Financial Disclosure I have no financial interests or relationships - PDF document

4/13/2018 ADVANCES IN THE TREATMENT OF THYROID EYE DISEASE M. Reza Vagefi, M.D. Associate Professor of Ophthalmology Division of Oculofacial Plastic Surgery University of California, San Francisco Advances in Endocrinology and Metabolism 2018 MDM18E01 April 13, 2018 Financial Disclosure I have no financial interests or relationships to disclose. The presentation covers off-label application of certain drugs. M. Reza Vagefi, MD Associate Professor of Ophthalmology Division of Oculofacial Plastic Surgery 1

4/13/2018 Objectives To understand:  The epidemiology, pathogenesis and clinical course of thyroid eye disease  Traditional therapeutic approaches used to treat moderate to severe active disease  The cellular targets and newer biologic agents used to treat moderate to severe active disease M. Reza Vagefi, MD Associate Professor of Ophthalmology Division of Oculofacial Plastic Surgery Thyroid Eye Disease (TED)  Most common extrathyroidal manifestation of autoimmune hyperthyroidism  Pathogenic mechanisms are still being elucidated with the orbital fibroblast playing a key role  Disfiguring condition affecting ocular function & appearance M. Reza Vagefi, MD Associate Professor of Ophthalmology Division of Oculofacial Plastic Surgery 2

4/13/2018 The Eye Disease Caleb Hillier Parry Predominance Prevalence (1755-1822)  Peak incidence bimodal: Of patients with TED: 80 cases/100k  90% Autoimmune hyperthyroidism  ♀ : 40-44 years & 60-64 years Male 30 cases/100k 100 cases/100k Female  1% Primary hypothyroidism  ♂ : 45-49 years & 65-69 years  3% Chronic lymphocytic thyroiditis  Median age of diagnosis: 43 years  6% Euthyroid From: Herrick JB. A short History of Cardiology. Springfield, IL: Charles C Thomas, 1942. M. Reza Vagefi, MD Associate Professor of Ophthalmology Division of Oculofacial Plastic Surgery Pathogenesis of TED  Initiation of Thyrotropin Receptor Autoimmunity  Activation of Orbital Fibroblasts Bahn RS. Graves’ Ophthalmopathy. N Engl J Med 2010;362:726-38. M. Reza Vagefi, MD Associate Professor of Ophthalmology Division of Oculofacial Plastic Surgery 3

4/13/2018 Disease Course: Rundle’s Curve  Curve is a descriptor of the natural history of TED  Disease signs and symptoms are thought to worsen rapidly during a dynamic phase  Signs and symptoms then abate to a static plateau Bartley GB. Rundle and his curve. Arch Ophthalmol. 2011;129:356-8. M. Reza Vagefi, MD Associate Professor of Ophthalmology Division of Oculofacial Plastic Surgery Clinical Course of TED Active Inflammatory Phase Chronic Fibrotic Phase Clinical Severity Disease Activity Irreversible soft tissue changes Time M. Reza Vagefi, MD Associate Professor of Ophthalmology Division of Oculofacial Plastic Surgery 4

4/13/2018 The Acute Phase  What is the slope? Disease Activity Time M. Reza Vagefi, MD Associate Professor of Ophthalmology Division of Oculofacial Plastic Surgery The Acute Phase  What is the slope? Disease Activity  Where is the peak? Time M. Reza Vagefi, MD Associate Professor of Ophthalmology Division of Oculofacial Plastic Surgery 5

4/13/2018 The Acute Phase  What is the slope? Disease Activity  Where is the peak?  Is it a linear escalation? Time M. Reza Vagefi, MD Associate Professor of Ophthalmology Division of Oculofacial Plastic Surgery The Acute Phase  What is the slope? Disease Activity  Where is the peak? Clinical Severity  Is it a linear escalation?  Does disease activity predict clinical severity? Time M. Reza Vagefi, MD Associate Professor of Ophthalmology Division of Oculofacial Plastic Surgery 6

4/13/2018 Primary Goal of Treatment of TED Active Inflammatory Phase Chronic Fibrotic Phase Clinical Severity Disease Activity Irreversible soft tissue Intervention changes Time M. Reza Vagefi, MD Associate Professor of Ophthalmology Division of Oculofacial Plastic Surgery Prevalence of TED in setting of Hyperthyroidism Moderate to severe disease 6% Mild 2.4% will develop disease moderate to severe 20% disease at 18 months. No 2.6% will develop disease moderate to severe 74% disease at 18 months. Tanda ML, et al . Prevalence and natural history of Graves’ orbitopathy. J Clin Endocrinol Metab. 2013;98:1443 – 1449. M. Reza Vagefi, MD Associate Professor of Ophthalmology Division of Oculofacial Plastic Surgery 7

