Case 35: Rheumatoid Arthritis

Question 1

what is rheumatic disease?

Answer 1

inflammation and damage to joint and other tissues

Question 2

what causes rheumatic disease?

Answer 2

it’s caused by a subset of autoimmune

diseases

Question 3

what is rheumatoid arthritis?

Answer 3

chronic, debilitating disease is chiefly characterized by inflammation of the synovium,
the thin tissue layer lining the joint

as the disease progresses, inflamed
synovium invades cartilage and bone, leading to areas of focal injury termed erosions

local inflammation also recruits neutrophils into the joint fluid, where they
produce cytokines and proteolytic enzymes that perpetuate inflammation and also
injure the cartilage directly

this all leads to joint destruction

Question 4

which diseases are rheumatic diseases caused by autoimmunity?

Answer 4

Systemic lupus erythematosus (SLE)

Rheumatoid arthritis

Juvenile arthritis

Sjögren’s syndrome

Scleroderma (progressive systemic sclerosis)

Polymyositis–dermatomyositis

Behçet’s disease

Ankylosing spondylitis

Reiter’s syndrome

Psoriatic arthritis

Question 5

which gene is associated with rheumatoid arthritis?

Answer 5

MHCII alleles

since MHC class II molecules present
antigen to CD4 T cells, the connection between the disease and MHC class II molecules
strongly implicates CD4 T cells in the pathogenesis of rheumatoid arthritis

Question 6

which autoantibodies are involved in rheumatoid arthritis?

Answer 6

RF = rheumatoid factor

these are antibodies that are directed against the Fc portion of IgG

complement-fixing immune complexes are abundant in the joints
of most RF-positive patients,

Question 7

what is the pathology of rheumatoid arthritis?

Answer 7

in a genetically susceptible host
who encounters an unknown environmental trigger, a break in tolerance results in
the generation of autoreactive CD4 T cells

these cells infiltrate the joint to induce
inflammation and tissue injury via the elaboration of cytokines and chemokines

cytokines induce production of mMP and RANK ligand by fibroblasts

MMPs attack tissues. activation of bone-destroying osteoclasts, resulting in joint destruction

T cells also provide help to autoreactive B cells, leading to their differentiation into
plasma cells that produce arthritogenic autoantibodies

beyond immune
elements, the joint stroma likely plays a key role:

synovial fibroblasts provide the
environment in which the immune response becomes established within the joint

further, under the influence of inflammatory cytokines, fibroblasts themselves
assume a pro-inflammatory and invasive phenotype, and join osteoclasts and activated
chondrocytes as major effectors of structural injury to the joint

Question 8

what is rheumatoid arthritis?

Answer 8

an inflammatory, destructive polyarthritis that characteristically
affects the small joints of the hands and feet, most typically including the
wrists and second and third MCPs and PIPs, though inflammation and injury in
larger joints is also common

Question 9

in what population is rheumatoid arthritis most common?

Answer 9

3x more likely to effect females than males

most patients present in early adulthood

Question 10

what is CCP?

Answer 10

antibodies against cirtullinated proteins

CCP are commonly found in patients with RA

Question 11

what is the criteria used to diagnose rheumatoid arthritis?

Answer 11

Morning stiffness lasting at least 1 hour before maximal improvement

Arthritis of three or more joints simultaneously with swelling and/or fluid in the joints

Arthritis in hand joints with swelling in the wrists, or metacarpophalangeal joints or proximal
interphalangeal joints

Symmetrical arthritis of the same joint areas

Rheumatoid nodules

Serum rheumatoid factor

Typical radiographic changes

Question 12

what do people think the process leading up to RA is?

Answer 12

deposition of IgG autoantibodies in joints either because the target antigen resides there or because the target becomes deposited upon the negatively charged cartilage surface

Question 13

how do you treat RA?

Answer 13

NSAIDs provide symptomatic pain relief

glucocorticoids can help control swelling and pain but you can’t use them long term

usually you have to use methotrexate which is a folate antagonist that also increases tissue adenosine, an anti-inflammatory mediator

Question 14

what is the biological disease-modifying drug used to treat RA?

Answer 14

TNFα inhibitors

anti-TNF monoclonal antibodies also work but they function differently

Question 15

The presence of rheumatoid factor in the serum of a patient is not diagnostic
of rheumatoid arthritis. Why is this?

Answer 15

rheumatoid factors can be found in the serum of patients with other immune-complex
diseases, such as mixed essential cryoglobulinemia

patients with hypergammaglobulinemia
and chronic infection can also have circulating immune complexes
and rheumatoid factor.

Question 16

How do TNF-α and IL-1 enhance the infiltration of leukocytes into the joint
space?

Answer 16

They upregulate the expression of the integrin CD11:CD18 (LFA-1) on the leukocytes,
and this increase in integrin expression promotes the binding of the leukocytes to
the blood vessel wall and their emigration from the blood vessels

the soluble IL-1
receptor antagonist anakinra (Kineret) has been used successfully in the treatment
of rheumatoid arthritis

Question 17

What might be the risks of TNF-α inhibitor therapy?

Answer 17

the monoclonal antibody infliximab is a chimeric human–mouse immunoglobulin
against which patients may develop antibodies

these antibodies would render the
therapy useless and might even cause anaphylactic reactions. Better anti-TNF monoclonal
antibodies are those that are completely humanized, such as adalimumab,
and therefore do not elicit an immune response

a more general risk is that of the
reactivation of a preexisting infection, such as tuberculosis, because TNF-α is normally
important in containing infections - this risk applies to all classes of anti-TNF
agents

patients about to receive infliximab or another anti-TNF agent should have
a tuberculin skin test to ensure they are free of tuberculosis

the activation of tuberculosis
in the absence of TNF-α suggests that this cytokine is critical in activating
macrophages to contain the latent infection