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
Direct costs
Indirect costs
Total costs
Costs per patient in $ per year
RA CAD
3790
2735
6525
7929
1051
8980
4

Immunology
5

6

Rheumatoid Arthritis: Pathogenesis
Current
Treatment
Targets
T cell
B cell
Antigenpresenting cells
B cell or macrophage
Pannus
Synoviocytes
IFN-

& other cytokines
Rheumatoid
Factors, anti-CCP
Macrophage
TNF

IL-1
Immune complexes
Complement
Neutrophil
Chondrocytes
Mast cell
Osteoclast
Articular cartilage Production of collagenase and other neutral proteases
Bone
Adapted from Arend WP, Dayer JM. Arthritis Rheum. 1990;33:305 –15
7

Immunology of RA
8

Imbalance in Mediators – Chronic Inflammation
9

The Mediators of Joint Destruction
Chemokines
IL-1, IL-6
Cytokines
TNF
MMP
VEGF
Immune destruction
10

The Natural Course of RA
Undifferentiated
Polyarthritis
Early RA – Mild
Disease
Severe RA with
Deformities
11

Time Line of Function Loss in RA
Moderate loss of function
Severe loss of function
Very severe loss of function
0 2 5
Years from onset of symptoms
10
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
Class II
Class III
Class IV
Complete ability to perform daily activities self-care, vocational and avocational
Ability to perform usual self-care and vocational activities; limited avocational activities
Ability to perform usual self-care activities; limited vocational or avocational activities
Limited ability to perform usual self-care or vocational or avocational activities
17

Extra Articular Manifestations of RA
Systemic involvement Special Features
Musculoskeletal wasting
Tenosynovitis, Bursitis
Osteoporosis, Rh nodules
Vasculitis, Arteritis
Pericarditis, Myocarditis
Episcleritis, Scleromalacia
Pleural effusion, Nodules
Cervical cord compression
Mononeutitis, carpel tunnel
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
Advanced Rheumatoid Arthritis
Rheumatoid Arthritis (over all)
Sjögren's syndrome
Systemic Lupus Erythematosis (SLE) 30%
Sub acute bacterial endocarditis (SABE) 40%
Tuberculosis
Old Age
Normal healthy individuals
15%
20%
5%
Frequency
100%
70%
90%
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
Pathology
Rheumatoid Arthritis Osteoarthritis
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
Disability
Rapidly progressive
Highly disabling
Slowly progressive
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

Presence of rheumatoid nodules


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.
2.
6.
7.
3.
4.
5.
Relief of pain
Reduction of inflammation
Protection of articular structures
Maintenance of functional activity
Control of systemic involvement
Slow the progression of disease
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
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.

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
Constituent pathway
Renal and GI homeostasis
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

Ibuprofen

Ketoprofen

Diclofenac

Aceclofenac

Piroxicam

Lornaxicam

Naproxen

Indomethacin
NSAIDs used as analgesics

Ketorolac

Aspirin (NSAID)
Selective COX-2

Celecoxib, Etoricoxib

Meloxicam
Analgesics

Tramadol

Paracetamol
43

Pros and Cons of NSAID Therapy
PROS

Effective control of inflammation and pain

Effective reduction in swelling

Improves mobility, flexibility, range of motion

Improve quality of life

Relatively low-cost
CONS

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
CONS

Does not conclusively affect disease progression

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

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
Current Treatment
Traditional DMARDs
• Early
Aggressive Rx.
• Biological
• Combination treatment
47

48

49

New Treatment Paradigm for RA
Orthopedic surgery
Occupational therapy
Physical therapy
Patient education
Weaver AL, 2008.
Higher dose steroids for flares or extraarticular disease
Intraarticular steroids
Simple analgesic
50

Biological Agents in RA

TNFα antagonists



Adalimumab (Humira)
Etanercept (Enbrel)
Infliximab (Remicade)

Interleukin-1 antagonist

Anakinra (Kineret)

Suppressors of T-Cell activation

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
Target
Half Life
TNF
3-5 Days
TNF
8-10 Days
TNF
10-20 Days
IL-1
Receptor
4-6 Hrs
T-Cell
Activation
13-16
Days
Rituximab
Rituxan
B-Cell
19 Days
Construct Human Chimeric Human Human Human Chimeric
Dosing
Route
Once
Biweeklyweekly
Sub-Cut
Once every
4-8 weeks
Once every
1-2 weeks
I.V.
Sub-Cut
Once
Daily
Sub-Cut
Once
Monthly
I.V.
Twice every 6-12 months
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

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