands & Feet
 Peripheral to Proximal
 MCP and PIP Joints
 SPARES DIP
 MTP & Plantar subluxation
 Leads to Deformity & Destruction of Joints
 Erosion of cartilage and bone

22. Stiffness
 AM or after Prolonged Inactivity
 Bilateral
 In/Around Joints
 > 1 hours
 Reflects severe joint inflammation
 Better with movement
 Present >6 weeks

23. Rheumatoid Nodules
 Extensor surfaces
 elbows
 Very Specific
 Only occur in ~30%
 Late in Disease

24. Laboratory Features
 RF
 70-80% of pts
 Overlap with HCV/Cryoglobulinemia
 Anti-Cyclic Citrulline Peptide (anti-CCP)
 Rare overlap with HCV
 Acute Phase reactants
 ESR, CRP  monitoring disease activity

25. Rheumatoid Factor
 IgM against IgG
 IgM+ pts: more severe disease & poorer outcome
 Non-specific
 SLE, Sjögren's, Sarcoidosis, Chronic infections

26. Anti-CCP
 IgG against synovial membrane peptides damaged
via inflammation
 Value in IgM-RF negative
 Sensitivity (65%) & Specificity (95%)
 Predictive of Erosive Disease
 Disease severity
 Radiologic progression
 Poor functional outcomes

27. Other Lab Abnormalities
 AOCD
 Thrombocytosis
 Leukocytosis
 ANA
 30-40%
 Inflammatory synovial fluid
 Hypoalbuminemia

28. Radiology
 Evaluate disease activity & joint damage
 Bony decalcification
 Baseline AP views
 Initiation of DMARDs(disease-Modifying
Anti-Rheumatic Drugs)

29. Radiological Studies
 Plain Films
 Bilateral hands & feet
 Only 25% of lesions
 Less expensive
 Through bone cortex around joint margins
 Color Doppler U/S & MRI
 Early signs of damage i.e. Erosions
 Bone Edema - even with normal findings on radiography

32.  Arthralgias
 >3 inflamed joints
 Mild functional limitation
 Minimally elevated ESR & CRP
 No erosions/cartilage loss
 No extraarticular disease i.e. anemia
Mild Disease

33. Moderate Disease
 6-20 Inflamed joints
 Moderate functional limitation
 Elevated ESR/CRP
 Radiographic evidence of inflammation
 No extraarticular disease

34. Severe Disease
 >20 persistently inflamed joints
 Rapid decline in functional capacity
 Radiographic evidence of rapid
progression of bony erosions & loss of
cartilage
 Extraarticular disease:
 AOCD, Hypoalbuminemia

35. Prognostic Features
 RF & Anti-CCP antibodies
 Early development of multiple inflamed joints
and joint erosions
 Severe functional limitation
 Female
 HLA epitope presence
 Lower socioeconomic status & Less education
 Persistent joint inflammation for >12 weeks

36. CV Disease
 Leading cause of death ~50%
 2x more likely to develop MI
 chronic, inflammatory vascular burden  premature atherosclerosis
 MTX: elevated homocysteine levels
 Control inflammatory process = Decreased
atherosclerosis/morbidity
 Lipid screening & treatment
 Control of obesity, Hyperhomocystinemia, DM, HTN
 ASA

37. Other diseases
 70% more likely to have a stroke
 70% higher risk for developing infection
 Likely 2/2 treatment
 44x more likely to develop NHL

38. Staging
 Early
 <3 months
 Established/Persistent
 6-12 months
 End-stage
 Significant joint destruction
 Functional disability

39. Management
 Early and aggressive disease control
 Rheumatologist Referral
 Early/Undiagnosed: NSAIDs, short course Corticosteroids
 Late/Uncontrolled: DMARD therapy
 depends on the presence or absence of joint damage, functional
limitation, presence of predictive factors for poorer prognosis
 Goals
 achieve NED & inflammation
 no treatment to resolve erosions once they occur

