Transcript Rheumatoid Arthritis by Dr Sarma

Website: www.drsarma.in
You Tube: drsarmaji channel
Prof. Dr. Sarma. R.V.S.N
M.D.(Med), M.Sc.(Canada),
RCGP, FCGP, FIMSA
Consultant Physician and
Cardio-Metabolic Specialist
National Professor of Medicine
Visiting Faculty – Frontier Life Line
Visiting Professor of Medicine – SBMC
BioEd Online
Rheumatoid Arthritis (RA): Definition

Progressive, systemic, Autoimmune inflammation

Often aggressive, devastating consequences

Unknown etiology (auto immune, ?infection, smoking)

Characterized by
Symmetric synovitis – Chronic Polyarthritis
Joint erosions, cartilage and bone destruction
Multisystem - extra-articular manifestations
Onset usually slow & insidious over months
In 15 to 20% may have rapid or acute
Aggressive management leads to good control
2
Rheumatoid Arthritis (RA): Epidemiology

Prevalence of - 0.8% to 2.1% of the population

Gender predilection ratio – Women: Men – 3:1

Prevalence increases with age – Juvenile RA

About 40-60% have severe disease – 3 fold  mortality

Median life expectancy is shortened by 3 to 7 years

Onset mostly between ages of 35 – 60 years

Genetic – HLA-DR1( 1*0101, 0401) – Class II HCA

Exact etiology is not known
3
Cost of RA versus CAD
Costs per patient in $ per year
RA
CAD
Direct costs
3790
7929
Indirect costs
2735
1051
Total costs
6525
8980
4
Immunology
5
6
Rheumatoid Arthritis: Pathogenesis
Current
Treatment
Targets
Rheumatoid
Factors,
anti-CCP
B cell
Immune complexes
Complement
T cell
IFN- &
Neutrophil
other
cytokines
Antigenpresenting
cells
B cell or
macrophage
Synoviocytes
Pannus
Macrophage
Mast cell
TNF
Chondrocytes
IL-1
Osteoclast
Articular cartilage
Production of collagenase and other
neutral proteases
Bone
7
Adapted from Arend WP, Dayer JM. Arthritis Rheum. 1990;33:305–15
Immunology of RA
8
Imbalance in Mediators – Chronic Inflammation
9
The Mediators of Joint Destruction
Chemokines
IL-1, IL-6
Cytokines
MMP
TNF
VEGF
Immune
destruction
10
The Natural Course of RA
Severe RA with
Deformities
Early RA – Mild
Disease
Undifferentiated
Polyarthritis
11
Time Line of Function Loss in RA
Moderate
loss of
function
0
2
Severe
loss of
function
Very severe
loss of
function
5
10
Years from onset of symptoms
25% require surgical Rx.
Wolfe F, Cathey MA. J Rheumatol. 1991;18:1298-1306.
12
Rheumatoid Arthritis: Diagnosis - ACR Criteria

Four or more of the following criteria must be present:

Morning stiffness > 1 hour

Arthritis of > 3 joint areas of the possible 28 joints

Arthritis of hand joints (MCPs, PIPs, wrists)

Symmetric swelling (arthritis) – same joints on both sides

Serum rheumatoid factor – RA Factor (antibody to IgG)

Rheumatoid nodules

Radiographic changes
 First
four criteria must be present for 6 weeks or more
13
Rheumatoid Arthritis: Typical Involvement

Wrist joints and MCP joints - very commonly involved

Index and middle Metacarpophalangeal joints

Proximal interphalangeal joints (PIP)

Metacarpophalangeal joints (MCP)

Metatarsophalangeal joints (MTP)

Elbows, Shoulders

Knees, Ankles, Hips. Lumbosacral area is not involved

Spine: only Atlanto-axial joint (C1– C2), subluxation

Terminal interphalangeal (TIPS) joints are not involved

14
The Joints Involved in RA
15
DAS28 (Disease Activity Scoring) for RA - EULAR

Calculated using a formula that includes

Counts for tender and swollen joints – (28 joints)

General health by the patient (on a scale of 0 to 100)

