2/7/2019

Rheumatoid Arthritis

Dr. ABDEL-RAHMAN YOUSSEF, MBBCh, MD, PhD

Assistant Professor in Microbiology & Immunology
Faculty of Dentistry
Umm Al-Qura University

Learning objectives

• Classification of autoimmune diseases

• Hypersensitivity reactions
• Rheumatoid Arthritis
– Definition
– Development
– Pathogenesis
– Immunological markers

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Classification of autoimmune diseases

• Organ specific
➢ Autoimmune hemolytic anemia
➢ Graves' disease

• Systemic
➢ Systemic lupus erythematosus (SLE)
➢ Rheumatoid arthritis

• The mechanisms of tissue damage in autoimmune diseases

are due to any hypersensitivity reactions except type I

Type II hypersenstivity

Type II hypersensitivity results from reaction of an antibody

(IgG or IgM) with antigen on the cell surface e.g. blood
transfusion reaction due to ABO incompatibility & Rh-
incompatability

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Type III Hypersensitivity

Type III responses are
mediated by immunoglobulin
directed against soluble
antigens

Immune complexes deposited

in tissues and on the
basement membrane of blood
vessels and cause tissue injury
as in SLE and rheumatoid
arthritis

Type IV hypersensitivity reaction

(delayed or cell mediated)

Antigen is presented by APCs to antigen CD4 T cells that

become activated and produce cytokines that cause
inflammatory cells to move into area , leading to tissue
injury e.g. tuberculosis.

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What could cause the immune system to

attack the self?
• Changes in self-antigens, that make them look like
non-self to the immune system, due to:
– Viral or bacterial infection
– Irradiation
– Medication
– Smoking
• Changes in the immune system:
– Mutations in B cells may make them produce auto-
antibodies.
– Problems with control of lymphocyte development
and differentiation.

Rheumatoid Arthritis (RA)

• Rheumatoid arthritis (RA) is a progressive inflammatory

autoimmune disease with articular and systemic effects

• The cause of RA is unknown (autoimmune, infection,

smoking)

• Evidence of autoimmunity: presence of auto-antibodies

[anti-cyclic citrullinated peptides (anti-CCP) and
rheumatoid factor] before the onset of clinical arthritis.

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Rheumatoid Arthritis (RA)

• Many cell types are involved in RA including, T cells, B
cells, macrophages, neutrophils, fibroblasts and
chondrocytes

• Rheumatoid arthritis is characterized by:

1. Synovial inflammation and hyperplasia → swelling
2. Autoantibody production → rheumatoid factor
3. Cartilage and bone destruction → deformity

Development of Rheumatoid Arthritis

The loss of tolerance to self-protein in rheumatoid
arthritis (RA) is induced by interactions of environmental
and genetic factors
1. Environmental factors such as:
– Infectious agents (e.g. Epstein–Barr virus,
cytomegalovirus, proteus, and Escherichia coli)
– Smoking

2. Genetic factors: such as HLA–DR4 & HLA-DRβ1 alleles

3. Host factors: the risk of RA is greater in women than in

men

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Development of Rheumatoid Arthritis

– Tolerance is a state of unresponsiveness of the

immune system to substances or tissue that have the
capacity to elicit an immune response

– The loss of tolerance to joint-associated self-proteins is

due citrullination of amino acid arginine → amino
acid citrulline

– Alteration of self proteins may be a possible

mechanism in the induction of auto-reactive CD4 T-cell
responses in RA

Human leukocyte antigen (HLA) molecules play a central role in the

immune response by presenting processed antigenic peptides to T cells.
A specific sequence, present within the peptide-binding cleft of HLA
class II molecules, has been implicated in genetic susceptibility to RA.
People with specific HLA genes have a greater chance of developing
rheumatoid arthritis than people who do not have the HLA genes.

