Immune Checkpoint Inhibitors and Associated Immune-Related Adverse Events

IrAE

Common clinical manifestations

Initial investigations

General approach to treatment

Skin lesions

– The most common irAE (20%-40% of patients)

– Typically rash (grade 1)

– Other various presentations including bullous pemphigoid, psoriatic lesions, SJS/TEN

– Desquamation is considered grade 4 irAE

– Physical examination

– Consider skin biopsy if the diagnosis is unclear or indicates a severe disease

– Mild (grade 1) skin lesions can be treated with 1% hydrocortisone or 0.1% betamethasone cream for symptomatic pruritic rashes. Symptomatic treatment includes cold compresses and systemic antihistamines

– Systemic glucocorticoids can be considered for grade ≥2 symptoms, and high-dose therapy for symptoms of grade ≥3 with a dermatology consultation

– Consider tocilizumab or infliximab in glucocorticoid-refractory cases

Gastrointestinal abnormalities

– Diarrhea can be the sole symptom

– Diarrhea with abdominal discomfort or bloody stool is more suggestive of immune therapy-induced colitis

Abdominal CT to assess bowel thickening, areas affected, and complications

– Mild (grade 1) diarrhea can be treated with antidiarrheal agents (eg, loperamide) and should be closely monitored. Start glucocorticoids in grade 1 diarrhea if it is refractory to loperamide or in grade 2 unless transient

– For symptoms of grade ≥3, consider hospital admission for resuscitation and high-dose glucocorticoids, with gastroenterology/general surgery consultation

– Consider infliximab or vedolizumab in glucocorticoid-refractory cases

Liver abnormalities

– Elevated levels of transaminases, GGT, and rarely bilirubin, without symptoms

– Possible fatigue, abdominal pain, and nausea

– AST, ALT, ALP, GGT, bilirubin, and albumin levels; INR

– Abdominal ultrasonography or CT

– Exclude other causes (eg, viral hepatitis)

– Systemic glucocorticoids for sustained symptoms of grade ≥2 and high-dose treatment for grade ≥3

– Consult a gastroenterology/hepatology specialist regarding symptoms of grade ≥2. Consider liver biopsy to exclude alternative etiologies when considering nonglucocorticoid immunosuppressants

– Consider MMF, tacrolimus, azathioprine, and cyclosporine in glucocorticoid-refractory cases

Pulmonary abnormalities

– Shortness of breath—new or worsening from baseline

– Cough, chest pain, hypoxia

– Chest CT (ground-glass opacities, consolidation, reticular infiltrates, pneumonitis, granulomas, or organizing pneumonia)

– Oxygen saturation

– Exclude other causes (infections, venous thromboembolism)

– High-dose glucocorticoids for symptoms of grade ≥2. Consider empiric antibiotics

– Consider hospital admission for symptoms of any grade ≥3 or of grade 2 if not improved within 48 h

– Consult respirology and infectious disease specialists and perform bronchoscopy as needed

– Consider tocilizumab, infliximab, MMF, or cyclosporine if refractory to glucocorticoids

Thyroid abnormalities

– Hyperthyroidism or hypothyroidism

– Autoimmune thyroiditis can lead to hypothyroidism

TSH, FT₄, and FT₃ levels

– For symptomatic hyperthyroidism initiate a beta-blocker (eg, PO propranolol 10-40 mg qid). To provide urgent relief of symptoms of a higher grade, consider using methimazole (20-30 mg/d) with endocrinology guidance

– Consider high-dose glucocorticoid treatment and hospital admission for symptoms of grade ≥3

– In hypothyroidism, replace thyroid hormones for irAEs of grade ≥2 (symptomatic). In case of severe symptoms (grade ≥3), admit the patient to hospital and administer high doses of glucocorticoids until hypoadrenalism is excluded

Hypophysitis (pituitary gland inflammation)

Headache, visual impairment, labile moods, weakness, fatigue, confusion

– TSH, FT₃, FT₄, morning cortisol, ACTH, LH, FSH, GH, prolactin, and, if the patient is symptomatic, testosterone or estrogen

– MRI of the pituitary gland

– High-dose glucocorticoids for symptoms of grade ≥2, with slow tapering

– Hospitalization for severe symptoms (grade ≥3)

– Hormone replacement depending on endocrinology studies (eg, replace thyroid hormones and cortisol as indicated)

