Rheumatoid arthritis

RHEUMATOID ARTHRITIS

ByDr.ESSAM T. ATWA

PROFESSOR OF RHEUMATOLOGY & REHABILITATION

Rheumatoid arthritis (RA) is a systemic disease characterized predominantly by a chronic inflammatory polyarthritis, with frequent progression to joint destruction and disability.

The clinical picture seen in RA is the result of a complex cascade involving T cells, B cells, antigen-presenting cells, and a complex set of costimulation signals that lead to the production of proinflammatory cytokines, including tumor necrosis factor (TNF)-alpha, interleukins, and other mediators.

Definition

The hallmarks of RA are inflammation and synovitis leading to joint damage, and an overexpression of inflammatory cytokines, such as TNF-alpha, IL-1, and IL-6.

Although disease activity is the major cause for active joint damage in RA leading to disability, measuring disease activity in patients with RA remains a challenging issue.

A number of composite disease scoring systems have been developed over the past decade, which consider physical and radiographic evaluations as well as overall physician and patient assessment.

In addition, acute-phase reactant inflammatory markers, such as CRP and ESR, can provide additional information of the disease state.

RA Is Characterized by Synovitis and Joint Destruction

NORMAL RA

Synovial membrane

Cartilage

CapsuleSynovial

fluid

Inflamed synovial

membrane

Pannus

Major cell types•T lymphocytes•macrophages

Minor cell types•fibroblasts•plasma cells•endothelium•dendritic cells

Major cell type•neutrophils

Feldmann M, et al. Annu Rev Immunol. 1996;14:397-440.

Cartilage thinning

Pannus formation

Expansion of the synovial membrane forms an invasive pannus1

Synovial cells and chondrocytes release destructive enzymes that degrade cartilage1

Pannus invades cartilage, leading to bone erosion and joint instability1

1Harris ED Jr. N Engl J Med. 1990;322:1277-1289 .

Surgically resected pannus from a patient with

advanced RA

Antigen presentation

Foreign antigens bind to receptors on antigen-presenting cells1

Complementary receptors on T cells recognize the antigens, triggering an immune response1

1Harris ED Jr. N Engl J Med. 1990;322:1277-1289.

The inflammatory cascade

Activation of T cells triggers a series of intercellular reactions1

Lymphocytes and macrophages release proinflammatory cytokines1,2

Cytokines induce synovial proliferation and release of destructive enzymes1,2

1Rosenberg AE. In: Cotran RS, Kumar V, Robbins SL, eds. Robbins Pathologic Basis of Disease. 5th ed. Philadelphia, Pa: W.B. Saunders Company; 1994:1213-1271 .

2Goronzy JJ, Weyand CM. In: Klippel JH, ed. Primer on the Rheumatic Diseases. 11th ed. Atlanta, Ga: Arthritis Foundation; 1997:155-161.

Protein

Inflammation

Cytokine in Inflammation

PROINFLAMMATORY

ANTI-INFLAMMATORY

TNF

IL-1

IL-6

IL-8

IFN-LT

IL-4

IL-10

TGF

sTNFR

sIL-1R

IL-1Ra

Adapted from Feldmann M et al. Cell 85:307-310, 1996 and Moreland LW et al. Arthritis Rheum 40:397-409, 1997.

disequilibrium

TNF Is a Key Pathogen in Rheumatic Disease

TNF

Macrophages

Endothelium

Hepatocytes

Synoviocytes

Pro-inflammatory cytokines Chemokines

Adhesion molecules

Acute phase response

Metalloproteinase synthesis

Vascular endothelial growth factor (VEGF)

Articularcartilage

degradation

IncreasedCRP in serum

Increasedangiogenesis

Increased cellinfiltration

Increasedinflammation

Osteoclast Progenitors RANKL expression

Bone erosions

TNF

osteoclasts synoviocytes chondrocytes

bone resorption

bone erosion

joint inflammation

cartilage degradation

joint space narrowing

pain/joint inflammation

Central Role of TNF in Rheumatoid Arthritis

The diagnosis of RA is made using :

The patient's history and examination results

In conjunction with laboratory and radiographic data.

