risk factors for RA
1) increased prevalence up to 70 yo
2) peak incidence 40 - 50 yo
3) women 3x more common
4) human leukocyte antigen: HLA-DRB1
5) family history
- 3x higher odds if 1st degree
- 2x higher odds if 2nd degree
6) smoking
pathophysiology of RA
1) injury -> activation of macrophage in synovial tissue -> secretion of IL-8 and MCV1 -> recruit monocytes
2) monocytes differentiate into macrophage -> +ve feedback to recruit more monocytes -> stimulate release of TNF -> stimulate macrophages to produce
- more chemokines and cytokines -> induce synovial fibroblast to secrete cytokines and break down connective basement membrane
- IL-1 that binds to IL-1 receptor -> stimulate more cytokine secretion -> inflammation
3) neutrophils secrete toxic peroxidases and MPO -> further tissue breakdown
4) IL-6 important for recruitment of other cells and stimulate bone destruction
clinical presentation of RA
1) inflammation
2) location: symmetrical polyarthritis
- bilateral
- small joints: knuckles, row of bones in front of it, wrist, some parts of toes
- large joints: elbow, shoulder, hip, knees, ankles
3) morning stiffness > 30 mins
4) systemic symptoms
- more present if > 60 yo
- generalised aching/stiffness, fatigue, fever, weight loss, depression
5) extra-articular symptoms
- eyes: Sjogren’s syndrome
- heart: CAD
- haematology: Fetty’s syndrome
- skin: rheumatoid nodules
- vascular: Rheumatoid vasculitis
6) deformities
- swan neck (^ at first joint from fingernail), boutonniere (^ in middle joint)
- loss of physical function and ability to carry out ADL
lab finding for RA
1) autoantibodies
- rheumatoid factor RF (+ve)
** not specific for RA, will show for all autoimmune disease
** not all RA pt will have +ve RF in early stage - anti-CCRP assays (+ve)
2) acute phase response
- increase ESR, CRP
3) FBC
- decreased haematocrit
- increased platelet and WBC
4) radiologic
- baseline for treatment efficacy monitoring
- findings
** narrowing of joint space
** erosion around margin of joint
** hypertrophic synovial tissue
diagnosis of RA
at least 4 of
1) early morning stiffness ≥ 1 hr for ≥ 6 wks
2) swelling of ≥ 3 joints for ≥ 6 wks
3) swelling of wrist/MCP/PIP joints for ≥ 6 wks
4) rheumatoid nodules
5) +ve RF +/- anti-CCRP test
6) radiographic change
goals of RA therapy
1) remission or low disease activity
- ≥ 6 months of remission/low disease activity
- Boolean 2.0 inclusion criteria for remission
** tender joint count (TJC) ≤ 1
** swollen joint count (SJC) ≤ 1
** CRP ≤ 1mg/dL
** patient global assessment ≤ 2cm - gradually taper dose after 6 months of remission
2) maximal functional improvement
3) Stop disease progression
4) prevent joint damage
5) alleviate pain
nonpharmaco for RA
1) patient education
2) psychosocial intervention
- CBT for enhancing self-efficacy and QoL
3) rest inflamed joint, use splint to support joint and reduce pain
- caution when promoting rest for fatigue symptoms, ensure no sedentary lifestyle
4) physical activities and exercise
- range of motion exercises: preserve joint motion
- increase muscle strength -> avoid contractures and muscle atrophy -> prevent decrease in joint stability and improve function
- aerobic exercise: reduce fatigue and pain, improve sleep
- avoid high intensity weight bearing exercises
5) physiotherapy, occupational therapy
6) nutrition and diet
- overcome anorexia and poor dietary intake during RA
- weight management if obese to reduce stress on weight-bearing joints
- dietary intervention for reducing inflammation (fish oil) and ASCVD risk
treatment for acute RA flares
1) NSAID
- short term relief of pain and minor inflammation
- can take PPi to reduce GI SE
2) glucocorticoid
- low dose bridging therapy when initiating DMARD before DMARD take effect
** tapered and discontinued within 3 months
** discontinue if bsMARD/tsDMARD initiated - ≤ 7.5mg/day prednisolone up to 3 months
types of csDMARD
1) methotrexate
2) hydroxychloroquine
3) sulfasalazine
4) leflunomide
initial treatment algorithm with csDMARD
1) moderate to high disease state
- 1st line methotrexate
- CI methotrexate: hydroxychloroquine, sulfasalazine, leflunomide
2) low disease state
- hydroxychloroquine (best tolerated) -> sulfasalazine (less immunosuppressive) -> methotrexate (greater dosing flexibility and lower cost) -> leflunomide
methotrexate dose
- initiation dose 7.5mg once weekly
- dose increment 2.5 - 5mg every 4-12 wks based on response
- target dose 15mg/wk within 4-6 wks initiation
- max dose 25mg/wk
methotrexate MOA
1) major action
- increase adenosine levels by AICAR transformylase and ATIC inhibition -> more adenosine acting on adenosine receptor -> anti-inflammatory effect
2) minor action
- inhibit dihydrofolate reductase -> decrease pyrimidine synthesis and DNA methylation (cause GI effect and hair loss)
- inhibit thymidylate synthetase
3) overall effect
- increase extracellular adenosine level and activation of A2a receptor
- anti-proliferative effect on T cells and inhibition of macrophage function
- decrease in pro-inflammatory cytokines, adhesive molecules, chemotaxis, phagocytosis
methotrexate SE
- N/V, mouth & GI ulcer, hair thinning
- leukopenia, hepatic fibrosis, pneumonitis
- increase transaminases, myelosuppression, TENS, SJS
how to cope with methotrexate SE?
folic acid supplementation 5mg/wk 12 - 24 hr after methotrexate dose
- SE caused by inhibition of dihydrofolate reductase
- folic acid downstream of dihydrofolate reductase so bypass effects of dihydrofolate reductase inhibition = rescue methotrexate toxicity
- can also use high dose of folate (cheaper)
methotrexate CI/caution
avoid use if CrCl < 30
special population for methotrexate
X pregnant cuz teratogenic
hydroxychloroquine dose
- 200-400mg in 1-2 divided dose
- max 5mg/kg/day
hydroxychloroquine MOA
- reduce MHC class II expression and antigen presentation
- reduced TNF-alpha and IL-1 and cartilage resorption
- antioxidant activity
hydroxychloroquine SE
N/V, stomach pain, dizziness, hair loss, ocular toxicity (Retinopathy)
hydroxychloroquine CI
pre-existing retinopathy
hydroxychloroquine caution
G6PD deficiency
sulfasalazine dose
- initiate 500mg OD/BD
- increase 500mg/wk until 1mg BD maintenance
- max 3g/day
sulfasalazine MOA
unknown, poorly absorbed, mediated by gut flora
sulfasalazine SE
N/V, headache, rash, haemolytic anemia, neutropenia, reversible infertility in men
