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RMSK > 05: Rheumatoid Arthritis Presentation & Pathophysiology > Flashcards

05: Rheumatoid Arthritis Presentation & Pathophysiology Flashcards

1
Q

What are the cardinal features of rheumatoid arthritis?

A
  • Genetic predisposition
  • Environment
  • Autoimmunity
  • Inflammation
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2
Q

What is the epidemiology of RA?

A
  • Prevalence ~1%
  • Peak incidence 35-60yrs
  • F>M 2-4x
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3
Q

What is the pattern of joint involvement in early RA?

A
  • MCP, PIP 90%
  • Wrists 80%
  • Knees 65%
  • Shoulders 65%
  • Ankles 50%
  • Feet 45%
  • Elbows 40%
  • Hips 20%
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4
Q

What are some common signs of RA? (Old criteria for classification)

A
  • Morning stiffness > 1 hr
  • Simultaneous arthritis of >/= 3 joints
  • Arthritis of hand joints
  • Symmetrical arthritis
  • Rheumatoid nodules (image below)
  • Serum rheumatoid factor
  • Typical radiographic changes in hands/wrists
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5
Q

What is the target population for considering RA?

A

At least one joint w/ synovitis, not better explained by another disease.

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6
Q

What are the criteria for “definite” RA?

A

Greater than/equal to 6/10 points

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7
Q

True or false: RA does not affect DIPs?

A

True

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8
Q

What occurs in the joint space during RA?

A
  • Synovitis: inflammation of the synovial membrane, leading to pannus formation
  • Pannus: membrane of granulation tissue composed of mesenchyme- and bone marrow-derived cells.
  • Formation of pannus stimulates release of IL-1, platelet-derived growth factor, prostaglandins, and substance P by macrophages, which ultimately cause cartilage destruction and bone erosion.
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9
Q

What is the pathophysiology of bone erosion in RA?

A
  • Synovial invasion of contiguous bone
  • Activated synovial lining cells (macrophages, fibroblasts)
  • Release of MMPs, prostaglandins, etc.
  • Release of osteoclast activating factors (TNF-a, RANK-L)
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10
Q

What is the pathophysiology of cartilage loss?

A
  • Fluid phase: activated PMNs
    • Release of free radicals and proteases
  • **Chondrocyte **activation
    • Release of MMPs
    • Degradation of pericellular matrix
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11
Q

What are the systemic manifestations of RA?

A
  • Constitutional: fever, wt loss
  • Cachexia: muscle atrophy, osteopenia
  • Extra-articular involvement
  • Systemic serological indicators
    • ↑ESR, CRP
    • ↓albumin
    • polyclonal gammopathy
    • anemia (normochromic normocytic)
      • ↑production of inflammatory cytokines –> ↓erythropoietin response in bone marrow –> inadequate erythropoiesis
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12
Q

Common extra-articular sites of inflammation in RA

A
  • Rheumatoid scleritis: inflammation of sclera (white part of eye)
  • Rheumatoid vasculitis: Inflammation within blood vessel walls
    • May cause ischemia and gangrene
    • Nerves can be affected 2/2 ischemia
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13
Q

What does this image show?

A

Rheumatoid scleritis (inflammation of the white of the eye 2/2 enzymatic degradation of collagen fibrils by resident cells and infiltrating leukocytes)

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14
Q

What does this image show?

A

Rheumatoid vasculitis (serious complication of long standing RA in which inflammation spreads to involve small to medium sized and rarely, large blood vessels in the body. When inflamed, blood vessel walls become thickened and their lumen narrows down, often to the point of complete blockage;this image shows a blood flow deficiency in the tip of the finger caused by an obstruction of the digital artery)

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15
Q

What does this image show?

A

Rheumatoid nodules (commonly occur at points of pressure [subQ], but may be pulmonary); local swelling or tissue lump, usually rather firm to touch, like an unripe fruit, which occurs almost exclusively in association with rheumatoid arthritis.

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16
Q

What is the major cause of death in patients with RA?

A

Cardiovascular disease (RA fuels atherosclerotic pathology –> plaque ruptures)

17
Q

What are the major features of genetic predisposition in RA?

A
  • Familial clustering (may not be FDR, but in extended family)
  • Monozygotic > dizygotic twins
    • However, concordance not high (only 1 out of every ~4 pairs)
  • Major histocompatibility Ag: ​DR4
18
Q

What rheumatic diseases have MHC associations, and what is their relative risk?

A
  • Ankylosing spondylitis (B27): RR = 69
  • Reactive arthritis (B27): RR = 37
  • RA (DR4): RR = 4
  • SLE (DR3): RR = 3
19
Q

What DR4 variants do NOT have an RA association?

A

DR4*0402 and DR4*0403

20
Q

What is the role of MHC Class II molecules?

A

Present antigens to CD4 T cells (in RA, it is hypothesized that autoantigens are presented by APCs to T cells, which are present in lymphoid follicles within joints).

21
Q

What are the target T-cell antigens in RA?

A
  • CD4
  • Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4): binding leads to the termination of immune response (abatacept)
22
Q

What is the HLA-DRB1 shared epitope?

