The diagnosis and treatment of side effects
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Background: Treatment with checkpoint inhibitors such as anti-programmed death-1 (anti-PD-1), anti-PD-ligand 1 (anti-PD-L1), and anti-cytotoxic T-lymphocyte antigen-4 (anti-CTLA-4) antibodies can prolong the survival of cancer patients, but it also induces autoimmune side effects in 86–96% of patients by activating the immune system. In 17–59% of patients, these are severe or even life-threatening.
Methods: This review is based on pertinent articles retrieved by a search in PubMed and on an evaluation of a side-effect registry.
Results: Checkpoint-inhibitor-induced autoimmune side effects manifest themselves in all organ systems, most commonly as skin lesions (46–62%), autoimmune colitis (22–48%), autoimmune hepatitis (7–33%), and endocrinopathies (thyroiditis, hypophysitis, adrenalitis, diabetes mellitus; 12–34%). Rarer side effects include pneumonitis (3–8%), nephritis (1–7%), cardiac side effects including cardiomyositis (5%), and neurological side effects (1–5%). Severe (sometimes lethal) side effects arise in 17–21%, 20–28%, and 59% of patients undergoing anti-PD-1 and anti-CTLA-4 antibody treatment and the approved combination therapy, respectively. With proper monitoring, however, these side effects can be recognized early and, usually, treated with success. Endocrine side effects generally require long-term hormone substitution. Patients who have stopped taking checkpoint inhibitors because of side effects do not show a poorer response of their melanoma or shorter survival in comparison to patients who continue to take checkpoint inhibitors.
Conclusion: The complex management of checkpoint-inhibitor-induced side effects should be coordinated in experienced centers. The creation of an interdisciplinary “tox team” with designated experts for organ-specific side effects has proven useful. Prospective registry studies based on structured documentation of side effects in routine clinical practice are currently lacking and urgently needed.
Immune checkpoint inhibitors activate anti-tumor defenses either through the disruption of inhibitory interactions between antigen-presenting cells and T lymphocytes at so-called checkpoints (anti-PD-1/PD-L1, anti-CTLA-4, anti-TIM-3, anti-LAG-3) or else through the stimulation of activating checkpoints (CD27, CD40, GITR, CD137). They are now used to treat various types of cancer, including lung cancer, renal cell carcinoma, Merkel cell carcinoma, Hodgkin’s lymphoma, and urothelial carcinoma (eTable) and special groups of patients, e.g., patients with microsatellite instability (1). In patients with metastatic melanoma, the anti-CTLA-4 antibody ipilimumab, the anti-PD-1 antibodies nivolumab and pembrolizumab, and combination therapy with ipilimumab and an anti-PD-1 antibody can prolong survival and induce response rates of 19% (2), 36–44% (2, 3), and 58–61% (2, 4), respectively. Severe and even life-threatening side effects (classified according to the Common Terminology Criteria for Adverse Events“ [CTCAE]; grade 3/4) arise in 17–21% of patients receiving anti-PD-1 monotherapy (2, 3), 20–28% of those receiving ipilimumab (2, 3), 45% of those receiving ipilimumab (1 mg/kg) plus pembrolizumab (4), and 59% of those receiving approved combination therapy with ipilimumab (3 mg/kg) and nivolumab (2) (Table 1).
Immune checkpoint inhibitors often induce autoimmune side effects, which can affect all organ systems. These differ from the corresponding spontaneously occurring autoimmune diseases in many ways, including phenotypically, histologically, and serologically. The mechanisms of autoimmune side effects include the activation of T lymphocytes with infiltration of the organ in question (5), direct binding of the checkpoint inhibitor with activation of complement (CTLA-4 expression in the pituitary gland) (6), and immune reactions due to soluble factors (autoantibodies, cytokines). Moreover, the intestinal microbiome seems to influence the development of side effects (7, 8). No predictive factors for the appearance of side effects have yet been identified.
Common side effects include colitis, hepatitis, skin reactions, and endocrinopathies (thyroiditis or hypophysitis); rarer ones are myositis, cardiomyositis, and neurological side effects. The side effects are usually readily controllable. Checkpoint inhibitor treatment must be discontinued because of side effects in 7–12% of patients receiving anti-PD-1 therapy, 9–16% of those receiving ipilimumab therapy (2, 3), and 39% of those receiving combination therapy (2). Treatment-associated deaths have been reported in the setting of both primary and adjuvant treatment (Table 2) (9–16).
