Active Eye Disease Research Articles

Role of Eye Muscle Antibody Measurement in Diagnosis of Thyroid-Associated Ophthalmopathy: A Laboratory Update

To review the current role of measurement of serum eye muscle antibodies in thyroid-associated ophthalmopathy (TAO). We conducted laboratory studies to determine the prevalences of serum autoantibodies reactive with eye muscle antigens in patients with active and inactive TAO, Graves' hyperthyroidism, and Hashimoto's thyroiditis as well as in normal subjects. The two antigens most often recognized in immunoblotting with crude human or porcine eye muscle membranes by serum autoantibodies in patients with TAO are eye muscle membrane proteins of 55 and 64 kd. One 64-kd eye muscle protein has recently been cloned by screening a human eye muscle expression library with two different antibody probes and identified from a computer gene bank search as the calcium-binding protein calsequestrin. A fragment of a 220-kd eye muscle protein, called G2s, has also been cloned by screening the eye muscle library with affinity-purified antibodies reactive with a 55-kd eye muscle membrane protein. The prevalences of autoantibodies reactive with these two antigens in our study groups were as follows. Antibodies against calsequestrin were detected in 38% of patients with TAO for <1 year, in 17% of those with TAO for >3 years, in 17% of patients with Graves' hyperthyroidism without ophthalmopathy, in 12% of patients with Hashimoto's thyroiditis without ophthalmopathy, and in 21% of normal subjects. Antibodies reactive with the 64-kd protein were demonstrated in 62% of patients with recent-onset active TAO, in 33% with eye disease for >3 years, in 39% of patients with Graves' hyperthyroidism without ophthalmopathy, in 25% of patients with Hashimoto's thyroiditis, and in 16% of normal control subjects. Antibodies reactive with G2s fusion protein were detected in 67% of patients with recent-onset active TAO, in 46% of patients with Graves' hyperthyroidism, and in 20% of normal subjects. Antibodies reactive with the parent protein, of which G2s is a fragment, may be markers of early eye muscle swelling and inflammation, whereas those reactive with the 64-kd protein and, less often, calsequestrin are associated with established eye disease. Measurement of serum eye muscle antibodies is recommended as an aid to the early diagnosis of ophthalmopathy in predisposed patients and first-degree relatives of patients with TAO as well as to monitor active or progressive eye disease.

HPLC glycosaminoglycan analysis in patients with Graves' disease.

1. Orbital accumulation of hydrophilic, interstitial glycosaminoglycans (GAGs) and subsequent expansion of retrobulbar tissue lead to the clinical manifestation of exophthalmos in patients with Graves' eye disease. 2. A highly specific method to determine the concentration and biochemical composition of different GAGs was developed in order to obtain a sensitive test system for the activity of the disease. By means of this method, GAG excretion in 24 h urine collections of 56 patients and 21 controls was analysed by precipitation with cetylpyridinium chloride and potassium acetate in ethanol, followed by sequential enzymic hydrolysis with chondroitin AC lyase, chondroitin ABC lyase and hyaluronate lyase, with HPLC analysis of the resulting alpha, beta-unsaturated disaccharides by anion-exchange chromatography. 3. Concentrations of GAG, chondroitin sulphate A (CA), dermatan sulphate (DS) and hyaluronic acid (HA) were determined in patients and controls, with high recovery rates [72.2 +/- 5.3%, mean +/- SEM; detection limit, 4.2 micrograms/l (0.01 mumol/l)], revealing marked differences in urinary concentrations of total GAG and HA, as well as an elevation of CA in patients compared with controls. 4. Method sensitivity was 0.86 for patients with active Graves' eye disease, and 0.87 for patients with untreated ophthalmopathy, whereas specificity was 1.0 for patients with inactive disease. Patients with increased GAG concentration responded well to steroids and/or orbital irradiation (before therapy: GAG, 111.49 +/- 40.32; CA, 59.58 +/- 21.34; DS, 25.05 +/- 8.12; HA, 26.88 +/- 11.63 mg/24 h; during therapy: GAG, 54.22 +/- 10.94; CA, 20.52 +/- 4.58; DS, 17.65 +/- 3.46; HA, 16.05 +/- 3.69 mg/24 h), whereas GAG excretion increased markedly 2-3 months after stopping prednisone therapy in patients with still active eye disease (GAG, 109.9 +/- 10.51; CA, 63.8 +/- 7.34; DS, 24.1 +/- 5.07; HA, 22.0 +/- 6.28 mg/24 h). 5. This sensitive method determines the nature of renally excreted GAGs, reflecting the aberrant synthesis pattern of fibroblasts in patients with Graves' disease.

Advances in medical therapy of thyroid-associated ophthalmopathy

Immunosuppressive treatment of thyroid-associated ophthalmopathy with high doses of oral prednisone has a response rate of 65% at the expense of major side effects. Retrobulbar irradiation is almost devoid of side effects and has an identical response rate of 65%. Newer treatment modalities have a similar response rate, except cyclosporin A which is effective in only 22% of patients. Intravenous pulses of methylprednisolone might be useful in optic neuropathy. Intravenous immunoglobulin and subcutaneous octreotide, although reasonably well tolerated, are laborious and expensive. Consequently, retrobulbar irradiation is still the treatment of choice in moderately severe cases; it is contra-indicated in diabetes mellitus.The efficacy of immunosuppression can be increased by combination therapy (e.g., prednisone + irradiation). Another way of increasing efficacy is restriction of immunosuppression to those patients who are likely to respond, i.e., patients with active eye disease. Disease activity can be ass...

