1. Rheumatoid Arthritis
John Imboden MD

2. Rheumatoid arthritis: typical presentation
Prevalence 1%
Female > male (3:1)
Peak onset: age 30s to 40s
Insidious onset of joint pain & AM stiffness lasting hours
Swelling of wrists and small joints of the hands

3. The natural history of rheumatoid arthritis
at presentation after 5 years after 15 years
- Chronic disease
- Progressive damage leading to joint deformity & disability
Extra-articular disease: nodules, lung, eye, vasculitis, etc
Diminished life expectancy

4. Rheumatoid Arthritis Polyarthritis of synovial lined joints
Characteristic pattern of joint involvement
Inflammatory arthritis
autoimmune
Destructive arthritis
Cartilage degradation
Erosion of bone adjacent to joints
Joint deformities
Systemic disease

5. Rheumatoid Arthritis: pathogenesis
Etiology uncertain
Autoimmune disease
Characteristic autoantibodies
Genetic predisposition
Mechanisms of joint damage

6. Rheumatoid Arthritis: autoantibodies
Rheumatoid factor
Autoantibody to Fc region of IgG
Occur in c. 70% of RA patients
Despite the name, not specific for RA
Antibodies to citrullinated protein epitopes
Highly specific for RA
May be pathogenic

7. Posttranslational modification of proteins:
PAD converts arginine to citrulline
Peptidylarginine
deiminase (PAD)

8. RA-associated autoantibodies recognize protein epitopes containing citrulline
Peptide sequence Antibody recognition
ESSRDGSRHPRSHD No
PAD
ESSRDGScitHPRSHD Yes

9. Protein Citrullination
Constitutive citrullination of proteins in skin and elsewhere
Physiological roles of citrullination are diverse and incompletely understood
Citrullination of proteins occurs in inflamed joints in many forms of arthritis
NOT specific for RA
Loss of tolerance to citrullinated proteins is specific for RA

10. Antibodies to Citrullinated Protein Epitopes
Detected using synthetic cyclic citrullinated peptides
“anti-CCP antibodies”
Anti-CCP positive RA:
Genetically distinct form of RA
More aggressive arthritis

11. RA: genetic susceptibility
Heritability 60%
Multiple genes involved
Most important: HLA-DRB1
Encodes b chain of a MHC class II antigen
Linked to “CCP-positive” RA

12. Environmental event(s) Genetic predisposition
Loss of tolerance to self antigens
Preclinical autoimmunity
Clinically apparent joint inflammation (synovitis)

13. Synovial inflammation in RA

14. Synovial inflammation in RA
normal rheumatoid
joint joint
Synovitis:
- proliferation of synovial
lining cells
- influx of mononuclear cells
- angiogenesis
Pannus:
- the component of the
inflamed synovium that
invades cartilage and bone
Joint effusion:
- influx of neutrophils into
synovial fluid

15. Joint inflammation in RA
Rheumatoid wrist Normal wrist
Inflammation within bone synovial inflammation
3 Tesla MRI provided by Xiaojuan Li PhD

16. Cytokine production in rheumatoid synovium
Large number of cytokines produced
Macrophage-derived cytokines:
Proinflammatory cytokines: TNF-a, IL-1, IL-6
Dominant cytokines in quantitative terms
T cell cytokines:
Interleukin-17 > interferon-g (Th17 cells may be more important than Th1)

17. Mechanisms of joint inflammation and destruction in RA: conclusions from trials with selective inhibitors
Response
Target Clinical Joint damage
T cell co-stimulation
B cell
Proinflammatory cytokines
tumor necrosis factor
interleukin
interleukin

18. Roles of TNF and IL-1 in cartilage degradation and erosion of bone
Induce chondrocytes and
fibroblasts to produce matrix
metalloproteinases and other
proteases that degrade
cartilage
Together with RANK-RANKL
interactions, promote
differentiation of precursors
into osteoclasts, which are
the destructive element where
the pannus invades bone
cartilage
bone

19. RA: clinical presentation
Onset: usually insidious
Patients typically present after weeks to months of symptoms
Articular symptoms dominate
Constitutional symptoms
Common: fatigue, low grade fever (<38°C)
Uncommon: extensive weight loss,
fever > 38°C

20. RA: articular symptoms
RA is an inflammatory arthritis:
Morning stiffness
Often lasts hours
Can be the dominant symptom
Joint pain and stiffness improve with activity
“gel phenomenon”
Stiffness recurs after prolonged inactivity

21. RA: joint involvement Symmetric Additive
e.g., both wrists, both knees
Additive
Polyarthritis (>5 joints involved)
Arthritis, not just arthralgias
Involved joints: tender and swollen
Larger joints: warm, effusions
Not erythematous

22. RA: pattern of joint involvement
Hands (involved in >90%)
Wrists, metacarpophalangeal (MCP) & proximal interphalangeal (PIP) joints
Spares distal interphalangeal (DIP) joints
Axial skeleton
Cervical spine can be involved
Spares thoracic, lumbosacral spine, SI joints
Large joints
Feet

