Thyroid dysfunction is the most common adverse effect of ICI use amongst all endocrine irAE [14
]. Despite this, the clinical factors to predict de novo thyroid dysfunction in patients receiving ICI remain unclear. Ours is the first study to report that the history of receiving RT to the head and neck region is a significant predictor of developing ‘de novo’ thyroid dysfunction in patients who are treated with ICI and have a normal value of TSH and free T4 before starting therapy. In our study, 28 patients (26.9%) treated with ICI developed thyroid dysfunction. The cumulative incidence of thyroid dysfunction is similar to recent studies that report 14–21% of thyroid dysfunction with the use of anti-PD-1 ICI [9
]. Eight patients (44.45%) who had received RT to the neck developed thyroid dysfunction after starting treatment with ICI. Out of these eight patients, six patients developed thyroid dysfunction within 1–3 cycles of starting ICI therapy. It must be noted here that we excluded the patients who were diagnosed with functional thyroid dysfunction before starting the ICI treatment. Our study did not identify any significant association between age, gender, race, or type of cancer, and the development of thyroid dysfunction, which is congruent with the existing literature [8
]. Kobayashi et al., in their prospective study, reported that the presence of anti-thyroglobulin antibodies and antithyroid peroxidase antibodies before starting nivolumab had been associated with a higher incidence of developing thyroid-related irAE [10
]. However, other authors have reported no statistically significant relationship between the presence of these antibodies before the development of thyroid-related irAE [7
]. In our practice, we do not routinely check for these antibodies. None of the patients in our study developed thyroid emergencies or required interruption or termination of treatment. The majority of patients with thyroid dysfunction became hypothyroid (89%, 25/28 patients), amongst whom twelve patients developed thyroiditis like the picture (hyperthyroidism followed by hypothyroidism). A similar pattern of thyroid irAE has been reported by other authors [4
]. Although we excluded patients with functional thyroid dysfunction, we did observe a worsening of TSH and free T4 after starting treatment with ICI.
The mechanism of thyroid dysfunction caused by ICI remains anecdotal. CTLA-4 is a central regulator of the immune system that prevents autoreactive T-cells from getting activated in the naïve stages. On the other hand, PD-1/PDL-1 has a more ‘’peripheral’’ action: it downregulates activated T-cells to prevent autoimmunity [1
]. It is also known that polymorphisms and mutations in CTLA-4 or PD-1/PDL-1 lead to a wide array of autoimmune conditions, including autoimmune thyroiditis [1
]. It is widely believed that the use of ICI can lead to a block of T-cell regulatory pathways and activates autoreactive T-cells; however, the theory yet remains to be proven conclusively [4
]. The combination of radiotherapy with ICI is currently a topic of investigation for multiple trials. It is postulated that the tumoricidal effects of RT lead to exposure of tumor antigens that can lead to clonal expansion of activation of T-cells [18
]. In addition to this, RT also increases the pro-inflammatory cytokines (CD91, MHC-1, Interferon-1) that can further activate T-cells in the periphery [18
]. In theory, this effect could also explain the inflammatory responses seen in the thyroid gland. Although no patients received RT and ICI concomitantly in our group, we postulate that the subtle changes in the thyroid gland brought about by RT to the neck were worsened by the introduction of ICI, leading to precipitation of frank thyroid dysfunction. Our proposition is further strengthened by our observation in patients with functional thyroid dysfunction before starting ICI, in whom we noticed a worsening of TSH and free T4 after starting treatment with ICI. Harding et al. have reported an increase in pre-existing antithyroid antibodies after treatment with ipilimumab [20
]. Likewise, Snozl et al. have also observed (in unpublished data) a marked increase in antithyroid antibodies that could, in theory, explain the worsening of thyroid dysfunction after starting ICI therapy [4
]. We recently conducted a database analysis, where we report that patients with head and neck cancer (HNC), who were treated with ICI, developed thyroid dysfunction at a higher rate than other cancers where ICI was used [21
]. We think that this disparity is primarily because RT to the head and neck region is a principal treatment modality for patients with HNC. In our study as well, six out of eight patients who received RT to the neck belonged to the HNC group.
The strength of our study lies in the diversity of tumor types included in the analysis and the fact that we excluded all patients who had any form of thyroid dysfunction (functional or anatomical). We included all kinds of ICI that were approved by USFDA at the time of this study period. These factors help in the generalization of the results and mimicry of real-world scenarios. Our study has certain limitations. First, the retrospective nature of the study introduces selection bias; however, to minimize this, we strictly adhered to the study protocol. The second limitation of this study is including very few patients receiving the combination of anti-CTLA-4 and anti-PD-1, which skews the data pertaining to the incidence of thyroid dysfunction with dual ICI. We have acknowledged this in the results section.