Immune-related Endocrinopathy- how to manage Tania Gallant MD, FRCPC Endocrinologist, The Moncton Hospital
Disclosures Ad board honoraria: Abbott, Astra-Zeneca
Objectives By the end of this presentation, the participant will be able to: Recognize thyrotoxicosis and become familiar with initial investigations and early management Initiate investigations for possible adrenal insufficiency, including distinguishing central from primary adrenal insufficiency Initiate therapy for adrenal insufficiency
Jama Oncology Feb 2018 Meta-analysis Included 38 studies involving 7551 patients (not all studies reported all outcomes) incidence of endocrine adverse effects Hypothyroidism – overall 6.6% (range 3.8-13.2%) Hyperthyroidism-- overall 2.9% (range 0.6-8%) Hypophysitis – overall 6.4% (range 0.1 to 6.4%) Of note, PD-1 or PD-L1 inhibitors have incidence at low end of that range Primary adrenal insufficiency – overall 0.7% (4.2% in combo treatment) Insulin deficient diabetes – overall 0.2% (13 cases and all but one was on PD-1 inhibitor) Of note, the high end of all of these were in patients on combination of ipilimumab and nivolumab
Case# 1 JP
Presentation 70 M with Stage IV non-small cell lung CA On nivolumab since April 2018 In later January 2019, complaining of increased fatigue and somnolence No headaches, vision changes, weight loss, presyncope/syncope, salt-craving Investigations were ordered
Jan 22 2019 investigations A.M. cortisol < 28 nmol/L Lytes, creatinine, random glucose normal TSH 3.697 mIU/L
Where is the problem? Pituitary vs adrenal--- NEED TO DO AN ACTH Of note, primary adrenal insufficiency is reported but not as common as secondary adrenal insufficiency in patients on immune checkpoint inhibitors Need to know as will impact treatment Do before you start glucocorticoids Cannot diagnosed adrenal insufficiency in a patient already on at least replacement doses of glucocorticoids Dexamethasone 0.5 to 0.75mg daily or Prednisone 5mg daily or Hydrocortisone 20-25mg daily Also assess for any other significant sources of glucocorticoid exposuresure Especially intra-articular steroid injections or high potency inhaled corticosteroids
JP’s ACTH was 0.3 However, it was done 3 days after he was initiated on Prednisone 20mg daily TSH normal, free T4 not done, lytes/creatinine/glucose normal, total testosterone levels low end of normal range Sellar MRI done a few weeks later – pituitary completely normal Of note, studies show that this does not rule out hypophysitis Patient’s a.m. cortisol repeated a few times but patient couldn’t recall his prednisone dose at those times On a dose of prednisone 6-7mg daily, a.m. cortisol remained <28 nmol/L with ACTH 0.2 (almost 5 months after initial treatment) free T4 normal and total testosterone levels remained low normal but stable Switched to hydrocortisone to see if could prompt some recovery with a shorter acting steroid, but no change in a.m. cortisol or ACTH levels a month later
Key Points re Adrenal insufficiency CANNOT diagnose adrenal insufficiency in a patient already on supraphysiologic doses of glucocorticoids Baseline a.m. cortisol, ACTH, lytes/creatinine and glucose prior to initiating steroids Do not need to have the results prior to initiating steroids if high index of suspicion, especially in an ill patient Initial doses depend on severity (stress p.o. dosing for moderate illness vs IV therapy in adrenal crisis) If asymptomatic or mild symptoms and tests indeterminant – may need other confirmatory testing If acute hypophysitis with mass symptoms Can consider high dose steroids with prednisone 1mg/kg/day initially As hypophysitis is most likely cause, check further pituitary profile: TSH with free T4 (even if TSH normal), LH, total testosterone (before 10 AM) Consult Endocrinologist or General Internal Medicine
Case#2 CP
Presentation 61 F, stage IVa non-small cell lung CA Started on Pembrolizumab June 30 2018 for disease progression Since about mid-August until seen by her oncologist in mid-September, noted the following symptoms: Increased sweating, heat intolerance, palpitations, hand tremours, weight loss (approx. 8 lbs), muscle weakness, exertional dyspnea, muscle weakness, dry/itchy skin, L eye discomfort, fatigue, irritability Tests are performed
Tests for CP Baseline thyroid indices 2 days before initiation of Pembrolizumab in June showed TSH 0.232 mIU/L with free T4 15.7 and free T3 4.4 Early August 2019: TSH 0.008 and free T4 20.3 (ULN 19) September 19 2019: TSH <0.004 with free T4 39.4
