Immunotherapy-induced thyroid dysfunction

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ACHAIKI IATRIKI | 2025; 44(2):93–101

Review

George C. Kyriakopoulos

Department of Biochemistry, School of Medicine, University of Patras, Greece

Received: 20 Jun 2024; Accepted: 02 Aug 2024

Corresponding author: George C. Kyriakopoulos, MPharm, MSc, MD, PhD. Tel.: +30 2610 642 141, E-mail: gkyriakop.123@gmail.com

Key words: Immunotherapy, adverse effects, thyroid dysfunction, hypothyroidism, hyperthyroidism

 

Abstract

Immune checkpoint inhibitors (ICIs) are a groundbreaking class of drugs that significantly advance cancer treatment by leveraging the immune system against cancer cells. However, their efficacy as anti-cancer agents is accompanied by a broad range of immune-related adverse effects (irAEs), including endocrinopathies. Thyroid dysfunction is among the most common endocrinopathies induced by ICI therapy, making it a major concern. The pathophysiology typically involves destructive thyroiditis, leading to the common patterns of thyrotoxicosis followed by hypothyroidism or isolated hypothyroidism. Diagnosis relies mostly on clinical presentation and laboratory tests. Treatment varies from levothyroxine substitution to the use of beta blockers, based on the severity of thyroid dysfunction. As immunotherapy evolves, recognizing and managing ICI-induced thyroid dysfunction is essential for improving patient safety and outcomes. This review aims to explore the significance of ICI-induced thyroid dysfunction, detailing the patterns, mechanisms, diagnostic approaches, and treatment strategies.

Introduction

In recent years, immune checkpoint inhibitor (ICI) therapy has become a promising advancement in cancer treatment. This innovative approach utilizes the body’s immune system to target cancer cells, offering patients new therapeutic options and improved survival rates. Initially used for treating malignant melanoma and lung cancer, this therapy involves administering monoclonal antibodies that target specific cell proteins, such as cytotoxic T lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), and its ligand (PD-L1), thereby inducing T cell activation against neoplasms [1].

However, despite its benefits, ICI therapy is associated with various adverse effects, with thyroid disorders being among the most common endocrine complications. Thyroid dysfunction can appear as either primary hypothyroidism or thyrotoxicosis. The most common type of thyroid abnormality is destructive thyroiditis, which initially causes a phase of thyrotoxicosis followed by permanent hypothyroidism. Rarely, Graves’ disease could also occur. The pathophysiology is primarily linked to destructive thyroiditis caused by a T cell-mediated acute autoimmune response [2]. Additionally, research consistently points to the role of autoantibodies against thyroglobulin (Tg), thyroid peroxidase (TPO), and thyroid-stimulating hormone (TSH) receptor, as well as the role of cytokines in the disease’s pathogenesis [3]. Consequently, laboratory tests measuring TSH, free thyroxine (fT4), and antibodies are crucial for accurate diagnosis and for monitoring before and during ICI therapy. ICI-induced thyroidopathy can range from asymptomatic cases to severe conditions, including fatalities. Addressing these complications requires prompt diagnosis and therapeutic strategies customized to the clinical manifestations and their severity. Close monitoring and collaboration between oncologists and endocrinologists are essential to manage these effects effectively [4,5].

Possible mechanisms of immunotherapy-induced adverse effects

The immune activation responsible for most immune-related adverse events (irAEs) may be linked to the mechanisms driving antitumor immune responses. This tumor-specific hypothesis is supported by the consistent positive correlation between therapeutic responses and the incidence of irAEs [6–8]. Correlative studies offer further evidence of this association, showing shared T cell receptor sequences and upregulated organ-specific transcripts between tumors and non-malignant tissues affected by toxicities [9,10]. Additionally, the development of vitiligo, an autoimmune response targeting melanocytes, serves as a reliable indicator of ICI antitumor activity, particularly in melanoma patients. This suggests a mechanistic link between irAEs and antitumor immunity [11]. If both the beneficial and adverse outcomes stem from the same processes, long-term responders might face a higher risk of chronic toxicities compared to those who do not benefit from the therapy.

Evidence also suggests that certain irAEs may emerge from mechanisms unrelated to antitumor activity, including factors such as the microbiome and viral or tissue-specific elements [12–15]. The diversity of irAEs likely reflects distinct and varied mechanisms for each type of event. Different cell types are implicated as dominant drivers in various preclinical models and biopsy samples from affected tissues. For instance, tissue-resident memory CD8+ T cells were predominant in colon biopsy samples from patients with ICI-induced colitis, while cytotoxic activated memory CD4+ T cells were most prevalent in the brain of a patient with fatal encephalitis [13,16–18]. Targeted inhibition of specific cytokines, such as IL-6, could potentially separate antitumor from antihost immune responses in preclinical models [19,20]. Ultimately, a single mechanistic explanation for irAEs is unlikely; they probably result from both tumor-related and tumor-unrelated factors. Additionally, the mechanisms distinguishing acute versus chronic irAEs remain poorly understood.

