Immune Checkpoint Inhibitor Toxicity — Written Clinical Reasoning

Prompt 1 — multisystem immune-related toxicity on combination checkpoint inhibition (15 marks)

Using the clinical stem above, address the following in a structured written answer: [1]

(a) Formulate a prioritised problem list and justify your ordering. (4 marks) [1]

(b) Outline your immediate and definitive management of the two highest-priority problems, including specific drug doses, monitoring, and the timing of second-line therapy. (8 marks) [1]

(c) Explain the investigation strategy for the colitis and the rationale for the order of investigation. (3 marks) [1]

Model answer — Prompt 1

(a) Prioritised problem list [1]

1. Secondary adrenal insufficiency from checkpoint-inhibitor hypophysitis with evolving adrenal crisis — the immediate life threat. The postural drop, hyponatraemia (126), hyperkalaemia (5.1), and low cortisol with inappropriately low ACTH, in a patient on ipilimumab, are diagnostic. Untreated adrenal crisis is fatal and is the first thing to treat.
2. Grade 3 immunotherapy colitis — the index emergency with perforation risk. Eight bloody stools per day with abdominal pain and a systemic inflammatory response is CTCAE grade 3.
3. Grade 2 immunotherapy hepatitis — the ALT and AST are 5 to 6 times the upper limit of normal with a mildly raised INR; needs exclusion of viral, drug and obstructive causes but is consistent with an irAE.
4. Hypophysitis with central hypothyroidism (low TSH, low free T4) and likely hypogonadism — to be replaced, but only AFTER cortisol replacement.
5. Grade 2 maculopapular skin rash — 25 per cent body surface area without mucosal involvement; manageable alongside the other problems.
6. Metastatic melanoma — the underlying disease; the oncological decision on continuation of therapy follows recovery.
7. Acute kidney injury (pre-renal and possibly interstitial) — likely a combination of hypovolaemia from colitis and adrenal insufficiency; will improve with resuscitation. [1]

(b) Immediate and definitive management of the two highest-priority problems [1]

Adrenal crisis (problem 1):

• Intravenous hydrocortisone 100 mg stat then 50 mg every 6 hours — do not wait for the pituitary MRI.
• Intravenous fluids: 1 litre normal saline over the first hour, then continue resuscitation guided by haemodynamics and sodium.
• Correct sodium slowly (no more than 8 to 10 mmol/L in 24 hours) to avoid osmotic demyelination.
• Do not give levothyroxine until hydrocortisone is running — thyroid replacement increases cortisol clearance and can precipitate cardiovascular collapse.
• Arrange a pituitary MRI once stable to confirm an enlarged, homogeneously enhancing gland.
• Plan lifelong replacement with hydrocortisone, levothyroxine, and (after a repeat panel) testosterone; involve endocrinology. [1]

Grade 3 colitis (problem 2):

• Admit; intravenous fluids and electrolyte correction; thromboprophylaxis (high VTE risk).
• Stool studies MUST be sent before steroids — culture, C. difficile toxin, ova cysts and parasites. (Already done per stem.)
• Once the stool is sent, intravenous methylprednisolone 1 to 2 mg/kg per day (here, around 80 to 100 mg per day).
• Hold both checkpoint inhibitors; plan for permanent discontinuation of the combination after this multisystem grade 3 event.
• Gastroenterology and surgical review at the first opportunity; CT abdomen if peritonism develops or perforation is suspected.
• Infliximab 5 mg/kg at weeks 0, 2 and 6 at 48 to 72 hours if there is no response to steroid — screen with QuantiFERON and hepatitis B surface antigen first (already pending).
• Plan a slow corticosteroid taper over at least 4 to 6 weeks once the colitis has resolved to grade 1. [1]

(c) Investigation strategy for the colitis and the rationale [1]

The order is: exclude infection first, then confirm the irAE, then assess for complications.

