scholarly journals Myxoedema coma caused by immunotherapy-related thyroiditis and enteritis

2021 ◽  
Vol 2021 ◽  
Author(s):  
Darran Mc Donald ◽  
Eirena Goulden ◽  
Garret Cullen ◽  
John Crown ◽  
Rachel K Crowley
Keyword(s):  
Malignant Melanoma ◽  
Thyroid Function ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Adverse Reactions ◽  
Checkpoint Inhibitors ◽  
Thyroid Function Tests ◽  
Absorption Test ◽  
Function Tests ◽  
Painless Thyroiditis

Summary Thyroid dysfunction is among the most common immune-related adverse reactions associated with immune checkpoint inhibitors. It most commonly manifests as painless thyroiditis followed by permanent hypothyroidism. This usually causes mild toxicity that does not interfere with oncological treatment. In rare instances, however, a life-threatening form of decompensated hypothyroidism called myxoedema coma may develop. We present a case of myxoedema coma in a woman in her sixties who was treated with a combination of CTLA-4 and PD-1 immune checkpoint inhibitors; for stage four malignant melanoma. She became hypothyroid and required thyroxine replacement after an episode of painless thyroiditis. Six months after the initial diagnosis of malignant melanoma, she presented to the emergency department with abdominal pain, profuse diarrhoea, lethargy and confusion. She was drowsy, hypotensive with a BP of 60/40 mmHg, hyponatraemic and hypoglycaemic. Thyroid function tests (TFTs) indicated profound hypothyroidism with a TSH of 19 mIU/L, and undetectable fT3 and fT4, despite the patient being compliant with thyroxine. She was diagnosed with a myxoedema coma caused by immune-related enteritis and subsequent thyroxine malabsorption. The patient was treated with i.v. triiodothyronine (T3) and methylprednisolone in the ICU. While her clinical status improved with T3 replacement, her enteritis was refractory to steroid therapy. A thyroxine absorption test confirmed persistent malabsorption. Attempts to revert to oral thyroxine were unsuccessful. Unfortunately, the patient’s malignant melanoma progressed significantly and she passed away four months later. This is the first reported case of myxoedema coma that resulted from two distinct immune-related adverse reactions, namely painless thyroiditis and enterocolitis. Learning points Myxoedema coma, a severe form of decompensated hypothyroidism is a rare immunotherapy-related endocrinopathy. Myxedema coma should be treated with either i.v. triiodothyronine (T3) or i.v. thyroxine (T4). Intravenous glucocorticoids should be co-administered with thyroid hormone replacement to avoid precipitating an adrenal crisis. Thyroid function tests (TFTs) should be monitored closely in individuals with hypothyroidism and diarrhoea due to the risk of thyroxine malabsorption. A thyroxine absorption test can be used to confirm thyroxine malabsorption in individuals with persistent hypothyroidism.

THYROID DYSFUNCTION, RECOVERY, AND PROGNOSIS IN MELANOMA PATIENTS TREATED WITH IMMUNE CHECKPOINT INHIBITORS: A RETROSPECTIVE REVIEW

2020 ◽  
Vol 26 (1) ◽  
pp. 36-42 ◽  
Author(s):  
Mazen Al Mushref ◽  
Paul A. Guido ◽  
Frances A. Collichio ◽  
Dominic T. Moore ◽  
David R. Clemmons
Keyword(s):  
Thyroid Function ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Thyroid Dysfunction ◽  
Checkpoint Inhibitors ◽  
Thyroid Stimulating Hormone ◽  
Thyroid Function Tests ◽  
Melanoma Patients ◽  
Recovery Group ◽  
Stimulating Hormone