Immunosuppressive treatment of Graves' ophthalmopathy.

Glucocorticoids and retrobulbar irradiation are the most employed immunosuppressive treatment modalities in Graves' ophthalmopathy. The response rate is approximately 60%. Efficacy is good for improvement of appearance and visual acuity, moderate for correction of extraocular muscle dysfunction, and poor for reduction of proptosis. Immunosuppression seldom cures the eye disease. Its main advantage is to stabilize the eye disease by inactivating the inflammation of orbital tissues, thereby permitting corrective eye surgery to be performed at an earlier time. Future developments in immunosuppression aim at reduction of side effects and enhancement of efficacy. Alternative treatment schedules (e.g., methylprednisolone pulses, intravenous immunoglobulin) may have equal efficacy but less side effects than classic high-dose oral steroids. Efficacy can be improved by restriction of immunosuppression to patients with active eye disease who are more likely to respond. Disease activity might well be the main determinant of therapeutic outcome of immunosuppression in Graves' ophthalmopathy.

Practical Treatment Recommendations for Pharmacotherapy of Behcetʼs Syndrome

Behçet's syndrome is a disease of unknown aetiology classified among the vasculitides. It runs a course of exacerbations and remissions which gradually abate with time. Eye disease, the most frequent cause of serious morbidity, may lead to blindness in 20% of those affected. The syndrome may occasionally be fatal due to vasculitis leading to arterial occlusion, ruptured arterial aneurysms or pulmonary vasculitis, or involvement of the central nervous system. Immunosuppressive drugs have been shown to be moderately successful in inducing and maintaining remissions. Azathioprine at a dose of 2.5 mg/kg/day has been shown to control the progression of existing, and the development of new, eye disease. Cyclosporin A is also beneficial in controlling active eye disease and although it has a more rapid action than azathioprine, its toxicity limits its long term use. Colchicine, although widely prescribed, has been shown in a controlled trial to be effective only in reducing the development of erythema nodosum and arthralgia. Systemic corticosteroids, once widely used, are now reserved only for the most severe cases of inflammatory eye disease and vasculitis, where they are frequently used as intravenous pulse therapy. Local mydriatics are used to prevent synechiae. Local treatment with corticosteroids, sometimes in conjunction with antibiotics, control oral and genital ulcers which may also be controlled by immunosuppressives, which are reserved for the most severe cases. Thrombophlebitis usually only requires antiplatelet agents, whereas arteritis is treated conventionally with a combination of corticosteroids and immunosuppressive drugs, usually cyclophosphamide.

Pregnancy in patients with a history of juvenile rheumatoid arthritis

The present investigation was undertaken to study the relationship between pregnancy and juvenile rheumatoid arthritis (JRA), with regard to possible reactivation of the disease, complications at delivery, and postpartum complications. Data on 76 pregnancies in 51 JRA patients were collected retrospectively. Comparison of pre-pregnancy disease activity with the course during gestation showed that pregnancy did not cause reactivation of the symptoms of quiescent JRA. Patients with minor symptoms at conception and the majority of those with active inflammation experienced improvement or total remission in the second half of gestation. Four JRA patients with active anterior uveitis had active eye disease during pregnancy also. Seventy-four of the pregnancies resulted in births of infants that were healthy and of normal birth weight; 1 infant had low birth weight and 1 was stillborn. Twenty children were delivered by cesarean section, and in 15 cases this was related to sequelae of JRA. A flare 3-6 months postpartum was reported after 45 pregnancies. However, in none of the patients whose disease was quiescent before or during pregnancy did this cause permanent reactivation of the JRA. Comparison of these 51 patients with 45 age-matched female patients without children revealed that disease severity and functional impairment were the limiting factors in the decision for or against having children.

Cellular hypersensitivity to toxoplasmal and retinal antigens in patients with toxoplasmal retinochoroiditis.

To investigate the possible role of hypersensitivity to toxoplasmal and retinal antigens in patients with toxoplasmal retinochoroiditis, we examined their in vitro lymphoproliferative responses to antigens prepared from Toxoplasma gondii and human retina. The magnitude of patients' responses, determined by incorporation of [3H]-thymidine, was compared to those of Toxoplasma seropositive and seronegative controls. Patients were indistinguishable from seropositive controls in terms of antitoxoplasmal antibody titer (dye test, indirect hemagglutination and enzyme-linked immunosorbent assay) and in vitro lymphoproliferative responses to toxoplasmal antigens. Furthermore, there was no relationship between antibody titer and the magnitude of proliferative responses in seropositive individuals. Four of four patients with active eye disease and six of 13 with inactive disease, but none of the seropositive or seronegative controls, had significant lymphoproliferative responses to human retinal antigens. These observations raise the possibility of an autoimmune component in the pathogenesis of relapses in toxoplasmal retinochoroiditis.