The mechanism underlying immune checkpoint inhibitor (ICI)-induced thyroid disorders also remains unclear. In a study conducted by Osario et al., among ten patients who developed thyroid dysfunction following pembrolizumab administration, eight patients were found to have antithyroglobulin or antimicrosomal antibodies [21]. Another study reported ten cases of thyroiditis following anti-PD-1 treatment. Among these cases, six patients experienced transient thyrotoxicosis followed by hypothyroidism, while four patients developed hypothyroidism without a preceding thyrotoxic phase. All patients tested positive for antithyroid antibodies [22]. Iyer et al. also observed that thyroid peroxidase and thyroglobulin antibodies were present in 44.7% and 33% of patients, respectively, after ICI therapy [23]. However, other immune pathways, involving T-cells, natural killer cells, and monocytes might also contribute to thyroid dysfunction during anti-PD-1 therapy, independent of antibody presence [24]. Interestingly, positron emission tomography (PET) scans of patients affected by thyroid irAEs frequently show a diffuse increase in 18-fludeoxyglucose (18-FDG) uptake, suggesting it may serve as a better biomarker for thyroid irAEs. Thyroid antibodies, on the other hand, might indicate the severity and increased risk of needing hormone replacement [25]. Finally, certain cytokines are associated with thyroid irAEs. Elevated levels of cytokines, such as IL-1β, IL-2, and GM-CSF, and lower levels of IL-8, G-CSF, and MCP-1, indicating a shift in the Th1/Th2 balance, may be linked to the development of these immune-related thyroid disorders [26].

Risk factors for immunotherapy-induced thyroid dysfunction

Patients undergoing ICI therapy are exposed to several risk factors that may predispose them to thyroid dysfunction and other endocrine-related adverse effects (Table 1). One significant risk factor is gender, as women are more likely to develop thyroid dysfunction during ICI therapy compared to men. Age is another critical factor, with younger patients being at a higher risk for thyroid-related issues [27,28]. The presence of elevated anti-TPO or anti-TG antibodies before starting ICI therapy is another important risk factor. Patients with higher levels of these antibodies have an increased likelihood of developing thyroid dysfunction. Additionally, higher baseline TSH levels at the commencement of therapy are associated with a greater risk of experiencing thyroid problems during treatment [29–31]. The number of immunotherapy cycles a patient undergoes also influences the risk, with a higher number of cycles correlating with an increased incidence of thyroid and other endocrine issues. Obesity further compounds this risk, as it has been identified as a significant factor in the development of thyroid dysfunction during ICI therapy [30,32]. Finally, racial background impacts the type of thyroid dysfunction experienced. Caucasians and Latinos are more prone to developing hypothyroidism as a result of ICI therapy, whereas African Americans are more likely to experience thyrotoxicosis [33]. Recognizing these risk factors can aid healthcare providers in monitoring and managing potential endocrine side effects more effectively in patients undergoing ICI therapy.

Thyroid disorders induced by immunotherapy

Thyroid dysfunction is one of the most common endocrinopathies following therapy with immune checkpoint inhibitors (ICIs). The clinical spectrum ranges from overt hypothyroidism to overt thyrotoxicosis, with destructive thyroiditis being the common underlying pathophysiological mechanism. Thyroid dysfunction is more frequently observed in patients treated with anti-PD-1 agents or a combination of ipilimumab and nivolumab, and less commonly in those treated with anti-CTLA-4 or anti-PD-L1 monotherapies [34–37].

More specifically, primary hypothyroidism affects 6%-9% of patients undergoing anti-PD-1 and/or anti-PD-L1 therapy, 4% of those on anti-CTLA-4 therapy, and approximately 16% of patients receiving a combination of anti-PD(L)1 and anti-CTLA-4 therapies (Figure 1) [38]. It can be preceded by a hyperthyroid state, which may be subclinical. Most cases arise within the first three months of treatment initiation, but onset can occur at any time during the therapy [39].

Figure 1. Incidence of thyroid adverse events in patients treated with ICIs.

