Transcript rheumatoid arthritis

Inflammatory Joint
Diseases
Prof. Dr. Ece AYDOĞ
Physical Medicine and Rehabilitation
1
Learning objectives:



be able to describe epidemiology and
etiopathogenesis of rheumatoid arthritis
be able to describe clinical forms of rheumatoid
arthritis according to initial patterns (insidious,
acute, intermediate)
be able to enumerate the old and new diagnostic
criteria formed the League of American College
of Rheumatism.
2



be able to describe the laboratory findings,
radiographic findings of early and late stage,
articular (disease-specific deformities), and extraarticular signs of rheumatoid arthritis
be able to enumerate pharmacological and non
pharmacological treatment and poor prognostic
criteria of rheumatoid arthritis.
be able to describe the clinical signs of
polimyalgia rheumatica and Sjögren's syndrome
3
RHEUMATOID ARTHRITIS
(RA)
4
DEFINITION
Systemic autoimmune inflammatory disorder of
unknown etiology that primarily affects the synovial
lining of the diarthrodial joints. This chronic, symmetric
erosive synovitis develops in the joints and leads to
destruction. These erosions are pathognomonic of RA.
5
EPIDEMIOLOGY



Female to male ratio is 3:1
Prevalence: approximately 1% of the population
Age range from 20 to 60 years, prevalence rises with
age, peak incidence between 4th and 5th decade
6
ETIOLOGY





Multiple and multifactorial
Genetic
Sex and sex hormones
İnfectious agents
Diet, trauma, stress, cigarette
7
ETIOLOGY
Genetic factors



Twin studies
Major Histocompatability Complex (MHC) on
chromosome 6
Class II MHC allele HLA-DR4 (HLA-DR4
haplotype) and DR1
8
ETIOLOGY
Two major theories:
 1. Infectious agents
 2. Immunogenetic→ Class II surface antigenspresenting cells
9
Immun response in RA
Antigen presenting cells +CD4+ T cells (sinovial)--macrophage activation, cytokine release (IL-1)--T cell infiltration of sinovia, cytokine release (IL2,IL-4)---B lenfosit proliferation and activation--Ig production and immuncomplexes
Fagositosis of IC by PNL and monosits--Tissue injury
10
Numerous Cellular Interactions Drive
the RA Process
Rheumatoid
factors
B cell
Immune complexes
Bacterial products
IL-1, TNF-, etc
IL-1
T cell
Soluble factors
and direct
cell–cell
contact
Antigenpresenting
cells
B cell or
macrophage
Macrophage
Synoviocytes
IL-1 and
TNF-
Chondrocytes
Pannus
Articular
cartilage
Production of collagenase and
other neutral proteases
Arend W. Semin Arthritis Rheum. 2001;30(suppl 2):1-6.
11

Cytokines
• synovial lining proliferation, pannus
• endothelial activation, angiogenesis
• fibroblast activation, fibrosis
12
Results of Joint Destruction in RA

Injury to synovial microvasculature





Synoviocytes are activated via class III HLA Ag (cellular
process): Synovial cells proliferate
Leads to congestion, edema, and fibrin exudation
T Lymphocytes infiltrate
Synovium is hypertrophied (cartilage is destroyed)
Pannus formation
13
Pannus Formation is the Most Important
Destructive Element in RA

Pannus:



Membrane of granulation tissue that covers the articular cartilage at joint
margins
Fibroblast-like cells invade and destroy the periarticular bone and cartilage
at joint margins
Vascular granulation tissue is composed of:





