Steroid-Resistant Graves’ Orbitopathy Treated with Tocilizumab in Real-World Clinical Practice: A 9-Year Single-Center Experience

Abstract

This study aimed to assess the effectiveness and safety of tocilizumab use for the treatment of active steroid-resistant Graves’ orbitopathy (GO). A retrospective longitudinal study was conducted by reviewing the medical records at a single center between November 2009 and December 2018. A total of 114 patients with steroid-resistant Graves’ orbitopathy were examined and treated with tocilizumab, of which 54 adults met the inclusion criteria. No concomitant medication for the treatment of orbitopathy was used. The main primary outcomes included changes from baseline in the Clinical Activity Score (CAS) and thyrotropin receptor antibody (TRAb) levels throughout therapy with tocilizumab. The absolute responses to treatment were defined as the achievement of CAS ≤ 1 and TRAb ≤ 10 U/L. A composite ophthalmic score including CAS, proptosis, eyelid retraction, and diplopia was used to evaluate individual improvement in GO. Adverse drug reactions were also assessed. Analysis of the patient’s CAS and TRAb levels showed meaningful reductions during tocilizumab treatment. Differences between values at baseline and subsequent time points were statistically significant (p < 0.001 for all comparisons). The absolute CAS response (CAS = 0 or 1) was achieved in 74% (37/50) of patients after the fourth dose of tocilizumab (at week 16), with a TRAb response being achieved in 55% (23/42) of patients. The relative CAS response (reduction ≥ 2 points) was achieved in 90.9% of patients (40/44) after the first dose of tocilizumab (at week 4). Measurements of proptosis (reduction ≥ 2 mm in 78% of patients, 42/54) and eyelid retraction (reduction ≥ 2 mm in 75%, 33/44), and the prevalence of diplopia (improvement in 68%, 19/28) were significantly reduced after the last dose of tocilizumab (p < 0.001 for all comparisons). GO improved in 98% (53/54) of patients when at least two criteria of the composite evaluation were required. Four patients exhibited disease recurrence, defined as an increase in CAS of ≥2 points in the six months following the date of inactivation. Most adverse drug reactions were mild or moderate in severity. In conclusion, our data suggest that a course of at least 4 months (one monthly dose) of tocilizumab therapy provides a significant benefit to patients with active moderate-to-severe steroid-resistant GO.

The 2021 European Group on Graves’ orbitopathy (EUGOGO) clinical practice guidelines for the medical management of Graves’ orbitopathy

“…Likewise, a small study of eight glucocorticoidresistant patients with moderate-to-severe and active GO, showed a beneficial effect of tocilizumab on CAS and exophthalmos (150). Similar findings were recently reported in a single-center retrospective observation over nine years with 54 patients analyzed (151), nevertheless larger RCTs including tocilizumab in naive patients with GO of short duration are warranted. Currently, data suggests that tocilizumab may cause rapid resolution of inflammatory signs in glucocorticoidresistant moderate-to-severe and active GO.…”

Current concepts regarding Graves’ orbitopathy

“…GO [263][264][265], but larger multicenter RCTs are warranted to better define its role. For the time being, tocilizumab may be considered as a secondline treatment for active moderate-to-severe GO, particularly if refractory to ivGCs.…”

“…Tocilizumab had limited efficacy on exophthalmos and diplopia [262]; it was well tolerated, but there was a higher rate of infections and headache [262]. Other small uncontrolled or retrospective studies seem to confirm tocilizumab efficacy, particularly in GC‐resistant GO [263–265], but larger multicenter RCTs are warranted to better define its role. For the time being, tocilizumab may be considered as a second‐line treatment for active moderate‐to‐severe GO, particularly if refractory to ivGCs.…”

Management of thyroid eye disease: a Consensus Statement by the American Thyroid Association and the European Thyroid Association

“…The primary end point (improvement in CAS by ≥2 at 16 weeks) was achieved in significantly more treated patients than those receiving placebo (93%, 14/15 vs 59%, 10/17); however, there was no difference between groups by week 40. A real-world report of 54 patient with GC-resistant TED treated with TCZ for 9 years from the same center as the original open label study cited inactivation in 74% of patients ( 84 ).…”

“…The open-label study showed reduction in proptosis by a mean 3.92 mm in patients with GC-resistant TED and resolution of diplopia in 54% (7/13) of patients ( 111 ). The real-world study reported proptosis reduction ≥2 mm from baseline in 78% (42/54) of patients, and improvement in diplopia in 68% (19/28) of patients ( 84 ). In the RCT, proptosis values in TCZ-treated patients were significantly lower than those in placebo-treated patients at 16 weeks by a median of 1.5 mm; however, no differences in proptosis were demonstrable at 40 weeks, and diplopia improved in only 7% (1/15) of patients treated with TCZ.…”