Cancer immunotherapy is changing the landscape of treatment of several cancers. However, these drugs are mostly immune checkpoint inhibitors, immunomodulatory antibodies that are used to enhance the immune system.

Checkpoint inhibition is associated with a unique spectrum of side effects termed immune-related adverse events (irAEs). IrAEs include dermatologic, gastrointestinal, hepatic, endocrine, and other less common inflammatory events. IrAEs are believed to arise from general immunologic enhancement, and temporary immunosuppression with corticosteroids, tumour necrosis factor-alpha antagonists, mycophenolate mofetil, or other agents can be an effective treatment in most cases.

In general, treatment of moderate or severe irAEs requires interruption of the checkpoint inhibitor and the use of corticosteroid immunosuppression.

Some of the side effects include:

Fatigue — Fatigue is among the most common side effects seen for anti PD-1 and PD-L1 and anti-CTLA4. When fatigue is present, it is important to exclude thyroid, pituitary,  and  other  endocrine  disorders, such as primary adrenal insufficiency.

Infusion-related reactions — Mild infusion-related side effects have been reported in up to 25 percent of patients treated with anti-PD-1 or anti-PD-L1 agents.

Dermatologic and mucosal toxicity - Dermatologic toxicity is the most common irAE associated with checkpoint inhibitors. Alopecia has been reported in approximately 1 to 2 percent of  cases.  Typical physical examination findings consist of a reticular, maculopapular, faintly erythematous  rash  on  the trunk or extremities. Vitiligo is also seen commonly. Oral mucositis and/or complaints  of  dry  mouth appear to be more frequent with programmed cell death-1 (PD-1) receptor checkpoint inhibitors than with CTLA-4 blockade. Oral candidiasis remains an important consideration in the differential diagnosis, particularly    if    a    patient    has    been    on    oral

corticosteroids for management of other irAEs. Severe rashes such as Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported in rare cases. Such reactions typically require hospitalization, intravenous steroids, dermatologic evaluation, and vigilant monitoring to treat abnormalities in fluid and electrolyte status.

Diarrhoea/colitis — Diarrhea is a common clinical complaint in patients undergoing treatment with checkpoint-blocking antibodies. The differential diagnosis of patients with diarrhea on treatment with a checkpoint inhibitor includes infections  with Clostridium difficile or other bacterial/viral pathogens.

Hepatotoxicity — Elevations of the hepatic enzymes, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) can be seen with both CTLA-4 and PD-1 receptor blockade. Hepatic function (transaminases and bilirubin) should be monitored prior to each dose of immunotherapy.

Pneumonitis — Pneumonitis is an uncommon but potentially severe or fatal complication of  treatment with checkpoint inhibitor immunotherapy. Drug- induced pneumonitis is a diagnosis of exclusion, and alternative diagnoses, including infection and malignancy, need to be excluded. Pulmonary toxicity may also manifest as a radiation recall pneumonitis limited to previously irradiated areas of the lung.

Endocrinopathies

Inflammation of the pituitary, thyroid, or adrenal glands as a result of checkpoint blockade often presents with nonspecific symptoms such as nausea, headache, fatigue, and vision changes. The most common endocrinopathies are hypophysitis and  hypothyroidism.

Hypophysitis is manifested by clinical symptoms of fatigue and headache. The diagnosis is established by low levels of the hormones produced by the pituitary (adrenocorticotropic hormone [ACTH], thyroid- stimulating hormone  [TSH],  follicle-stimulating hormone [FSH], luteinizing hormone [LH], growth hormone [GH], prolactin).

Autoimmune thyroid disease — Thyroid function should be monitored prior to each dose of a checkpoint inhibitor. Autoimmune thyroid disease can be manifested as primary hypothyroidism secondary to a destructive thyroiditis or by hyperthyroidism associated with Graves'  disease.

Adrenal insufficiency — The most critical endocrinopathy is adrenal insufficiency, which can cause dehydration, hypotension, and electrolyte imbalances (hyperkalaemia, hyponatremia), and constitutes an emergency.

Neurologic — A wide range of neurologic syndromes have been associated with checkpoint blockade involving Ipilimumab and anti-PD-1 agents. Cases of Guillain-Barre syndrome, myasthenia gravis, posterior reversible encephalopathy  syndrome  (PRES), aseptic meningitis,  enteric  neuropathy, transverse myelitis, and  autoimmune encephalitis have been reported.

Cardiotoxicity may develop in the absence of a history of significant cardiac risk factors and may be associated with a more general myositis as well as other irAEs.

Hematologic — Red cell aplasia, neutropenia, thrombocytopenia, acquired haemophilia A, and cryoglobulinemia have been described in patients treated with checkpoint inhibitors. Eye

CTLA-4 blockade has been  associated  with eye inflammation, which can be manifested by episcleritis, conjunctivitis, uveitis, or orbital inflammation.

Rheumatologic and musculoskeletal — A wide range of rheumatologic toxicities has been observed with checkpoint inhibition immunotherapy including inflammatory arthritis, salivary gland dysfunction (sicca syndrome), and inflammatory myositis, among others.

With the advent of cancer immunotherapy, all physicians should be aware of some of the above irAEs. If patients experience them they should be referred to the treating oncologists as they will benefit from  corticosteroids.

If symptoms do not improve with intravenous steroids, the approach is to administer infliximab  rather  than  continue with a prolonged course of high-dose IV corticosteroids.

Frequent and consistent communication between patients, caregivers, and the clinical team is vital to successful irAE management.