BioEd Online

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

Website: www.drsarma.inWebsite: www.drsarma.inYou Tube: drsarmaji channelYou Tube: drsarmaji channel

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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

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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

44

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

Immunology

55

66

Rheumatoid Arthritis: Pathogenesis

77Adapted from Arend WP, Dayer JM. Arthritis Rheum.

1990;33:305–15

B cell

T cell

Antigen-presenting

cells

B cell ormacrophage Synoviocytes

Pannus

Articular cartilage

Chondrocytes

Macrophage

HLA-DRother cytokines

IFN- &

Production of collagenase and other

neutral proteases

Osteoclast

TNF

IL-1

Rheumatoid

Factors, anti-CCP

Immune complexes

Bone

Complement

Neutrophil

Mast cell

Current Treatment Targets

Immunology of RA

88

Imbalance in Mediators – Chronic Inflammation

99

The Mediators of Joint Destruction

1010

The Natural Course of RA

1111

Time Line of Function Loss in RA

1212Wolfe F, Cathey MA. J Rheumatol. 1991;18:1298-1306.

Moderate loss of function

Severe loss of function

Very severe loss of

function

0 1052

Years from onset of symptoms

Years from onset of symptoms

25% require surgical Rx.25% require surgical Rx.

Rheumatoid Arthritis: Diagnosis - ACR Criteria

1313

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

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

1414

The Joints Involved in RA

1515

1616

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)

Rheumatoid Arthritis – ACR Functional Classes

Classification

Specifications of activity levels

Class IComplete ability to perform daily activitiesself-care, vocational and avocational

Class IIAbility 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 IVLimited ability to perform usual self-care or vocational or avocational activities

1717

Extra Articular Manifestations of RA

1818

1919

2020

Swan-Neck and Boutonniere Deformities in RA

2121

http://images.rheumatology.org – Album of American College of Rheumatology

2222

2323

Radiological Changes in Rheumatoid Arthritis

2424

2525

Erosion of the Odontoid processErosion of the Odontoid process

Atlanto-Axial subluxationAtlanto-Axial subluxation

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

2626

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

2727

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

2828

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%

2929

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

3030

Serology in Rheumatoid Arthritis

3131

Test

RA Factor is IgM Antibody to the Fc portion of the IgG

Anti CCP: Antibodies to Cyclic Citrullinated Peptides

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 arthritis3232

Rheumatoid Arthritis v/s Osteoarthritis

3333

FeatureRheumatoid Arthritis

Osteoarthritis

Pathology Autoimmune Degenerative

AgeAny 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

CourseRapidly progressive

Slowly progressive

Disability Highly disabling Mild to moderate

Early Progression of Bone Erosions in RA

3434

Rheumatoid Arthritis: Predictors of Prognosis Presence of > 20 inflamed joints

Markedly elevated ESR

Radiographic evidence of bone erosions

Presence of rheumatoid nodules

High titers of RA Factor and 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

3535

40%-85% of RA pts unable to work in 8-10 years

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

3636

Rheumatoid Arthritis: Complications

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

3737

Non Pharmacological Management

Rest Exercise

Flexibility/stretching Muscle conditioning Cardiovascular/aerobic

Diet Weight management Physical and occupational therapy

3838

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.

Surgical Treatment will be mandated in 25%

Medical Management – Drug Classes

4141

NSAIDS in RA

4242

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

Constituent pathway

Renal and GI homeostasis

Inducible pathway

Inflammation

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

Paracetamol4343

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

4444

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 steroid-induced osteopenia

4545

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,

HCQ4646

Changing Paradigm of Treatment

4747

Current TreatmentTraditional DMARDs

4848

4949

New Treatment Paradigm for RA

5050

Orthopedic surgeryHigher dose steroids for flares or extraarticular disease

Occupational therapy

Physical therapy

Patienteducation

Intraarticular steroids

Simple analgesic

Weaver AL, 2008.

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)

5151

Characteristics of Biologicals used in RA

5252

Etanercept

Enbrel

Infliximab

Remicade

Adalimumab

Humira

Anakinra

Kineret

Abatacept

Orencia

Rituximab

Rituxan

Target TNF TNF TNFIL-1

ReceptorT-Cell

ActivationB-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

DosingOnce

Biweekly-weekly

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.

Biologics: Relative Contraindications

5353

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)

Safety Considerations of Biologicals

5454

Serious Infections

Opportunistic infections (TB)

Malignancies/lymphoma

Demyelination

Hematologic abnormalities

Administration reactions

Congestive heart failure

Hepatic

Autoantibodies and drug induced lupus

Vaccination

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