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
What are the side effects of the TNF-α inhibitors?
Resp/skin infection, inc risk of lymphoma, optic neuritis, exacerbation of multiple sclerosis, leukopenia, aplastic anemia
What are the contraindications for TNF-α inhibitors?
Live vaccines, hepatitis B
What are the monitoring parameters of TNF-α inhibitors?
Screen for latent or active TB
Which bDMARDs are IL-6 receptor antagonists?
Tocilizumab
What are the side effects of tocilizumab?
Infections, skin eruptions, stomatitis, fever, neutropenia, inc ALT/AST, hyperlipidemia
What bDMARDs are IL-1 receptor antagonists?
Anakinra
What are the side effects of anakinra?
Infections, injection site reactions
What are the treatment principles for rheumatoid arthritis?
Treatment decisions based on disease activity, safety, patient factors
DMARDs should be started as soon as diagnosis is made
→ MTX should be part of first Tx strategy
→ Consider sulfasalazine/leflunomide if MTX is contraindicated or not tolerated
→ Short-term glucocorticoids should be considered when initiating/changing DMARDs, but tapered and discontinued as rapidly as possible
→ 2nd line: bDMARD preferred – tofacinitinib has high risk of MACE and malignancy (similar to other JAKi)
Treatment should be aimed at reaching a target of sustained remission or low disease activity
Monitor frequently (Q1-3/12) in active disease
→ Adjust if no improvement by 3/12, or target not reached by 6/12
What are the precautions and monitoring to be done for bDMARDs/tsDMARDs
Pre-treatment screening
* TB (latent/active) – start bDMARD/tsDMARD after completing TB Tx
* Hep B & C – avoid use if untreated disease detected
Vaccination needed before Tx: Pneumococcal, Influenza, Hep B, Varicella zoster, Herpes zoster
Lab screening/monitoring
* CBC w differential WBC count and platelet count
* LFT – ALT, AST, bilirubin, ALP
* Lipid panel
SCr
What are the non-pharm strategies for rheumatoid arthritis?
Patient Education
→ Provide evidence-based information about disease & management
→ Manage patient’s expectations of disease & treatment
→ Correct patient’s misconceptions
Psychosocial Interventions – e.g. CBT for enhancing self-efficacy & QoL
Resting the inflamed joint/use of splits to support joints and reduce pain
→ Caution against promoting rest for fatigue symptoms – may lead to sedentary lifestyle
Physical Activity
→ Do exercises to maintain range of motion
→ Do exercises to increase muscle strength – avoid contractures & muscle atrophy – prevent decrease in joint stability and improve function
→ Do aerobic exercises to reduce fatigue & pain, improve sleep
→ Avoid high-intensity weight-bearing exercises/activities especially in those w structural damage of lower extremity joints
PT/OT Referral – supervised tailored exercises to disease activity by trained experts
Nutritional & Dietary Counselling
→ Overcome anorexia & poor dietary intake during active RA
→ Weight management if obese – reduce stress on weight-bearing joints
→ Dietary interventions for reducing inflammation e.g. fish oil
→ Dietary interventions for reducing ASCVD risk
