Immune-Related Thyroiditis with Immune Checkpoint Inhibitors

Abstract

Background: Although immune-related thyroiditis (irT) with immune checkpoint inhibitors (ICI) is a common consequence, its natural course and management recommendations are not well characterized in existing guidelines. This study sought to investigate the evolution of irT and describe its course and sequelae.

Methods: This was a retrospective study of cancer patients treated with ICI between November 2014 and July 2016 at MD Anderson Cancer Center and referred for endocrinology evaluation for suspected irT. Patients included had normal baseline thyroid function tests prior to starting ICI and developed thyrotoxicosis due to irT.

Results: Of 657 patients treated with ICI during the study period, 43(6.5%) met the inclusion criteria. ICI included: ipilimumab + nivolumab (40%), nivolumab (33%), pembrolizumab (21%), and other (7%). Cancer diagnoses observed were melanoma (23%), renal-cell carcinoma (21%), lung cancer (19%), bladder cancer (12%), colon cancer (9%), and other cancers (15%). Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.

Conclusions: IrT manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination ICI. Frequent monitoring of thyroid function tests during ICI is warranted. Future guidelines need to recognize this entity and incorporate their management.

Keywords: immunotherapy; nivolumab; pembrolizumab; side effects; thyroiditis.

FIG. 1.

Timeline of thyroiditis. The graph depicts the timeline of thyroiditis from the start of ICI until the last follow up. Median time to thyrotoxicosis was 5.3 weeks (range 0.57–19.57 weeks). Median time to hypothyroidism was 10.4 weeks (range 3.4–48.71 weeks). Median thyrotoxicosis phase was 6 weeks (2.6–39.7 weeks). Median hypothyroid phase was 57.4 weeks (range 1–156.7 weeks). There was no recovery in thyroid function seen in the patients who were started on levothyroxine, when followed until the date of last follow up at the time of data analysis. ICI, immune checkpoint inhibitors.

FIG. 2.

Comparison of timeline of thyroiditis with nivolumab versus combination of ipilimumab + nivolumab. The time to thyrotoxicosis with nivolumab was six weeks [confidence interval (CI) 3.6–8.4] versus two weeks [CI 1.19–2.8] with the combination of ipilimumab + nivolumab (p = 0.26). The time to hypothyroidism from the start of ICI was 10 weeks with the combination of ipilimumab and nivolumab [CI 8.1–11.9] versus 17 weeks [CI 8.82–25.18] with nivolumab alone (p = 0.029). Two patients on ipilimumab and nivolumab died prior to developing hypothyroidism.

FIG. 3.

Proposed algorithm for management of immune checkpoint inhibitor (ICI)-mediated thyroiditis. The figure below outlines a proposed algorithm for evaluation in patient on ICI therapy in whom thyroiditis is suspected. Common Terminology Criteria for Adverse Events (CTCAE) v.4 criteria: grade 1—asymptomatic; clinical or diagnostic observations only; intervention not indicated; grade 2—symptomatic; thyroid suppression therapy indicated; limiting instrumental activities of daily living (ADL); grade 3: severe symptoms limiting self-care ADL and hospitalization indicated; grade 4—life-threatening consequences; urgent intervention indicated; grade 5: death.