Friday, 16 Nov 2018

You are here

Update on Immune Checkpoint Inhibitor Toxicity

JAMA has a 2018 update/review of the safety issues seen with mmune checkpoint inhibitors (ICIs) - important new cancer therapies, with 14 cancer indications, that have significantly improved survival in several.  ICIs are monoclonal antibodies that block inhibitors of T-cell activation and function.

ICIs block cytotoxic T lymphocyte antigen 4 (CTLA-4; ie, ipilimumab), programmed death 1 (PD-1; ie, nivolumab, pembrolizumab), or programmed death ligand 1 (PD-L1; ie, atezolizumab, avelumab, durvalumab).

Immune checkpoints on T cells normally prevent autoimmunity by inhibiting dendritic cell-mediated T-cell activation (CTLA-4) or by inducing T-cell exhaustion at sites of inflammation (PD-1/PD-L1).  By removing inhibition of T-cell function, ICIs facilitate T-cell–mediated actions on tumors but in doing so they may promote T-cell autoimmune activity against host tissues. As such ICIs have been associated with numerous examples of organ-specific inflammation, and autoimmune events described within this  review.

Autoimmune AEs associated with anti–CTLA-4 regimens occur earlier, more frequently, and are more severe than autoimmune AEs associated with anti–PD-1/PD-L1 monotherapy.  Thus will AE arise acutely, they may respond to steroids within 1 to 7 days. Low-dose steroids (prednisone, 0.5 mg/kg) are generally used for mild AEs and high dose glucocorticoids (1-2 mg/kg) for more severe AEs. AEs may reappear after discontinuation of steroids in approximately 10% of patients, and cause hospitalization in 5% (anti-PD-1 monotherapy) to 36% (combination anti-CTLA-4/anti-PD-1) of patients. Steroid nonresponders should be considered for second-line immunosuppression, such as infliximab or mycophenolate mofetil.

Common manifestations of immune-mediated adverse events with ICIs include:

  • Colitis: occurs 25% of patients treated with ipilimumab and < 5% of patients treated with anti–PD-1/PD-L1 monotherapy. Colitis may be life-threatening or mild watery diarrhea. Colonoscopy, steroids and even biologic therapies may be necessary.
  • Pneumonitis: also potentially life-threatening, may be seen in 2% to 5% of patients treated with ICIs. Symptoms may prompt evaluation with computed tomographic imaging - revealing ground glass opacities and/or interstitial thickening, High-dose steroids (1-2 mg/kg/d) are indicated in symptomatic patients.
  • Cutaneous: up to 30% of patients treated with ICIs and include pruritus, acneiform rash, and toxic epidermal necrolysis. Blisters or mucosal involvement are rare (<1%) but suggest a bullous disorder or Stevens-Johnson syndrome and require prompt dermatology evaluation and high-dose steroids.
  • Endocrine Dysfunction: Hypophysitis (pituitary inflammation) is one of the more common AE with anti–CTLA-4 therapy (up to 10% incidence), but is rarely seen with other ICIs. Patients with hypophysitis present with signs and symptoms of adrenal insufficiency, such as hypotension and fatigue and headaches. Hypothyroidism occurs in up to 20% of treated patients, is often preceded by asymptomatic inflammatory thyroiditis, and requires thyroid hormone replacement. Hyperthyroidism is less common, may be transient and followed by hypothyroidism.
  • Hepatitis: seen in 1% of patients prescribed anti‐PD1/PD‐L1 agents and 10% of patients prescribed anti-CTLA-4 agents.
  • Myocarditis and myositis: inflammatory myocarditis occurs in less than 1% of patients treated with ICIs, often presents with concurrent skeletal muscle myositis, may be fulminant or smoldering in nature, and has a 20% to 50% risk of death. Patients with myocarditis present with fatigue, shortness of breath, chest discomfort, and troponin elevations and conduction disturbances.
  • Neurotoxicity: tends to be rare (<1% of patients treated with ICIs) but severe neurotoxicities include Guillain-Barré syndrome, myasthenia gravis, and encephalitis.9 Guillain-Barré syndrome and myasthenia gravis require prompt disease-specific management 





The author has no conflicts of interest to disclose related to this subject

Add new comment

More Like This

Musculoskeletal Events with Statin Use

Analysis of the FDA Adverse Event Reporting System data examined the association between statins' musculoskeletal adverse events (MAEs).

Review of the data shows that atorvastatin and rosuvastatin (with strong low‐density lipoprotein cholesterol‐lowering effects) had a higher risk and a faster onset of MAEs when compared with simvastatin.

They could not detect whether concomitant drugs shifted the onset timing of MAEs. 

Low Short-Term Risks of NSAIDs in High Risk Patients

JAMA has published a large Canadian claims-based study showing that nonsteroidal anti-inflammatory drug (NSAID) use in patients with hypertension, heart failure, or chronic kidney disease was not associated with a significant safety risk - but this only looked at short-term outcomes (7-37 days of exposure). 

Update on Checkpoint Inhibitor Safety

“Autoimmunity is the Achilles heel of onco-immunotherapy” per Dr. Leonard Calabrese, which leaves a dilemma for rheumatologists. Onco-immunotherapy induces immune dysregulation to allow patients to develop an immune response to their cancer cells. An unfortunate side effect for patients taking onco-immunotherapy is often autoimmune-like diseases referred to as immune adverse reactions (irAEs). Studies in France and the United States have shown that irAEs can be a good prognostic sign, suggesting these therapies are working. Rheumatology is faced with new problems as onco-immunotherapies may induce new chronic diseases in multiple different forms secondary to the treatment.

Anti-phospholipid Antibodies and Myocardial Infarction.

The Annals of Internal Medicine features a communique from the Karolinska Institutet in Sweden demonstrating that elevated levels of antiphospholipid antibodies may be found in patients with myocardial infarction without any autoimmune co-morbidity, published in Annals of Internal Medicine reports.

New BSR Guidelines on Biologic Safe Use with Inflammatory Arthritis

The British Society of Rheumatology has produced a set of NICE accredited guidelines for the use of biologic therapies in patients with inflammatory arthritis.

It addresses safety recommendations for all biologic therapies approved by the National Institute for Health and Care Excellence (NICE) up to June 2016, for use in all inflammatory arthritides [RA, PsA and axial SpA (SpA) including AS].