Objective: To describe thyroid dysfunction, factors associated with thyroid recovery, and survival in melanoma patients treated with immune checkpoint inhibitors that developed thyroid immune-related adverse events (irAEs). Methods: This was a retrospective study in a tertiary center from 2010–2017. We reviewed the charts of patients with melanoma that developed thyroid dysfunction after checkpoint inhibitor therapy. Cases with thyroid irAEs were grouped by recovery of thyroid function at 1 year. We collected a timeline of thyroid function tests, medication exposure, and survival and compared variables between the groups. We studied survival in comparison to a matched group without thyroid dysfunction. Results: A total of 186 melanoma patients received checkpoint inhibitors, and 17 (9%) had thyroid irAEs. Median time to abnormal thyroid-stimulating hormone was 38 days and followed a pattern of thyroiditis. Seven of 17 had thyroid recovery. In the no-recovery group, free thyroxine (T4) was often above 2 ng/dL (5/10 in no recovery, 0/7 in recovery; P = .04). In the recovery group, irAE grade was significantly lower, with 7/7 grade 1 ( P = .004). Exposure to glucocorticoids was associated with recovery (3/10 in no recovery, 6/7 in recovery; P = .049). There was no difference in overall survival between the thyroid dysfunction group and controls, or between those that received glucocorticoids or not. Conclusion: Certain aspects of thyroid irAEs may correlate with thyroid recovery, including grade 1 thyroid irAEs, exposure to glucocorticoids, and peak free T4 levels less than 2 ng/dL. Thyroid irAEs did not appear to be associated with change in survival nor did exposure to glucocorticoids. Abbreviations: ASCO = American Society of Clinical Oncology; CTLA-4 = cytotoxic T-lymphocyte–associated protein 4; irAE = immune-related adverse event; PD-1 = programmed cell death protein 1; T4 = thyroxine; TSH = thyroid-stimulating hormone

scholarly journals SAT-491 Transient Thyrotoxicosis with Immune Checkpoint Inhibitors Therapy: The Importance of Endocrine Evaluation

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Diana Cruz Martins ◽  
Daniela Guelho ◽  
Nuno Vicente ◽  
Mara Ventura ◽  
Alexandra Vieira
Keyword(s):  
Medical History ◽  
Thyroid Function ◽  
Survival Data ◽  
Immune Checkpoint ◽  
Crucial Role ◽  
Checkpoint Inhibitors ◽  
Whole Body ◽  
Thyroid Function Tests ◽  
Function Tests ◽  
The Impact

Abstract Introduction The immune checkpoint-blocking antibody nivolumab is recognized as having a crucial role in different malignancies by blocking programmed death-1 (PD-1) receptor immune cells. Besides its benefits, nivolumab may cause endocrine immuno-related adverse events (irAEs), including thyroid dysfunction (TD). Clinical case A 71-year-old man, with an uneventful past medical history, was diagnosed with stage IIIB (T4N2M0), epithelial-growth-factor-receptor (EGFR) wild type, lung adenocarcinoma. The patient underwent 4 cycles of first line chemotherapy with cisplatin/vinorelbine and then radiotherapy, obtaining a partial response. After 4 months, tumor progression was identified, as assessed by whole-body 18-Fluorodeoxyglucose positron emission tomography (FDG-PET) scan, showing pleural and nodal metastasis. Nivolumab, 3 mg/kg every 2 weeks, was started at this point. While pre-nivolumab thyroid function was normal, 3 months after starting the therapy, a low serum TSH level of 0.04 mUI/mL (0.38-5.33) was found, associated with a normal level of FT4, of 10.8 pmol/L (7.9-14.4). Thyroid antibody (Ab) tests, including TSH-receptor Ab, were negative. At ultrasound examination, thyroid gland parenchyma was normo-echoic, demonstrating an isoechoic thyroid nodule in the right lobe, with regular margins, measuring 14mm diameter. Previous medical history was negative for thyroid disease. One week after the referred thyroid function tests, nivolumab was discontinued due to progressive disease as assessed by abdominal magnetic resonance, demonstrating right adrenal metastasis and patient started cisplatin/permetrexed chemotherapy. One month after nivolumab suspension, patient had already normalized thyroid tests, with TSH 2.27 mUI/mL and FT4 9.1 pmol/L. More recently (6 months after nivolumab discontinuation), thyroid function tests continued stable, with TSH 1.05 mUI/ml and T4L 9.4 mmol/l. At this point, patient was receiving permetrexed maintenance therapy. Conclusions Immune checkpoint molecules as nivolumab, play a crucial role in anti-tumor immunity evasion. Besides its benefits, it may cause irAEs, including TD. We believe it’s essential to perform thyroid function tests at baseline and before the administration of each nivolumab dose, if possible. Additionally, large prospective studies are required in order to assess, the impact of autoimmunity on the development of TD induced by nivolumab, and its potential effect on overall survival and specific cancer survival data.