A measurement of ESR or CRP

Score > 5.1 – High disease activity,

Score 5.1 to 3.2 – Moderate disease activity

Score < 3.2 – Low disease activity

Score < 2.6 – Being in Remission

Response to Rx. –  of ≥ 1.2 – Good and < 0.6 – Poor
European League Against Rheumatism (EULAR)
16
Rheumatoid Arthritis – ACR Functional Classes
Classification Specifications of activity levels
Class I
Complete ability to perform daily activities
self-care, vocational and avocational
Class II
Ability to perform usual self-care and vocational
activities; limited avocational activities
Class III
Ability to perform usual self-care activities;
limited vocational or avocational activities
Class IV
Limited ability to perform usual self-care or
vocational or avocational activities
17
Extra Articular Manifestations of RA
Systemic involvement
Special Features
Musculoskeletal wasting
Episcleritis, Scleromalacia
Tenosynovitis, Bursitis
Pleural effusion, Nodules
Osteoporosis, Rh nodules
Cervical cord compression
Vasculitis, Arteritis
Mononeutitis, carpel tunnel
Pericarditis, Myocarditis
Felty’s syndrome, Caplan’s
18
19
20
Swan-Neck and Boutonniere Deformities in RA
http://images.rheumatology.org – Album of American College of
Rheumatology
21
22
23
Radiological Changes in Rheumatoid Arthritis
24
Erosion of the Odontoid process
Atlanto-Axial subluxation
25
Blood Parameters in RA

Acute Phase Reactants (APR )
 C-Reactive Protein (CRP) - > 4 mg% -

It is the single most useful marker
ESR is raised > 30 mm – other confounders
Ceruloplasmin

Haptoglobin (Hp)



Leukocytosis, Nutrophilia

Normocytic normochromic anemia

Thrombocytosis
26
Synovial Fluid in RA

No need in general for joint aspiration

Required to exclude other causes of arthritis

Inflammatory arthritis picture
 Turbid fluid with reduced viscosity
 Increased protein content

Decreased glucose content

WBC count from 2,000 to 50,000/l
PMNLs predominate

Total compliment, C3 and C4 are markedly 

27
Rheumatoid Factor (RA Factor)

Developed by Eric Waller in 1937 – Rose Waller Test

Agglutinating Abs - Latex particle agglutination assay

Isotype specific enzyme immunoassays – New technique

Antibodies to Fc portion of our own IgG - These Abs are IgM

Positive in 5% of normal persons and in only 70-80% of RA

Low specificity (false +ves) & low sensitivity (false –ves.)

It is not a screening or Dx. tool – More a prognostic tool

It is negative in 30% cases of RA – Sero negative RA

RF are commonly seen other disease – see next slide
28
Positive Rheumatoid Factor is seen in:
Disease
Frequency
Advanced Rheumatoid Arthritis
100%
Rheumatoid Arthritis (over all)
70%
Sjögren's syndrome
90%
Systemic Lupus Erythematosis (SLE)
30%
Sub acute bacterial endocarditis (SABE)
40%
Tuberculosis
15%
Old Age
20%
Normal healthy individuals
5%
29
Anti-CCP Antibody Test in RA (ACPA)

Antibodies to Cyclic Citrullinated Peptides (anti-CCP)

Similar sensitivity for RA (70%)

Specificity for RA (>95%) better than RA Factor

In early polyarthritis anti-CCP are useful for Dx.

Anti-CCP are associated with more severe disease

They spell a poor prognosis and rapid progression

They may be positive in asymptomatic patients years
before the onset of symptoms
30
Serology in Rheumatoid Arthritis
Test
RA Factor is IgM Antibody to the Fc portion of the IgG
Anti CCP: Antibodies to Cyclic Citrullinated Peptides
31
Differential Diagnosis of RA

