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Isabella Lupi, Alessandro Brancatella, Mirco Cosottini, Nicola Viola, Giulia Lanzolla, Daniele Sgrò, Giulia Di Dalmazi, Francesco Latrofa, Patrizio Caturegli and Claudio Marcocci

Summary

Programmed cell death protein 1/programmed cell death protein ligand 1 (PD-1/PD-L1) and cytotoxic T-lymphocyte antigen 4/B7 (CTLA-4/B7) pathways are key regulators in T-cell activation and tolerance. Nivolumab, pembrolizumab (PD-1 inhibitors), atezolizumab (PD-L1 inhibitor) and ipilimumab (CTLA-4 inhibitor) are monoclonal antibodies approved for treatment of several advanced cancers. Immune checkpoint inhibitors (ICIs)-related hypophysitis is described more frequently in patients treated with anti-CTLA-4; however, recent studies reported an increasing prevalence of anti-PD-1/PD-L1-induced hypophysitis which also exhibits slightly different clinical features. We report our experience on hypophysitis induced by anti-PD-1/anti-PD-L1 treatment. We present four cases, diagnosed in the past 12 months, of hypophysitis occurring in two patients receiving anti-PD-1, in one patient receiving anti-PD-1 and anti-CTLA-4 combined therapy and in one patient receiving anti-PD-L1. In this case series, timing, clinical presentation and association with other immune-related adverse events appeared to be extremely variable; central hypoadrenalism and hyponatremia were constantly detected although sellar magnetic resonance imaging did not reveal specific signs of pituitary inflammation. These differences highlight the complexity of ICI-related hypophysitis and the existence of different mechanisms of action leading to heterogeneity of clinical presentation in patients receiving immunotherapy.

Learning points:

  • PD-1/PD-L1 blockade can induce hypophysitis with a different clinical presentation when compared to CTLA-4 blockade.
  • Diagnosis of PD-1/PD-L1 induced hypophysitis is mainly made on clinical grounds and sellar MRI does not show radiological abnormalities.
  • Hyponatremia due to acute secondary adrenal insufficiency is often the principal sign of PD-1/PD-L1-induced hypophysitis and can be masked by other symptoms due to oncologic disease.
  • PD-1/PD-L1-induced hypophysitis can present as an isolated manifestation of irAEs or be in association with other autoimmune diseases
Open access

Hiroto Minamino, Hidefumi Inaba, Hiroyuki Ariyasu, Hiroto Furuta, Masahiro Nishi, Takashi Yoshimasu, Akinori Nishikawa, Masanori Nakanishi, Shigeki Tsuchihashi, Fumiyoshi Kojima, Shin-ichi Murata, Gen Inoue and Takashi Akamizu

Yang SH Maurano MM Lee K Abbas AK & Rosenblum MD 2013 Cutting Edge: memory regulatory t cells require IL-7 and not IL-2 for their maintenance in peripheral tissues . Journal of Immunology 190 4483 – 4487

Open access

V Larouche and M Tamilia

Summary

Enteroviruses, including coxsackieviruses and Echovirus, are well known pathogens responsible for the development of thyroiditis. We describe the case of a 49-year-old woman with no personal or family history of thyroid disease who presented to the emergency room with a two-week history of daily fevers up to 39°C, a sore throat, occasional palpitations and diaphoresis, decreased appetite and an unintentional 10 kg weight loss over the same time course Physical examination revealed mild tachycardia, an intention tremor and a normal-sized, nontender thyroid gland without palpable nodules. The remainder of the physical examination was unremarkable and without stigmata of Graves’ disease. Her initial blood tests revealed overt thyrotoxicosis, elevated liver enzymes, an elevated C-reactive protein, a negative monospot and a positive CMV IgM antibody. Thyroid sonography revealed areas of hypoechogenicity and relatively low vascularity. Fine-needle biopsy showed a lymphocytic infiltrate. The patient was treated symptomatically with propranolol. On follow-up, the patient became euthyroid, and her liver enzymes normalised. Previous cases of CMV-induced thyroiditis occurred in immunosuppressed patients. This is the first reported case of a CMV-mononucleosis-induced thyroiditis in an immunocompetent adult patient and serves as a reminder that viral illnesses are a common cause of thyroiditis with abnormal liver enzymes.

Learning points:

  • The differential diagnosis of thyrotoxicosis with abnormal liver enzymes includes severe hyperthyroidism and thyroid storm caused by Graves’ disease as well as the thyrotoxic phase of a thyroiditis, usually caused by a virus such as coxsackievirus or, in this case, cytomegalovirus.
  • Cytomegalovirus appears to be a recently recognized causal agent for thyroiditis, both in immunosuppressed and immunocompetent patients.
  • Careful follow-up of thyroid function tests in patients with thyroiditis allows clinicians to determine if patients’ thyroid hormone secretion normalizes or if they remain hypothyroid.
Open access

Hans-Christof Schober, Christian Kneitz, Franziska Fieber, Kathrin Hesse and Henry Schroeder

Internal Medicine, Rheumatology/Immunology, TIO-specific diagnostic investigation; Dr Med. Franziska Fieber: Resident physician, Department of Internal Medicine, Rheumatology/Immunology; Dr Med. Kathrin Hesse: Resident physician, Department of Internal

Open access

S A A van den Berg, N E van ‘t Veer, J M A Emmen and R H T van Beek

: Clinical and therapeutic implications . Journal of Allergy and Clinical Immunology 63 1292 – 1300 . ( doi:10.1111/j.1398-9995.2008.01750.x ) 2 Tripathy I Levy A Ratner P Clements D Wu W Philpot E 2009 HPA axis safety of fluticasone

Open access

Daramjav Narantsatsral, Takagi Junko, Iwayama Hideyuki, Inukai Daisuke, Takama Hiroyuki, Nomura Yuka, Hirase Syo, Morita Hiroyuki, Otake Kazuo, Ogawa Tetsuya and Takami Akiyoshi

in patients with Hashimoto’s thyroiditis and concurrent non-endocrine autoimmune disorders . Clinical and Experimental Immunology 2011 165 148 – 154 . ( https://doi.org/10.1111/j.1365-2249.2011.04419.x ) 3 Lee JH Son SW Cho SH . A

Open access

Ali A Zaied, Halis K Akturk, Richard W Joseph and Augustine S Lee

Chiec L Mohindra N Gentzler R Patel J Giles F. A case of pembrolizumab-induced type-1 diabetes mellitus and discussion of immune checkpoint inhibitor-induced type 1 diabetes . Cancer Immunology, Immunotherapy 2017 66 25 – 32 . ( https

Open access

Dimitrios Haidopoulos, George Bakolas and Lina Michala

-304617 ) Mortensen KH Cleemann L Hjerrild BE Nexo E Locht H Jeppesen EM & Gravholt CH 2009 Increased prevalence of autoimmunity in Turner syndrome – influence of age . Clinical and Experimental Immunology

Open access

Laila Ennazk, Ghizlane El Mghari and Nawal El Ansari

discovery of new auto-antigenic targets in neuroendocrine immunology allowed the consideration of new autoimmune diseases. Therefore, new entities are recognized as part of the polyglandular autoimmune syndromes. The diagnosis of autoimmune pancreatitis

Open access

R Bou Khalil, M Abou Salbi, S Sissi, N El Kara, E Azar, M Khoury, G Abdallah, J Hreiki and S Farhat

Yang YH & Chiang BL 2003 Methimazole-induced lupus erythematous: a case report . Journal of Microbiology, Immunology, and Infection . 36 : 278 – 281 . Haq I Sosin MD Wharton S & Gupta A