scholarly journals SAT-463 Thyrotoxicosis from Nivolumab in a Patient with Preexisting Graves’ Disease

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Preethi Polavarapu ◽  
Padmaja Akkireddy
Keyword(s):  
Adverse Events ◽  
Thyroid Function ◽  
Autoimmune Thyroiditis ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Thyroid Dysfunction ◽  
Checkpoint Inhibitors ◽  
Graves Disease ◽  
Thyroid Function Tests ◽  
Free T4

Abstract Introduction Thyroid dysfunction is one of the common immune-related adverse events associated with immune checkpoint inhibitors like Nivolumab. Thyroiditis or primary hypothyroidism is the most commonly reported presentation. Graves’ disease is less frequently reported. We report a case of preexisting Graves’ disease patient, on antithyroid meds who developed thyrotoxicosis followed by hypothyroidism after receiving Nivolumab therapy. Case 66 y/o female patient with newly diagnosed metastatic melanoma presented to us for evaluation of abnormal thyroid test after her second cycle of Nivolumab. She has a long-standing history of Graves’ disease and has been on methimazole since her diagnosis. Her baseline thyroid labs before the start of Nivolumab were within normal limits (on methimazole 2.5 mg daily). She presented with weight loss, palpitations, and tremors four weeks after the start of Nivolumab. On exam, she was tachycardic with tremors noted to outstretched hands and had diffusely enlarged thyroid. Repeat lab work done before her second cycle revealed suppressed TSH 0.02 (0.4-4.5 uIU/ml) with elevated free T4 and T3. Her TSI titers were elevated. Methimazole dose was increased to 10 mg daily, and follow up labs done in a month revealed TSH of 89 uIU/ml, Free T4 0.16 (0.76-1.8 ng/dl). Methimazole was completely stopped at this time. She continued to have elevated TSH despite being off of methimazole for more than a month, concerning for the development of hypothyroidism. She was started on levothyroxine, after which labs returned to normal. The patient continued on immunotherapy during this period. Discussion Immune checkpoint inhibitors have been increasingly used for cancer therapy. Endocrinopathies are the most common immune-related adverse events associated with the use of these agents, with thyroid dysfunction being more common. Our patient had well-controlled Graves’ disease and was on a stable dose of methimazole for years. She developed autoimmune thyroiditis four weeks after receiving immunotherapy and subsequently developed hypothyroidism. The literature search did not reveal cases of autoimmune thyroiditis in a patient with preexisting Graves’ disease. One study reported that the timeline for developing the thyrotoxic phase is five weeks, which is followed by the rapid development of either euthyroid or hypothyroid phase. Management during the thyrotoxic phase is usually beta-blockers. Current guidelines recommend checking thyroid function test before initiation of therapy and every two weeks after the diagnosis of thyrotoxicosis until they become euthyroid or hypothyroid. Our case illustrates that patients with preexisting Graves’ disease can develop thyroiditis after receiving immune checkpoint inhibitors, and hence, frequent monitoring with thyroid function tests is needed.