Connective tissue diseases - Scleroderma and SLE

Fibromyalgia, Palindromic Rheumatism

Infectious endocarditis, Acute Rheumatic Fever

Poly articular gout

Polymyalgia Rheumatica

Sarcoidosis, Hemochromatosis

Sero negative spondylo arthropathies

Reactive arthritis - evaluate for psoriasis, Reiter’s, IBD

Still’s disease, Thyroid disease, Viral arthritis
32
Rheumatoid Arthritis v/s Osteoarthritis
Feature
Rheumatoid Arthritis
Osteoarthritis
Pathology
Autoimmune
Degenerative
Age
Any age – usually 35+
Increases with age
Joints involved
Small joints MCP, PIP
Large joints, TIP
Spine (Axial)
C1-C2 - Subluxation
Lumbosacral
Extra articular
Many systemic effects
Few systemic effects
Course
Rapidly progressive
Slowly progressive
Disability
Highly disabling
Mild to moderate
33
Early Progression of Bone Erosions in RA
34
Rheumatoid Arthritis: Predictors of Prognosis

Presence of > 20 inflamed joints

Markedly elevated ESR

Radiographic evidence of bone erosions
40%-85%
of RA pts
unable to work in 8Presence of rheumatoid
nodules
High titers of RA Factor10
andyears
anti CCP



Higher class of functional disability

Persistent inflammation; comorbidities

Advanced age of onset

Low socio-economic status, low education level

HLA-DR*0401 or DR*0404
35
Rheumatoid Arthritis: Complications

Carpal tunnel syndrome,

Baker’s cyst, Subcutaneous nodules,

Systemic Vasculitis,

Sjögren’s syndrome,

Peripheral neuropathy,

Cardiac and pulmonary involvement,

Felty’s syndrome, and anemia

Risk of lymphomas three times greater

Risk of infection due to disease and treatment
36
Goals of Therapy
1.
Relief of pain
2.
Reduction of inflammation
3.
Protection of articular structures
4.
Maintenance of functional activity
5.
Control of systemic involvement
6.
Slow the progression of disease
7.
Increase the over all quality of life
37
Non Pharmacological Management

Rest

Exercise

Flexibility/stretching

Muscle conditioning

Cardiovascular/aerobic

Diet

Weight management

Physical and occupational therapy
38
Therapeutic Window of Opportunity


Erosive changes occur early in disease
Even a brief delay of therapy can have a significant
impact on disease parameters years later

Early DMARD treatment to arrest progression

MTX is the sheet anchor – Combination of DMARDs

Bridge the gap initially with NSAID and GC

Biologics only for refractory case – with caution; cost

Surgical treatment options in selected patients
O’Dell JR. Arthritis Rheum. 2002;46:283-285.
Van der Heijde DM. Br J Rheum. 1995;34 (suppl 2):74-78.
Therapeutic Window of Opportunity


Erosive changes occur early in disease
Even a brief delay of therapy can have a significant
impact on disease parameters years later
Surgical Treatment will be mandated in
 Early DMARD treatment to arrest progression
25%

MTX is the sheet anchor – Combination of DMARDs

Bridge the gap initially with NSAID and GC

Biologics only for refractory case – with caution; cost

Surgical treatment options in selected patients
O’Dell JR. Arthritis Rheum. 2002;46:283-285.
Van der Heijde DM. Br J Rheum. 1995;34 (suppl 2):74-78.
Medical Management – Drug Classes
Classes
NSAIDs – Cox-1 & Cox-2 inhibitors
Glucocorticoids – Prednisolone, MP
IAS – Intra articular steroids
DMARDs – MTX, SSZ, HCQ, CQ
Immunosuppressive Rx.– AZT, Leflunomide, CS
Cytotoxic agents – Cyclophosphamide
Biologics – TNF-
antibodies, IL-1 R antagonist
Old drugs – Gold salts, D-Penicillamine
41
NSAIDS in RA

NSAIDs
COX 1
Constituent pathway
Renal and GI
homeostasis
COX2
Inducible
pathway
Inflammation
Selective COX 2 Inhibitors

Improved GI tolerability

Reduced effects on RBF

No effect on platelets

Called as COXIBs

May have adverse effect
on heart

Celecoxib

Etoricoxib

Meloxicam
42
NSAID Class of Drugs
Non Selective
NSAIDs used as analgesics

Ibuprofen

Ketorolac

Ketoprofen

Aspirin (NSAID)

