Immune-related endocrine disorders in novel Immune checkpoint inhibition therapy

Abstract

Immune checkpoint inhibition against advance malignancies was named breakthrough discovery by the science magazine in 2013. In numerous clinical studies, monoclonal antibodies against the immune checkpoints, CTLA4, PD1 and PD1 ligand PDL1 have shown promising tumor response in different type of metastatic malignancies. The adverse events are autoimmune-related. The endocrine disorders, hypothysitis and thyroiditis are among the most common side effects associated with immune checkpoint inhibition treatment. Hypophysitis, a very rare endocrine disorder occurs in about one tenth of the patients receiving anti-CTLA4 treatment. Thyroiditis, on the other hand, is more commonly seen in patients receiving anti-PD1 treatment. In addition, both thyroiditis and hypophysitis are common in patients receiving combination treatment with anti-CTLA4 and anti-PD1 treatment. The time to onset of hypophysitis and thyroiditis is short. Most of the endocrine disorders occur within 12 weeks after initiation of the immune checkpoint inhibition therapy. Hypohysitis can manifest as total anterior pituitary hormone deficiency or isolated pituitary hormone deficiency. Diabetes insipidus is rare. TSH and gonadotropin deficiencies may be reversible but ACTH deficiency appears permanent. Thyroiditis can present as hypothyroidism or thyrotoxicosis followed by hypothyroidism. Hypothyroidism appears irreversible. Early identifying the onset of hypophysitis and thyroiditis and proper management of these endocrine disorders will improve the quality of the life and the outcome of this novel immunotherapy.

Fig. 1

Dynamic change of pituitary size in brain MRI. A 55-year old male with history of metastatic melanoma presented with headache and fatigue. He had history of hypothyroidism. He had been on stable levothyroxine dose for 1 year. He was on a clinical trial of ipilimumab, an anti-CTLA4 monoclonal antibody, therapy. He received the ipilimumab infusion every 3 weeks. After 3 infusions of ipilimumab, he noted headache and fatigue. He denied palpitations, tremors and heat intolerance. His TSH and free T4 were normal 1 week prior to his first ipilimumab infusion. After 3 ipilimumab infusions, his TSH was very low, but his free T4 is normal. He is compliant with his levothyroxine. Both his morning cortisol and ACTH levels were very low. His MRI of pituitary showed pituitary enlargement (B). Prior to the initiation of ipilimumab treatment, his pituitary MRI was normal (A). He was started with hydrocortisone replacement. Six weeks after replacement of hydrocortisone for his central adrenal insufficiency, his pituitary normalized in size (C).

Fig. 2

Timeline of thyroid function in a patient who developed anti-PD1-related thyroiditis. A 37-year-old female with history of advanced melanoma who received pembrolizumab (anti-PD1) treatment and developed thyroid disorders. Prior to the initiation of anti-PD1 treatment, she had no history of thyroid disorder. She did well with the first treatment. The infusion of pembrolizumab was given every 3 weeks. Prior to her second infusion of pembrolizumab, her routine blood tests revealed high T4 and suppressed TSH. She reported palpitation, hyperdefecation and 2–3 lbs weight loss over the past 3 weeks. On exam, her heart rate was 99 beats per minutes. She has not history of cardiovascular disease. She was started with propranolol 10 mg orally three times daily. Four weeks later, her repeated tests for thyroid function show overt hypothyroidism. She reported gained back her weight and endorsed fatigue. Propranolol was discontinued. She was started with levothyroxine replacement. Her autoantibody tests were negative for both thyroid peroxidase antibody (TPO) and thyroid-stimulating globulin (TSI). She became clinically and biochemically euthyroid a few weeks later after a proper replacement of levothyroxine.