4/13/2018 Assessing Activity  Clinical Activity Score  VISA Inflammatory Index  NO SPECS Ophthalmopathy Index M. Reza Vagefi, MD Associate Professor of Ophthalmology Division of Oculofacial Plastic Surgery Traditional Therapeutic Approaches to Active Disease Glucocorticoids Immunosuppression Intravenous Methylprednisolone Pulses: Side Effects The eye disease routinely flares 500 mg Diabetes upon withdrawal of steroids. weekly for Cardiovascular 6 weeks disease Infection susceptibility There is a 20 to 25% non- 250mg responder rate. Hepatotoxicity weekly for 6 weeks Major depression Psychosis * Cumulative doses greater than 8 g should be avoided. M. Reza Vagefi, MD Associate Professor of Ophthalmology Division of Oculofacial Plastic Surgery 8

4/13/2018 Traditional Therapeutic Approaches to Active Disease American Academy of Ophthalmology Immunosuppression Technology Assessment 2008 Evidence based assessment of role of XRT to 1 treat non-sight-threatening TED is limited by the heterogeneity and variable quality of published reports. Orbital Radiotherapy Based on the highest-quality RCT evidence, 2 orbital radiation has a limited role in treating non – sight-threatening TED. Several well-conducted RCTs indicate that the 3 effect of orbital radiation may be limited to improving ocular dysmotility or halting its progression. M. Reza Vagefi, MD Associate Professor of Ophthalmology Division of Oculofacial Plastic Surgery Traditional Therapeutic Approaches to Active Disease Indications for Urgent Decompression: Immunosuppression  Compressive optic neuropathy  Severe corneal exposure from lid Orbital Radiotherapy retraction/lagophthalmos Right Eye Left Eye VA 20/70 20/25  Uncontrolled glaucoma from Pupils APD 3  2 mm orbital congestion Orbital Decompression Color 6/14 14/14 Plates Fundus Disc Swelling Normal M. Reza Vagefi, MD Associate Professor of Ophthalmology Division of Oculofacial Plastic Surgery 9

4/13/2018 An Evolving Treatment Paradigm Moderate to Severe Active TED Glucocorticoids (IV/Oral/Retrobulbar) Partial or No Inactive TED Response Rehabilitative Glucocorticoids Alternative Biologics Surgery +/- XRT Immunomodulator M. Reza Vagefi, MD Associate Professor of Ophthalmology Division of Oculofacial Plastic Surgery Immunologic Soup  Immunologic response is mediated through antigen, humoral and cellular immunity, cytokines, and the effector cell (fibroblast)  There are therefore a number of potential targets to combat the inflammatory response. Khong JJ, McNab AA, Ebeling PR, Craig JE, Selva D. Pathogenesis of thyroid eye disease: review and update on molecular mechanisms. Br J Ophthalmol. 2016 Jan;100(1):142-50. M. Reza Vagefi, MD Associate Professor of Ophthalmology Division of Oculofacial Plastic Surgery 10

4/13/2018 What have we targeted with biologics? IGF- B-Cell 1R IL-6 TNF- α M. Reza Vagefi, MD Associate Professor of Ophthalmology Division of Oculofacial Plastic Surgery Tumor Necrosis Factor- α  Cytokine involved in systemic inflammation and a part of the acute phase reaction.  TNF- α expression has been demonstrated in orbital tissue specimens from patients with TED.  Two classes of drugs have been used:  TNF- α monoclonal antibody  Soluble TNF receptor-Fc protein M. Reza Vagefi, MD Associate Professor of Ophthalmology Division of Oculofacial Plastic Surgery 11

4/13/2018 Etanercept  It is a dimeric fusion protein consisting of the extracellular ligand-binding portion of the human 75 kDa (p75) tumor necrosis factor receptor (TNFR) linked to the Fc portion of human IgG1.  Etanercept binds specifically to TNF and blocks its interaction with cell surface TNF receptors.  It is FDA approved for RA, polyarticular juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, and moderate-to-severe plaque psoriasis. M. Reza Vagefi, MD Associate Professor of Ophthalmology Division of Oculofacial Plastic Surgery Study Design • Non-controlled interventional pilot study • 10 patients (7 females; 3 males) Cohort • Recent-onset, active, mildly to moderately severe TED • Subcutaneous injections of 25 mg of etanercept Intervention twice weekly for 12 weeks • Clinical Activity Score Outcome Measure • Ophthalmopathy Index M. Reza Vagefi, MD Associate Professor of Ophthalmology Division of Oculofacial Plastic Surgery 12