Inflammatory arthritis can be acute or chronic. Acute arthritis has a rapid onset and can lead to joint destruction, while chronic arthritis has a more gradual onset and is mediated by the adaptive immune response. Rheumatologic diseases can be classified as either inflammatory or immunologically-mediated. Ankylosing spondylitis is a chronic inflammatory disease that is classified as a spondyloarthropathy and is characterized by inflammation of the spine and entheses. It can cause significant pain and functional limitation.

1. Understanding inflammatory arthritis
Evaluation and Management principles

2. CDC: Census Bureau 2004

3. 3
What is inflammation?
 Normal body defence mechanism
 Increased blood flow
 Blood cells produce chemical messengers to
continue the process
 Heat, swelling, redness, pain, loss of function

4. Acute vs Chronic Inflammatory Arthritis
Acute Arthritis
Rapid onset (hours or days)
Severe symptoms
Mediated by components of innate immune response,
especially neutrophils (proteases, leukotrienes, prostaglandins
Can result in rapid joint destruction
Can also evolve into chronic disease
Examples: Gout and Infectious Arthritis
Chronic Arthritis
More gradual onset (days to weeks)
Symptoms are more moderate, AM stiffness is a prominent symptom
Mediated by the adaptive immune response, especially T cells
and macrophages - a Th1 disease
Cytokines and chronic inflammation lead to joint remodeling and
destruction via erosions
Examples: Rheumatoid Arthritis, Ankylosing Spondylitis, SLE,
Lyme Disease

5. Diversity of Rheumatologic Diseases:
Inflammatory and Immune Responses
Inflammatory Diseases (innate immunity)
Osteoarthritis
Gout
Pseudogout
Immunologically-Mediated Diseases (adaptive immunity)
Rheumatoid Arthritis*
Systemic Lupus Erythematosus
Spondyloarthropathies*
Ankylosing spondylitis *
Reactive Arthritis (Reiter’s Syndrome)
Psoriatic Arthritis *
Spondylitis associated with IBD
Sjogren’s Syndrome
Polymositis/Dematomyositis
Lyme Disease
Rheumatic Fever
Behcet’s Syndrome
Systemic Sclerosis (Scleroderma)
Wegener’s Granulomatosis
Giant Cell Arteritis
* Diseases that will be covered in depth later in lecture of this course.

6. Pattern of Joint Involvement is Distinct in Different Diseases
Monoarticular vs Polyarticular
Mono Poly
Gout RA
Infection SLE
Reactive
Joint distribution
PIPs and MCPs: RA, SLE
DIPs: Osteoarthritis, Psoriatic
MTP: Gout
Symmetrical vs Asymmetrical
Symmetrical: RA, SLE
Asymmetrical: Psoriatic, Reactive

7. Multiple Factors Contribute to the Development of Arthritis
Nature Reviews Immunology, 2007

8. Genetic Basis of Rheumatic Diseases:
Genotype contributes to rheumatic disease susceptibility
________ Twin Studies____________
Monozygotic Dizygotic Genetic Component
Disease Concordance (%) Concordance (%) Explained by HLA (%)
Rheumatoid Arthritis 15-34 0-6 35
SLE 25-57 0-3
Ankylosing Spondylitis 50-75 13-18 37
______________________________________________________________________________
Most often rheumatic diseases are polygenic. A certain
genotype predisposes an individual to a disease, but does
not make disease development a certainty.

9. October 2009: >30 RA Risk Loci
Plenge RM, ACR Annual Meeting Presentation, October 2009
Together explain ~35% of the genetic
burden of disease
HLA
DR4
“Shared
epitope”
hypothesis PADI4 PTPN22 CTLA
4
TNFAIP4
STAT4
TRAF1-C5
IL2-IL21
CD40
CCL21
CD244
IL2RB
TNFRSF14
PRKCQ
PIP4K2C
IL2RA
AFF3
REL
BLK
TAGAP
CD28
TRAF0
PTPRC
FCGR2A
PRDM1
CD2-CD58
1978 1987 2003 20072004 2005 2008 2009

10. Oral Health and RA
 Periodontal disease more common in people with
RA than controls
 Oral bacterium, Porphyromonas gingivalis, may
be the connection
x Associated with autoantibodies (CCP)
x Could be part of causal pathway
x Many ongoing studies of role in RA
Rosenstein ED et al. Inflammation 2004;28:311-8

11. 11
Symptoms
 Joint pain
 Joint swelling
 Morning stiffness
 Fatigue
 Weight loss
 Flu-like symptoms

