Rheumatoid arthritis

Question 1

What’s RA?

Answer 1

A chronic autoimmune disease characterised by persistent synovitis, systemic inflammation and presence of autoantibodies.

Question 2

RA is characterised by systemic inflammation. What is the consequence of this?

Answer 2

• low grade fevers –> inhibits cells’ ability function and replicate at a normal rate which may lead to anaemia and fatigue.
• inflammation can affect the vascular system which may lead to CVD.
• we expect to see an increase in CRP and ESR
• can affect the brain (neurological): fatigue and depression

Question 3

Clinical presentation of RA?

Answer 3

• pain and swelling and swelling at the PIP and MCP.
• may be asymmetric initially but eventually becomes symmetric.
• prolonged stiffness in the morning (as you sleep, cortisol levels drop but its responsible for inflammation suppression).

Question 4

Risk factors for RA?

Answer 4

• can occur at anytime but more likely if >60 y.o.
• sex: 2-3 times more likely in women
• smoking (history or former)
• history of nulliparous births (a woman who hasn’t given birth before)
• obesity
• genetics: HLA genes that encode for the MHCII protein (antigen presentation)

Question 5

Early B cell antigen recognition & autoantibody production in RA

Answer 5

in early stages of B cell development, 60-70% of B cells are able to recognise and react to self and foreign antigens. This poly-reactivity means it can attack self-antigens. Usually the body culls it by a process called central tolerance but in RA, a mutation arises where these cells are not properly removed, leading to RA and other conditions such as Crohn’s disease, psoriasis and eczema.

Question 5

pathogenesis of RA

Answer 5

1. environmental factors such as smoking or infections can result in disorderly immunity.
2. this causes proteins to undergo citrullination (arginine –> citrulline).
3. APCs recognise this as foreign cells, binds to them and presents them to the lymph nodes.
4. CD4+ T helper cells stimulate the conversion of B cells to ACPA and RF.
5. These immune cells migrate to the synovium where they release proinflammatory cytokines like TNF-gamma, IL which triggers neighbouring cells like macrophages, monocytes and synovial fibroblasts (TNF IL6 and IL1).
6. Leads to synovial fibroblasts proliferation = joint inflammation.
7. Prolonged abnormal proliferating cells can cause a tumour-like growth (pannus) to form which can erode cartilage and bone, leading to articular bone loss and osteoporosis.

Question 5

Why is early treatment of RA so important?

Answer 5

• joint erosion within the first two years and significant BMD loss in the first year.
• Disability occurs early: joint function is lost early.
• Spontaneous remission is rare: with RA treatment, remission is unlikely.

Question 6

How does MTX work?

Answer 6

inhibits DHFR = inhibition of DNA synthesis. This primarily affects rapidly dividing cells such as B cells and T cells, hence leads to immune suppression. This may also affect other cells like WBC, platelets, etc.
dosage: 10-25 mg/ week (oral/ sc/ iv) but if no positive prognosis after 3 months of 25 mg, add a secondary agent.
because this suppresses the immune system, important before treatment to sus out chest infections such as TB and rule out hepatitis.
while on it, do FBC, LFT and chest radiography.

Question 7

How does leflunomide work?

Answer 7

inhibits pyrimidine synthesis (by supressing DHODH enzymes) which is important for DNA synthesis which primarily affects rapidly dividing cells such as T and B cells, thus suppressing the immune system and suppressing inflammation.
dosage: 20 mg daily. works similar to MTX so we usually don’t prescribe them both at the same time.
CI: bone marrow disorders, TB, Hep B, severe renal disease, preg, etc.
adverse effects: abdominal pain, GI effects, raised LFT, allergic rash, weight loss.

Question 8

how does sulfasalazine work?

Answer 8

Mechanism: anti-inflammatory modulator (thought to act by inhibiting COX, NFKB) to reduce production of cytokines and prostaglandins.
Dosage: 500 mg daily (orally), slowly titrating to 3g/ day as 1 g tds.
Adverse effects: nausea, vomiting, oligospermia, haemolysis, rash.
CI: patients with sulphur or salicylate allergy, bone marrow disorders, asthma, G6PD deficiencies, renal or liver failure.
Safe to use in b/f and pregnancy.
Practice points: take with food to avoid stomach upset.

Question 9

How does hydroxychloroquine work?

Answer 9

Mechanism: inhibits APC to prevent immune cell activation and proliferation.
Works by preventing lysosome enzyme function by increasing pH → reduces antigen degradation + presentation on MHCII and inhibition of T or B cells proliferating to self-antigens.
Dosage: 200-400 mg once daily (orally).
Adverse effects: ocular (blurred vision, retinopathy), nausea, vomiting, diarrhoea, abdominal cramps, rash, headache, hyperpigmentation, dizziness, vertigo, ototoxicity (tinea, deafness), muscle weakness.
CI: patients with allergies, ocular conditions, diabetes, renal impairment, children (?), asian ancestry (ocular), risk factors for QT syndrome.
Safe to use in b/f and pregnancy.
Practice points:
ocular screening before starting and during treatment.
Take with food to reduce stomach upset.

Question 10

Criteria for biologics in RA?

Answer 10

MTX for 3 months
A second DMARD for 3 months
Active disease:
ESR > 25 or CRP> 15
≥ 20 swollen joints or ≥ 4 large swollen joints