Inducing Graves’ ophthalmopathy

Abstract

The majority of patients with Graves' disease (GD) have some degree of ocular involvement and this requires surgical or medical intervention in about 5% of cases. There are autoimmune and inflammatory processes operating in Graves' ophthalmopathy (GO), which together induce glycosaminoglycan production, edema and adipogenesis resulting in an increase in the volume of the orbital contents. GO is a heterogeneous disorder, i.e.: 1) whilst usually associated with hyperthyroidism it may occur in euthyroid (and even hypothyroid) patients; 2) expansion of orbital tissues may be due to 'big-fat' or 'big muscles'. The heterogeneity is further exemplified by the spectrum of protocols which have succeeded in inducing aspects of the disease both in animal models and in humans including: 1) Production of severe hypothyroidism in guinea pigs by thyroidectomy and administration of pituitary extract (TSH); 2) Induction of T cells autoreactive to the thyrotropin receptor (TSHR) in mice; 3) Depletion of regulatory T cells in humans susceptible to autoimmunity; 4) Modulation of adipose tissue metabolism in mice and men. In addition, identical induction protocols result in different pathological features depending on the environment, e.g. TSHR primed T cells produce thyroiditis and ocular pathology in BALBc mice in Brussels but thyroid stimulating antibodies accompanied by elevated thyroxine in these animals (from the same supplier) in Cardiff. Thus, experiences in the induction of GO have confirmed the polygenic, multifactorial nature of the disorder and highlight the importance of careful disease classification to promote further progress in understanding.

Current Insights into the Pathogenesis of Graves’ Orbitopathy

“…Myocytes themselves show few microscopically visible changes. Other than edema, two mechanisms increase intraorbital volume: overproduction of extracellular matrix by orbital fi broblasts and increased adipogenesis [18] . The underlying pathomechanisms of tissue remodeling in GO are not yet fully understood.…”

Simultaneous induction of Graves’ hyperthyroidism and Graves’ ophthalmopathy by TSHR genetic immunization in BALB/c mice

“…It has been recognized that an ideal GO mouse model should manifest the following features [23]: 1) Increased serum T4 or decreased serum TSH; 2) The production of TRAb in the serum, preferably TSAb; 3) Alterations of thyroid structure and size; 4) Lymphocytic infiltration in thyroid glands; 5) Clinical manifestations of hyperthyroidism; 6) Gender difference, female animals are more susceptible; 7) Orbital manifestations including extraocular muscles swelling, edema, immune cell infiltration and increased adipose tissue. Here in this study, the TSHR immunized mouse model do exhibit several typical pathological features of GO including extraocular muscle volume expansion based on the MRI scanning result and the mild lymphocytic infiltration in the orbital muscles.…”

PO MATERIALAM KONSENSUSA EVROPEYSKOY GRUPPY PO IZUChENIYu OFTAL'MOPATII GREYVSA

“…Этот цикл был повторен дважды с последующим назначением 10 мг в течение 4 нед с последующим снижением и отменой препарата через 2 нед. 7 60 мг ежедневно в течение 2 нед, затем -40 мг в течение 2 недель, 30 мг -4 нед и 20 мг -4 нед с постепенным сниже нием дозы и отменой препарата через 8 нед. 8 500 мг однократно в неделю в течение 6 нед, 250 мг однократно в неделю в течение 6 нед.…”