Proliferating fibroblasts
Numerous small blood vessels
Various number of inflammatory cells mainly T lymphocytes (Polymorphic
Neutrophil PMN are in fluid)
Occasionally collagen fibers are seen within phagolysosomes of cells at the
leading edge of pannus
Joint ankylosis may occur in later stages
14
RA Is Characterised by Synovitis and
Joint Destruction
NORMAL
RA
Inflamed
synovial
membrane
Synovial
membrane
Pannus
Cartilage
Major cell types
• T lymphocytes
• macrophages
Minor cell types
• fibroblasts
• plasma cells
• endothelium
• dendritic cells
Synovial
fluid
Capsule
Major cell type
• neutrophils
Cartilage thinning
Adapted from Feldmann M, et al. Annu Rev Immunol. 1996;14:397-440.
15
IL-1 and TNF- Have a Number of
Overlapping Proinflammatory Effects
Proinflammatory
effects of IL-1
TNF-
Osteoclast
activation
Angiogenic
factors
Proinflammatory
effects of TNF-
COX-2
PGE2
NO
Adhesion molecules
Chemokines
Collagenases
IL-6
IL-1
cell death
COX-2 = cyclo-oxygenase type 2; PGE2 = prostaglandin-E2; NO = nitric oxide
16
IL-1 Plays a Pivotal Role in the Inflammatory
and Destructive Processes of RA
IL-1
Activates
monocytes/ Induces fibroblast
proliferation
macrophages
Inflammation
Synovial pannus
formation
Activates
chondrocytes
Activates
osteoclasts
Cartilage
breakdown
Bone
resorption
17
PATTERN OF ONSET

Insidious → 50%–70%









Initial symptoms can be systemic or articular
Slow onset from weeks to months
Constitutional symptoms: fatigue, malaise
Diffuse musculoskeletal pain may be the first nonspecific complaint with
joint involvement later
Most commonly symmetric involvement although asymmetric
involvement may be seen early
Morning stiffness in the involved joints lasting one hour or more
Swelling, erythema
Muscle atrophy around the affected joints
Low grade fever without chills
18

Acute Onset → 10%–20%




Onset over several days
Less symmetric in presentation
Severe muscle pain
Intermediate Onset→ 20%–30%
Onset over several days to weeks
 Systemic complaints more noticeable

19
DIAGNOSIS OF RA
1988 American Rheumatologic Association (ARA) Criteria


Must satisfy 4–7 criteria
Criteria 1 through 4 must be present for at least six weeks
ARA Criteria:
 1. Morning Stiffness



In and around the joint
Must last at least one hour before maximal improvement
2. Arthritis of Three or More Joints



Three or more joint areas simultaneously affected with soft tissue swelling or
fluid
Observed by a physician
14 possible joint areas are bilateral proximal interphalangeal (PIP), metacarpal
phalangeal (MCP), wrist, elbow, knee, ankle and metatarsal phalangeal (MTP)
20
ARA Criteria

3. Arthritis of the Hand Joints


4. Symmetric Arthritis





Simultaneous involvement at the same joint area on both sides of the body
Absolute symmetry is not needed
5. Rheumatoid Nodules


At least one joint area swollen in the wrist, MCP and/or PIP
Subcutaneous nodules over extensor surfaces, bony prominence or in juxtaarticular regions
Observed by a physician
6. Serum Rheumatoid Factor (RF [+])
7. Radiographic Changes (Hand and Wrist)

Erosions, bony decalcification, and symmetric joint-space narrowing
21
The 2010 American College of Rheumatology/European
League Against Rheumatism classification criteria for
rheumatoid arthritis
Patients who:
1) have at least 1 joint with definite clinical synovitis (swelling)
2) with the synovitis not better explained by another disease
Classification criteria for RA (score-based algorithm: add score of categories A–
D; a score of ≥6/10 is needed for classification of a patient as having definite
RA)
A. Joint involvement:
Score:
 1 large joint
0
 2-10 large joints
1
 1-3 small joints (with or without involvement of large joints)
2
 4-10 small joints (with or without involvement of large joints)
3
 >10 joints (at least 1 small joint)
5
22
B. Serology (at least 1 test result is needed for classification)
Score
 Negative RF and negative ACPA
0
 Low-positive RF or low-positive ACPA
2
 High-positive RF or high-positive ACPA
3
C. Acute-phase reactants (at least 1 test result is needed for classification)
 Normal CRP and normal ESR
0
 Abnormal CRP or abnormal ESR
1
D. Duration of symptoms
 < 6 weeks
0
 ≥ 6 weeks
1
23
LABORATORY





Rheumatoid factor
ESR and C-reactive
protein
Thrombocytosis,
Hypochromic normocytic
anemia,
Eosinophilia
Hypergammaglobulinemi
a
Hypocomplementemia

Synovial fluid analysis
 Low viscosity
 WBC → 1,000–75,000
mm3
 > 70% PMNs
 Transparent - cloudy
24
Rheumatoid Factor