The early initiation of corticosteroid treatment can shorten the duration of autoimmune side effects and prevent complications (e.g., intestinal perforation) (17). Algorithms for side-effect management, including recommended courses of action, are now available. Checkpoint inhibitors are no less effective in melanoma patients who stop taking them because of side effects (18–20). In 25% of patients treated with ipilimumab and nivolumab, side effects arose in more than one organ system (18). Thus, patients presenting with symptoms in one organ system must be carefully checked for side effects elsewhere (18, 21, 22). This article is based on information from pertinent publications retrieved by a literature search in PubMed and on an evaluation of a side-effect registry.
General considerations on monitoring
The management of a side effect is independent of the checkpoint inhibitor that caused it. These drugs all cause the same spectrum of side effects, but with differing frequencies (Table 1) (2, 3, 23). Anti-PD-L1 antibodies do not interrupt the interaction between PD-1 and PD-Ligand 2, but have similar side effects (24, 25).
Avelumab is the only checkpoint inhibitor that commonly causes infusion reactions (e.g., back pain, hypotension). Thus, according to the manufacturer’s instructions, it should be given after premedication with acetaminophen and an antihistamine, at least for the first four infusions.
The cornerstones of side-effect management
The goals of side-effect management are
- to detect and diagnose side effects, including rare ones;
- to prevent severe and lethal side effects;
- to treat side effects appropriately and without delay;
- to interrupt, terminate, or continue anti-tumor therapy as appropriate;
- and to help patients deal optimally with the consequences of side effects.
Before starting treatment, patients should be explicitly informed that the efficacy of checkpoint inhibitors is not diminished even if they must be discontinued because of side effects. If they are not so informed, they might be disinclined to report side effects for fear of having to stop the treatment. The patient’s family should also be present during informed consent discussions, as the endocrine or neurological side effects may result in a loss of drive or in personality changes that can hinder the patient’s ability to seek help independently.
Monitoring during treatment
Patients should be monitored before treatment and at regular intervals during treatment, i.e., before every cycle of monotherapy and once a week in patients receiving ipilimumab and nivolumab, clinical symptoms and laboratory abnormalities (electrolyte changes, transaminases, lipase/amylase, creatine kinase, thyroid function tests, creatinine, complete blood count and differential) (Table 3) (26). If a side effect is suspected, the origin of the symptoms should be investigated before the next administration of a checkpoint inhibitor.
Monitoring after the end of treatment
Side effects can also arise long after the termination of checkpoint-inhibitor therapy, as is shown by a reported case of paraplegia arising five months after the end of treatment with ipilimumab (27). The German Federal Institute for Drugs and Medical Devices (Bundesinstitut für Arzneimittel und Medizinprodukte, BfArM) recommends the continuation of monitoring for at least five months after the last dose; we continue to monitor patients for up to two years after the last dose.
Gastrointestinal side effects
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%) (Table 1) (2, 3, 28). The most serious such occurrences, involving intestinal perforation and death (<1%), were mainly described in earlier treatment studies (29, 30). Whenever a patient under checkpoint inhibitor therapy presents with gastrointestinal symptoms (26), 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 (Table 3, eFigure a) (31–34). 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-α (TNF-α) antibody infliximab should be administered as well (26, 31, 35). If the symptoms persist for more than two weeks, parenteral nutrition is also recommended.
Hepatitis and pancreatitis
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 (Table 1) (2, 28, 36). Typically, no liver-specific autoantibodies are found (36, 37). Once infection and tumor progression have been ruled out (Table 3), 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 (26, 31, 35). Liver biopsy can be helpful in establishing the diagnosis and as a guide to further therapeutic decision-making (31, 36, 38). The successful administration of antithymocyte globulin has been described in cases refractory to glucocorticoids and mycophenolate mofetil (37, 39, 40). If hepatitis takes a persistent or severe course, other causes, such as CMV reactivation, should be ruled out once again (e1).
Asymptomatic elevations of lipase and amylase do not usually require treatment (2). If the problem becomes symptomatic, steroids can be given (31). Pancreatitis with and without ensuing pancreatic insufficiency has been described (9).