40. Therapy
 Non-Pharmacologic:
 Referral to PT/OT
 Evaluate ADLs
 Assistive
devices/splints
 Weight loss
 Smoking cessation
 Pharmacologic:
 Anti-inflammatory
 Interrupt progression
 Development of erosions
 Joint space narrowing

41. Pharmacologic Therapy
 Analgesics
 NSAIDs
 Glucocorticoids
 SAARD(slow-acting)/DMARD
 Anticytokine therapy

42. Analgesics
 Topical
 Capsaicin
 Diclofenac
 Oral
 Tylenol
 Opiods

43. NSAIDs
 Pros:
 Analgesic, Antipyretic, Anti-
inflammatory
 Cons:
 Don’t alter disease progression
 Ineffective in Erosive disease
 GI/Ulcers
 Hepatotoxicity
 Nephrotoxicity
 AIN
 Bleeding – antiplatelet
 Rash
 Aseptic meningitis

44. Corticosteroids
 Decrease cytokines
 Slow Joint Inflammation
 Insomnia
 Emotional lability
 Fluid retention
 Weight gain
 HTN
 Hyperglycemia
 Osteoporosis
 Bisphosphonates: >5mg/d for >3months
 Cataracts
 Avascular necrosis
 Myopathy
 Psychosis

45. Disease modification
 SAARD – slow acting antirheumatic drugs
 DMARD – disease modifying antirheumatic drugs

46. Methotrexate
 Dihydrofolate reductase
inhibitor
 Well tolerated, Mono/Combo
 Onset: 6-12 weeks
 Metabolism: Liver
Clearance: Kidneys
 Monitoring:
 Baseline:CXR, PFTs, HIV,
HBV/HCV
 CBC, LFTs Q4-8 weeks
 Caution with CRI
 Nausea
 Mucosal ulcerations
 Fatigue & Flu-like symptoms
 BM Toxicity
 Hepatotoxicity
 Treat with Folic acid, 1 mg/d

47. Leflunomide
 Inhibits dihydrooratate
dehydrogenase
 Dec. activated T-cells
 Onset: rapid
Efficacy: ≤6 weeks
 Monitoring:
 CBC, LFTs
 Derm - rash, alopecia
 Diarrhea
 BM toxicity
 Hepatotoxicity

48. Azathioprine
 Corticosteroid-
sparing
 Monitoring:
 CBC Q1-2 months
 AST/ALT
 Infection
 BM Toxicity
 Hepatitis
 Malignancy

49. Cyclophosphamide
 Alkylating agent
 Monitoring:
 CBC, UA monthly
 Yearly UA +/- Cytology
 Alopecia
 Nausea
 Infection
 BM suppression 
pancytopenia
 Infertility – pretreat women with
Leuprolide
 Renal: hemorrhagic cystitis,
bladder malignancy – treat with
acrolein
 Oral more toxic than IV

50. Anticytokine therapy
 Anti-TNF alpha agents
 Etanercept
 Infliximab
 Adalimumab
 IL-1 receptor antagonist (Anakinra)

51. TNF-a Inhibitors
 Anti-inflammatory
 Block TNF-α
(proinflammatory cytokine)
 Etanercept, Adalimumab
(SQ), Infliximab (IV)
 Very expensive:
> $15,000/patient
 Combo therapy with MTX
 Injection site reaction
 Infection
 Reactivated TB
 Infliximab
 infusion reaction
 Pancytopenia
 Autoantibody/SLE-like
 Exacerbate CHF
 Malignancy – lymphoma

52.  More aggressive approach
 Combo therapy
 Adjunctive therapy: TNF-α antagonist

53. Disease Course
 Long Remission
 10%
 Intermittent Disease
 15-30%
 Progressive Disease

54. Summary
 Approach to Arthritis
 Number of Joints Affected
 Inflammatory vs. Non-Inflammatory
 Rheumatoid Arthritis
 Diagnostic Criteria
 Pathophysiology
 Therapeutic Approach
 Disease Severity and Course