Additional info Patient had a previous history of congestive heart failure and atrial fibrillation Was already on bisoprolol 10mg daily Had been on amiodarone previously but it had been stopped in March 2018 Oncologist put her pembrolizumab on hold after Sept. labs On examination: no signs of Graves’ eye disease Heart rate 110/minute Notable bilateral hand tremor Thyroid painful on palpation so limited exam possible, especially on the right side (of note, it did not bother her when it was not being palpated)
Further investigations/management September 24 2019: Nuclear medicine scintigraphy: thyroid poorly visualized c/w likely thyroiditis However, most thyrotoxicosis phase of thyroiditis resolves on average after 4-6 weeks and this was already 7 weeks of overt thyrotoxicosis biochemically In addition, amiodarone can result in falsely poor uptake on thyroid scintigraphy even many months after cessation of therapy and noted asymptomatic subclinical hyperthyroidism biochemically even prior to starting pembrolizumab So I opted to start her on methimazole while pursuing other investigations Later results, TSH receptor antibodies and TPO antibodies negative
Further update on CP Oct 2019 f/u: improved but still hyperthyroid so methimazole increased to 20mg daily Early Dec 2019: TSH 0.572 with free T4 9.5 and free T3 3.9 and liver enzymes high Decreased methimazole to 10mg daily One week later, liver enzymes still high and CT liver/GB normal, so methimazole stopped Jan 2019: TSH 0.981 with free T4 13.1 March 2019: TSH 1.135 mIU/L
Key points on Thyroid disease More common with PD-1 and PD-L1 inhibitors Most appear to be related to a destructive thyroiditis but few cases of Graves’ disease How to distinguish Nuclear medicine thyroid uptake and scan can help – will be increased in Graves’ disease and low in thyroiditis TSH receptor antibodies are elevated in Graves’ disease Thyroiditis is self-limited Supportive therapy – eg. Beta-blocker If unclear or severe, treat with antithyroid drugs (eg. Methimazole) initially At risk of post-thyroiditis transient or permanent hypothyroidism So need to monitor TSH every 4-6 weeks until stable on two consecutive readings
Thyroid disease continued Hyperthyroidism is reasonable to consult endocrinologist No evidence that stopping immune checkpoint inhibitor is necessary/alters trajectory of disease If hypothyroidism If TSH is above 10 mIU/L but free T4 is still in normal range, may consider starting with partial replacement Levothyroxine dose as could be a transient problem vs monitoring If TSH is above 10 mIU/L with free T4 below the lower limit of normal, consider full replacement (1.6 mcg/kg ideal body weight/day) Levothyroxine replacement – may start at 25mcg daily with weekly titration if elderly patient and concerned re tachyarrhythmia with too rapid replacement If Myxedema coma, medical emergency, ICU, IV levothyroxine, etc If start Levothyroxine, it takes several weeks to reach steady state so typically monitor TSH every 6-8 weeks initially and then make dose adjustments accordingly Family physicians are typically first line physicians for the management of primary hypothyroidism (except myxedema)
Summary of Key Points If suspect adrenal (primary or secondary) insufficiency Always do a.m. cortisol and ACTH at baseline as well as lytes/creatinine/glucose Start steroids promptly – dose depending on initial presentation If primary adrenal insufficiency, also needs fludricortisone replacement Consult endocrinology/internal medicine If hypophysitis Also check TSH with free T4 and LH/total testosterone levels Always replace steroids for at least 1-2 days prior to replacement with Levothyroxine Thyrotoxicosis Most self-limited thyroiditis – symptom control with beta-blocker and investigate Refer to endocrinology if unclear etiology or moderate/severe
Further key points Primary hypothyroidism – Levothyroxine replacement if indicated No evidence that interrupting immune checkpoint inhibitors impacts the course of these diseases once they are established Therefore, leave to oncologist’s discretion as to the degree of severity of the patient’s illness at presentation as to whether interruption is reasonable Good clinical practice guideline from the American Society of Clinical Oncology published in June 2018 (see reference list)
Thank you! Questions?
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