IC13.3, ic16 RA Flashcards by Nathaniel Chan

What are the cytokines involved in RA

TNF, IL1, IL6, IL17

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What is the pathology of RA

Macrophage secretes TNF
TNF is the most important cytokine in inflammation, stimulate synovial fibroblast to secrete other cytokines and MMP (Matrix Metalloproteinase)
MMP and Neutrophils will break down cartilage, cause bone destruction

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Symptoms of RA (7 points)

Pain
Swelling
Redness, warmth
Early morning stiffness > 30 mins
Systemic symptoms eg. General aching, Fatigue, Fever, Weight loss, Depression
Deformities eg. swan neck, boutonniere
Loss of function, ability to carry out ADL

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What are the 4 types of lab findings for RA

Autoantibodies tests
Rheumatoid factor (RF): +ve
Anti-CCP assay: +ve
Patients may have either, so need do both

Acute phase response
Erythrocyte sedimentation rate (ESR): High
C-reactive protein (CRP): High

FBC
Hematocrit: Low
Platelets, WBC: High

X-ray
Not used for diagnosis
Monitor disease progression, late in course of disease
Monitor for narrowing joint space, erosion around margin of joint, hypertrophic synovial tissue

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How to diagnose RA

At least 6 points in the American College of Rheumatology test
At least 6 weeks duration of symptoms
Joint involvement (single or multiple)
Acute phase reactants CRP, ESR
+ve RF or Anti-CCP test

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Criteria for remission

6 months
At most 1 joint swollen or tender
CRP ≤ 1mg/dL (low inflammation)

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What are the types of drugs used in RA

To reduce inflammation
NSAIDs (used before RA is diagnosed)
Glucocorticoids

Maintenance therapy
csDMARDs (Methotrexate, Sulfasalazine, Hydroxychloroquine, Leflunomide)
bDMARD (TNFa inhibitor, IL6 receptor antagonist, CD20)
tsDMARD (JAK inhibitor Tofa, Bari)

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Principle for glucocorticoid use

what is the max duration

Given to bridge DMARD therapy, prescribed together
Eg. Prednisolone ≤ 7.5mg / day
Used for shortest duration possible

Max duration is 3 months, Taper and discontinue
Discontinue when b/tsDMARD started

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Side effects of glucocorticoids

Osteoporosis / osteonecrosis
Insulin resistance
Gastric ulcer
Cataract, glaucoma
Increased CVD risk

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For low disease activity, what DMARD to use?

Moderate - severe disease activity?

Low: Hydroxychloroquine or Sulfasalazine preferred

Mod - Severe: MTX monotherapy + short term glucocorticoid

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What is the starting dose of Methotrexate

Target dose

7.5mg once a week
Give folic acid 5mg once a week, the next day

Target: 15mg a week

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What is the MOA of Methotrexate

1) (major) Increase adenosine levels via ATIC inhibition
ATIC inhibition → Increased adenosine act on adenosine receptors
Immune response: Stop T cells production, inhibition of macrophage function
Anti-inflammatory: Decrease in pro-inflammatory cytokines

2) (minor) Inhibit dihydrofolate reductase → resulting in side effects
Inhibit DNA methylation, synthesis of DNA bases (Purine - AG, Pyrimidine - CUT), essential amino acid synthesis

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Side effects of MTX (7 points)

Nausea, vomiting
Mouth, GI ulcers
Hair thinning
Liver: increased transaminases, cirrhosis
Myelosuppression
Photosensitivity (protect from light)
SJS / TEN

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Contraindication of MTX

Pre-existing liver disease
Immunodeficiency
Blood dyscrasia
Pregnancy (teratogenic)
Avoid in CrCl < 30ml/min

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Monitoring of MTX

FBC
LFT (AST, ALT, Albumin, Bilirubin)
SCr

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Why is folic acid needed with MTX

Folate enters cells, converted to Dihydrofolate by Dihydrofolate reductase → Tetrahydrofolate → eventually produce DNA bases and amino acids

Methotrexate inhibit Dihydrofolate reductase, cause nausea, hairloss

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Folic acid vs Folinic acid

Folic acid / Folate
Cheaper, but need higher doses

Folinic acid
Expensive, but more efficient

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MOA of Sulfasalazine

Starting dose of Sulfasalazine

Metabolised to Sulfapyridine (active) and 5-aminosalicylic acid (5 ASA)

suppress T cell, B cell, macrophages
Decrease inflammatory cytokines IL1, 6, TNF

500mg 1-2x a day

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Side effects of Sulfasalazine (7 points)

Nausea, vomiting
Headache, dizziness
Rash
G6PD Haemolytic anaemia
Neutropenia
Reversible infertility in men (Oligospermia)
Urine discolouration

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Which csDMARD does not have hair loss / alopecia as side effect