A Case of Malignant Melanoma Associated with Polymyositis Treated with Immune Checkpoint Inhibitors

2019 ◽  
Vol 81 (5) ◽  
pp. 396-400 ◽  
Author(s):  
Hayato NOMURA ◽  
Osamu YAMASAKI ◽  
Tatsuya KAJI ◽  
Hiroshi WAKABAYASHI ◽  
Yoshia MIYAWAKI ◽  
...  
Keyword(s):  
Malignant Melanoma ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors

scholarly journals Successful Treatment of Sudden Hepatitis Induced by Long-Term Nivolumab Administration

2017 ◽  
Vol 10 (1) ◽  
pp. 368-371 ◽  
Author(s):  
Keisuke Imafuku ◽  
Koji Yoshino ◽  
Kei Yamaguchi ◽  
Satoshi Tsuboi ◽  
Kuniaki Ohara ◽  
...  
Keyword(s):  
Malignant Melanoma ◽  
Liver Function ◽  
Immune Checkpoint ◽  
Fulminant Hepatitis ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Corticosteroid Treatment ◽  
Sudden Onset ◽  
Oral Corticosteroids

Immune checkpoint inhibitors have drastically changed in the treatment of many kinds of malignancies, especially malignant melanoma. The focus of the recent experiments has not only been on their efficacy but also immune-related adverse events (irAEs). We report a case of fulminant hepatitis due to nivolumab. In this case, the patient had undergone long-term nivolumab therapy. He did not complain of any symptoms but his liver enzyme levels were extremely elevated (grade 4). We promptly decided to start oral corticosteroids in the patient. His liver function rapidly improved. The dose of corticosteroids was gradually reduced. Our case demonstrates that sudden onset fulminant hepatitis can occur despite the safe use of long-term nivolumab therapy. The irAE can improve rapidly with proper corticosteroid treatment. This report will be useful for the physicians who always use immune checkpoint inhibitors.

scholarly journals HBV-related acute hepatitis due to immune checkpoint inhibitors in a patient with malignant melanoma

2017 ◽  
Vol 28 (12) ◽  
pp. 3103-3104 ◽  
Author(s):  
A.S. Koksal ◽  
B. Toka ◽  
A.T. Eminler ◽  
İ Hacibekiroglu ◽  
M.I. Uslan ◽  
...  
Keyword(s):  
Malignant Melanoma ◽  
Acute Hepatitis ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors

scholarly journals Multiple treatment comparison of seven new drugs for patients with advanced malignant melanoma: a systematic review and health economic decision model in a Norwegian setting

BMJ Open ◽  
2017 ◽  
Vol 7 (8) ◽  
pp. e014880 ◽  
Author(s):  
Eva Pike ◽  
Vida Hamidi ◽  
Ingvil Saeterdal ◽  
Jan Odgaard-Jensen ◽  
Marianne Klemp
Keyword(s):  
Cost Effectiveness ◽  
Malignant Melanoma ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Cost Effective ◽  
Mek Inhibitor ◽  
New Drugs ◽  
Advanced Malignant Melanoma ◽  
Quality Adjusted Life

ObjectiveTo assess the relative effectiveness and cost-effectiveness of seven new drugs (cobimetinib, dabrafenib, ipilimumab, nivolumab, pembrolizumab, trametinib and vemurafenib) used for treatment of patients with advanced malignant melanoma in the Norwegian setting.DesignA multiple technology assessment.PatientsPatients with advanced malignant melanoma aged 18 or older.Data sourcesA systematic search for randomised controlled trials in relevant bibliographic databases.MethodsWe performed network meta-analyses using both direct and indirect evidence with dacarbazine as a common comparator. We ranked the different treatments in terms of their likelihood of leading to the best results for each endpoint. The cost-utility analysis was based on a probabilistic discrete-time Markov cohort model. The model calculated the costs and quality-adjusted life years (QALYs) with different treatment strategies from a healthcare perspective. Sensitivity analysis was performed by means of Monte Carlo simulation.ResultsMonotherapies with a programmed cell death 1 (PD-1) immune-checkpoint-inhibitor had a higher probability of good performance for overall survival than monotherapies with ipilimumab or BRAF/MEK inhibitors. The combination treatments had all similar levels of effectiveness to the PD-1 immune-checkpoint-inhibitors.PD-1 immune-checkpoint-inhibitors are more effective and more costly compared with ipilimumab in monotherapy. Nivolumab in combination with ipilimumab had higher costs and the same level of effectiveness as the PD-1 immune-checkpoint-inhibitors in monotherapy.BRAF/MEK inhibitor combinations (dabrafenib and trametinib or vemurafenib and cobimetinib) had both similar effectiveness and cost-effectiveness; however, the combination therapies are more likely to give higher quality adjusted life year gains than BRAF or MEK inhibitor monotherapies, but to a higher cost.ConclusionsNone of the drugs investigated can be considered cost-effective at what has normally been considered a reasonable willingness-to-pay (WTP) in Norway. Price reductions (from the official list prices) in the region of 63%–84% would be necessary for these drugs to be cost-effective at a WTP of €55 850 per QALY.