12. 12

13. 13

14. Rheumatoid Arthritis: PIP Swelling
 Swelling is confined to
the area of the joint
capsule
 Synovial thickening
feels like a firm
sponge

15. Rheumatoid Arthritis:
Ulnar Deviation and MCP Swelling
 An across-the-room
diagnosis
 Prominent ulnar
deviation in the right
hand
 MCP and PIP swelling
in both hands
 Synovitis of left wrist

16. Rheumatoid Arthritis
Early erosion at the tip of the ulnar styloid

17. 2010 ACR/EULAR
Classification Criteria for RA
JOINT DISTRIBUTION (0-5)
1 large joint 0
2-10 large joints 1
1-3 small joints (large joints not counted) 2
4-10 small joints (large joints not counted) 3
>10 joints (at least one small joint) 5
SEROLOGY (0-3)
Negative RF AND negative ACPA 0
Low positive RF OR low positive ACPA 2
High positive RF OR high positive ACPA 3
SYMPTOM DURATION (0-1)
<6 weeks 0
≥6 weeks 1
ACUTE PHASE REACTANTS (0-1)
Normal CRP AND normal ESR 0
Abnormal CRP OR abnormal ESR 1
≥6 = definite RA
What if the score is <6?
Patient might fulfill the criteria…
 Prospectively over time
(cumulatively)
 Retrospectively if data on all
four domains have been
adequately recorded in the past

18. 18
Extraarticular ?
 Eyes: dryness, inflammation, uveitis
 Lungs: fluid, inflammation, nodules
 Skin: nodules, ulcers, psoriasis,
balanitis, keratoderma blenorhagia
 Heart: fluid, inflammation, ischaemic
heart disease
 Blood: anaemia, low counts

19. Spondyloarthritis, Psoriasis and PsA
Spondyloarthritis (SpA)
 The prevalence of SpA is comparable to that of RA (0.5–1.9%)1,2
Psoriasis (Pso)
 Psoriasis affects 2% of population
 7% to 42% of patients with Pso will develop arthritis3
Psoriatic Arthritis
 A chronic and inflammatory arthritis in association with skin psoriasis4
 Usually rheumatoid factor (RF) negative and ACPA negative5
x Distinct from RA
 Psoriatic Arthritis is classified as one of the subtypes of spondyloarthropathies
x Characterized by synovitis, enthesitis, dactylitis, spondylitis, skin and nail
psoriasis4
1
Rudwaleit M et al. Ann Rheum Dis 2004;63:535-543; 2
Braun J et al. Scand J Rheumatol 2005;34:178-90;
3
Fitzgerald “Psoriatic Arthritis” in Kelley’s Textbook of Rheumatology, 2009;
4
Mease et al. Ann Rheum Dis 2011;70(Suppl 1):i77–i84. doi:10.1136/ard.2010.140582;
5
Pasquetti et al. Rheumatology 2009;48:315–325
Juvenile SpA
Reactive
arthritis
Arthritis
associated with
IBD
PsA
Undifferentiated
SpA (uSpA)
Ankylosing
spondylitis (AS)
RA: Rheumatoid arthritis

20. AS: A Debilitating Rheumatic DiseaseAS: A Debilitating Rheumatic Disease
1
Linden VD et al. Chapter 10. In: Firestein, Budd, Harris, McInnes, Ruddy and Sergent, eds. Kelley’s
Textbook of Rheumatology: Spondyloarthropathies. 8th
ed. Saunders Elsevier;2009:p.1171
2
Braun J & Sieper. J Rheumatology 2008;47:1738-40

21. Ankylosing
Spondylitis
“Bamboo Spine”
Repeated process of healing
and bone formation leads to
formation of syndesmophytes
‘bone bridges’
ACR Slide Collection on the Rheumatic Diseases; 3rd
edition. 1994.

