4.5.1　Adverse Reactions

Serious and life-threatening diarrhea and colitis occur most commonly under combination therapy with ipilimumab and nivolumab (15%) and much less commonly under anti-PD-1 therapy (1%-4%)(1%-4%).The most serious such occurrences, involving intestinal perforation and death (＜1%),were mainly described in earlier treatment studies.Whenever a patient under checkpoint inhibitor therapy presents with gastrointestinal symptoms, the stool should be investigated for pathogens.In severe or therapy-refractory cases, cytomegalovirus (CMV) reactivation should be ruled out by CMV-PCR (PCR = polymerase chain reaction) in the serum and by colonoscopic biopsy with immunohistochemical CMV staining and CMV-PCR.The treatment is managed depending on severity according to the CTCAE classification.Gastrointestinal side effects of grade 3/4 require the prompt initiation of high-dose treatment with methylprednisolone at 1-2 mg/kg of body weight per day.In case of steroid resistance, or recurrence of the symptoms after reduction of the steroid dose, the neutralizing anti-tumor-necrosis-factor-a (TNF-a) antibody infliximab should be administered as well.If the symptoms persist for more than two weeks, parenteral nutrition is also recommended [34].

Severe or life-threatening autoimmune hepatitis arises in 20% of patients undergoing combination therapy, usually as an asymptomatic elevation of transaminases with or without elevation of the bilirubin concentration.Typically, no liver-specific autoantibodies are found.Once infection and tumor progression have been ruled out, immunosuppressive therapy with 1-2 mg/kg of methylprednisolone per day should be initiated.If there is no response, mycophenolate mofetil should be added on.Liver biopsy can be helpful in establishing the diagnosis and as a guide to further therapeutic decision-making.The successful administration of anti-thymocyte globulin has been described in cases refractory to glucocorticoids and mycophenolate mofetil.If hepatitis takes a persistent or severe course, other causes, such as CMV reactivation, should be ruled out once again.Asymptomatic elevations of lipase and amylase do not usually require treatment.If the problem becomes symptomatic, steroids can be given.Pancreatitis with and without ensuing pancreatic insufficiency has been described [34].

Thyroid dysfunction and hypophysitis are among the more common endocrine side effects, arising mainly under combination therapy (28% and 7%, respectively) and anti-PD-1 antibody therapy(15% and 1%).Adrenalitis is found in 1%-4% of patients, diabetes mellitus and diabetes insipidus in ＜1%.Under combination therapy, there is often more than one endocrine side effect at the same time.Endocrinopathies often have nonspecific symptoms, such as fatigue, weakness, dizziness,nausea/vomiting, anorexia, weight loss, headache, confusion, loss of libido, visual disturbances,abdominal pain, sweating, or tachycardia, and may thus be hard to differentiate from other causes,such as infection or progression of the underlying malignant disease.Thyroiditis usually causes transient hyperthyroidism and subsequent hypothyroidism.Hypophysitis, which arises in 1%-7%of patients, causes secondary adrenocortical insufficiency, presenting with fatigue, confusion, and electrolyte disturbances.Adrenalitis with primary adrenocortical insufficiency can arise as well.Loss of the corticotropic axis leads to an Addison crisis presenting with dehydration, hypotension,and hyponatremia, and possibly with fever and abdominal pain.This is an emergency that calls for the immediate intravenous administration of glucocorticoids.Cases of insulin-dependent diabetes mellitus have been reported.Regular blood-sugar checks are recommended.In addition to hormone-replacement therapy, symptom-oriented treatment and/or immunosuppression with glucocorticoids may be useful in some cases as well.In adrenocortical insufficiency,hormone-replacement therapy should be adjusted in situations that involve an elevated glucocorticoid requirement (infection/stress).The patient must be instructed accordingly and must be given an “emergency passport”.Checkpoint blockade can be continued under appropriate hormone replacement therapy [35].

The incidence of pneumonitis in patients taking checkpoint inhibitors is 3%-10%; this complication is lethal in 0.2%-2% The most common symptoms are dyspnea (53%), cough (35%),fever (12%), and chest pain (7%).One-third of patients are asymptomatic when pneumonitis is first diagnosed and are given the diagnosis upon a staging evaluation.Chest x-rays fail to reveal pneumonitis in one-quarter of patients.Checkpoint inhibitors should be temporarily discontinued, and methylprednisolone 1-2 mg/kg qd should be given, under antibiotic coverage if indicated.If this treatment fails, additional immune suppression with infliximab,mycophenolate mofetil, or cyclophosphamide is recommended.In most cases, checkpoint inhibition can be resumed.Manifestations resembling those of sarcoidosis, with central lymphadenopathy and potential involvement of other organs such as bone, can also be induced by checkpoint inhibitors and can present a differential diagnostic challenge [36, 37].

