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. 2020 Aug 31;9(9):2816.
doi: 10.3390/jcm9092816.

Anti-IL-6 Receptor Tocilizumab in Refractory Graves' Orbitopathy: National Multicenter Observational Study of 48 Patients

Lara Sánchez-Bilbao  1 , David Martínez-López  1 , Marcelino Revenga  2 , Ángel López-Vázquez  2 , Elia Valls-Pascual  3 , Belén Atienza-Mateo  1 , Beatriz Valls-Espinosa  3 , Olga Maiz-Alonso  4 , Ana Blanco  4 , Ignacio Torre-Salaberri  5 , Verónica Rodríguez-Méndez  5 , Ángel García-Aparicio  6 , Raúl Veroz-González  7 , Vega Jovaní  8 , Diana Peiteado  9 , Margarita Sánchez-Orgaz  9 , Eva Tomero  10 , Francisco J Toyos-Sáenz de Miera  11 , Valvanera Pinillos  12 , Elena Aurrecoechea  13 , Ángel Mora  13 , Arantxa Conesa  14 , Manuel Fernández-Prada  15 , Juan A Troyano  16 , Vanesa Calvo-Río  1 , Rosalía Demetrio-Pablo  1 , Íñigo González-Mazón  1 , José L Hernández  1 , Santos Castañeda  10   17 , Miguel Á González-Gay  1 , Ricardo Blanco  1
Affiliations

Anti-IL-6 Receptor Tocilizumab in Refractory Graves' Orbitopathy: National Multicenter Observational Study of 48 Patients

Lara Sánchez-Bilbao et al. J Clin Med. .

Abstract

Graves' orbitopathy (GO) is the most common extrathyroidal manifestation of Graves' disease (GD). Our aim was to assess the efficacy and safety of Tocilizumab (TCZ) in GO refractory to conventional therapy. This was an open-label multicenter study of glucocorticoid-resistant GO treated with TCZ. The main outcomes were the best-corrected visual acuity (BVCA), Clinical Activity Score (CAS) and intraocular pressure (IOP). These outcome variables were assessed at baseline, 1st, 3rd, 6th and 12th month after TCZ therapy onset. The severity of GO was assessed according to the European Group on Graves' Orbitopathy (EUGOGO). We studied 48 (38 women and 10 men) patients (95 eyes); mean age ± standard deviation 51 ± 11.8 years. Before TCZ and besides oral glucocorticoids, they had received IV methylprednisolone (n = 43), or selenium (n = 11). GO disease was moderate (n =29) or severe (n = 19) and dysthyroid optic neuropathy (DON) (n = 7). TCZ was used in monotherapy (n = 45) or combined (n = 3) at a dose of 8 mg/kg IV every four weeks (n = 43) or 162 mg/s.c. every week (n = 5). TCZ yielded a significant improvement in all of the main outcomes at the 1st month that was maintained at one year. Comparing the baseline with data at 1 year all of the variables improved; BCVA (0.78 ± 0.25 vs. 0.9 ± 0.16; p = 0.0001), CAS (4.64 ± 1.5 vs. 1.05 ± 1.27; p = 0.0001) and intraocular pressure (IOP) (19.05 ± 4.1 vs. 16.73 ± 3.4 mmHg; p = 0.007). After a mean follow-up of 16.1 ± 2.1 months, low disease activity (CAS ≤ 3), was achieved in 88 eyes (92.6%) and TCZ was withdrawn in 29 cases due to low disease activity (n = 25) or inefficacy (n = 4). No serious adverse events were observed. In conclusion, TCZ is a useful and safe therapeutic option in refractory GO treatment.

Keywords: Graves’ disease; Graves’ ophthalmopathy; Tocilizumab; corticoid-resistant; extrathyroidal manifestations; thyroid-associated ophthalmopathy.

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Conflict of interest statement

Disclosures that might be interpreted as constituting of possible conflict(s) of interest for the study: Elia Valls-Pascual received grants/research supports from Roche, Novartis and AbbVie and had consultation fees/participation in company sponsored speaker’s bureau from AbbVie, Lilly, Pfizer, MSD, Novartis, Janssen, Bristol Myers Squibb and UCB Pharma. Ana Blanco had consultation fees/participation in company sponsored speaker’s bureau from AbbVie. Vega Jovani received grants/research supports from AbbVie, MSD, Novartis and Pfizer and had consultation fees/participation in company sponsored speaker’s bureau from AbbVie. Diana Peiteado López received grants/research supports from AbbVie, Lilly, MSD and Roche and had participation in company sponsored speaker’s bureau from AbbVie, Roche and MSD. Vanesa Calvo-Río received grants/research supports from MSD and Roche and had consultation fees/participation in company sponsored speaker’s bureau from AbbVie, Lilly, Celgene, Grünenthal and UCB Pharma. Santos Castañeda is assistant professor of the cátedra UAM-Roche, EPID-Future, Universidad Autónoma de Madrid (UAM). Miguel A. González-Gay received grants/research supports from AbbVie, MSD, Jansen and Roche and had consultation fees/participation in company sponsored speaker’s bureau from AbbVie, Pfizer, Roche, Sanofi, Celgene and MSD. Ricardo Blanco received grants/research supports from AbbVie, MSD and Roche and had consultation fees/participation in company sponsored speaker’s bureau from AbbVie, Pfizer, Roche, Bristol-Myers, Janssen, Lilly and MSD. The following authors did not declare financial disclosure: Lara Sánchez-Bilbao, David Martínez-López, Marcelino Revenga, Ángel López-Vázquez, Belén Atienza-Mateo, Beatriz Valls-Espinosa, Olga Maiz-Alonso, Ignacio Torre-Salaberri, Verónica Rodríguez-Méndez, Ángel García-Aparicio, Raúl Veroz González, Margarita Sánchez-Orgaz, Eva Tomero, Francisco J. Toyos Sáenz de Miera, Valvanera Pinillos, Elena Aurrecoechea, Ángel Mora, Arantxa Conesa, Manuel Fernández-Prada, J. Antonio Troyano, Rosalía Demetrio-Pablo, Íñigo González-Mazón, José L. Hernández.

Figures

Figure 1
Figure 1
Improvement of the main ocular parameters with TCZ therapy. (A) Best-corrected visual acuity (BVCA); (B) Clinical Activity Score; (CAS) evolution and Low Disease Activity (LDA); (C) Intraocular pressure (IOP) evolution. Data are expressed as mean ± SD or median (IQR). * p < 0.05 compared with baseline.
Figure 1
Figure 1
Improvement of the main ocular parameters with TCZ therapy. (A) Best-corrected visual acuity (BVCA); (B) Clinical Activity Score; (CAS) evolution and Low Disease Activity (LDA); (C) Intraocular pressure (IOP) evolution. Data are expressed as mean ± SD or median (IQR). * p < 0.05 compared with baseline.
Figure 2
Figure 2
Patient included in this series with severe and refractory Graves’ orbitopathy at (A) Tocilizumab onset and (B) after five months of Tocilizumab therapy. (Courtesy of Dr. Torre-Salaberri, Basurto Hospital, Bilbao).
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