22. • Mortality figures parallel RAMortality figures parallel RA6,7,86,7,8
 ““Rare”Rare”
 ““Not” a serious disease, functional limitation isNot” a serious disease, functional limitation is
mildmild
 ““Rarely shortens life”Rarely shortens life”
AS (“Mis-”) Perceptions
• Burden of disease significant in pain, sick leave, earlyBurden of disease significant in pain, sick leave, early
retirementretirement3,4,53,4,5
• 0.1-0.9%0.1-0.9%1,21,2
11
Sieper J et al.Sieper J et al. Ann Rheum Dis.Ann Rheum Dis. 2002; 61 (suppl 3);iii8-18.2002; 61 (suppl 3);iii8-18.
22
Lawrence RC., Arthritis Rheum 1998; 41:778-99.Lawrence RC., Arthritis Rheum 1998; 41:778-99.
33
Zink A., et al.,Zink A., et al., J RheumatolJ Rheumatol 2000; 27:613-22.2000; 27:613-22.
44
Boonen A.Boonen A. Clin Exp RheumatolClin Exp Rheumatol. 2002;20(suppl 28):S23-S26.. 2002;20(suppl 28):S23-S26.
55
Gran JT, et al.Gran JT, et al. Br J RheumatolBr J Rheumatol. 1997;36:766-771.. 1997;36:766-771.
66
Wolfe F., et al. Arthritis Rheum. 1994 Apr;37(4):481-94.Wolfe F., et al. Arthritis Rheum. 1994 Apr;37(4):481-94.
77
Myllykangas-Luosujarvi R, et al.Myllykangas-Luosujarvi R, et al. Br J Rheumatol.Br J Rheumatol. 1998;37:688-690.1998;37:688-690.
88
Khan MA, et al.Khan MA, et al. J Rheumatol.J Rheumatol. 1981;8:86-90.1981;8:86-90.
99
Braun J., Pincus T., Clin Exp Rheumatol. 2002; 20(6 Suppl 28):S16-22.Braun J., Pincus T., Clin Exp Rheumatol. 2002; 20(6 Suppl 28):S16-22.

23. AS: Signs and SymptomsAS: Signs and Symptoms
Axial manifestations:
• Chronic low back pain
• With or without buttock pain
• Inflammatory characteristics:
– Occurs at night (second
part)
– Sleep disturbance
– Morning stiffness
• Limited lumbar motion
Sengupta R & Stone MA. Nat Clin Pract Rheumatol 2007;3:496-503
Hultgren S et al. Scand J Rheumatol 2000;29:365-369
Linden VD et al. Chapter 10. In: Firestein, Budd, Harris, McInnes, Ruddy and Sergent, eds. Kelley’s
Textbook of Rheumatology: Spondyloarthropathies. 8th
ed. Saunders Elsevier;2009:p.1175
Inflammatory back
pain (IBP) =
Characteristic symptom
MRI sacro-iliac joint

24. Peripheral manifestations
Enthesitis Peripheral arthritis Dactylitis
AS: Signs and SymptomsAS: Signs and Symptoms
50% patients with
enthesitis1
1
Cruyssen BV et al. Ann Rheum Dis 2007;66:1072-1077
2
Sidiropoulos PI et al. Rheumatology 2008;47:355-361
Up to 58% patients
ever had arthritis1
Much smaller number
of patients2

25. Why are Dactylitis and Enthesitis Important?
The first abnormality to appear in swollen
joints associated with
spondyloarthropathies is an enthesitis2
Likelihood of erosions is higher
for digits with dactylitis than
those without1
1
Brockbank. Ann Rheum Dis 2005;62:188-90;
2
McGonagle et al. The Lancet 1998;352.

26. AS: Extra-skeletal Signs and SymptomsAS: Extra-skeletal Signs and Symptoms
Other common symptoms seen during the early
stages of disease include:
• Anorexia
• Malaise
• Low grade fever
• Weight loss
• Fatigue
1
Missaoui B. et al. Ann Readapt Med Phys 2006;49:305-8, 389-391
Linden VD et al. Chapter 10. In: Firestein, Budd, Harris, McInnes, Ruddy and Sergent, eds. Kelley’s
Textbook of Rheumatology: Spondyloarthropathies. 8th
ed. Saunders Elsevier;2009:p.1176
Fatigue is a frequent complaint
of patients with AS1

27. AS:AS: Extra-articular Manifestations (EAM)Extra-articular Manifestations (EAM)
EAM Prevalence in AS
Patients (%)
Anterior uveitis 30-50
IBD 5-10
Subclinical inflammation of the gut 25-49
Cardiac abnormalities
Conduction disturbances
Aortic insufficiency
1-33
1-10
Psoriasis 10-20
Renal abnormalities 10-35
Lung abnormalities
Airways disease
Interstitial abnormalities
Emphysema
40-88
82
47-65
9-35
Bone abnormalities
Osteoporosis
Osteopenia
11-18
39-59
Elewaut D & Matucci MC. Rheumatology 2009;48:1029-1035
Terminal ileitis
Anterior uveitis
Cardiac
abnormalities

