Rheumatoid Arthritis Flashcards
What are the risk factors for rheumatoid arthritis?
- Family history
→ 3 times higher if positive Hx in first-degree relative
→ 2 times higher if positive Hx in second-degree relative - Genetic predisposition
→ HLA-DRB1 in MHC region is major genetic susceptibility locus for RA - Smoking
What is the pathophysiology behind rheumatoid arthritis?
Genetic predisposition + immunologic trigger results in T-cell immune response being triggered
→ Inflammatory cytokines (IL-17, TNF, IL-1, IL-6 etc) released by T cells, B cells, macrophages
→ Angiogenesis in synovium leading to synovial cell proliferation and activation
→ Recruitment of inflammatory cells, release of proteases & prostaglandins
→ Ultimately leads to destruction of articular cartilage and underlying bone
What are the specific symptoms observed in rheumatoid arthritis?
→ Pain
→ Swelling
→ Erythema and warmth
→ Early morning stiffness > 30min – duration correlated with disease activity
→ Symmetrical polyarthritis (may start unilateral at first)
What are the systemic symptoms commonly seen with rheumatoid arthritis?
→ Generalised aching/stiffness
→ Fatigue
→ Fever
→ Weight loss
→ Depression
What are some extra-articular complications of rheumatoid arthritis?
→ Eye: episcleritis, scleritis, Sjogren’s syndrome
→ Heart: pericarditis, myocarditis, coronary heart disease, atrial fibrillation, heart failure, nodules
→ Haematology: anemia, Felty’s syndrome, lymphoproliferative disease
→ Lung: Pleural effusion, interstitial lung disease
→ Renal: glomerulonephritis, amyloidosis
→ Skin: Rheumatoid nodule
What are the possible lab findings of rheumatoid arthritis?
Autoantibodies (test both bec not all will have both positive)
→ Rheumatoid factor (RF) – positive
→ Anticitrullinated peptide antibodies (ACPA) using anti-CCP assays – positive
Acute phase response (active disease/inflammation)
→ Erythrocyte sedimentation rate (ESR) ↑
→ C-reactive protein (CRP) ↑
FBC – findings consistent with chronic inflammation
→ Hematocrit ↓
→ Platelets ↑
→ WBC ↑
X-Ray/MRI – usually occur at late stage, take at beginning to have a baseline
→ Narrowing of joint space
→ Erosion (around margin of joint)
→ Hypertrophic synovial tissue
What is the diagnosis criteria for rheumatoid arthritis?
At least 4 of the following:
→ Early morning stiffness ≥ 1h x ≥ 6/52
→ Swelling of ≥3 joints x ≥ 6/52
→ Swelling of wrist/MCP/PIP joints x ≥ 6/52
→ Rheumatoid nodules
→ +ve RF and/or anti-CCP tests
→ Radiographic changes
What are the goals of treatment for rheumatoid arthritis?
Achieve remission or low disease activity
→ At least 6 months
→ Boolean 2.0 criteria (remission: Tender Joint Count (TJC) ≤ 1, Swollen Joint Count (SJC) ≤ 1, CRP ≤ 1 mg/dL, Patient Global Assessment (PGA) using 10cm VAS ≤ 2cm)
→ DAS 28 scoring
Achieve maximal functional improvement
Stop disease progression
Prevent joint damage
Control pain
What are the pharm options to treat rheumatoid arthritis?
NSAIDs - adjunct to relief pain and minor inflammation
Glucocorticoids - low-dose bridging for DMARD initiation
csDMARDs - Methotrexate, Sulfasalazine, Leflunomide, Chloroquine, Hydroxychloroquine
tsDMARDs - Tofacitinib
bDMARDs - Etanercept, Infliximab, Adalilumab, Tocilizumab, Anakinra
What is the MOA of methotrexate>
Folic acid analogue
MOA: Mainly ↑adenosine due to ATIC inhibition
* Also inhibit dihydrofolate reductase
and thymidylate synthetase
* Inc extracellular adenosine level and activation of adenosine A2a receptor
* Anti-proliferative effects on T cells and inhibition of macrophage functions
* Dec pro-inflammatory cytokines, adhesion molecules, chemotaxis and phagocytosis
What are the side effects of methotrexate?
N/V, mouth and GI ulcers, hair thinning
Leukopenia, hepatic fibrosis, pneumonitis
How does administering folic acid or folinic acid prevent methotrexate toxicity?
Admin folic acid or folinic acid 12-24h after methotrexate to decrease toxicity
* Folate cheaper but need high dose as it does not efficiently rescue toxicity due to depletion of N5,N10-Methylene-FH4 from dihydrofolate reductase inhibition
* Folinic acid bypassed dihydrofolate reductase activity, thus more efficient
What is the MOA of sulfasalazine?
Metabolized to sulfapyridine (active) + 5-ASA
Mechanism of action not known but poorly absorbed – may be mediated by effect on gut microflora
* Dec IgA and IgM rheumatoid factors
* Suppression of T and B cells, and macrophages
* Dec in inflammatory cytokines e.g. IL-1β, TNF and IL-6
What are the side effects of sulfasalazine?
N/V, headache, rash, haemolytic anemia, neutropenia, reversible infertility in men
What is the MOA of leflunomide?
- Rapidly converted to active metabolite teriflunomide
- Inhibits dihydrofolate dehydrogenase
- Dec pyrimidine synthesis and growth arrest at G1 phase
- Inhibits T cell proliferation and B cell autoantibody production
- Inhibits NF-κB activation pro-inflammatory pathway
What are the side effects of leflunomide?
D, ↑LFT, alopecia, weight gain, teratogenic
What is the MOA of chloroquine/hydroxychloroquine?
- Reduced MHC Class II expression and antigen presentation
- Reduced TNF and IL-1 and cartilage resorption
- Antioxidant activity
What are the side effects of chloroquine/hydroxychloroquine?
N, V, stomach pain, dizziness, hair loss, ocular toxicity
Which csDMARDs can be used in pregnancy and breastfeeding?
Sulfasalazine: need folate supplementation
Chloroquine/Hydroxychloroquine
Which csDMARDs are contraindicated with pregnancy and breastfeeding?
Methotrexate, Leflunomide
What is the MOA of tofacitinib?
JAK pathway inhibitor – blocks cytokine production by blocking JAK/STAT-activation of gene transcription
What are the side effects of tofacitinib?
- Cytopenia – neutrophils, lymphocytes, platelets, NK cells
- Immunosuppression → opportunistic infections
- Anemia – affects JAK2 activation by erythropoietin
- Hyperlipidemia – inc total, LDL, HDL and triglycerides
What are the prescribing considerations for tofacitinib?
Give w MTX for mod-severe RA (monotx if MTX-intolerant), also can use for psoriatic arthritis
DO NOT COMBINE WITH BIOLOGIC DMARDS
Which bDMARDs are TNF-α inhibitors?
Etanercept, Infliximab, Adalimumab