Renal function very often worsens under anti-PD-1 monotherapy (13%-22%).Nephritis has been reported to arise in only 0.4%-0.9% of cases (summary of product characteristics, but can manifest itself after a single infusion).Renal failure has also been described as a complication of various checkpoint inhibitors.Renal side effects include tubulo-interstitial nephritis, glomerulonephritis,and thrombotic microangiopathy.There have been rare case reports of lupus nephritis and possibly associated IgA nephropathy.Renal failure usually returns to baseline values under glucocorticoid therapy [39].(https://www.daowen.com)

Cardiac side effects including myocarditis, cardiomyopathy, and acute heart failure can take a lethal course, even in the adjuvant setting.Thus, even minimal elevation of creatine kinase or troponin values or other clinical manifestations should prompt a cardiological evaluation.After the first case of cardiotoxicity with myocardial fibrosis was reported in 2013 in the context of a retrospective study of 752 patients treated with ipilimumab, anti-PD-1 therapy was also found to be associated with an elevated incidence of cardiotoxic side effects (5% versus 0% in the control group[manufacturer’s information]).The cardiac complications of checkpoint inhibition can take many different forms, including heart failure, cardiomyopathy, conduction disorders, and myocarditis.Myocarditis, the most common cardiac complication (1%), is often associated with myositis and myasthenia-like symptoms or rhabdomyolysis, and it is lethal in ca.44%-50% of cases.There have also been reports of checkpoint inhibition inducing pericarditis, pericardiac effusion and tamponade,intracardiac conduction disorders, and cardiomyopathy with manifestations resembling takotsubo cardiomyopathy.Monitoring of all patients taking checkpoint inhibitors, including creatine kinase measurement and the meticulous evaluation of cardiac symptoms before each infusion, is essential.Corticosteroids given in conjunction with symptomatic treatment can save lives [39, 40].

Neurological side effects arise in 1%-5% of patients and carry high morbidity with damaging sequelae and significant mortality; these include Guillain-Barré syndrome, encephalopathy, and paralysis.Symptoms such as headache, dizziness, apathy, ataxia, tremor, weakness, aphasia,memory impairment, and impaired wakefulness call for neurological evaluation.Side effects involving the central nervous system (CNS) include encephalopathy, granulomatous CNS inflammation, limbic encephalitis, non-infectious meningitis, Tolosa-Hunt syndrome, and transverse myelitis.Focal seizures and epilepsy can arise and may be followed by Parkinson-like bradykinesia.There have also been reports of dysgeusia and hypogeusia, insomnia and hypersomnia, lethargy, memory impairment, and vertigo.A case of myelopathy causing paraplegia has been reported.In another case, checkpoint-inhibitor-induced brainstem encephalopathy led to death within one week.The reported side effects involving the peripheral nerves include peripheral neuropathies (among them facial palsy and abducens palsy), chronic inflammatory demyelinating polyneuropathy, meningoradiculoneuritis, enteric neuropathy and necrotic myelopathy,demyelination, hyperesthesia, neuralgia, and optic neuritis.Myasthenia gravis that has been induced or exacerbated by checkpoint inhibitors is lethal in one-third of cases.Antibodies against acetylcholine are only rarely found.Systemic diseases such as sarcoidosis can also have neurological manifestations.Glucocorticoid administration can improve the neurological manifestations.Further treatments include intravenous immunoglobulins (IVIG), plasmapheresis,and/or the co-stimulation inhibitor abatacept.The differential diagnosis encompasses brain metastases, ischemia, and infection, as well as endocrinopathies, which should be particularly borne in mind as a potential cause of personality changes [41].

Lichenoid skin reactions, sometimes with mucosal involvement, arise in 17%-22% of patients.Moreover, psoriasiform skin changes can be induced, or pre-existing psoriasis or psoriatic arthritis exacerbated.There have also been reports of Grover’s disease, reactions resembling chronic lichenoid pityriasis, dermatomyositis, and panniculitis resembling erythema nodosum [42].

Autoimmune side effects involving the eyes include blindness, anterior uveitis, sicca syndrome,ischemia or neuritis of the optic nerve, and temporal arteritis.Hematological side effects include anemia (2.8%), thrombocytopenia (1.2%), leukopenia (0.5%), lymphopenia (6.4%), and neutropenia (0.7%).Blood-count alterations such as pancytopenia and agranulocytosis can be very dangerous.In 43% of fully documented cases, the associated refractory autoimmune hemolytic anemia took a lethal course.Acquired hemophilia after treatment with ipilimumab has been reported as well.Glucocorticoid therapy can be effective, as can the administration of granulocyte colony stimulating factor (GCSF).Infusion reactions arise mainly with avelumab (17%) and less commonly with other checkpoint inhibitors (4%) [43].