On the other hand, Immune-related (IR) hyperthyroidism occurs less frequently. It is reported in approximately 2%-5% of patients treated with immune checkpoint inhibitor (ICI) monotherapy and in about 10% of those receiving a combination of anti-PD(L)1 and anti-CTLA-4 therapies (Figure 1) [38]. Transient thyroiditis remains the most common cause of IR hyperthyroidism. Among these cases, around 40% are present with symptomatic thyrotoxicosis, while 60% manifest as subclinical thyrotoxicosis, which is usually followed by hypothyroidism [40]. Primary hyperthyroidism due to Graves-like disease is rarely reported. When it occurs, persistent hyperthyroidism, diffuse goiter, and ophthalmopathy may indicate this diagnosis (41). Thyroid dysfunction typically emerges within a few weeks of ICI initiation and can occur after a single dose (42). Median onset time ranges from 18 to 123 days, but cases have been reported as early as seven days or as late as three years after initiation [34–37]. The dysfunction often starts as painless thyroiditis, beginning with a transient thyrotoxic phase that is usually mild or asymptomatic, lasting a few weeks before transitioning to euthyroidism or hypothyroidism. Symptoms are generally nonspecific, such as fatigue and weight loss, but can include tremor, anxiety and heat intolerance [43,44]. Physical examination may reveal tachycardia or warm, smooth skin, although severe thyrotoxicosis (thyroid storm) is rare [45,46].

The median time for progression to euthyroidism or hypothyroidism is four-seven weeks [24,42]. In some cases, hypothyroidism, whether subclinical or clinical, is the initial presentation and may be transient or permanent. Symptoms are usually mild and nonspecific, including fatigue and weight gain, but may also involve bradycardia, cold skin, constipation, and cold intolerance [43,44]. Myxedema coma, a complication resulting from untreated hypothyroidism, is very rare [47].

Elevated autoantibodies against thyroid peroxidase (anti-TPO) and thyroglobulin (anti-Tg) are found in some patients developing thyroid dysfunction after ICI therapy [34–37]. High titers of these antibodies prior to therapy appear to be related to ICI-induced thyroid dysfunction, though they are not necessary but represent a risk factor [26]. Stimulating autoantibodies for the TSH receptor (TRAb or TSI) were negative in most patients, though in rare cases, TRAb positivity suggests co-existing Graves’ disease [34–37,48,49].

Measurement of TSH, FT4, and occasionally T3 levels is typically sufficient for diagnosis. In thyrotoxicosis due to thyroiditis, FT4 levels are more elevated compared to T3 levels due to the release of stored thyroxine (T4) into the bloodstream. In hyperthyroidism, T3 levels are higher due to stimulation of the thyroid gland. Differentiating between primary and central hypothyroidism is crucial, as hypophysitis should be considered in these patients [43,44,50,51]. More detailed information can be found in Table 2.

Monitoring and management of immune-related hypothyroidism

The management of endocrine adverse events related to immunotherapy, specifically thyroid dysfunction, follows a structured approach based on the assessment of thyroid function tests (TFTs). For patients with asymptomatic or subclinical hypothyroidism, it is recommended to monitor TSH and free T4 every four-six weeks. If TSH is elevated, the next steps depend on the levels of TSH and free T4. If TSH levels range between 4 and less than 10 mIU/ml, the patient is asymptomaticwith normal free T4 levels, the patient should continue immunotherapy and regular monitoring of TFTs. If TSH exceeds 10 mIU/ml but free T4 is normal, immunotherapy can continue, and the consideration of levothyroxine treatment is advised. In cases where TSH is normal or low and free T4 is low, it is important to investigate for central hypothyroidism or hypophysitis and exclude recovery from thyrotoxicosis [50,51].

For patients with clinical (overt) primary hypothyroidism, TSH should be monitored every four-six weeks. Management includes continuing immunotherapy and considering endocrine consultation. Thyroid hormone supplementation with levothyroxine should be initiated, and TSH levels should be reassessed in four-six weeks to guide dosing adjustments. Additionally, it is essential to exclude concomitant adrenal insufficiency by checking the morning cortisol level. This approach ensures that thyroid dysfunctions are identified and managed effectively without discontinuing necessary immunotherapy, thus maintaining the therapeutic benefits while mitigating adverse endocrine effects (Figure 2) [50,51].

Figure 2. Monitoring and management of immune-related hypothyroidism.