Endocrinopathies: thyroiditis, hypophysitis, and diabetes mellitus
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%) (Table 1) (2). Adrenalitis is found in 1–4% of patients, diabetes mellitus and diabetes insipidus in <1% (9, 26, 28, e2–e4). Under combination therapy, there is often more than one endocrine side effect at the same time (e5).
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 (31), and may thus be hard to differentiate from other causes, such as infection or progression of the underlying malignant disease (Table 3).
Thyroiditis usually causes transient hyperthyroidism and subsequent hypothyroidism (28, e6). Hypophysitis (eFigure b), which arises in 1–7% of patients, causes secondary adrenocortical insufficiency, presenting with fatigue, confusion, and electrolyte disturbances (2, e2, e3, e5). 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 (26, 31, e2).
In addition to hormone-replacement therapy, symptom-oriented treatment and/or immunosuppression with glucocorticoids may be useful in some cases as well (26, 31, e12). 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” (31). Checkpoint blockade can be continued under appropriate hormone replacement therapy.
Pulmonary side effects: pneumonitis
The incidence of pneumonitis in patients taking checkpoint inhibitors is 3–10%; this complication is lethal in 0.2–2% (18, e13–e15). The most common symptoms are dyspnea (53%), cough (35%), fever (12%), and chest pain (7%) (e14). One-third of patients are asymptomatic when pneumonitis is first diagnosed and are given the diagnosis upon a staging evaluation (Figure a) (e15). Chest x-rays fail to reveal pneumonitis in one-quarter of patients (e14). 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 (31). In most cases, checkpoint inhibition can be resumed (e14).
Manifestations resembling those of sarcoidosis, with central lymphadenopathy and potential involvement of other organs such as bone (e16–e19), can also be induced by checkpoint inhibitors and can present a differential diagnostic challenge.
Renal side effects
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 [www.fachinfo.de]; Table 1) (e20), but can manifest itself after a single infusion (e21). Renal failure has also been described as a complication of various checkpoint inhibitors (e22, e23). Renal side effects include tubulo-interstitial nephritis (16, e24–e26), glomerulonephritis (e27, e28), and thrombotic microangiopathy (e29). There have been rare case reports of lupus nephritis (e28) and possibly associated IgA nephropathy (e30).
Renal failure usually returns to baseline values under glucocorticoid therapy (26).
Cardiac side effects
Cardiac side effects including myocarditis, cardiomyopathy, and acute heart failure can take a lethal course (10, e31, e32), even in the adjuvant setting (29) (Table 2). Thus, even minimal elevation of creatine kinase or troponin values or other clinical manifestations should prompt a cardiological evaluation (Table 3). 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 (16), 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 (11). Myocarditis, the most common cardiac complication (1%) (e33, e34), is often associated with myositis and myasthenia-like symptoms or rhabdomyolysis, and it is lethal in ca. 44–50% of cases (e35, e36). There have also been reports of checkpoint inhibition inducing pericarditis, pericardiac effusion and tamponade (22, e37, e38), intracardiac conduction disorders (e39), and cardiomyopathy with manifestations resembling takotsubo cardiomyopathy (e40).
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 (e33, e41).
Musculoskeletal side effects
The musculoskeletal side effects include myositis, sometimes with cardiomyositis (e36). Myositis involving the diaphragm can present with dyspnea (e42). In checkpoint-inhibitor-induced myositis, autoantibodies are usually negative. Polymyalgia rheumatica and arthritis arise in 6–11% of patients (26, e43, e44) and can take a severe course leading to physical deformity (e45). There have been documented cases of rhabdomyolysis (21, e46, e47), dermatomyositis (e48), eosinophilic fasciitis (e44), tenosynovitis (e49), and giant cell arteritis (e50). The treatment is with glucocorticoids, possibly supplemented by immune-modulating drugs such as methotrexate or biological agents such as the interleukin-6 receptor antibody tocilizumab (e51).
Neurological side effects
Neurological side effects arise in 1–5% of patients (13, 16, 31, e52) and carry high morbidity with damaging sequelae (13) and significant mortality; these include Guillain-Barré syndrome (29), encephalopathy, and paralysis (Table 2) (e53). Symptoms such as headache, dizziness, apathy, ataxia, tremor, weakness, aphasia, memory impairment, and impaired wakefulness call for neurological evaluation (Table 3).
