L22 - RA & Autoimmune disease Flashcards
What systems are affected in RA and their symptoms?
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
What factors relating to RA contribute to increased mortality?
1) blood vessel changes - arterial atheroma/atherosclerosis –> heart attack/stroke
2) neoplasia/cancers esp. lymphoma
Tendons and bursas commonly affected by RA:
1) front of knee
2) tip of elbow (lateral epicondyle - tennis elbow & olecranon bursa)
3) side of hip bones
Differences in pattern of body involvement of RA and OA
RA: upper limb (shoulder, elbow, wrist), metacarpophalangeal joint, metatarsophlangeal joint, mid tarsal joint
OA: distal interphalangeal joint
Similarities of pattern of joint involvement in RA and OA
1) neck
2) lower limb (hip and knee)
3) proximal interphalangeal joint
What happens to synovium in RA?
It becomes:
- hypertrophic
- hyperplasic
- hypervascular
- WBC infiltration
- panus formation
- proteoglycan loss at cartilage
Specificity and sensitivity of Rheumatoid Factor?
85% and 69% respectively
What are the two main enzymes involved in citrullination of proteins in humans? And where are they expressed?
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)
What activates PAD?
Ca2+ from apoptosis
Environmental stressors at mucosal barrier: Lung (smoking, industrialisation)
Mouth
Gut
What are the citrulinnated proteins found in RA patients?
Fibrogen a-enolase Vimentin Fibronectin Collagen
What are the sensitivities and specificity of ACPA?
67% and 95% respective
What is the combined specificity for RA for with ACPA and RF?
99%
Normal functions of citrullination
Epithelial differentiation
Gene regulation
Immune activation
ACPA functions:
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
What are the genetic factors that contribute to RA?
- HLA-DRB1
- shared epitope hypothesis
- ethnicity
- MHC genes (30% of risk)
What are some of the triggers of RA?
- Industrialisation
- Smoking
- Peridontal disease
What are the modifiers of phenotypic expression in RA?
- oestrogen
- pregnancy
- infection
- adverse life events/stress
What is the disease activity of RA in pregnant women?
- 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
Provide examples of how infection links to pathogenesis and disease in RA
- 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
List the predictors of future RA disease
- 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
What are the measures of current disease severity (disease activity)?
- Patient symptoms
- Anaemia
- C-reactive proteins
- Erythrocyte sedimentation rate (ESR)
- Signs of joint inflammation
What are the immediate and long term treatment goals of RA?
Immediate: no pain, dysfunction or disability
Long term: preventation of synoival hypertrophy & hyperplasia –> decreases inflammatory mediators –> prevent damage of cartilage and bone
What are the methods of measuring effectiveness of RA treatments?
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)