23. Early RA with fusiform swelling of the 3rd and 4th PIP joints

24. Rheumatoid arthritis: irreversible damage
can occur early in disease course
1 year prior to months after years after onset
onset of RA onset of symptoms of symptoms
Radiographic changes in the same joint over time

25. Radiographic changes occur early and precede joint deformities by years (adapted from Wolfe & Sharp, Arth Rheum 41: 1571, 1998)
Arbitrary scale

26. Characteristic joint deformities in RA
“Swan neck”
deformities:
hyperextension
of PIPs and
flexion of DIPs
“Boutonniere” deformity:
flexion of PIP and hyperextension of DIP

27. Characteristic joint deformities in RA
Ulnar deviation
of the fingers
Volar
subluxation
of MCPs
Rheumatoid nodules
Note the symmetry of the joint involvement

28. Characteristic joint deformities in RA
Subluxation of the metatarsals as a
consequence of MTP arthritis

29. RA: extraarticular manifestations
Common:
Rheumatoid nodules
Sicca (Sjögren) syndrome
Interstitial lung disease
Ocular inflammation: Scleritis and episcleritis
Uncommon:
Vasculitis
Clinically apparent pleuritis or pericarditis
Felty syndrome (RA, splenomegaly, neutropenia)

30. Rheumatoid nodule

31. RA: Laboratory findings
Routine laboratory:
Mild to moderate anemia
Mild to moderate thrombocytosis
High erythrocyte sedimentation rate or elevated C-reactive protein
Synovial fluid analysis
Inflammatory
WBC counts usually in 5,000 – 50,000 range
Neutrophil predominance

32. RA: Autoantibodies Anti-CCP Antibodies Rheumatoid factor
High specificity
Identifies patients with more aggressive joint disease
Rheumatoid factor
Limited specificity
Patients who develop extra-articular disease are almost always “sero-positive” for RF

33. Diagnosis of RA Clinical diagnosis
Key feature: inflammatory polyarthritis affecting proximal joints of the hands
Compatible laboratory data, serologies, and radiographs
Exclusion of other causes of inflammatory polyarthritis

34. Diagnosis: some mimics of RA
Acute viral infections: self-limited polyarthritis
Acute parvovirus B19 infection in adults
Chronic hepatitis C infection
RF-positive non-erosive chronic polyarthrtis
Systemic lupus and other systemic rheumatic diseases
Spondyloarthropathies
Primary osteoarthritis of the hands
Systemic vasculitis

35. Goals of therapy for RA Reduce signs and symptoms of inflammation
Prevent joint deformities

36. Treatments for RA Nonsteroidal anti-inflammatory drugs
Aspirin 1890s
Low dose glucocorticoids
Early 1950s
Disease-modifying antirheumatic drugs (DMARDs)
Methotrexate mid-1980s
Biological agents
Anti-TNF agents late 1990s

37. Raoul Dufy “La Cortisone” 1951

38. Methotrexate: most commonly used DMARD
Mainstay of treatment for RA
reduces signs and symptoms in majority
slows radiographic progression
Works slowly (weeks)
Uncertain mechanism of action in RA

39. Biological agents for RA
Monoclonal antibodies, receptor/antibody chimeras
Targets:
Tumor necrosis factor (TNF)
T cell-costimulation
B-cells
IL-6 receptor
Parenteral administration (SQ or IV)
Toxicity (infection, ?malignancy)
$$$

40. Anti-TNF therapy of RA
Reduces signs and symptoms for patients with active disease despite methotrexate
Combination of anti-TNF and methotrexate:
superior to either agent alone for reducing disease activity
prevents radiographic progression for most patients, at least for 1-2 years
Not all patients respond, and many responses are incomplete

41. Treatment of RA: general principles
Patients should be started on effective therapy (eg, a DMARD) within 3 months of diagnosis
Combination therapy appears more effective than monotherapy
Goal is remission or “mild” activity by standardized assessments
There are few head-to-head comparisons to guide therapeutic decisions

42. A therapeutic approach to new onset RA
Start prednisone 5 mg/day
Acts quickly, joint-protective
Start methotrexate
Initiate long term therapy with an agent shown to retard radiographic progression
If disease still active despite optimal methotrexate, add an anti-TNF agent
Alternative: start with methotrexate plus anti-TNF
If disease refractory to anti-TNF, switch to another biological agent

43. Rheumatoid arthritis: 2010
Treatable, but not curable
Therapies can slow or even prevent joint damage
Early RA is a therapeutic opportunity
Clinical remission achieved in 50%
Most treated RA patients have residual mild to moderate activity
10-20% have refractory disease

44. Rheumatoid arthritis: key points
Pathogenesis
Genetic predisposition
Anti-CCP antibodies
Connection between proinflammatory cytokines and joint destruction
Clinical course of RA: descriptors of common joint deformities, extraarticular manifestations
Distinguish RA from osteoarthritis, spondyloarthropathies, and lupus
Major classes of therapies