55. Clinical History
 The patient is a
50-year-old female
who is complaining
of pelvic pain
Ankylosing Spondylitis

56. AS:flat lumber
spine, loss of
lordosis, use
hips for bending

58. Radiographic Findings
 Ankylosis of sacroiliac joints
 Syndesmophytes in the lumbar spine
 Fusion of the interspinous ligament
 Arthropathy of both hips
 Enthesopathy of ischial tuberosity

59. Imaging Modalities
 Radiographs are the most important for
detection, diagnosis, and follow-up
 limited in early sacroiliac changes
 CT useful in equivocal sacroiliac
involvement
 MRI able to assess early cartilage
abnormalities and bone marrow edema

60. Recurrent Iritis caused
Synechiae(adhesions
between the lens and iris

61. Early Sacroiliitis

62. Advanced Sacroiliitis, Fused
SI joints

63. Syndesmophytes, apophyseal joint
fusion, disc peripheral ossification
(Ankylosing Spond)

64. Ankylosing Spond.Left:squaring
of vertebra,Rt.:ant.longitudinal
lig.calcification

65. Ankylosing Spondylitis :Bamboo spine
,ossification follow the contour of
intervertebral discs

66. Ankylosing
Spondylitis:calcaneal spur and
erosion

67. Apical fibrosis in Ankylosing
Spondylitis

68. Differential Diagnosis
 Ankylosing spondylitis
 Diffuse idiopathic skeletal hyperostosis
 Gout
 Psoriatic arthritis
 Rieter syndrome
 Rheumatoid arthritis
 Spondylodiskitis

69. Ankylosing Spondylitis
Features
 Chronic & progressive form of
seronegative arthritis with axial skeleton
predominance
 Affects 0.1-0.2% of the population
 90-95% of patients are HLA-B27 positive
 7% of general population is positive, only 1%
of positives will develop ankylosing
spondylitis
 Male:female 4-10:1

70. Features cont.
 Age of onset 15-35 years old
 juvenile onset associated with more frequent
& severe hip & peripheral joint involvement
 Life expectancy unaffected, although
20% morbidity
 most patients able to maintain a normal
lifestyle

71. Features cont.
 Starts with sacroiliac joints
 begins with sclerosis, eventually get
ankylosis
 Progresses to include facet joints, spine,
iliac crest, ischial tuberosity, greater
trochanter, hips, patella, calcaneus,
glenohumeral joints
 peripheral joint involvement in 30%

72. Features cont.
 Enthesopathy - calcification & ossification
of ligaments, tendons, joint capsules at
insertion into bone
 Erosion of subligamentous bone due to
inflammatory response
 Fusion of interspinous ligament
 Dagger sign

74. Features cont.
 Syndesmophytes - bony bridges between
vertebrae & ossification of joint capsule
 Bamboo spine
 Resorption of vertebral endplates
 Soft tissue findings are new bone
formation in outer layers of annulus
fibrosis as well as chronic synovitis and
capsular fibrosis

76. Physical Findings
 Patients usually present with low back
pain and stiffness, which improves with
activity
 Decreased range of motion in lumbar
spine
 Thoraco-cervical kyphosis (late)
 One-third of patients will have acute,
unilateral uveitis

77. Other Complications
 Pseudoarthrosis (Anderson lesion),
cervical spine fracture, C1-C2
subluxation, cauda equina syndrome
 Peripheral joint ankylosis
 Restrictive lung disease, upper lobe
fibrosis
 Aortic root dilation (20%) & murmur (2%)

78. Treatment
 Posture training & range of motion
exercises to prevent kyphosis
 Sleep prone or supine in firm bed, no
pillow
 Breathing exercises
 NSAIDs for symptomatic relief

79. Gout

80. Gout
 Gout is defined as a peripheral arthritis
resulting from the deposition of sodium
urate crystals in one or more joints.