A

Five amino acid sequence motif in residues 70–74 of the HLA-DRβ chain, associated with severe rheumatoid arthritis (must be positive or neutral charge to be susceptible).

23
Q

What environmental triggers lead to RA?

A
  • Smoking
    • ​Only if anti-CCP positive
  • Periodontal disease (inflammation and infection of the ligaments and bones that support the teeth)
  • Gut microbiome
24
Q

What autoantibodies are implicated in RA?

A
  • Rheumatoid factor (RF): IgM vs. self-IgG
  • Anti-citrullinated protein antibodies (ACPA)
    • ​Detected via anti-CCP test
  • Antibodies against cartilage derived proteins (type II collagen, aggrecan, glycoprotein 39)
  • Antibodies against glucose-6-phosphate isomerase
25
Q

Do patients present with autoantibodies before clinical signs and symptoms of RA?

A

Yes; anti-CCP in 40%, IgM-RF in 28%.

26
Q

What is rheumatoid factor?

A
  • IgM against Fc portion of IgG
  • Seen in 45% of RA pts in 1st 6mos of dz
  • Seen in 85% of RA pts w/ estalished dz
  • Non-specific for RA; may also indicate:
    • Chronic infx (endocarditis, osteomyelitis, HepC)
    • Chronic liver/lung dz
    • Sarcoidosis
27
Q

What are anti-citrullinated peptide antibodies (ACPA)?

A
  • Detect peptides with modified residues from arginine (positive charge) to **citrulline **(neutral charge)
  • Altered charge leads to change in tertiary structure of protein –> unmasking of neoantigens (hidden epitopes) –> increased affinity of arthritogenic peptides for SE+ MHC II molecules –> easier CD4 T cell activation
  • High specificity and PPV for RA
  • Highly associated w/ HLA-DR SE+
  • Detectable earlier than RF and present in 40% of RF negative patients
  • Predictive of erosive disease and joint damage
  • Not 100% specific for RA
28
Q

What is an **anti-CCP **antibody?

A

Antibody against cyclic citrullinated peptides (CCP); frequently used to detect these antibodies with high sensitivity in patient serum or plasma (then referred to as anti–citrullinated peptide antibodies); low anti-CCP titer indicates few ACPAs recognized.

29
Q

What is the origin of anti-CCP and RF antibodies?

A
  • Activation of **peptidyl arginine deiminase (PADI) **via:
    • Bacterial pathogen
    • Inflammation/smoking (tissue/cellular damage)
    • PADI mutations
  • PADI catalyzes the transformation of pep-Arginine to pep-Citrulline
  • Citrullinated peptides (e.g., vimentin, keratin, filaggrin, fibrinogen) bind MHCs on APCs with high affinity
  • Peptides are presented to T cells, which:
    • Activate other T cells
    • Present the antigen to B cells
  • B cells produce anti-CCP and RF antibodies
30
Q

What T cells are upregulated and downregulated in RA?

A
  • ↑Th17
  • ↓Tregs
31
Q

What does “epitope spread” mean with regards to RA?

A

Even at initial onset of disease, no one citrullinated protein is key to RA development; epitope spread of ACPA response is consistent over disease course.

32
Q

What are the cellular sources of synovial cytokines in RA?

A
  • Although T cells produce cytokines, the predominant cytokines expressed in synovium come from–
  • Macrophages: IL-1, IL-6, TNF-alpha
  • Fibroblasts: IL-6
    • ​Lead to activation of chondrocytes, osteoclasts, and synoviocytes which produce collagenase and other neutral proteases (e.g., MMP)
    • This cytokine storm leads to disability and the need for joint surgery
  • NB: T cells activate macrophages via IFN-gamma
33
Q

Describe the hierarchy of cytokine networks in RA

A
  • TNF-alpha is the primary driver of inflammation in symptomatic RA patients
  • Immunological inciting events activate TNF-alpha
  • TNF-alpha activates **IL-1 **and pro-inflammatory molecules:
    • Cytokines (IL-6)
    • Prostaglandins
    • MMPs
    • Adhesion molecules
  • IL-1 assists in driving pro-inflammatory response (minor)
34
Q

What is the cytokine desequilibrium in RA?

A

Proinflammatory cytokines (TNF-a and IL-1) outweigh antiinflammatory cytokines (IL-1ra, sIL-1R, sTNFR, IL-10, IL-4, IL-11)

35
Q

Describe how the inflammatory response in RA is amplified.

A
  • One mediator has multiple effects: TNF-R’s on most cells, coupled to different downstream signals
  • One mediator induces production of another: TNF induces IL-1 and itself (and vice versa for IL-1)
  • One mediator activates or inactivates another:
    • TNF/IL-1 induces collagenase
    • TNF/IL-1 inhibits collagen synthesis
      • “Double hit”
  • Two mediators synergize with one another:
    • TNF <–> IL-1 = ↑↑biological response
36
Q

What factors predict a good outcome with RA?

A
  • Early tx
  • High SES
  • Good health behaviors (Rx adherence, wt management, exercise)
  • No co-morbid illness
37
Q

What factors predict a poor outcome with RA?

A
  • Delayed tx
  • Low SES
  • Depression
  • Poor health behaviors
  • Co-morbid illness (particularly, CV dz)

RMSK (16 decks)

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