Autoimmune abnormalities are a known complication of immunotherapy drugs, which can be used to treat a wide range of malignancies including lung and breast cancer and melanoma, to name a few [2]. Specifically, autoimmune endocrine adverse effects resulting from cancer immunotherapy drugs include hypophysitis, hyperthyroidism, hypothyroidism and adrenal insufficiency. There are several immune checkpoint inhibitor drugs already on the market for cancer immunotherapy, such as the anti-CTLA-4 (ipilimumab and tremelimumab) and anti-PD1 antibodies (pembrolizumab, nivolumab and pidilizumab), all of which have been shown to have autoimmune side effects. Ipilimumab, pembrolizumab and nivolumab, however, are the most commonly used and studied for their adverse effects. Anti-PD-L1 agents are being developed as well (atezolizumab, durvalumab and avelumab), which have similar side effect profiles to pembrolizumab [3-5]. Ipilimumab was the first immune checkpoint inhibitor targeting CTLA-4 and was FDA-approved in 2011. In 2014, pembrolizumab was introduced as an alternative to ipilimumab for the treatment of metastatic melanoma. Later, combined ipilimumab and pembrolizumab therapy was used with improved therapeutic efficacy, though this regimen showed an increased rate of immune-related thyroid dysfunction and toxicity. Currently, the indications of combined therapy have been expanded to treat unresectable and metastatic melanoma, metastatic small and non-small cell lung cancers, head and neck squamous cell carcinoma, Hodgkin lymphoma, and advanced clear cell renal cell carcinoma [3, 4].

Pembrolizumab is a monoclonal antibody which binds to and blocks target programmed death receptor-1 (PD-1) receptors, re-activating T cells and allowing them to generate an immune response against cancer cells. PD-1 receptors are minimally expressed on resting immune cells. Upon receiving inflammatory signals, PD-1 becomes overexpressed on T-cells, B-cells, NK cells, and macrophages, among others. Binding of PD-1 with its ligand (PD-L1) inhibits the inflammatory response. Unfortunately, many tumor cells express PD-L1, suppressing T-cell activation and allowing them to escape the immune response. Similar negative T-cell regulatory effects are produced by CTLA-4 receptors. Therefore, immune-related thyroid dysfunction is similar in both ipilimumab (targeting CTLA-4) and pembrolizumab (targeting PD-1), but with varying frequency of adverse events. Ipilimumab is reported to have a higher incidence of hypophysitis compared to thyroid dysfunction, whereas the reverse happens with pembrolizumab [4]. Autoimmune thyroiditis is one of the common side effects seen with the use of immunotherapy in cancer treatment. The pathogenesis of this immunotherapy-induced autoimmune thyroiditis is related to the immunological activation at the level of the thyroid by immunological mechanisms, inflammatory mechanisms or both. Elevated free T3 and T4 followed by hypothyroidism after immunotherapy treatment in these patients is compatible with autoimmune etiology causing inflammatory thyroid destruction. Immunotherapy-induced hyperthyroidism accompanied by low or absent I-123 uptake on thyroid scintigraphy and negative anti-TSH receptor antibodies is suggestive of inflammatory/destructive disease. This is different from the common presentation of hyperthyroidism in Graves' disease, where patients present with hyperthyroidism, increased uptake on I-123 thyroid scintigraphy, and positive anti-TSH receptor [3].

Recently, pembrolizumab use has been identified as a cause of immune-related thyroid dysfunction. Delivanis et al studied 93 patients who had at least one infusion of pembrolizumab. 13 of 93 patients developed thyroid dysfunction, of which 7 patients (54%) had thyroiditis, while 3 had hypothyroidism (23%). Data from phase 2 and 3 clinical trials reported that 3.2% - 10.1% of patients developed thyroid dysfunction. They also reported that anti-TPO antibodies were abnormal in several patients; however, few were patients with pre-existing hypothyroidism, and, interestingly, none of their patients with thyroiditis had abnormal anti-TPO antibodies prior to taking pembrolizumab. They also showed that 4 of the 7 patients who developed thyroiditis recovered [4]. Pembrolizumab-induced thyroiditis demonstrates diffuse increased FDG uptake on PET/CT with a median time of onset at 12 weeks from the start of immunotherapy [4, 6]. The differential diagnosis for this pattern of diffuse FDG uptake includes other inflammatory processes such as Hashimoto thyroiditis.

There is a significant risk of developing severe hypothyroidism in patients who have pre-existing thyroid disease [4]. The literature reports an increased risk of worsening hypothyroidism in patients with high anti-TPO antibodies at baseline or a history of hypothyroidism. It is debated whether this worsening thyroid function is due to autoantibodies or is the result of the humoral immunologic response to thyroid antigens released during thyroiditis phase [3,4]. It is also reported by multiple studies that there is an acute but transient thyroiditis which is followed by resolution or progression to hypothyroidism [4-8]. The literature reports that patients on pembrolizumab may present as subclinical or overt hypo- or hyperthyroidism, though subclinical presentations and hypothyroidism are more common. It is also documented that patient may present initially with biochemical thyrotoxicosis with subsequent hypothyroidism or as recurrent severe hypothyroidism in patients with pre-existing hypothyroidism [3]. In conclusion, it is important to understand the incidence and presentation of thyroid dysfunction in patients on pembrolizumab in order to optimize therapy and allow close monitoring for functional balance during cancer immunotherapy