scholarly journals Challenge of immune-mediated adverse reactions in the emergency department

2019 ◽  
Vol 36 (6) ◽  
pp. 369-377 ◽  
Author(s):  
Gregory A Daniels ◽  
Angela D Guerrera ◽  
Donna Katz ◽  
Jayne Viets-Upchurch
Keyword(s):  
Immune System ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Adverse Reactions ◽  
Checkpoint Inhibitors ◽  
Immune Checkpoints ◽  
High Dose ◽  
Clear Understanding ◽  
Immune Mediated ◽  
Multiple Drugs

Multiple drugs of a new class of cancer treatments called immune checkpoint inhibitors, which work by enabling the immune system to attack tumour cells, have been approved for a variety of indications in recent years. Immune checkpoints, such as cytotoxic T-lymphocyte antigen-4 and programmed death-1, are part of the normal immune system and regulate immune activation. Treatment with inhibitors of these checkpoints can significantly improve response rates, progression-free survival and overall survival of patients with cancer; it can also result in adverse reactions that present similarly to other conditions. These immune-mediated adverse reactions (IMARs) are most commonly gastrointestinal, respiratory, endocrine or dermatologic. Although patients’ presentations may appear similar to other types of cancer therapy, the underlying causes, and consequently their management, may differ. Prompt recognition is critical because, with appropriate management, most IMARs resolve and patients can continue receiving immune checkpoint inhibitor treatment. Rarely, these IMARs may be life-threatening and escape detection from the usual evaluations in the emergency environment. Given the unusual spectrum and mechanism of IMARs arising from immune checkpoint inhibitors, emergency departmentED staff require a clear understanding of the evaluation of IMARs to enable them to appropriately assess and treat these patients. Treatment of IMARs, most often with high-dose steroids, differs from chemotherapy-related adverse events and when possible should be coordinated with the treating oncologist. This review summarises the ED presentation and management of IMARs arising from immune checkpoint inhibitors and includes recommendations for tools and resources for ED healthcare professionals.

scholarly journals Successful Treatment of a Patient with anti-PD1 Antibody-Resistant Advanced Mucosal Melanoma with Nivolumab, Ipilimumab plus Denosumab Combination Therapy

2020 ◽  
Vol 13 (1) ◽  
pp. 271-275 ◽  
Author(s):  
Taku Fujimura ◽  
Yumi Kambayashi ◽  
Kentaro Ohuchi ◽  
Ryo Amagai ◽  
Yota Sato ◽  
...  
Keyword(s):  
Malignant Melanoma ◽  
Combination Therapy ◽  
Nasal Cavity ◽  
Immune Checkpoint ◽  
Cutaneous Melanoma ◽  
Japanese Population ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Mucosal Melanoma ◽  
Mutation Burden

Since the incidence of mucosal melanoma is higher in the Japanese population compared to Caucasians, and since mucosal melanoma possesses a lower mutation burden compared to cutaneous melanoma, the efficacy of anti-PD1 antibody (Ab) monotherapy for mucosal melanoma is limited. Therefore, other targeting molecules that enhance the anti-tumor effects of immune checkpoint inhibitors are needed. In this report, we present a case with anti-PD1 Ab-resistant recurrent malignant melanoma of the nasal cavity successfully treated with nivolu­mab, ipilimumab plus denosumab combination therapy.

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