Management of Persistent/Recurrent Severe Anaemia in RA on Methotrexate

Step 1 - Immediate Assessment

• Heart rate, blood pressure, symptoms of hypoperfusion (chest pain, dyspnoea, lightheadedness)
• Hb 5.5 is critically low - consider urgent transfusion again if symptomatic

Step 2 - Identify the Cause (Critical Before Treatment)

A. Methotrexate-Induced Bone Marrow Suppression / Megaloblastic Anaemia

• Renal function is impaired (MTX accumulates - check urea, creatinine, eGFR)
• Patient is taking NSAIDs concurrently (compete for protein binding, raise MTX levels - fatalities have been reported)
• Trimethoprim-sulfamethoxazole is co-prescribed
• Hypoalbuminaemia is present
• Patient is elderly or has intercurrent infection
• Dosing errors occurred

B. Anaemia of Chronic Inflammation (ACI)

C. Iron Deficiency Anaemia (IDA)

D. Other causes to rule out

• Haemolytic anaemia (Coombs test, LDH, bilirubin, haptoglobin) - drug-induced haemolysis is rare with MTX
• GI malignancy (if >50 years, PR bleeding, weight loss)
• Renal anaemia if CKD present

Step 3 - Investigations to Order Simultaneously

Step 4 - Treatment

If MTX toxicity is confirmed or strongly suspected (pancytopenia, macrocytosis, renal impairment):

1. Hold methotrexate immediately - this is mandatory
2. Leucovorin (folinic acid) rescue - this bypasses the DHFR blockade caused by MTX and directly rescues the bone marrow. Administer promptly:
   • Oral or IV leucovorin (folinic acid), dose guided by severity
   • Do NOT use folic acid for rescue - it cannot bypass the DHFR block
   • Switch the patient's weekly folic acid to leucovorin temporarily
   • (Brenner & Rector's The Kidney: "Leucovorin rescue is most beneficial when administered promptly after methotrexate exposure")
3. Transfuse if Hb <7 g/dL (or <8-9 g/dL if symptomatic or cardiac disease) to buy time while marrow recovers
4. Hydrate well and ensure adequate urine output - alkalinize urine if high MTX levels suspected
5. Once Hb recovers and counts normalise, MTX can be restarted at a lower dose with closer monitoring and adequate folate supplementation

If Iron Deficiency is confirmed:

• Oral iron (ferrous sulphate 200 mg TDS) or IV iron if oral not tolerated or malabsorbed
• Identify and treat the source of bleeding (endoscopy if GI loss suspected)
• IV iron sucrose or ferric carboxymaltose are preferred in active inflammatory disease as hepcidin-driven block on oral iron absorption is common

If Anaemia of Chronic Disease with active RA:

• Better control of RA disease activity is the primary treatment (DMARDs, biologics)
• Erythropoiesis-stimulating agents (EPO) are occasionally used in severe ACI refractory to disease control, but not first-line
• IV iron can be used if concurrent functional iron deficiency

If B12/Folate deficiency:

• Replace accordingly: IM hydroxocobalamin for B12, folic acid 5 mg daily for folate deficiency
• Note: if MTX is the cause, increase the dose of folic acid supplementation (up to 5 mg/day on non-MTX days) or switch to leucovorin

Step 5 - Ongoing Monitoring

• Active ongoing haemorrhage (GI bleed - urgent endoscopy)
• Active bone marrow suppression (MTX toxicity - hold MTX, leucovorin rescue)
• Haemolysis (screen urgently)

• FBC monthly for 3 months after MTX dose change, then every 3 months
• Renal function and LFTs at same intervals
• If MTX resumed: ensure no NSAIDs co-prescribed or at minimum use the lowest dose with PPI cover
• Increase folic acid to 5 mg daily (on non-MTX days) rather than once weekly

Summary Algorithm

Hb 5.5 in RA on MTX
       ↓
Assess haemodynamic stability → transfuse if symptomatic
       ↓
FBC + film + reticulocyte count
       ↓
Macrocytosis / Pancytopenia? → HOLD MTX + Leucovorin rescue
Microcytic?                  → Iron studies → treat IDA + find source
Normocytic?                  → ACI likely → control RA, IV iron if functional deficiency
Reticulocytosis?             → Haemolysis screen / active bleed workup