Long‐term outcomes in corticosteroid‐refractory Graves' orbitopathy treated with tocilizumab

Abstract

Background Up to 20% of patients with moderate to severe Graves' orbitopathy (GO) do not respond to high‐dose glucocorticoids (GC). A few studies, including a randomized trial, have demonstrated the efficacy of interleukin‐6 (IL‐6) blockade with tocilizumab (TCZ) in GC‐refractory GO. However, data on predictors of response to TCZ and long‐term outcomes are lacking. Methods Observational single‐center study on ten consecutive patients treated with TCZ for GC‐refractory GO, between 2016 and 2020. Median (interquartile range) follow‐up was 24 (12–36) months. Results Inflammation and exophthalmos improved dramatically in all patients within months after starting TCZ. Mean Clinical Activity Score decreased from 4.80 ± 1.13 to 0.70 ± 0.82 points at 6 months (mean change: −4.10 ± 1.52; p < .0001). Proptosis improved from 23.2 ± 2.1 to 20.6 ± 2.0 mm at 6 months (mean change: −2.9 ± 1.4 mm; p < .0001). Diplopia resolved in 7 patients. Thyroid receptor antibodies decreased markedly during TCZ treatment. Baseline serum IL‐6 levels did not predict clinical response. TCZ was well‐tolerated. During follow‐up, 3 patients were diagnosed with cancer (breast cancer in 2 and urothelial cancer in 1). Conclusions TCZ was rapidly effective and well‐tolerated in our patients with GC‐refractory GO. Four patients experienced mild/moderate adverse events as neutropenia, hyperlipidemia, and infections; nearly a third developed cancer during the follow‐up. The increased incidence observed could be explained by the high prevalence of smokers, that are at higher risk for Graves' orbitopathy and solid malignancies as breast cancer. Thus, regular cancer screening could be proposed to this vulnerable population receiving high doses of immunosuppressants.

Monoclonal Antibodies for the Treatment of Graves Orbitopathy: Precision Medicine?

“…Of the 24 articles on this Mab, 62.5% originated from European countries. 34,39,41,49,58,59,63,68,69,71,72,79,80,84 The same trend is true for Rituximab (64.3% articles from Europe). 26,27,30,33,35,37,42–44,46–48,54,55,61,62,65,67,73,89 In contrast, Teprotumab has only been tested in the USA.…”

“…1 shows that 76 articles of the 954 screened records were included in the review. The literature on the use of Mabs for treating GO has been centered on blockage of IL-6 (Tocilizumab), 34,39,41,49,50,53,56,[58][59][60]63,64,[68][69][70][71][72]79,80,84,87,90,[96][97][98] anti-CD20 lymphocytes (Rituximab), [26][27][28][29][30][31][32][33]35,37,38,40,[42][43][44][45][46][47][48]51,54,55,61,62,65,…”

“…1 shows that 76 articles of the 954 screened records were included in the review. 25–101 The literature on the use of Mabs for treating GO has been centered on blockage of IL-6 (Tocilizumab), 34,39,41,49,50,53,56,58–60,63,64,68–72,79,80,84,87,90,96–98 anti-CD20 lymphocytes (Rituximab), 26–33,35,37,38,40,42–48,51,54,55,61,62,65,67,73,89 and IGF1R (Teprotumumab). 52,66,74–78,82,85,86,88,91,92,94,95,99–101 Three articles have described Mabs that block TNF-α, 25,36,83 and one article has described Mabs that block the B-lymphocyte stimulator (BLyS) protein (Belimumab).…”

“…27,40,50,56,[69][70][71]73,76,78,86,90,95,100,102 Some collateral effects depended on the drug that was being used (Table 6). For instance, hyperlipidemia and neutropenia were common with Tocilizumab, 80,84,97 and infusion-related reactions (rash, cytokines release syndrome, bronchospasm, and erythroderma) and hypotension were the main concern with Rituximab. Among these infusion reaction episodes, five patients developed orbital edema, compressive optic neuropathy, and decreased vision.…”

Tocilizumab as a Useful Tool for Thyroid Eye Disease in Pediatric Population: A Case Report

“…Tocilizumab constitutes a humanized monoclonal antibody against interleukin 6 (IL-6). Recent studies evidence that IL-6 increases the expression of TSH-R on fibroblasts and tocilizumab use has been documented as an effective treatment for TED in adults [12][13][14][15][16][17]. Recently, tocilizumab has been also approved in children for use in systemic juvenile arthritis and polyarticular juvenile idiopathic arthritis (JIA) both by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) [18,19].…”