Side effects involving the central nervous system (CNS) include encephalopathy (e54–e61), granulomatous CNS inflammation (16), limbic encephalitis (e62), non-infectious meningitis (e63), Tolosa-Hunt syndrome (16), and transverse myelitis (e64). Focal seizures and epilepsy can arise (e65) and may be followed by Parkinson-like bradykinesia (13). 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 (e66). In another case, checkpoint-inhibitor-induced brainstem encephalopathy led to death within one week (12).
The reported side effects involving the peripheral nerves include peripheral neuropathies (among them facial palsy and abducens palsy) (e67, e68), chronic inflammatory demyelinating polyneuropathy (e64), meningoradiculoneuritis, enteric neuropathy and necrotic myelopathy (e66), demyelination (e69), hyperesthesia, neuralgia, and optic neuritis.
Myasthenia gravis that has been induced or exacerbated by checkpoint inhibitors is lethal in one-third of cases (e70). Antibodies against acetylcholine are only rarely found. Systemic diseases such as sarcoidosis can also have neurological manifestations (e71).
Glucocorticoid administration can improve the neurological manifestations (13, e72). Further treatments include intravenous immunoglobulins (IVIG), plasmapheresis, and/or the costimulation inhibitor abatacept (13, e73). 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.
Side effects on the skin and eyes
Cutaneous reactions arise in 46–62% of patients but are mild more than 90% of the time (e74, e75) and can be treated with topical emollients and glucocorticoid-containing ointments (e76). Severe cutaneous side effects arise in 2–6% of patients and include drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome, toxic epidermal necrolysis, and bullous changes such as bullous pemphigoid (e77–e80) and herpetiform dermatitis (e81). Problems of the latter type require dermatological evaluation, including immunofluorescence (e82). Leukotrichia is a further side effect (Figure b).
Lichenoid skin reactions, sometimes with mucosal involvement, arise in 17–22% of patients (e82, e83). Moreover, psoriasiform skin changes can be induced, or pre-existing psoriasis or psoriatic arthritis exacerbated (e84–e86). There have also been reports of Grover’s disease, reactions resembling chronic lichenoid pityriasis, dermatomyositis, and panniculitis resembling erythema nodosum (e48, e87–e90).
Hematological and other side effects
Hematological side effects include anemia (2.8%) (e95, e96), thrombocytopenia (1.2%) (e97, e98), leukopenia (0.5%), lymphopenia (6.4%), and neutropenia (0.7%) (26, e99). Blood-count alterations such as pancytopenia and agranulocytosis (e100) can be very dangerous (e35) (Table 2). In 43% of fully documented cases, the associated refractory autoimmune hemolytic anemia took a lethal course (e35). Acquired hemophilia after treatment with ipilimumab has been reported as well (e101). Glucocorticoid therapy can be effective (e102), 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%) (Table 1).
General considerations of management
Most side effects can be adequately treated by the prompt administration of glucocorticoids (methylprednisolone, 1–2 mg/kg of body weight per day; taper over 28 days). Prolonged glucocorticoid therapy can cause adrenocortical insufficiency and other problems.
Endocrine side effects require hormone replacement therapy, usually for life (e12). It is unclear whether high-dose glucocorticoid therapy helps maintain hormonal function. With respect to hypophysitis, at least, this seems not to be the case (e12).
If the side effects fail to respond to glucocorticoids in 3–4 days, the immune suppression should be escalated without delay. If the addition of a second immunosuppressive agent fails to achieve a response, or is followed by a protracted or complicated clinical course, then there should be a repeated evaluation to rule out infection (34, e103).
Recurrent side effects (re-exposure)
The repeated administration of checkpoint-inhibitor therapy in a patient who previously experienced side effects should be discussed with the patient in relation to the following factors:
- the severity of the side effect and the likelihood that it will recur;
- the extent of the malignant disease and the probability of it leading to death;
- the availability, if any, of effective alternative treatments.
A history of life-threatening side effects is a contraindication to the reintroduction of immunotherapy (5). The reintroduction of anti-PD-1 therapy induces side effects once again in ca. 25% of patients (19, e14). Exacerbations of cardiomyositis, thrombocytopenia, and bullous skin diseases after re-exposure have been reported (e32, e80, e104).