Diclofenac
Selective COX-2

Aceclofenac

Celecoxib, Etoricoxib

Piroxicam

Meloxicam

Lornaxicam
Analgesics

Naproxen

Tramadol

Indomethacin

Paracetamol
43
Pros and Cons of NSAID Therapy
PROS



Effective control of
inflammation and pain
Effective reduction in
swelling
CONS



Improves mobility,
flexibility, range of motion

Improve quality of life

Relatively low-cost
Does not affect disease
progression
GI toxicity common
Renal complications
(eg. Irreversible renal
insufficiency, papillary
necrosis)

Hepatic dysfunction

CNS toxicity
44
Pros and Cons of Corticosteroid Therapy
PROS



Anti-inflammatory and
immunosuppressive effects
Can be used to bridge
gap between initiation
of DMARD therapy and
onset of action
Intra-articular steroid (IAS)
injections can be used for
individual joint flares
CONS




Does not conclusively
affect disease progression
Tapering and
discontinuation of use
often unsuccessful
Low doses result in skin
thinning, ecchymoses, and
Cushingoid appearance
Significant cause of steroidinduced osteopenia
45
Methotrexate (MTX)









MTX is given 10 to 30 mg orally, IM, or SC per week
It is DHF reductase inhibitor – Supplemental folic acid
The clinical improvement takes one to two months
Nausea, diarrhea; mouth ulcers; rash, alopecia; Abnormal LFT
Rare: low WBC & platelets; pneumonitis; sepsis; liver disease;
EBV related lymphoma;
CBC, creatinine, and LFTs monthly for six months, then every one
to two months; repeat AST or ALT in two to four weeks if initially
elevated, and adjust dose as needed;
Rapid onset (six to 10 weeks); tends to produce more sustained
results over time than other DMARDs and lowers all-cause
mortality;
Can be used when cause of polyarthritis uncertain;
Often combined with other DMARDs like Leflunomide, SSZ, HCQ
46
Changing Paradigm of Treatment
Evolving paradigm
Current Treatment
Traditional DMARDs
• Early
Aggressive Rx.
• Biological
• Combination
treatment
47
48
49
New Treatment Paradigm for RA
Orthopedic surgery
Occupational therapy
Higher dose steroids
for flares or extraarticular disease
Intraarticular steroids
Physical therapy
Patient
education
Simple
analgesic
Weaver AL, 2008.
50
Biological Agents in RA


TNFα antagonists

Adalimumab (Humira)

Etanercept (Enbrel)

Infliximab (Remicade)
Interleukin-1 antagonist


Suppressors of T-Cell activation


Anakinra (Kineret)
Abatacept (Orencia)
Anti B-Cell monoclonal antibody

Rituximab (Rituxan)
51
Characteristics of Biologicals used in RA
Etanercept
Enbrel
Infliximab
Remicade
Adalimumab
Humira
Anakinra
Kineret
Abatacept
Orencia
Rituximab
Rituxan
Target
TNF
TNF
TNF
IL-1
Receptor
T-Cell
Activation
B-Cell
Half Life
3-5 Days
8-10 Days
10-20 Days
4-6 Hrs
13-16
Days
19 Days
Construct
Human
Chimeric
Human
Human
Human
Chimeric
Dosing
Once
Biweeklyweekly
Once every
4-8 weeks
Once every
1-2 weeks
Once
Daily
Once
Monthly
Twice
every 6-12
months
Route
Sub-Cut
I.V.
Sub-Cut
Sub-Cut
I.V.
I.V.
52
Biologics: Relative Contraindications

Active Hepatitis B Infection

Multiple sclerosis, optic neuritis

Active serious infections

Chronic or recurrent infections

Current neoplasia

History of TB or evidence of Koch’s

Congestive heart failure (Class III or IV)
53
Safety Considerations of Biologicals


Serious Infections
Opportunistic infections
(TB)

Malignancies/lymphoma

Demyelination

Hematologic
abnormalities

Administration reactions

Congestive heart failure

Hepatic


Autoantibodies and drug
induced lupus
Vaccination
54
www.drsarma.in
BioEd Online