L22 - RA & Autoimmune disease

Question 1

What systems are affected in RA and their symptoms?

Answer 1

1) Musculoskeletal - predominantly joints (synovial/diarthroidial joints)
2) Skin - rashes
3) Lungs - nodules
4) Eyes - connective tissue inflamed
5) Peripheral nerves - Tingling and numbness in toes
6) Connective tissue - nodules on tendon/bursae
7) Blood - All things in bloodstream affected; low RBCs, WBCs and platelets

Question 2

What factors relating to RA contribute to increased mortality?

Answer 2

1) blood vessel changes - arterial atheroma/atherosclerosis –> heart attack/stroke
2) neoplasia/cancers esp. lymphoma

Question 3

Tendons and bursas commonly affected by RA:

Answer 3

1) front of knee
2) tip of elbow (lateral epicondyle - tennis elbow & olecranon bursa)
3) side of hip bones

Question 4

Differences in pattern of body involvement of RA and OA

Answer 4

RA: upper limb (shoulder, elbow, wrist), metacarpophalangeal joint, metatarsophlangeal joint, mid tarsal joint
OA: distal interphalangeal joint

Question 5

Similarities of pattern of joint involvement in RA and OA

Answer 5

1) neck
2) lower limb (hip and knee)
3) proximal interphalangeal joint

Question 6

What happens to synovium in RA?

Answer 6

It becomes:

• hypertrophic
• hyperplasic
• hypervascular
• WBC infiltration
• panus formation
• proteoglycan loss at cartilage

Question 7

Specificity and sensitivity of Rheumatoid Factor?

Answer 7

85% and 69% respectively

Question 8

What are the two main enzymes involved in citrullination of proteins in humans? And where are they expressed?

Answer 8

Peptidylarginine deaminase 2 and 4
PAD2 - expressively expressed and found in many tissues
PAD4 - expressed only on neutrophils and eosinophils
(There are 5 isoforms identified in humans)

Question 9

What activates PAD?

Answer 9

Ca2+ from apoptosis
Environmental stressors at mucosal barrier: Lung (smoking, industrialisation)
Mouth
Gut

Question 10

What are the citrulinnated proteins found in RA patients?

Answer 10

Fibrogen
a-enolase
Vimentin
Fibronectin
Collagen

Question 11

What are the sensitivities and specificity of ACPA?

Answer 11

67% and 95% respective

Question 12

What is the combined specificity for RA for with ACPA and RF?

Answer 12

99%

Question 13

Normal functions of citrullination

Answer 13

Epithelial differentiation
Gene regulation
Immune activation

Question 14

ACPA functions:

Answer 14

Increases self-reactivity, initiates and augments arthrtis in murine models
Recognises native collagen
Activates Fc receptor-positive cells
Activates complement
Certain polymorphisms in PAD4 gene linked to RA
Long latency between the production of AutoAb and the development of symptoms

Question 15

What are the genetic factors that contribute to RA?

Answer 15

• HLA-DRB1
• shared epitope hypothesis
• ethnicity
• MHC genes (30% of risk)

Question 16

What are some of the triggers of RA?

Answer 16

• Industrialisation
• Smoking
• Peridontal disease

Question 17

What are the modifiers of phenotypic expression in RA?

Answer 17

• oestrogen
• pregnancy
• infection
• adverse life events/stress

Question 18

What is the disease activity of RA in pregnant women?

Answer 18

• Oligosaccharide modification of IgG associated with functional change: galactosylation if IgG found to reduce the inflammatory properties of Ig autoAb (eg RhF)
• Hypothalamic-pitutary-adrenal axis activity linked to cytokine production

Question 19

Provide examples of how infection links to pathogenesis and disease in RA

Answer 19

• Peridoncal disease - Phorphyromonas gingivalis expresses PAD4, resulting in citrullination of peptides
• Cytokine production up-regulated in hypothalamus during peripheral inflammation eg. generated by infection (local or systemic). Can result in flares of disease acitivty

Question 20

List the predictors of future RA disease

Answer 20

• Family history of RA
• Systemic features (eg non-joint - inflammation of lungs, eyes, skin etc)
• HLA DR4 shared epitope alleles
• ACPA positive
• Poor response to treatment
• Early bone erosion in course of disease

Question 21

What are the measures of current disease severity (disease activity)?

Answer 21

• Patient symptoms
• Anaemia
• C-reactive proteins
• Erythrocyte sedimentation rate (ESR)
• Signs of joint inflammation

Question 22

What are the immediate and long term treatment goals of RA?

Answer 22

Immediate: no pain, dysfunction or disability
Long term: preventation of synoival hypertrophy & hyperplasia –> decreases inflammatory mediators –> prevent damage of cartilage and bone

Question 23

What are the methods of measuring effectiveness of RA treatments?

Answer 23

1) Health Assessment Questionnaire (HAQ)
Patient self-rated score from 20qs and visual analogues of pain
2) Disease Activity Score (DAS28)
Based on patient and investigator assessment
-No of swollen joints, tender joints, ESR, patient global health
3) Americal College Rheumatology (ACR20,50,70)
- Improvement calculated as a %
- swelling joint count, ESR, CRP, Hb levels, pain and stiffness (how patient feels)