Muskuloskeletal - Rheumatoid arthritis Flashcards
Describe the pathophysiology of RA
Type II collagen or vimentin in body modified (arginine residues –> citrullinated)
Citrullinated proteins recog as self Ag
Self Ag presented to Th cells by APC –> triggers B cells to produce auto Ig
Auto Ig and Th cells recruited to site
- Th cells secre IL-17
- Macrophages secre TNF-a, IL-1, IL-6
Increase in synoviocytes and inflamm cells lead to formation of pannus = thickened synovial mem w granulation and scarring from fibroblasts
Over time pannus can damage cartilage, soft tissue and can even damage bones
Synovial mem secretes lysosomal enzymes –> break downs protein in articular cartilage
Joint damage exposes bone –> friction between bones leads to further damage and pain
Inflamm cytokines increase surface protein RANKL which binds to RANK and stimulates the maturation of pre-osteoclasts to osteoclasts
Increased osteoclasts –> increase bone resoprtion (break down)
Ig enters synovial space
- Binding of Ig to Ag –> immune complexes –> activation of complement sys, promote joint inflamm and damage by enzymatic cascade
Chronic inflamm promotes angiogenesis which further promots inflamm
What is rheumatoid arthritis?
An autoimmune polyarthritic condition characterised by inflamm and pain
What are the risk factors of RA?
- Genetics
- HLA-DR4 Ag
- HLA-DRB1 gene in MHC region
- Fam Hx
- 3x higher if Hx in 1st deg relatives
- 2x higher if Hx in 2nd deg relative
- Female
- Age
- Smoking
Describe the epidemiology of RA
- Affects ~ 0.8% of adult population
- 1% of population
- Can occur at any age but has increased prevalence up to the 7th decade of lide
- Peak incidence: 40-50y.o.
- F:M = 3:1
- Genetic predispotion
- HLA-DR4 related antigen
What are the signs & symptoms of RA?
Signs:
Rheumatoid nodules
Anti-CCP +ve
Rheumatic factor +ve
Increased ESR, CRP, wbc, platelets, hematocrit
Radiographic changes
- Joint space narrowing, pannus, erosion
Synovial fluid
- Increased cytokines, T cells, B cells, macrophages, fibroblasts, dendritic cells
Symmetrical polyarthritic swelling, may start unilaterally
Symptoms:
>6 weeks
Pain
Erythema
Swelling
- Feels spongy
Tenderness
Warmth
Worse on rest, waking, >1h to get out of bed
Relief with activity
Systemic symptoms
- Fever, malaise, fatigue
- Depression
- Wt loss
What are the principles of pharmacological management of RA?
Symptomatic relief:
1st line GCs
PO 5-7.5mg once daily for max 3mo, taper slowly
Js short duration till DMARDs start working, then removing.
Continuous low dose GCs not reco
Alt NSAIDs
Disease modifying:
1st line csDMARDs
- Mod-high disease activity: MTX first line
- Low disease activity:
Hydroxychloroquine preferred
Sulfasalazine>MTX (less immunosuppressive)>Leflunomide (more cost effective)
- If at target (remission after 6mo) - cont
If not at target after 6mo
- 2nd line
a. Triple thera: MTX, sulfasalazine, hydroxychloroquine
Less ADR, cheaper than bDMARDs
b. +bDMARDs
- TNF-alpha modulators: infliximab, adalimumab, etanercept
- IL-1 blocker: anakinra
- IL-6 blocker: tocilizumab
- 3rd line
+tsDMARDs - a/w MACE and malignancy
If still not at target w bDMARDs, tsDMARDs
- Switch bDMARDs or tsDMARDs class/ MOA
- Do not use bDMARDs and tsDARDs tgt (both work on cytokine downreg, too immunosuppressive)
What other considerations are there with choice of DMARDs?
Pretreatment screening
- TB
- Hep B & C
Avoid if untreated. Tx disease first before starting
Immunisation
- Pneumococcal, influenza, Hep B & C, Varicella zoster, Herpes zoster
Do not use TNF-a inhib w HF (NYHA class II & III)
Caution of tsDMARDs due to a/w MACE and malignancy
What are the risk factors of tsDMARD assoc MACE?
CV risk factors: >65 y.o., HTN, DM, smoking, obesity
Current of Hx of malignancy
Thromboembolic events: DVT, PE, MI, HF, COC, HRT, surgery, immobility
What are the non-pharmacological reco for RA?
Range of motion exercises
Strengthen muscles
Aerobic exercise
Avoid high intensity, wt bearing exercise
PT/OT referral
Pt edu
Psychosocial intervention
- CBT
Healthy balanced diet
Wt management (for obese pts)
Describe the MOA of MTX
Inhib cytokine pdtn
Inhib purine, pyrimidine, adenosine synth
Inhib folinic acid/folinate pdtn
Describe the MOA of sulfasalazine
Modulates inflamm med, esp LT
TNF-a inhib
Describe the MOA of leflunomide
Inhib purine, pyramidine synth
Inhib T cell pdtn & prolif, B cell autoIg pdtn
Inhib NFkB activation pro inflamm pathway
Describe the MOA of hydroxychloroquine
Inhib locomotion of neutrophils, chemotaxis of eosinophils, complement dep Ag-Ig rxns
Decrease TNF-a, IL-1 cartilage resorption
Decrease MHC class II xp & APC
What are the S/E of MTX
Common S/E
GI: NV/CD, abdo cramping
CNS: headache, dizziness
Derm: hair thinning, photosensitivity
Rare but srs S/E
Teratogenic
Derm: SCAR (SJS,TEN)
Haem: leukopenia
Hepatic: elevated transaminases
Respi: pneuomonitis
What are the S/E of sulfasalazine?
Common S/E
GI: NV/D, abdo cramping
CNS: headache, dizziness
Derm: rash
Genitourinary: oligospermia (decreased sperm count)
Rare but srs S/E
Haem: hemolytic anemia, neutropenia
Derm: SCAR (SJS, TEN)