Monitoring and management of immune-related hyperthyroidism

For patients experiencing thyrotoxicosis induced by immunotherapy, the management process is detailed and depends on specific thyroid function test (TFT) results. Immunotherapy-induced thyrotoxicosis is typically caused by transient or evolving painless thyroiditis. Antithyroid medications such as methimazole or propylthiouracil are not recommended for this condition. When thyrotoxicosis is identified, indicated by low or suppressed TSH levels and high free T4/total T3, an endocrine consultation should be considered if the patient is symptomatic. If the patient is asymptomatic, immunotherapy can continue. Symptomatic patients may be treated with propranolol (10–20 mg every 4–6 hours as needed) or atenolol or metoprolol until thyrotoxicosis resolves. TFTs should be repeated every 4–6 weeks. If thyrotoxicosis resolves, no further therapy for thyrotoxicosis is necessary. However, it often evolves into hypothyroidism in 50%–90% of cases, requiring treatment with thyroid hormone replacement, as mentioned above. Rarely, painful thyroiditis can occur, and in such cases, prednisolone 0.5 mg/kg should be prescribed [50]. If thyrotoxicosis persists, an evaluation for Graves’ disease should be considered (Figure 3) [50,51].

Figure 3. Monitoring and management of immune-related hyperthyroidism.

Role of glucocorticoids in immunotherapy-induced thyroid dysfunction

Even though thyroid disorders have emerged as one of the most common immune-related adverse events (irAE) associated with immunotherapy, optimum management strategies and predictive biomarkers for vulnerable individuals remain to be fully explored. High-dose glucocorticoid (HDG) therapy is routinely recommended for irAEs [52,53]. However, a systematic analysis of the impact of glucocorticoid therapy on the outcome of immune-checkpoint inhibitor (ICI)-induced thyroid disorders is lacking. In a study analyzing 151 patients with or without ICI-related thyroid disorders, the patients with ICI-related thyroid disorders were divided into two subgroups: those receiving HDG treatment and those not. The results showed no significant differences between the HDG and no HDG groups in terms of the median duration of thyrotoxicosis (28 vs 42 days), the median time to conversion from thyrotoxicosis to hypothyroidism (39 vs 42 days), the median time to onset of hypothyroidism (both 63 days), and the median maintenance dose of levothyroxine (1.5 vs 1.3 mg/kg/day). The median pretreatment TSH was higher in patients with ICI-related thyroid disorders compared to those without (2.3 vs 1.7 mIU/L). Baseline TSH was significantly higher in patients who developed ICI-related thyroid disorders. Subgroup analysis revealed significantly higher baseline TSH in male patients with ICI-induced thyroid dysfunction, but not in female patients. This study concluded that HDG treatment did not improve the outcome of ICI-related thyroid disorders [54].

Conclusions

Immune checkpoints targeted by ICIs are crucial for maintaining immunological self-tolerance, making these therapies capable of triggering autoimmune adverse effects. Among the most common are thyroid disorders, as well as other endocrine complications like hypophysitis, diabetes mellitus, and primary adrenal insufficiency. Physicians managing such patients need to be well-informed about ICI-related endocrine adverse events, including their clinical presentation, laboratory findings, frequency, and severity. Effective screening and management require close collaboration between oncologists and endocrinologists. As survival rates improve, the monitoring and management of long-term consequences have become increasingly crucial, highlighting the necessity for joint clinics to provide comprehensive care.

To summarize, the management of thyroid-related adverse events from immunotherapy involves structured monitoring and intervention based on thyroid function tests (TFTs). For asymptomatic or subclinical hypothyroidism, TSH and free T4 levels should be monitored every four-six weeks. If TSH is elevated (ranging from 4 and less than 10 mIU/ml with normal free T4), immunotherapy may proceed with regular TFT monitoring. If TSH exceeds 10 mIU/ml, consideration of levothyroxine alongside ongoing immunotherapy is advised. In overt primary hypothyroidism, TSH is monitored similarly, with initiation of levothyroxine and adrenal insufficiency exclusion. Immune-related thyrotoxicosis management involves symptom-driven use of beta-blockers, ongoing immunotherapy if asymptomatic, and periodic TFT checks, anticipating potential transition to hypothyroidism. Persistent thyrotoxicosis may prompt evaluation for Graves’ disease. This approach ensures thyroid dysfunctions are effectively managed without interrupting essential immunotherapy, balancing therapeutic benefits with managing adverse endocrine effects [50,51]. A summary can be found in Figure 4.

Figure 4. Summary of monitoring the thyroid function of patients on ICI therapy.

Acknowledgements

The author would like to thank Prof. A. Koutras for the invitation and for all the support. G.C.K. is a recipient of a Fulbright Doctoral Dissertation Visiting Research Student Fellowship (2023–2024).

Conflict of interest disclosure

None to declare.

Declaration of funding sources

None to declare.

Author contributions

GK was responsible for the conception, research, writing and the final draft of this review.

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