28. Spondyloarthritis and Classification
Criteria
Spondyloarthropathies
Axial and Peripheral
AMOR criteria (1990)
ESSG criteria (1991)
Axial Spondyloarthritis
ASAS classification 2009
Ankylosing spondylitis
Prototype of axial spondylitidis
Modified New York criteria 1984
Peripheral Spondyloarthritis
ASAS classification 2010
Psoriatic arthritis
From Moll & Wright 1973 to CASPAR criteria 2006
Sieper et al. Ann Rheum Dis 2009;68:ii1-ii44
Taylor et al. Arthritis & Rheum 2006;54:2665-73
Van der Heijde et al. Ann Rheum Dis 2011;70:905-8
ESSG: European Spondyloarthropathy Study Group
ASAS: Assessment of Spondyloarthritis International Society
CASPAR: Classification criteria for psoriatic arthritis
Infliximab (IFX) and Golimumab (GLM)
indications

29. ASAS Classification Criteria for Axial SpAASAS Classification Criteria for Axial SpA
In patients with back pain ≥3 months and age at onset <45 years
Sacroiliitis* on imaging
plus
≥1SpA feature**
HLA-B27
plus
≥2 other SpA features**
**SpA features:
•Inflammatory back pain
•Arthritis
•Enthesitis (heel)
•Uveitis
•Dactylitis
•Psoriasis
•Crohn’s disease/ulcerative colitis
•Good response to NSAIDs
•Family history for SpA
•HLA-B27
•Elevated CRP
*Sacroiliitis on imaging:
•Active (acute) inflammation on
MRI highly suggestive of
sacroiliitis associated with SpA
or
•Definite radiographic sacroiliitis
according to modified New York
criteria
Rudwaleit M et al. Ann Rheum Dis 2009;68(6):770-6
OR

30. 30
Psoriatic Arthritis

31. Psoriatic Arthritis
ACR Slide Collection on the Rheumatic Diseases; 3rd
edition. 1994.
Data on file, Centocor, Inc.

32. Pso patients6-8
• Psychosocial burden
• Reactive depression
• Higher suicidal ideation
• Alcoholism

Metabolic Syndrome3-5
• Hyperlipidemia
• Hypertension
• Insulin resistent
• Diabetes
• Obesity
⇒ Higher risk of
Cardiovascular disease (CVD)
Ocular inflammation1
(Iritis/Uveitis/ Episcleritis)
IBD2
Comorbidities in PsA Patients
1
Qieiro et al. Semin Arth Rheum 2002;31:264; 2
Scarpa et al. J Rheum 2000;27:1241; 3
Mallbris et al. Curr Rheum Rep 2006;8:355;
4
Neimann et al. J Am Acad Derm 2006;55:829; 5
Tam et al. 2008;47:718; 6
Kimball et al. Am J Clin Dermatol 2005;6:383-392;
7
Naldi et al. Br J Dermatol 1992;127:212-217; 8
Mrowietz U et al. Arch Dermatol Res 2006;298(7):309-319

33. Classical Description of PsA Using the
Diagnostic Criteria of Moll and Wright
 Including 5 clinical patterns:
x Asymmetric mono-/oligoarthritis (~30% [range 12-70%])1-4
x Symmetric polyarthritis (~45% [range 15-65%])1-4
x Distal interphalangeal (DIP) joint involvement (~5%)1
x Axial (spondylitis and Sacroiliitis) (HLA-B27) (~5%)1,3
x Arthritis Mutilans (<5%)1,3
References see notes
• However patterns may change over time and are
therefore not useful for classification 5
HLA: Human leucocytes antigen

34. Paradigm shift in the treatment of
inflammatory arthritis
 Rationale for Treatment
x Large body of evidence which shows joint damage
is an early phenomenon of rheumatoid arthritis
x Joint erosions occur in up to 93% of patients with
less than 2 years of disease activity
x The rate of radiographic progression is greatest in
the first two years
x Disability occurs early – 50% of patients with RA
will be work disabled at 10 years
x Severe disease is associated with increased
mortality!

35. It’s like an Iceberg

36. It’s what you don’t see!

37. Approach to Inflammatory Arthritis
 “Window of Opportunity”
x Early and aggressive treatment may have
long-term benefits
 Principles of Treatment
x Treat Early
x Treat Appropriately

38. 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?

39. 39
Principles of Treatment
 Early diagnosis
 Early initiation of treatment
 Regular assessment (Disease Activity Scores)
 “Treat to Target”
 Annual review

40. 40
Reduction of Joint Damage
Disease-modifying Anti-
Rheumatic Drugs
Methotrexate
Sulfasalazine
Leflunomide
Hydroxychloroquine
Azathioprine
Ciclosporin
Gold
Penicillamine
Biologic drugs
 Anti-TNF therapy:
 Infliximab
 Etanercept
 Adalimumab
 Certolizumab
 Golimumab
 Rituximab
 Abatacept
 Tocilizumab

41. 41

42. 42

43. 43