Special pre-existing illnesses
Pre-existing autoimmune disease does not in itself contraindicate checkpoint-inhibition therapy (5). Among patients with pre-existing autoimmune disease who underwent checkpoint-inhibition therapy, 32–33% had a tumor response (e105, e106), while 38–42% of those receiving anti-PD-1 therapy (e105, e106) and 27% of those receiving anti-CTLA-4 therapy experienced a reactivation of their autoimmune disease (e107). Rheumatological diseases were the most likely to be exacerbated (>50%) (e105, e106); exacerbations of multiple sclerosis and myasthenia gravis have also been described (e70, e108).
In transplant patients, too, immunotherapy can lead to tumor response despite immune suppression (e109), but it can also induce rejection reactions (5). These are reportedly common under anti-PD-1 therapy, while ipilimumab was not associated with a single rejection reaction in five organ transplant recipients (two patients each with kidney and liver transplants, one with a heart transplant) (e109, e110). Anti-PD-1 therapy, in one study, caused rejection reactions (some of them fatal) in 46% of patients who had received liver transplants (e111–e113). Rejection reactions have also been described in 38% of patients who had received renal transplants (e109, e112, e114–e116). One heart-transplant recipient did not have a rejection reaction under anti-PD-1 therapy (e109).
Patients with complex side effects or relevant pre-existing diseases should be treated in an experienced center. If the side effects are refractory to treatment with glucocorticoids, the immunosuppression should be further escalated (after a repeated diagnostic evaluation, if indicated). Side-effect documentation in clinical studies needs to be improved: cases with a fatal outcome must be specifically documented, rather than being subsumed under “side effects of grade 3 or above”; side effects must be documented even if they arise in less than 5% of patients; and the percentage of patients who suffer permanent harm from side effects must be stated. The structured documentation of rare side effects, and of side effects in special patient groups, may aid in the identification of risk factors. An online side-effect registry for this purpose is now being created in collaboration with the Paul Ehrlich Institute.
We thank Prof. Dagmar Führer for her critical review of the manuscript.
Conflict of interest statement
Manuscript submitted on 5 May 2018, revised version accepted on 6 December 2018.
Translated from the original German by Ethan Taub, M.D.
Prof. Dr. med. Lucie Heinzerling, MPH
Hautklinik, Universitätsklinikum Erlangen
Ulmenweg 18, 91054 Erlangen, Germany
For eReferences please refer to:
toxicity from immune checkpoint blockade therapy - report of 2 patients. J Cutan Pathol 2017; 44: 1080–6.
case of immune thrombocytopenia as a rare side effect of an immunotherapy with PD1-blocking agents for metastatic melanoma. Transfus Med Hemother 2017; 44: 426–8.
Department of Internal Medicine II, University Hospital, Ludwig-Maximilians-University (LMU) Munich: PD Dr. med. Enrico de Toni
Department of Medicine 3, University Hospital Erlangen-Nürnberg: Prof. Dr. med. Georg Schett
Department of Medicine 1, University Hospital Erlangen-Nürnberg: Dr. med. Gheorghe Hundorfean
Clinic for Dermatology, Essen University Hospital, University of Duisburg-Essen:
PD Dr. med. Lisa Zimmer
Prof. Heinzerling has served as a paid consultant for BMS, MSD, Roche, Novartis, Amgen, Curevac, Pierre Fabre, and Sanofi. She has received reimbursement of meeting attendance fees and travel expenses from BMS, Novartis, Roche, and Amgen and lecture honoraria from BMS, Amgen, MSD, Roche, and Novartis. She has received third-party funding for scientific research from Novartis, Curevac, BMS, MSD, Amgen, and Roche.
PD Dr. De Toni has served as a paid consultant for AstraZeneca, Bayer, BMS, EISAI, Eli Lilly & Co, Pfizer, IPSE, and Roche. He has received reimbursement of meeting attendance fees and travel expenses from Arqule, BMS, Bayer, and Celsion and lecture honoraria from BMS and Falk. He has received third-party funding for scientific research from Arqule, AstraZeneca, BMS, Bayer, Eli Lilly, and Roche.
PD Dr. Zimmer has served as a paid consultant for BMS, Novartis, Sanofi, Pierre Fabre, Roche, and MSD. She has received reimbursement of meeting attendance fees and travel expenses from Novartis, BMS, Pierre Fabre, MSD und Amgen amd lecture honoraria from BMS, Novartis, Pierre Fabre, Roche, and MSD.
The other authors state that they have no conflict of interest.
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