85% of the patients with RA have a (+) Rheumatoid
Factor (RF [+])




Associated with severe active disease with increased systemic
manifestations (nodules)
Serial titers are of no value
Can still be RF (−) and have RA because (+) diagnosis needs
four to seven diagnostic criteria
+ RF can be seen in other diseases: Rheumatic (SLE,
scleroderma, Sjögren’s), viral, parasitic, bacterial, neoplasms,
hyperglobulinemic purpura
25
RADIOGRAPHIC FINDINGS

(+) Juxta-articular osteopenia (bone washout)(early RA)
26

Marginal bone erosions (near attachment
of joint capsule)
27

Erosion of the ulnar styloid
28

Ulnar deviation and volar subluxation seen
at the MCP joint of the phalanges
29

Radial deviation of the radiocarpal joint
30

Hallux valgus
31

Erosion of the metatarsal head of the MTP
joint
32

Atlantoaxial subluxation (> 2.5–3 mm)
33
RADIOGRAPHIC FINDINGS

Early findings


Soft tissue swelling
↑ joint space
34
RADIOGRAPHIC FINDINGS

Late findings
Uniform joint space narrowing due to loss of
articular cartilage (hips, knees, etc.)
 Axial migration of the hip (Protrusio Acetabulum)
 Malalignment and fusion of joints

35
Hand and Wrist Deformities
Boutonnière Deformity
Mechanism




Weakness or rupture of the terminal portion of the extensor
hood (tendon or central slip), which holds the lateral bands in
place
The lateral bands slip downward (or sublux) to the axis of the
PIP joint turning them into flexors
The PIP then protrudes through the split tendon as if it were
a button hole (boutonnière = button hole)
The distal phalanx hyperextends
36
Result
Hyperextension of the MCP
 Flexion of the PIP
 Hyperextension of the DIP

Note: Positioning of the finger as if you were
buttoning a button
Orthotic

Tripoint finger splint
37
Swan Neck Deformity
Mechanism

Contracture of the intrinsic and deep flexor muscles
and tendons of the fingers
Result



Flexion contracture of the MCP
Hyperextension of the PIP
Flexion of the DIP
Orthotic

Swan neck ring splint
38
Ulnar Deviation of the Fingers
Mechanism




Weakening of the extensor carpi ulnaris (ECU), ulnar and radial collateral
ligament
Wrist deviates radially
Increases the torque of the stronger ulnar finger flexors
Flexor/extensor mismatch deviates the fingers in the ulnar direction as
the patient tries to extend the joint
Result

Ulnar deviation is due to the pull of the long finger flexors
Orthotic

Ulnar deviation splint
39
Tenosynovitis of the Flexor Tendon Sheath


One of the most common manifestation of the hands in RA
Can be a major cause of hand weakness
Result


Diffuse swelling of the volar surfaces of the phalanges
between the joints with palpable grating of the flexor tendon
sheath
May be confused with de Quervain’s disease
40
Carpal Bones Rotate in Zig-Zag Pattern
Mechanism




Ligament laxity
Radial deviation of the wrist
Ulnar styloid rotates dorsally
Carpal bones rotate


Proximal row: volarly
Distal row: dorsally
Result

Zig-zag pattern
41
Cervical Spine


Atlantoaxial Joint Subluxations → Most Common are
Anterior Subluxation
Instability




Odontoid or Atlas can erode
With flexion, the Atlantoaxial (AA) space should not increase
significantly: any space larger than 2.5 or 3 mm is considered
abnormal
Tenosynovitis of the transverse ligament of C1
Cervical myelopathy → erosion of the odontoid process,
ligament laxity or rupture
42
Foot
Hammer Toe Deformities
 Hyperextension of the MTP and DIP with flexion
of the PIP
 Claw Toe Deformities
 Hyperextension at the MTP joint and flexion of
the PIP and DIP joints
 Pain on the metatarsal heads on weight bearing
 Hallux Valgus Deformity
 Lateral Deviation of the Toes

43
44
Ankle
Ligament weakness leading to pronation of the hindfoot
 Tarsal tunnel syndrome
 Synovial inflammation leads to compression of the
posterior tibial nerve
Hip Deformities
 Symmetric involvement
 Protrusio acetabulum: Inward bulging of the acetabulum into
the pelvic cavity
 Accompanied by arthritis of the hip joint, usually due to RA

