Case Presentation: 56-year-old Caucasian lady with a past medical history of recurrent stage 4 melanoma presented with nausea, vomiting, inadequate oral intake and weight loss of 20lbs over several weeks. She received nivolumab immunotherapy for one year and stopped 3-months prior to presentation due to stable lesions without recurrence. She also underwent an esophagogastroduodenoscopy (EGD) five months prior to presentation for dysphagia. EGD revealed distal esophagitis and biopsy was notable for >15/hpf eosinophilic dominant inflammation and was treated for eosinophilic esophagitis (EoE) with swallowed fluticasone. Despite treatment, her symptoms worsened. A repeat EGD revealed inflamed gastric mucosa with white fibrin-like membrane in the gastric body and antrum. She was admitted for clinical suspicion for GI and endocrine related checkpoint induced immune-related adverse events (irAEs). Her initial laboratory studies were non-significant except for endocrine work-up revealing hypothyroidism and adrenal insufficiency. Histopathology from her EGD revealed inflammation related to immune checkpoint therapy. At this juncture, after excluding other etiologies, she was started with intravenous methylprednisolone 1mg/kg/day for the treatment of irAEs. She also received thyroid hormone replacement. On day 4 of admission, her symptoms improved, and she was able to tolerate a liquid diet. She was discharged home with planned steroid taper. On 3-month follow-up, the patient was asymptomatic and tolerates oral intake. She continued to receive thyroid and cortisol replacement indefinitely.
Discussion: Checkpoint inhibitors are a class of immunotherapy that are used to enhance the immune system and have substantially improved the prognosis for patients with advanced malignancy.[1] Nivolumab targets PD-1 and has been approved for the treatment of various malignancies.[2] Despite important clinical outcomes, checkpoint inhibition is associated with a unique spectrum of side effects designated as irAEs.[3] Unbridled T-cell activity disrupts the immune homeostasis and induces these unique spectrum of side effects. The skin, gastrointestinal tract and endocrine are the most affected organ systems. Gastrointestinal irAEs can involve the esophagus, stomach, small bowel, colon, liver, and pancreas. Upper GI toxicity can occur as an isolated presenting symptom, but frequently coexists with lower GI tract side effects. Upon review of her initial EoE pathology, it was more consistent with irAE esophagitis that was predominantly eosinophilic in nature. Isolated severe esophagitis masquerading as EoE followed by severe gastritis several months after the discontinuation of immunotherapy has never been reported in the literature. Moreover, our patient also had endocrinopathy with hypophysitis makes it a unique case. The median time of onset for symptoms is 6-7 weeks from the initiation of therapy but this can vary with some case reports describing symptom onset as late as several months[3], as in our case. Management includes exclusion of other infectious etiologies followed by corticosteroids.[4]
Conclusions: Patients presenting with irAEs might have various clinical manifestations however irAEs typically respond well to corticosteroid therapy. After an irAE is discovered, physicians should make an active effort to investigate other concomitant underlying irAEs. Increased awareness of irAEs is paramount due to the growing use of immunotherapy to treat advanced malignancies.
