Tocilizumab in Corticosteroid-Resistant Graves' Orbitopathy (Thyroid Eye Disease)

Efficacy and Safety of Tocilizumab in Patients With Active Moderate-to-Severe Corticosteroid-Resistant Thyroid Eye Disease: Open, Prospective, Observational Study

The aim of this study is to evaluate the efficacy and safety of Tocilizumab as second/third line treatment in patients with Active Moderate-to-Severe Corticosteroid-Resistant Thyroid Eye Disease.

Graves' Orbitopathy (GO) is an autoimmune disease that involves orbital tissues, leading to temporary or permanent damage to the eye. Although GO is a rare condition, it negatively affects the quality of life in the majority of patients. In the majority of european centers, high-dose intravenous glucocorticoid (GCs) therapy remains the first-line treatment in patients with active, moderate-to-severe GO. However, GCs are effective in only 45-60% of patients, with a high probability of diseases relapse (10-40%) or disease progression to dysthyroid optic neuropathy (up to 10%). Due to limited efficacy of GCs, unpredictable relapses and progression of GO, the management of GO remains a challenge.

A few studies have demonstrated that interleukin-6 (IL-6) blockade with tocilizumab (TCZ) is effective in GC-refractory GO. However, the long-term outcomes of TCZ remain scarce.

Therefore, the investigators are planning to assess the therapy with Tocilizumab, regarding clinical outcomes and adverse events. The investigators plan to include a total of 30 patients with active, moderate-to-severe, corticosteroid-resistant GO over a period of approximately 4 years.

Inclusion Criteria:

• Written informed consent

• Male or female, 18-80 years old

• Patients with active (Clinical Activity Score ≥ 3 in 7-item scale) and moderate-to-severe GO, diagnosed according to the EUGOGO guidelines, after the completion of MP pulse treatment, WITH

  o Deterioration of GO (in 1 or 2 eyes) when two of the following occurred:

• increase in palpebral aperture by at least 2 mm;

• deterioration in CAS by at least 2 points (7-point CAS)

• increase in exophthalmos by at least 2 mm;

• worsening of diplopia (appearance or change in the degree)

• worsening in ocular motility by 8o

  o Incomplete response in both eyes to intravenous methylprednisolone pulse therapy; defined changes smaller than previously defined in any of the mentioned parameters.

• Euthyroid for at least 6-8 weeks (serum free hormone concentrations within 30% of normal range) on either anti-thyroid medications (tyonamides) to control hyperthyroidism or L-thyroxine for replacement therapy for hypothyroidism.

• Negative pregnancy test in women of fertile age.

• All female patients of fertile age must use a reliable contraceptive method to prevent pregnancy during the study period, and at least during a period of six months following the last dose of the investigational medicinal product.

Exclusion Criteria:

• Signs of sight-threatening TED (severe keratopathy, optic neuropathy)
• Pregnant or breastfeeding woman or woman planning to become pregnant during the study
• Patients who could need treatment with radioactive iodine or thyroidectomy during the study
• Treatment with any biological therapy at any time.
• Active infection.
• History of recurrent clinically significant infection or recurrent bacterial infections.
• Positive quantiferon without documentation of treatment for tuberculosis (TB) infection or documentation of no need for such therapy.
• Required management of infections, as follows: currently on any suppressive therapy for a chronic infection, hospitalization for treatment of infection within 60 days before Day 0, use of parenteral antibiotics within 60 days before Day 0, use of oral antibiotics within 30 days before Day 0.
• History of intestinal ulceration or diverticulitis
• Patients with a history of chronic liver disease or liver disorders: Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) above 5 times upper limit of normal (ULN)
• HBsAg positive test.
• HBcAb positive test, regardless of HBsAb status, will undergo HBV DNA which, if positive, will be excluded. HbcAb positive, HbsAg negative patients with undetectable HBV DNA will receive antiviral prophylaxis throughout the immunosuppressive therapy.
• Hepatitis C antibody positive test at screening.
• Positive test for Human Immunodeficiency Virus (HIV) antibody at screening or historically. Denied consent to HIV testing.
• Absolute neutrophil count (ANC) < 2.0 × 109/L or a platelet count < 100×103/μL
• Alkaline phosphatase and bilirubin>1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin is<35%).
• Cardiovascular or cerebrovascular disease clinically significant.
• Other serious chronic illness (including uncontrolled diabetes mellitus, renal disease, pulmonary disease, major depression).
• History of sarcoidosis.
• Primary or secondary immunodeficiency.
• History of IgE-mediated or non-IgE-mediated hypersensitivity.
• History of reactions or anaphylactic allergic severe human monoclonal antibodies, humanized or murine.
• Administration of live vaccines given within 30 days prior to administration of (Day 0) or concurrently with tocilizumab (during study).
• Splenectomy.
• Current drug or alcohol abuse or dependence.