45
Shoulders
 Glenohumeral arthritis
 Effusions can occur; decreased range of motion
(ROM) may lead to frozen shoulder
 Rotator cuff injuries
Elbow
 Subcutaneous nodules
 Olecranon bursitis
 Loss of full elbow extension is an early problem and
may lead to flexion deformities
 Ulnar Neuropathies
46
Knee Deformities
 Common symmetric joint involvement
 Loss of full knee extension which may lead to
flexion contractures
 Quadriceps atrophy leading to increased amount of
force though the patella
 Force leads to increased intra-articular pressure in
the knee joint causing the synovial fluid to drip into
the popliteal space called a popliteal (Baker’s) cyst
47
EXTRA-ARTICULAR MANIFESTATIONS


More common in patients that are:
 RF (+)
 With rheumatoid nodules
 Severe articular disease
 MHC class HLA DRB1 Alleles
General
 Malaise or fatigue
48

Skin
 Subcutaneous Nodules
 Present in 50% of RA patients
 Form subcutaneously, in bursae, and along tendon
sheaths
 Typically located over pressure points
 Extensor surface of the forearm
 Can occur singly or aggregate in clusters
 Methotrexate may enhance the development or accelerate
the development of rheumatoid nodules
 Vasculitic Lesions
 Leukocytoclastic vasculitis and palpable purpura
49


Ocular
 Keratoconjunctivitis sicca (dry-eye syndrome)
 Episcleritis → benign, self-limited
 Scleritis
Pulmonary
 Interstitial lung disease
 Interstitial fibrosis
 Rheumatoid nodules
 Pulmonary fibrosis
 Pleurisy
 Inflammation of the cricoarytenoid joint → dysphagia,
dysphonia
 Bronchiolitis obliterans
50


Cardiac
 Pericarditis
 May lead to constrictive pericarditis with right-sided heart
failure
 Valvular heart disease
Gastrointestinal
 Xerostomia—dryness of the mouth secondary to decreased
salivary secretion
 Gastritis and Peptic Ulcer Disease (PUD) associated with
non-steroidal anti-inflammatory drugs (NSAIDs) (not directly
linked to disease)
51


Renal
 Rare glomerular disease usually related to drug (gold)
 May see renal involvement if amyloidosis develops
Hematologic
 Hypochromic- normocytic anemia
 Felty’s syndrome
52

Neurologic
 Cervical spine
 Most common at C1-C2, destruction of the transverse
ligament or the dens itself
 Cervical myelopathy
 Gradual onset of bilateral sensory paraesthesia of the
hands and motor weakness
 Neurologic exam findings may include → Babinski,
Hoffman’s, hyperactive Deep Tendon Reflexes (DTRs)
 Entrapment neuropathies
 This is secondary to fluctuation in synovial inflammation
and joint postures
 Mononeuritis multiplex —inflammatory—not due to
compression
53
Felty’s Syndrome
 “She felt her spleen”
 Classic triad of RA, splenomegaly, leukopenia
 Seen in seropositive RA, usually with nodules
 Occurs in the fifth to seventh decades with RA
> 10 years
 Women comprise two-thirds of cases
 Often associated with leg ulcers
54
Caplan’s Syndrome
 Intrapulmonary nodules—histologically similar
to rheumatoid nodules
 (+) rheumatoid factor
 Associated with rheumatoid arthritis and
pneumoconiosis in coal workers
 Granulomatous response to silica dust
55
TREATMENT

Education
Joint protection
 Home exercise program


Relative Rest

Required for the acutely inflamed joint
56

Exercise


Acute disease: with
severely inflamed joints,
actual splinting to
produce immobilization
with twice daily full and
slow passive range of
motion to prevent soft
tissue contracture
Mild disease: (moderate
synovitis) requires
isometric program
57

Isometric Exercise
Causes least amount of periarticular bone
destruction and joint inflammation
 Restores and maintains strength
 Generates maximal muscle tension with minimal
work, fatigue and stress
 Isotonics and isokinetic may exacerbate the flare and
should be avoided

58


Modalities
Cryotherapy
Pain relief in an acutely inflamed joint
 Decreases the pain indicators of inflammation


