nivolumab17; typically, a transient period of subclinical hyperthyroidism proceeds a drop in function, ultimately requiring thyroid replacement therapy. A report of lung cancer patients treated with the PD1 inhibitor pembrolizumab recently reported that many patients with new thyroid dysfunction developed new thyroid antibodies. 18Development of isolated thyroid dysfunction does not require initiation of systemic corticosteroids in addition to thyroid replacement therapy. Immune mediated hypophysitis is the most feared endocrinopathy, in which all hormones released by the pituitary may be reduced simultaneously (adrenocorticotropic hormone ACTH, thyroid stimulating hormone TSH, follicle stimulating hormone, luteinizing hormone, growth hormone, prolactin). Typically, hypophysitis presents with headache, skin and constitu- tional changes, labile blood pressure, clinical hypogonadism and general malaise. Laboratory abnormalities include hyponatremia, secondary hypothyroidism, low ACTH and gonadotropins and sex hormones. A sellar MRI should be obtained which typically reveals inflammatory sequelae with enhancement and enlargement of the pituitary gland itself19,20 (low ACTH and TSH). Biochemical tests associated with hypophysitis are distinct from primary adrenal insuffıciency (low cortisol or inappropriate cortisol stimulation test; high ACTH) and primary hypothyroidism (low free T4; high TSH). If hypophysitis is suspected, anecdotal reports suggest that a course of high-dose corticosteroids (1 mg/kg of prednisone daily) given during the acute phase can reverse the inflammatory process and prevent the need for longer-term hormone replacement.21 In almost all patients, however, longer-term supplementation of affected hormones is necessary because of secondary hypothyroidism (treated with levothyroxine) or secondary hypoadrenalism (treated with replacement doses of hydrocortisone, typically 20 mg each morning and 10 mg each evening). Some authors have described that patients can be successfully weaned from replacement corticosteroids over time, but this is likely the exception.21 The immunologic mechanisms of hypophysitis are unknown, but they may be related to the development of humoral (antibody) immunity against the pituitary gland and subsequent complement activation.22 Urgent care for endocrinopathy is warranted when an adrenal crisis associated with dehydration, hypotension, and electrolyte imbalances such as hyperkalemia and hyponatremia occur. In this event, patients need to be hospitalized with intravenous corticosteroids administered. Consultation with an endocrinologist, aggressive hydration, and evaluation for sepsis is critical. For many patients the presentation is subclinical: Since routine monitoring of thyroid function tests (TSH) is frequently performed by oncologists, patients often are diagnosed with thyroid abnormalities (hyperthyroidism and hypothyroidism) as a result of checkpoint blockade. oxine). Hypophysitis rarely has been described in published 42 Kidney Cancer Journal trials of PD-1 blockade for patients with advanced melanoma.9,11 and was reported in only 0.5% of patients receiving niviolumab on the RCC registration trial. 17 Pneumonitis. There is a broad spectrum of less common AEs associated with checkpoint blockade; although they are rare, the toxicities may take the form of pancreatitis, hematologic AEs, neurologic events, pneumonitis, and nephritis. Pneumonitis is of particular concern because it may worsen despite immunosuppression and may result in infection and/or death. In RCC pneumonitis was reported in 4.4% of patients receiving nivolumab on the pivotal trial,17 high grade pneumonitis was only seen in 1% of patients.1 A report by Naidoo et al24 is noteworthy because it is a relatively large study and the clinical experience of patients with anti-PD-1/PD-L1 associated pneumonitis has not been comprehensively described. The study also addresses another gap in the literature because management and outcomes have not been thoroughly addressed. Naidoo described the clinical, radiologic, and pathologic features and management of 43 cases of pneumonitis from two separate institutions, Memorial Sloan Cancer Center and the Melanoma Institute of Australia. Patients received anti-PD-1/PDL1 monotherapy or a combined regimen with anti-cytotoxic T cell lymphocyte-4 mAb. Any grade pneumonitis developed in approximately 5% of patients treated with anti–PD-1/PD-L1 mAbs, and grade 3 and higher pneumonitis developed in 1%. Pneumonitis was more common in patients treated with anti–PD-1/PD-L1 mAbs plus anti–CTLA-4 mAb compared with anti–PD-1/PD-L1 monotherapy. 24 Clinically, nearly all cases of pneumonitis improved/ resolved with drug holding and/or immunosuppression. However, some cases worsened and were fatal. In this series, worsening cases were restricted to current and former smokers and were more common in patients with underlying lung conditions; such patients may require particularly careful management. Among patients in whom pneumonitis improved/resolved, 12 (all with grade 1 to 2) underwent rechallenge with anti–PD-1/PD-L1 mAbs, and recurrent pneumonitis occurred in three (25%). This may suggest that in mild cases, one may cautiously resume therapy after pneumonitis has improved/ resolved and after careful discussion with the patient. Although most instances of pneumonitis were not severe, five deaths occurred, and in three cases, infection from prolonged immunosuppression contributed to death. No patient who received immunosuppression beyond corticosteroids (infliximab with or without cyclophosphamide) recovered from pneumonitis. Improvement is needed in the choice, dose, and duration of therapies for pneumonitis with consideration of the role of antimicrobial prophylaxis. Renal events: acute interstitial nephritis. Immune-induced nephritis is uncommon (related all-grade events
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