– Involve an endocrinologist early

Adrenal insufficiency

Abdominal pain, fatigue, refractory hypotension, hyponatremia, hyperkalemia

Morning cortisol, ACTH, aldosterone, renin

– A clinically unwell patient (shock) should be admitted to hospital to exclude other causes

– Asymptomatic grade 1 irAE may not require glucocorticoid treatment. For grade ≥2, consider high-dose glucocorticoids, while for grade ≥3, consider a stress dose

– For grade ≥3, consider mineralocorticoid replacement (eg, fludrocortisone)

– Consult an endocrinologist

Diabetes

Polyuria, polydipsia, weight loss, fatigue

– Antibodies to GAD-65 or islet cells

– C-peptide, HbA_1c, fasting glucose levels

– Similar as in type 1 diabetes; insulin replacement therapy is recommended

– Refer the patient to an endocrinologist

Rheumatologic disease

– Rheumatoid arthritis, reactive arthritis, seronegative spondyloarthritis

– Inflammatory joint pain (joint ache, morning stiffness, improvement with exercise, erythema, swelling)

– Radiography and other imaging modalities, if appropriate, to exclude bone metastases

– Consider testing for antinuclear antibodies, rheumatoid factor, anti–citrullinated protein antibody

– NSAIDs for relief of mild (grade 1) symptoms

– For moderate symptoms (grade 2), use low-dose glucocorticoids (prednisone 10-20 mg/d). Use high doses for more severe symptoms

– Refer patient with symptoms of grade ≥2 to a rheumatologist, as workup depends on the presenting disease

– Tailored treatment for specific syndromes (eg, DMARDs)

– If biologics are considered, IL-6 receptor inhibitors are preferred over TNF-alpha inhibitors

Cardiac abnormalities

Myocarditis, pericarditis, cardiomyopathy, left ventricular dysfunction

– Troponin levels

– Electrocardiography, echocardiography

– For symptoms of all grades, admit the patient to hospital with urgent referral to a cardiologist

– High-dose glucocorticoids (1-2 mg/kg/d)

– Consider adjunct immunosuppression including tocilizumab, MMF, alemtuzumab, or abatacept

Renal abnormalities

– Increased serum creatinine

– If severe, failure can result in anuria, volume overload, acid-base disturbances, and electrolyte disorders

– Electrolyte, serum creatinine, urine protein levels

– Urine microscopy

– Renal ultrasonography

– Minimize nephrotoxic drug use

– Systemic glucocorticoids for symptoms of grade ≥2 and high doses for grade ≥3

– Consider MMF, infliximab, or azathioprine if symptoms are refractory to glucocorticoids

– Correct electrolyte imbalances and perform dialysis as guided by the specialist

– Consult a nephrologist

– Consider renal biopsy if the etiology is unclear

Neurologic abnormalities

– Peripheral nervous system: Sensory or motor neuropathy, myasthenia gravis, Guillain-Barré syndrome

– Central nervous system: Meningitis, autoimmune encephalitis, cerebral vasculitis, transverse myelitis, optic neuritis

– Head MRI

– Consider lumbar puncture, nerve conduction studies, electromyography

– Consult a neurologist

– Systemic glucocorticoids for symptoms of grade ≥2, high doses for grade ≥3, and glucocorticoids for all cases of Guillain-Barré syndrome, myasthenia gravis, encephalitis, and transverse myelitis

– If symptoms are refractory, consider additional immunosuppressive agents, such as infliximab, MMF, and IVIG, and plasmapheresis depending on the presenting illness

Hematologic toxicities

 – Anemia (aplastic or hemolytic)- Leukopenia including neutropenia or lymphopenia

–Thrombocytopenia (immune mediated)

– Pancytopenia (rarely consumptive thrombotic disorders or hemophagocytic lymphohistiocytosis)

– Acquired clotting disorders

 – Complete blood count with blood film, fractionated bilirubin, LDH, haptoglobin, reticulocytes, direct antiglobulin test (or the Coombs test)

– Consider syndrome-directed investigations including bone marrow examination, flow cytometry, and specific thrombotic or hemophilia workup

– Treatment depends on grade and specific syndrome

– Early consultation with a hematologist is recommended

– Supportive management including blood products and growth factor support may be necessary

– Most patients respond to glucocorticoid treatment, but refractory cases should be tailored to the clinical syndrome including IVIG, rituximab, plasmapheresis, MMF, or cyclosporine (INN cyclosporin)