05: Rheumatoid Arthritis Presentation & Pathophysiology

Question 1

What are the cardinal features of rheumatoid arthritis?

Answer 1

• Genetic predisposition
• Environment
• Autoimmunity
• Inflammation

Question 2

What is the epidemiology of RA?

Answer 2

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

Question 3

What is the pattern of joint involvement in early RA?

Answer 3

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

Question 4

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

Answer 4

• 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

Question 5

What is the target population for considering RA?

Answer 5

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

Question 6

What are the criteria for “definite” RA?

Answer 6

Greater than/equal to 6/10 points

Question 7

True or false: RA does not affect DIPs?

Answer 7

True

Question 8

What occurs in the joint space during RA?

Answer 8

• 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.

Question 9

What is the pathophysiology of bone erosion in RA?

Answer 9

• 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)

Question 10

What is the pathophysiology of cartilage loss?

Answer 10

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

Question 11

What are the systemic manifestations of RA?

Answer 11

• 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

Question 12

Common extra-articular sites of inflammation in RA

Answer 12

• 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

Question 13

What does this image show?

Answer 13

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

Question 14

What does this image show?

Answer 14

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)

Question 15

What does this image show?

Answer 15

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.

Question 16

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

Answer 16

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

Question 17

What are the major features of genetic predisposition in RA?

Answer 17

• 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

Question 18

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

Answer 18

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

Question 19

What DR4 variants do NOT have an RA association?

Answer 19

DR4*0402 and DR4*0403

Question 20

What is the role of MHC Class II molecules?

Answer 20

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).

Question 21

What are the target T-cell antigens in RA?

Answer 21

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

Question 22

What is the HLA-DRB1 shared epitope?

Answer 22

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).

Question 23

What environmental triggers lead to RA?

Answer 23

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

Question 24

What autoantibodies are implicated in RA?

Answer 24

• 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

Question 25

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

Answer 25

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

Question 26

What is **rheumatoid factor**?

Answer 26

* 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

Question 27

What are **anti-citrullinated peptide antibodies (ACPA)**?

Answer 27

* 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

Question 28

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

Answer 28

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.

Question 29

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

Answer 29

* 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

Question 30

What T cells are upregulated and downregulated in RA?

Answer 30

* **↑Th17** * **↓Tregs**

Question 31

What does "epitope spread" mean with regards to RA?

Answer 31

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.

Question 32

What are the cellular sources of synovial cytokines in RA?

Answer 32

* 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**

Question 33

Describe the hierarchy of cytokine networks in RA

Answer 33

* **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)

Question 34

What is the cytokine desequilibrium in RA?

Answer 34

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

Question 35

Describe how the inflammatory response in RA is amplified.

Answer 35

* 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

Question 36

What factors predict a good outcome with RA?

Answer 36

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

Question 37

What factors predict a poor outcome with RA?

Answer 37

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