1. Stool culture, C. difficile toxin, ova cysts and parasites — sent before steroids because steroids make interpretation impossible. C. difficile and Campylobacter produce an identical clinical picture.
2. Blood cultures and inflammatory markers — to capture systemic infection.
3. Faecal calprotectin — supports an inflammatory colitis.
4. Flexible sigmoidoscopy or colonoscopy with biopsies — confirms the diagnosis (mucosal oedema, loss of vascular pattern, ulceration; mixed inflammatory infiltrate) and excludes CMV and pseudomembranous colitis. Sigmoidoscopy suffices in the unstable patient.
5. CT abdomen with contrast — if perforation, toxic megacolon or an alternative diagnosis is suspected.
6. Exclusion of coexisting hepatitis — viral serology, autoimmune markers, abdominal ultrasound with Doppler. [1]

The rationale for sending stool first is that the management of an infective colitis (antibiotics, no immunosuppression) is the opposite of the management of immunotherapy colitis (immunosuppression). Giving steroids for C. difficile colitis is harmful; withholding steroids for grade 3 immunotherapy colitis risks perforation. The stool result resolves the dilemma, and in a high-probability case steroids are started once the stool is in the lab, not after the result returns. [1]

Prompt 2 — checkpoint-inhibitor myocarditis (10 marks)

A 70-year-old man on cycle 3 of nivolumab for metastatic non-small-cell lung cancer presents with 2 days of central chest pain, dyspnoea and palpitations. He is tachycardic (112), blood pressure 100/64, oxygen saturation 93 per cent on room air, with bibasal crackles. ECG shows a new right bundle branch block. Troponin I is 2.8 ng/mL. Coronary angiogram shows no obstructive disease. Echocardiography shows an ejection fraction of 40 per cent with anterior wall-motion abnormality. Creatine kinase is 1200 U/L. [1]

(a) State the most likely diagnosis and the pathophysiological basis for the troponin elevation. (2 marks) [1]

(b) Outline the immediate and definitive management, including specific drug doses and the threshold for escalation. (6 marks) [1]

(c) Name the two associated irAEs that should be actively screened for, and explain why. (2 marks) [1]

Model answer — Prompt 2

(a) Diagnosis and pathophysiology [1]

Checkpoint-inhibitor myocarditis. The mechanism is T-cell-mediated autoimmune injury to the myocardium — the same brake-release that restores antitumour immunity removes self-tolerance to cardiac myocytes, producing a lymphocytic myocarditis with myocyte necrosis. The troponin elevation reflects direct myocyte damage (not ischaemia, hence the normal coronary angiogram). Mahmood and colleagues reported a prevalence of around 1 per cent in their registry but a case fatality of 25 to 50 per cent, with deaths often within days of onset. The pathology can be confirmed by cardiac MRI (late gadolinium enhancement, T2 oedema) or endomyocardial biopsy. [1]

(b) Immediate and definitive management [1]

1. Admit to a monitored bed (CCU or ICU) — continuous ECG monitoring because conduction block and ventricular arrhythmia are common.
2. Permanently discontinue nivolumab — the guideline rule is permanent discontinuation at any grade of myocarditis.
3. Intravenous methylprednisolone at pulse doses: 500 mg to 1 g daily for up to 3 days, then 1 to 2 mg/kg per day. This is higher than the 1 to 2 mg/kg used for most other irAEs because undertreated myocarditis is fatal.
4. Standard heart-failure and arrhythmia management — diuretics, ACE inhibitor or ARB, beta-blocker once stable, and treatment of any ventricular arrhythmia; avoid cardiotoxic drugs.
5. Early cardiology and intensive-care involvement.
6. Escalation threshold: if there is no improvement at 48 to 72 hours, or in fulminant disease, add mycophenolate mofetil, consider antithymocyte globulin, and plasmapheresis (especially with myasthenia overlap). Mechanical circulatory support may be needed.
7. Slow corticosteroid taper over 4 to 6 weeks once cardiac function recovers. [1]

(c) Associated irAEs to screen for [1]

1. Myositis — the raised creatine kinase (1200 U/L) already indicates skeletal-muscle involvement; myositis frequently coexists with myocarditis and can involve respiratory muscles. Screen with serial creatine kinase and a clinical assessment of proximal weakness.
2. Myasthenia gravis — ptosis, diplopia, fatigability and respiratory muscle weakness can accompany myocarditis; check acetylcholine-receptor antibodies, perform a bedside fatigability assessment, and monitor the forced vital capacity because respiratory failure can develop rapidly. Myasthenia is managed with IVIG or plasmapheresis in addition to the corticosteroid. [1]

Examiner note

These two prompts together cover the two archetypes the FRACP DCE long case most often tests in immunotherapy: the multisystem irAE requiring integrated prioritisation and the single-organ fatal irAE requiring rapid escalation. The discriminating skills are (1) recognising that adrenal crisis takes precedence over colitis despite both being present, (2) sending stool before steroids, (3) the dose of corticosteroid for myocarditis (pulse, not 1 mg/kg), and (4) permanent discontinuation for vital-organ grade 3 events. Candidates who can articulate these four points will pass this topic at viva. [1]