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Pathogenesis of Rheumatoid Arthritis

1. Differentiation of naïve CD4 T cells (Th0) into Th17 cells

results in the production of IL-17, a potent cytokine that
promotes synovitis
2. Osteoclast destroys bone, whereas enzymes secreted by
synoviocytes and chondrocytes degrade cartilage
3. B cells → antigen presentation and autoantibody
production
4. Pro-inflammatory cytokines causes:
– Synovial inflammation
– Promote the development of systemic effects, including
production of C-reactive protein, anemia, cardiovascular
disease and osteoporosis

Rheumatoid Arthritis: Pathogenesis

Current Treatment Rheumatoid
Targets Factors, anti- Immune complexes
B cell CCP

Complement
T cell
IFN- &
Neutrophil
Antigen- other Macrophage
presenting cytokines
cells

B cell or Mast cell

macrophage Synoviocytes
TNF Chondrocytes
Pannus IL-1

Osteoclast

Articular cartilage Production of collagenase and other

neutral proteases
Bone
Adapted from Arend WP, Dayer JM. Arthritis Rheum. 1990;33:305–15

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Rheumatoid Arthritis v/s Osteoarthritis

Feature Rheumatoid Arthritis Osteoarthritis
Pathology Autoimmune Degenerative

Age Any age – usually 35+ Increases with age

Joints involved Small joints Large joints

C1-C2 – Subluxation
Spine (Axial) (significant structural Lumbosacral
displacement)
Extra articular Many systemic effects Few systemic effects

Course Rapidly progressive Slowly progressive

Disability Highly disabling Mild to moderate

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Diagnosis of Rheumatoid Arthritis

• Four or more of the following criteria must be present:
1. Morning stiffness > 1 hour
2. Arthritis of > 3 joint areas of the possible 28 joints
3. Arthritis of hand joints (MCPs, PIPs, wrists)
4. Symmetric swelling (arthritis) – same joints on both sides
5. Rheumatoid nodules
6. Radiographic changes
7. Immunological markers: are crucial in RA
• rheumatoid factor (RF)
• anti-cyclic citrullinated peptide antibodies (anti-CCP)
• First four criteria must be present for 6 weeks or more

Blood Parameters in RA

• Acute Phase Reactants (APR )

– C-Reactive Protein (CRP): the most useful marker
– ESR is raised > 30 mm – other confounders
– Ceruloplasmin
– Haptoglobin (Hp)

• Leukocytosis, Nutrophilia
• Normocytic normochromic anemia
• Thrombocytosis

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Rheumatoid Factor

• Rheumatoid factor is an self-

antibody against the Fc portion
of our own IgG in the serum

• The origin of rheumatoid factor (RF)

is incompletely understood.

• An abnormal immune response

appears to select, via antigenic
stimulation, high-affinity RF from the
host’s natural antibody repertoire.

Rheumatoid Factor (RA Factor)

• Rheumatoid factor is autoantibodies directed against the
Fc fragment of immunoglobulin G (IgG)
• RF are heterogenous but usually composed of IgM.
• RF is detected by its ability to agglutinate latex particles
(or red blood cells) coated with human IgG
• It is negative in 30% cases of RA – Sero negative RA
• High levels of rheumatoid factor (above 20 IU/ml or 1:40)
occur in rheumatoid arthritis (80%) and Sjögren's
syndrome (70%)
• The normal range for RF is less than 15 IU/mL or less than
1:16.
• RF are commonly seen in other diseases

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Positive Rheumatoid Factor is seen in:

Disease Frequency
Advanced Rheumatoid Arthritis 100%
Rheumatoid Arthritis (over all) 80%
Sjögren's syndrome 70%
Systemic Lupus Erythematosis (SLE) 30%
Sub acute bacterial endocarditis (SABE) 40%
Tuberculosis 15%
Old Age 20%
Normal healthy individuals 5%

IgG anti-CCP

• IgG anti-CCP is IgG-antibodies to anti-cyclic

citrullinated peptides
• Citrullination of joint-associated self-proteins occur due to
conversion of the amino acid arginine into the amino acid
citrulline
• Anti-CCP have similar sensitivity for Rheumatoid Arthritis
(70%) to Rheumatoid Factor
• Specificity of anti-CCP for Rheumatoid Arthritis (>95%) is
better than Rheumatoid Factor
• Anti-CCP are associated with more severe disease
• They may be positive in asymptomatic patients years
before the onset of symptoms

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Biological Agents in treatment of RA

• TNFα antagonists

• Interleukin-1 antagonist

• Suppressors of T-Cell activation

• Anti B-Cell monoclonal antibody (anti-CD20)

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