The development of immune checkpoint inhibitors (ICIs) has heralded a new era in cancer treatment, enabling the possibility of long-term survival in patients with metastatic disease. Unfortunately, ICIs are increasingly implicated in the development of autoimmune diseases.

We present a man with squamous cell carcinoma of the oropharynx on a combination of teriprizumab, docetaxel, and cisplatin therapy who developed autoimmune polyendocrine syndrome type II (APS-2) including thyroiditis and type 1 diabetes mellitus and Crohn’s disease (CD). He developed thirst, abdominal pain, and fatigue after two-week treatment with the protein 1 ligand inhibitor teriprizumab. Biochemistry confirmed APS-2 and thyrotoxicosis. He was commenced on an insulin infusion. However, his abdominal pain persisted. Follow-up surgery confirmed CD and his abdominal pain was relieved by mesalazine. He was continued on insulin and mesalazine therapy.

Immunotherapy can affect all kinds of organs. When clinical symptoms cannot be explained by a single disease, clinicians should consider the possibility of multisystem damage.

Immune checkpoint inhibitors (ICIs) such as programmed cell death protein 1 (PD1) or its ligand (PDL1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4) have revolutionized the treatment of many malignancies, such as melanoma, non-small cell lung cancer, and renal cell carcinoma. ICI therapy enhances the immune system and has been shown to improve survival in some cancer patients. However, ICIs occasionally induce immune-related adverse events (irAEs), which commonly affect the gastrointestinal tract, liver, skin, and endocrine system, but can affect virtually any organ system[1,2]. Thyroid disorders are common endocrinopathies associated with irAEs[3]. Hypophysitis is another well-recognized endocrine side effect[4]. Autoimmune diabetes mellitus especially type 1 diabetes mellitus (T1DM) has occasionally been reported[5], while adrenal insufficiency is observed even less frequently[6]. However, to the best of our knowledge, ICI-induced autoimmune polyendocrine syndrome type II (APS-2) including T1DM combined with Crohn’s disease (CD), has not yet been reported.

Here we report an elderly man who developed partial features of APS-2 combined with CD shortly after initiation of treatment with PDL1 antibody teriprizumab for squamous cell carcinoma of the oropharynx. This patient had an acute onset of T1DM with diabetic ketoacidosis (DKA), short-term thyrotoxicosis, and typical CD. This case report is supplemented by a literature review of PD1/PD-L1 inhibitor-associated APS-2 and CD. Our study may help improve the understanding of endocrinologists, oncologists, and gastroenterologists about rare irAEs.

The patient was diagnosed with APS 2 and CD.

Postoperatively, his blood glucose was difficult to control, then he was suggested to use immune modulators such as methotrexate or biological agents such as adalimumab for his CD, according to the serious adverse reactions induced by earlier treatment of nasopharyngeal carcinoma, he refused these medications. At last, he was administered mesalazine 4 g/d. The patient was discharged on oral mesalazine sustained-release granules with a dosage of 1 g quarter in die for 8 wk and then maintained at 1 g twice daily and daily insulin dosage of 36-42 IU administered via four injections per day.

After about two weeks of mesalazine treatment, there was complete remission of abdominal pain and the stool occult blood test was negative. Three months after withdrawal of teriprizumab, his thyroid hormone levels had returned to normal (Table 3). He received more than 20 sessions of local radiotherapy (nasopharyngeal) and cisplatin chemotherapy after his discharge from Shougang Hospital. In the first one-year follow-up, he showed good recovery with disappearance of hoarseness of voice and nasopharyngeal carcinoma. He was taking mesalazine and insulin intensive therapy, with CRP of 6.73 mg/L, negative stool occult blood and HbA1c of 7.8%.

Our patient developed low C-peptide level and modestly elevated HbA1c with positive T1DM auto-antibody two weeks after initiation of PDL1 antibody therapy pointing to acute, rapid destruction of -islets in pancreas. Increased amylase level indicated damage to the pancreatic exocrine gland. After admission, he was found to have thyroiditis and thyrotoxicosis. In addition, the increase in creatine kinase level was suggestive the possibility of rheumatic immune system damage. During following treatment, the patient developed IBD, especially CD. The overall clinical picture was suggestive of multi-system damage caused by teriprizumab. To the best of our knowledge, this is the first reported case of concurrent atypical APS-2 (including T1DM and thyrotoxicosis) and CD in a patient on immunotherapy for metastatic nasopharyngeal carcinoma.

The discovery of Checkpoint inhibitors has changed the landscape of cancer therapeutics. With the growing use of ICIs, the frequency of autoimmune complications has become increasingly apparent. The most common ICI-associated endocrinopathies are thyroid disorders and hypophysitis[7], but hypophysitis is nearly unique to patients receiving CTLA-4, which occurs more often (5% to 10%) and with an earlier onset (median 9 to 12 wk) in patients receiving ipilimumab-based regimens compared to those receiving anti-PD1/PD-L1 antibodies[8]. ICI-induced T1DM is uncommon, with a reported frequency ranging from 0.2% in randomized clinical studies[9] to 1.27% in real-life setting[5]. Primary adrenal insufficiency is less common, albeit with a similar presentation with hypophysitis, although this endocrinopathy may also involve mineralocorticoid deficiency and present with hypotension[10].

There are two definitions of APS-2, with some defining it as occurrence of any two of the three conditions, i.e., T1DM, autoimmune thyroiditis, and primary hypoadrenalism, while others specify that hypoadrenalism must exist, with at least one of the other two conditions. Spontaneous APS-2 is very rare, and anti-PD1/PDL1 antibodies-induced APS-2 has occasionally been reported. Out of the 14 cases reported in literature, three cases experienced primary hypoadrenalism and only one had all three features of APS-2[6]. Our case only presented T1DM and autoimmune thyroiditis, and his adrenocortical function needs further observation.

Regarding gastrointestinal irAEs, colitis occurs in up to 5% of patients receiving anti-PD-1/PD-L1 antibodies, and generally presents as diarrhea and less often as abdominal pain and hematochezia[11,12]. In addition, these irAEs-related chronic sequelae can also affect the rheumatological, pulmonary, neurological, and other organ systems[6]. These damages typically occur in one system and do not involve several systems at the same time. In our case, the damage involved the endocrine system and gastrointestinal system including T1DM, thyroiditis, and CD.

Abdominal pain was the chief complaint of our patient during treatment and the pain did not correlate with the severity of hyperglycemia. While DKA was cured, abdominal pain persisted. The pain aggravated after meals and was associated with increased CRP and positive occult blood in stool. These symptoms were suspicious of teriprizumab-induced gastrointestinal irAEs, especially IBD. However, no obvious lesions were observed on colonoscopy. Abdominal CT showed edema and thickening of small intestinal wall, and the subsequent pathological examination of the small intestine was consistent with CD, which made the case unique.

In conclusion, our patient had a few irAEs associated with PDL1 antibody teriprizumab treatment, especially APS-2 and CD. To the best of our knowledge, this is the first reported case of multi-organ damage associated with teriprizumab. Physicians should be aware of the chronic immune toxicities and the long-term implications of immunotherapy for cancer; especially, when clinical symptoms are not explained by a single disease, the possibility of multisystem damage should be considered.