What is the management approach for a patient admitted with suspected immune checkpoint inhibitor (ICI) induced myocarditis and acute interstitial nephritis?

Management of Immune Checkpoint Inhibitor-Induced Myocarditis and Acute Interstitial Nephritis

For patients with suspected immune checkpoint inhibitor (ICI)-induced myocarditis and acute interstitial nephritis, immediately discontinue the ICI therapy, admit the patient for cardiac monitoring, initiate high-dose corticosteroids, and consult cardiology and nephrology specialists. 1

Diagnostic Approach

For Suspected Myocarditis

1. Immediate cardiac evaluation:

   • Cardiac biomarkers: Troponin and BNP
   • ECG: Look for arrhythmias, conduction abnormalities
   • Echocardiography: Assess left ventricular function
   • Cardiac MRI with inflammatory sequences (T2STIR, T1, LGE)

2. Additional testing if diagnosis remains uncertain:

   • Cardiac PET-CT (preferably with 68Ga-DOTATOC) if CMR is unavailable or non-diagnostic
   • Endomyocardial biopsy if imaging is inconclusive 1, 2

3. Rule out other causes:

   • Acute coronary syndrome (especially in patients with CV risk factors)
   • Fasting lipid profile to distinguish between atherosclerosis-related troponin elevation 2

For Suspected Acute Interstitial Nephritis (AIN)

1. Laboratory evaluation:

   • Serum creatinine (≥50% increase from baseline is concerning)
   • Urinalysis: Look for sterile pyuria (≥5 WBCs/hpf)
   • Check for eosinophilia (≥500 cells per mL)

2. Diagnostic criteria for ICI-related nephritis:

   • Definite: Kidney biopsy-confirmed diagnosis
   • Probable: Sustained creatinine increase ≥50% on consecutive tests or need for RRT, absence of alternative etiology, AND sterile pyuria or eosinophilia
   • Possible: Creatinine increase ≥50% not readily attributable to other causes 1

Treatment Algorithm

For Myocarditis

1. Admit to level 2 or 3 care with ECG monitoring and resuscitation facilities 1

2. Corticosteroid therapy:

   • Initial treatment: IV methylprednisolone 500-1000 mg daily for 3 days 1
   • After initial 3 days: If troponin has fallen to <50% of peak level or normalized and patient is clinically stable, convert to oral prednisolone 1 mg/kg/day (maximum 80 mg/day)
   • Taper: Reduce by 10 mg/week with continued troponin monitoring 1

3. For severe or refractory cases:

   • Consider additional immunosuppression (mycophenolate mofetil, anti-thymocyte globulin)
   • Manage heart failure or cardiogenic shock according to standard guidelines 1

For Acute Interstitial Nephritis

1. Grade-based management:

   • Grade 1 (Creatinine increase >0.3 mg/dL; 1.5-2.0× baseline):

     • Temporarily hold ICI
     • Evaluate for alternative etiologies
     • Resume routine monitoring if improved to baseline 1

   • Grade 2 (Creatinine 2-3× baseline):

     • Temporarily hold ICI
     • Consult nephrology
     • If other etiologies ruled out, administer prednisone 0.5-1 mg/kg/day
     • If worsening after 1 week, increase to 1-2 mg/kg/day and permanently discontinue ICI
     • If improved to ≤Grade 1, taper steroids over at least 4 weeks 1

   • Grade 3-4 (Creatinine ≥3× baseline or ≥4.0 mg/dL; or life-threatening with dialysis indicated):

     • Permanently discontinue ICI
     • Consult nephrology
     • Administer prednisone 1-2 mg/kg/day
     • If improved to Grade 1, taper steroids over at least 4 weeks
     • If persistent elevation >3-5 days or worsening, consider additional immunosuppression (mycophenolate) 1

Monitoring and Follow-up

Myocarditis Monitoring

• Continuous cardiac monitoring during acute phase
• Serial troponin measurements to guide steroid tapering
• Follow-up echocardiography to assess ventricular function 1, 2

AIN Monitoring

• Monitor creatinine weekly during treatment
• Avoid kidney biopsy until steroid treatment has been attempted
• Monitor for electrolyte disturbances which commonly accompany ICI-related renal toxicity 1

Important Considerations and Pitfalls

1. Overlapping immune-related adverse events:

   • Myocarditis often co-occurs with myositis and other immune-related adverse events
   • Evaluate for other immune-related toxicities, as 54% of myocarditis cases have no other immune-related side effects 3

2. Early recognition is critical:

   • Median time of onset for myocarditis is 34 days after starting ICI
   • Mortality rates for ICI myocarditis can be up to 50% 4, 3
   • Normal ejection fraction does not rule out myocarditis (38% of major adverse cardiac events occur with normal EF) 3

3. Steroid dosing:

   • Higher steroid doses are associated with better outcomes in myocarditis
   • Lower steroid doses correlate with higher residual troponin and higher rates of major adverse cardiac events 3

4. Combination therapy risk:

   • Combination ICI therapy significantly increases risk of myocarditis compared to monotherapy (34% vs 2%) 3

5. Diagnostic challenges:

   • Ocular involvement in myositis is frequently misdiagnosed
   • Consider multidisciplinary assessment even in isolated myocarditis cases 5