Sulfasalazine

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Contraindication of Sulfasalazine

Sulfonamide allergy
G6PD Deficiency

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Which is the safest csDMARD for pregnancy

Sulfasalazine

Dose of hydroxychloroquine

200-400mg a day

Contraindication with hydroxychloroquine

Pre-existing retinopathy
G6PD deficiency

Which drugs are contraindicated in G6PD deficiency

Sulfasalazine Hydroxychloroquine

What is the MOA of Hydroxychoroquine (3 points)

Reduce MHC class 2 expression and antigen presentation Reduced TNF, IL1, cartilage resorption Antioxidant activity

Side effect of hydroxychloroquine

Nausea, vomiting Stomach pain Dizziness Hair loss Ocular toxicity (retinopathy) Photosensitivity, hyperpigmentation QT prolongation

Monitoring for hydroxychloroquine

eye exam

Indication of Hydroxychloroquine

Least potent, Best tolerated

Which medication dont need to monitor FBC

Hydroxychloroquine the rest need to monitor

Leflunomide dose

Loading dose: 100mg a day for 3 days Maintenance: 20mg a day

MOA of Leflunomide

Converted to active metabolite Teriflunomide Decrease pyrimidine synthesis Inhibit T cell proliferation and B cell autoantibody production

Which drugs decrease pyrimidine synthesis

Methotrexate and leflunomide

Contraindications of Leflunomide (4 points)

ALT > 2x ULN: avoid use Preexisting liver disease Immunodeficiency Pregnancy

PK of Leflunomide

Has long half life (years after last dose) Use Cholestyramine (bile salt binding resin) to remove Leflunomide

Side effect of Leflunomide

Diarrhea Increase transaminases Alopecia (hair loss) Weight gain Myelosuppression (bone marrow suppression) Teratogenic

similarities between mtx and leflunomide

both teratogenic, myelosuppression, may cause alopecia, increase transaminases (so need to monitor liver)

Monitoring of Leflunomide

FBC LFT (ALT, AST, Albumin, Bilirubin)

Which csDMARD can or cannot use with increased transaminase

Methotrexate: can use, 3x ULN just use 75% of dose Leflunomide: cannot use, ALT 2x ULN

What is the general MOA of bDMARD and tsDMARD

bDMARD are administered via SC injection or IV infusion Bind to cytokine or receptors to downregulate their functions, which reduces immune and inflammatory responses tsDMARD are administered orally Bind to JAK proteins inside cells to prevent JAK from transphosphorylating the associated cytokine and growth factor receptor

What are the bDMARDs

TNF-a (IAGE) Infliximab Adalimumab Golimumab Etanercept IL6 - Tocilizumab CD20 - Rituximab

What are the tsDMARDs

Tofacitinib Baricitinib

What needs to be done before initiating ts/bDMARD (3 points)

Pre-treatment screening Start after TB treatment Avoid if have untreated Hep B or C Vaccination before initiation Pneumococcal Influenza Hep B Varicella zoster / Herpes zoster Lab testing CBC with wbc, platelet count LFT (ALT, AST, bilirubin, ALP) Lipid panel SCr

When should ts/bDMARD be used

When patient does not achieve remission at 6 months

What to look out for for each ts/bDMARD drug class

TNF-A Monitor for anti drug antibodies Avoid in heart failure IL6 inhibitor (Tocilizumab) GI perforation, thrombosis JAK inhibitors Higher risk of MACE GI perforation, thrombosis Malignancy risk

Which TNF-a are IV, which are SC

IAGE IG are iv AE are sc

What are contraindicated with TNF-a

Live vaccination Hepatitis B heart failure

What is Anakinra

IL1 receptor antagonist Protein which blocks IL1 receptor

What is the MOA of Tofacitinib

Inhibit Jak 1 - 3 Block cytokine production by blocking JAK/STAT activation of gene transcription

Side effect of Tofacitinib (3 points)

Immunosuppression Opportunistic infections Anaemia (jak 2) Hyperlipidemia Increase HDL, LDL, TG

Which medications cannot be used together in RA

Glucocorticoids cannot be used together with b/tsDMARD, GC needs to be stopped when b/tsDMARD are started bDMARDs and tsDMARDs should not be used together

Why are JAK inhibitors last line?

Risk of MACE, malignancy, GI perforation, thrombotic events

Should treatment be stopped after patient achieve remission after 6 months?

No, dont discontinue DMARD abruptly, may result in flare

non pharm for RA

Patient education Rest during flares, Exercise (to increase muscle strength) if no flare Do range of motion exercises (similar to frozen shoulder) Do aerobic exercise to reduce fatigue, pain, improve sleep Avoid high intensity weight bearing exercises Diet Overcome anorexia, poor diet Weight management if obese Reduce inflammation eg. fish oil Reduce ASCVD risk