Rheumatoid Arthiris 🦴 Flashcards
Presentation of Rheumatoid Arthiritis…
Swollen
Stiff multiple symmetrical joints last > 1 hour in the morning
Is R.A chronic?
Yes.
Can get systemic symptoms:
Fevers + weight loss + fatigue
Pathophysiology of RA…
Auto-immune response:
T-cells activate B-cells > auto antibodies produced by body
Anti bodies:
1. RF, RHEUMATOID FACTORS
2. ANTI CITRULLINATED PROTEIN ANTIBODY
Process of changes in synovium, pannus formation:
T cell response to auto-immune antigen > increase cytokines > increased cellular proliferation > increase BV (OEDEMA)
- pannus promoting inflammatory response > layers of synovial cells & new blood vessels (HOT AND RED)
Risk Factors for RA
- Age >60
- Sex (2,3x Higher in woman)
- Smoking, former or current
- History of nulliparous births
- Obesity
- Genetics (HLA gene) HLA-DRB1
What is protein citrullination?
- Most common form of post-translational modification. (When changing Arg to another amino acid).
RA ANTIBODIES RECOGNISE PTM PROTEINS
Inflammatory feedback loops established?
- Self proteins (cartilage products + proteoglycans)
- They stimulate an inflammatory change/ that an immune cell change is happening.
Most important cytokine in RA JOINT
TNF - alpha
What are the microbiome linkages to RA?
- Environmental:
A. Respiratory diseases
B. Bronchiectasis, asthma
C. Smoking, occupational resp exposure
D. Periodontal diseas
E. Diet, obesity
All can change barrier function of mucosa sites leading to tiddue damage and further disease.
ALL have a shared risk of disease with HLADRB1
Many bacteria can cause PTM including citrullination
What are the symptomatic treatments of RA?
- Non pharma: weight management,
- Analgesics
- Anti inflammatory
What should treatment of RA aim for?
Remission or
Low disease activity
Synthetic DMARDs? (2)
Methotrexate, Leflunomide (antimetabolites)
Sulphasalazine
Hydroxyxhloroquone
Methotrexate
MOA
Reduces pyrimidine synthesis by inhibiting DHFR and TYMS enzymes in rapidly dividing t and b cells
Net result:
1. Decreased nucleotides for DNA synthesis
2. Increase cellular apoptosis
Methotrexate
ADVERSE EVENTS?
Common:
Decrease WBC, platelets
Fatigue
Musositis
Increase liver function tests
Infections
Methotrexate
CAUTIONS
Contraindictations in ppl with bone marrow disorders, immunodeficencies, infections (TB)
PREG and breastfeeding
Leflunomide
MOA
Reduces pyrimidine synthesis by inhibiting DHODH enzymes in rapidly dividing t and b cells
Luflunomide
CAUTIONS
IN PATIENTS WITH
allergy
Nine marrow disorders
Infections (TB, hepB)
Severe renal disease
Hepatitis
Preg and breastfeeding
Is leflunomide a PRODRUG?
Yes. Converts to Terflunimide.
Terflunomide inhbits DHODH in t and b cells
Sulfasalazine
MOA
Anti inflammatory modulator (act on COX, NFKB) to reduce production of cytokines and prostoglandins
Sulfasalazine
CAUTIONS
In patients with SULFER or salicylate allergy,
Bone marrow disorders
Asthma
***safe in pregnancy and breastfeeding
Hydroxychloroquine (HCQ)
MOA
Prevents lysosome enzyme function by increasing pH
>resulting in REDUCED antigen degradation + presentation on MHCII
>INHIBITION of the or b cells proliferating to self-antigens
Risks Vs benefits of combination Rx
Benefit > increased efficacy
Risk > abnormal liver function
(Esp with MTX + Leflunomide)
Criteria to meet before use of Biologics
1- MTX for 3 months
2. 2nd DMARD for 3 months
3. Active disease = erythrocyte sedimentation rate (ESR) > 25
Cytokine Antagonists - TNF, IL6, IL7, IL23
MOA
Inhibit cytokine signalling to prevent inflammation in joint and modulate bone changes