CLINICAL

◦ Symmetric joint pain◦ Swelling of small

peripheral joints◦ Morning joint stiffness of

variable duration◦ Other diffuse achingFatigue, malaise, and depressionmay precede other symptomsby weeks or months

Grassi W et al. Eur J Radiol. 1998;27(suppl 1):S18–S24.

RHEUMATOID ARTHRITISPresenting Signs and Symptoms

INVESTIGATIONS

RADIOLOGY

1987 Revised American Rheumatism Association Criteria for the Classification of Rheumatoid Arthritis

Definition Criterion

Morning stiffness in and around the joints, lasting at least 1 h.

1. Morning stiffness

At least three joint areas simultaneously have had soft tissue swelling or fluid (not bony overgrowth alone) observed by a physician. The 14 possible areas are right or left PIP, MCP, wrist, elbow, knee, ankle, and MTP joints.

2. Arthritis in three or more joint areas

At least one area swollen (as defined above) in a wrist, MCP, or PIP joint.

3. Arthritis of hand joints

Simultaneous involvement of the same joint areas (as defined in Criterion 2) on both sides of the body (bilateral involvement of PIPs, MCPs, or MTPs is acceptable without absolute symmetry).

4. Symmetric arthritis

Cont.Definition Criterion

Subcutaneous nodules over bony prominences or extensor surfaces or juxtaarticular regions observed by a physician.

5. Rheumatoid nodules

Demonstration of abnormal amounts of serum rheumatoid factor by any method for which the result has been positive in <5% of normal control subjects.

6. Serum rheumatoid factor

Radiographic changes typical of rheumatoid arthritis on the posteroanterior hand and wrist radiographs, which must include erosions or unequivocal decalcification localized in, or most marked adjacent to, the involved joints (osteoarthritis changes alone do not qualify).

7. Radiographic changes

MCP, metacarpophalangeal; MTP, metatarsophalangeal; PIP, proximal interphalangeal.

For classification purposes, a patient shall be said to have rheumatoid arthritis if he or she has satisfied at least four of these seven criteria.

Criteria 1 through 4 must have been present for at least 6 weeks.

Patients with two clinical diagnoses are not excluded.

Designation as classic, definite, or probable rheumatoid arthritis is not to be made.

The 2010 American College of Rheumatology/European League Against Rheumatism classificationcriteria for rheumatoid arthritis

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)

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

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)

Score

Normal CRP and normal ESR

0

Abnormal CRP or abnormal ESR

1

D.Duration of symptoms

Score

< 6 weeks 0

> 6 weeks 1

TREATMENT

Characteristics of ideal RA therapy

°Provides both rapid and sustained efficacy

°Highly effective for symptom relief

°Leads to prevention of joint destruction

° Prevents functional disability

° Useful in combination treatment

° Well tolerated, with minimal monitoring required

° Allows for simple dosing and administration

Modern history of RA treatment

1928

1948

1985

2000

Milestones Steps foreward

Parenteral Gold

Corticosteroids

Methotrexate

TNF blockers

Antimalarials

Modern NSAIDs

Azathioprine

D-Penicillamine

Sulfasalazine

Cyclosporin A

Leflunomide

COXIBS

DMARDCombination

If DiseaseControlled

Wolfe F, et al. J Rheumatol. 2001;28:1704-11 .Fleischmann RM. Clin Ther. 1999;21:1429-42 .Matteson EL. Mayo Clin Proc. 2000;75:69-74.

The Evolving RA Treatment Paradigm

Initial Treatment Initial Treatment

Monotherapy or Combination

Current Approach Evolving Paradigm

Conventional DMARDs DMARDBiologic

agent

If Poor Response

Add additional DMARDs

Add biologic

agent

If Poor Response

Combinationtherapy

Discontinuation/reduction of

DMARDs

THANK YOU