Superficial moist heat
Should not be used in acutely inflamed joints
 Depth of 1 cm
 Decreases pain and increases collagen extensibility


Other superficial heating/modalities: paraffin, fluidotherapy
59
ORTHOTICS

Indications




Decrease pain and inflammation
Reduce weight through joint
Decrease joint motion—stabilization
Joint rest
60



The MCP is thought to be the primary site of RA and
inflammation can lead to weakening of joint supporting
structures.
The major function of an orthosis used to combat early
deformity in RA is to prevent MCP flexion
Remember: There is no evidence that splinting will stop
these deformities, but stabilizing the MCP joint
accompanied with exercise may help prevent or slow
the progression.
61
Medications

Early diagnosis should be done within the first
month to prevent joint pathology
62
63
Biologic Response Modifiers





Infliximab (Remicade), adalimumab (Humira)
and etanercept (Enbrel)
Inhibit TNF
Administered once monthly, biweekly or twice
weekly depending on agent
Short term toxicity low, long term toxicity low
as well
Costly
64
IL-1b and TNF-: Proinflammatory Cytokines in
the Rheumatoid Joint
High endothelial
venule
Bone
Osteoblasts
Synovial
membrane
O steoclasts
Cartilage
IL-8
PGE2
IL-6
Capsule
TNF- 
IL-1b
Neutrophils
Synovial
space
C hondrocytes
Pannus
Osteoblasts
Osteoclasts
Bone
PGE2 = prostaglandin-E2
Dinarello C, Moldawer L. Proinflammatory and Anti-inflammatory Cytokines in Rheumatoid Arthritis:
A Primer for Clinicians. 3rd ed. Thousand Oaks, Ca, USA: Amgen Inc.; 2001.
65
Poor Prognosis
1. Extraarticular disease, rheumatoid nodules, vasculit
2. High RF (+)
3. X ray consistent with erosive disease within 2 years
4. Persistent elevated ESR and CRP
5. HLA DR4 (+)
6. Generalized polyarthritis involving both small and large
joints (20 and more)
66
Surgical Options




Synovectomy
Arthroplasty
Arthrodesis
Tendon repairs
67
Polymyalgia Rheumatica (PMR)







In view of clinical similarities between PMR patients with and
without signs of arteritis in a temporal artery biopsy, many
authors believe that PMR is an expression of giant cell
arteritis
Fever, weight loss, malaise
Proximal muscles—neck, shoulder, pelvic
Morning stiffness—muscle tenderness
Abrupt myalgias/arthralgia
Diagnosis: ↑ ESR > 50
Treatment: steroids
68
SJÖGREN’S SYNDROME


Autoimmune-mediated disorder of the exocrine
glands
Clinical presentation (sicca symptoms):
Dry eyes
 Dry mouth
 Skin lesions
 Parotid involvement

69


LABS: ANA (+), RF (+)
Classification: Primary and secondary forms
Primary—Dry eyes and mouth with ANA (+) , RF
(+)
 Secondary—sicca symptoms


Sjögren’s syndrome plus evidence of SLE, RA, PSS,
Polymyositis
70
Extraglandular manifestations:
 Arthralgias
 Raynaud’s phenomenon
71
72
73
74
The 2010 American College of
Rheumatology/European League Against
Rheumatism classification

Target population (Who should be tested?): Patients who
 1) have at least 1 joint with definite clinical synovitis
(swelling)
 2) with the synovitis not better explained by another disease

Classification criteria for RA (score-based algorithm: add score
of categories A–D; a score of ≥6/10 is needed for classification
of a patient as having definite RA)
75
A. Joint involvement

1 large joint

2-10 large joints

1-3 small joints (with or without involvement of large joints)

4-10 small joints (with or without involvement of large joints)

>10 joints (at least 1 small joint)
B. Serology (at least 1 test result is needed for classification)

Negative RF and negative ACPA

Low-positive RF or low-positive ACPA

High-positive RF or high-positive ACPA
C. Acute-phase reactants (at least 1 test result is needed for classification)

Normal CRP and normal ESR

Abnormal CRP or normal ESR
D. Duration of symptoms

< 6 weeks

≥ 6 weeks 1
Score
0
1
2
3
5
0
2
3
0
1
0
76
77