81. Gout
Gout encompasses a group of disorders
that occur alone or in combination and
include (1) hyperuricemia, (2) attacks of
acute, typically monarticular,
inflammatory arthritis, (3) tophaceous
deposition of urate crystals in and around
joints, (4) interstitial deposition of urate
crystals in renal parenchyma, and (5)
urolithiasis

82. Gout
 Affects less than 0.5% of the population
 Due to familial disposition, incidence may be as
high as 80% in families affected by disorder.
Stoffey et al, Emed 2002

83. Gout
 Typical sequence involves progression
through:
 asymptomatic hyperuricemia
 acute gouty arthritis
 interval or intercritical gout
 chronic or tophaceous gout

84. Pathophysiology Urate saturates in plasma at 7 mg/dL
 Assuming pH, temp, Na are WNL
 MSU deposits in less vascular tissue
 Cartilage
 Tendons/ligaments
 There is a predilection for peripheral joint/tissue

85. Pathophysiology
 Primary gout:
 Overproducers: 10%
 Under-excretors: 90%
 Secondary gout:
 Excess nucleoprotein turnover (lymphoma,
leukemia)
 Increased cell proliferation/death (psoriasis)
 Rare genetic disorder Lesch-Nyan Syndrome
 pharmaceuticals

86. Signs and Symptoms
 Acute attack:
 Over hours frequently nocturnal
 Excruciating pain
 Swelling, redness and tenderness
 Podagra: 1st
MTP classic presentation
 May effect knees, wrist, elbow, and rarely SI and hips.
 Chronic:
 Destructive tophacous
 Much greater chance if untreated
 Rarely presents as a chronic

87. Signs and Symptoms
 Renal lithiasis
 Uric acid nephropathy
 Urate nephropathy

88. Diagnosis
 Based on history and physical
 Confirmed by arthrocentesis
 Urate crystals: needle-shaped negatively
birefringent either free floating or within neutrophils
& macrophages.
 Uric acid level non specific.
 30% may show normal level
 Urine collection:
 <800 mg underexcertor(<600 purine-free
diet)
Microscopic Diagnosis

89.  X-ray
 Acute
 Soft tissue swelling
 Chronic
 chronic tophaceous gouty
arthritis, extensive bony
erosions are noted throughout
the carpal bones
 Sclerosis and joint-space
narrowing are seen in the first
metatarsophalangeal joint, as
well as in the fourth
interphalangeal joint .

90. Differential Diagnosis
 Septic arthritis: must be excluded
 CPPD
 Acute Rheumatic fever
 Palindromic Rheumatism
 Psoriatic arthritis

91. Treatment
 Acute:
 NSAID’s anti-inflammatory doses
 Colchicine 0.5 mg po q2 hours, may require 6 mg.
 Stop with response or side effect
 Can be used for chronic disease, increased risk for BM
suppression
 Aspirate followed by administration of corticosteroids
 Prednisone
 ACTH 40-80 IM/IV or Solumedrol
 Opiates and Tylenol

92. Treatment
 Chronic:
 Diet will decrease uric acid 1 mg/dL at best
 Weight loss
 Limit ETOH
 Modification of medications
 Avoid low dose ASA, diuretics, etc.

93. Treatment Chronic
 Uricosuric: for under-excretors
 Probenicid:
 Sulfinpyrazone: toxic side effects
 Avoid with renal disease
 Consider NSAIDs to avoid exacerbation of gout

94. Treatment
 Chronic
 Indications for Allopurinol
 Tophaceous deposites
 Uric acid consistently >9
 Persistent Sx with moderate UA levels
 Impaired renal function
 Prophylaxis for tumor-lysis syndrome
 Consider NSAID’s to avoid exacerbation

95. Prognosis
 Generally good
 More severe course when Sx present <
30 y/o
 Up to 50% progress to chronic disease if
untreated.
 Surgical intervention may be required for
tophi.

96. Questions?