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At least 19 recordsLinked to original sources
PubMed1991

Genetic differences shown by HLA typing among Japanese patients with euthyroid Graves' ophthalmopathy, Graves' disease and Hashimoto's thyroiditis: genetic characteristics of euthyroid Graves' ophthalmopathy.

Euthyroid Graves' ophthalmopathy (EO) is an ophthalmic disorder without persistent hyperthyroidism. To elucidate genetic differences among EO, Graves' disease (Gr) and Hashimoto's thyroiditis (H), we analysed HLA-A, B, C, DR, DQ, D and DP types in 23 Japanese EO patients, 88 Gr patients, 46 H patients and 186 control subjects utilizing assays of lymphocyte cytotoxicity and restriction fragment length polymorphism (RFLP). When compared with the control subjects, EO patients showed significant associations with HLA B40 (w61), DR9, DQw3, and Dw15 (P less than 0.01) and with HLA B12 and Cw1 (P less than 0.05). When allowance was made for the number of antigens tested, only DQw3 was significant. Significant differences were found between EO and Gr (DPw2), and between EO and H (Cw1) even after correction of P values. Comparisons between EO and related subgroups of Gr confirmed the heterogeneity of EO again. It is concluded from these results that EO is associated with different HLA types from Gr and H.

Adult↗
PubMed2006

[Current understanding of pathogenesis of Graves ophthalmopathy].

Graves ophthalmopathy most frequently develops in a patient suffering from Graves disease in which autoantibodies to a target antigen, thyrotropin receptor, activate the autoantigen leading to hyperthyroidism. It is well known that in Graves ophthalmopathy inflammatory cells infiltrate and hydrophobic glycosaminoglycan accumulates in the retro -occular tissues. However, in contrast to Graves disease, little has been known as to how this eye disease develops. Here we review recent advance in understanding of pathogenesis of Graves ophthalmopathy.

Autoantibodies↗
PubMed1996

Detectable serum IgE levels in Graves' ophthalmopathy.

Graves' ophthalmopathy is an organ-specific autoimmune disorder in which the target organs are infiltrated by T lymphocytes and polymorphonuclear neutrophils that release immunoregulatory cytokines in the thyroid and retrobulbar tissues. Th2-type cytokines (IL-4, IL-5, IL-6) support the inflammatory symptoms and immunoglobulin production, e.g. IgE isotype. IgE is thought to play a part not only in allergy but also in the normal immune responses, antigen processing and presentation. Since studies report IgE accumulation around the extraocular muscles in ophthalmopathy and a correlation between the total IgE levels and the severity of ophthalmopathy in Graves' disease, we measured the total IgE levels in 56 patients with Graves' disease (associated with ophthalmopathy in 47 patients) and in 42 healthy subjects as controls to determine if IgE plays a part in the autoimmune or the local inflammatory processes. For detection we used the Enzymun-Test IgE, which was a two-step ELISA sandwich assay. Elevated circulating IgE levels could be demonstrated in non-treated hyperthyroid Graves' patients in comparison with the controls (51.02 +/- 113.16 IU/ml vs 34.95 +/- 54.91 IU/ml, P < 0.01). The IgE levels were higher in patients with active inflammatory eye signs (63.65 +/- 130.41 IU/ml) than in controls (P < 0.007). The anti-thyroid drug and glucocorticoid management decreased the total IgE levels, and the difference was significant after the treatment compared with the values at the beginning of the therapy in the Graves' patients without ophthalmopathy (17.34 +/- 6.34 IU/ml vs 13.01 +/- 9.86 IU/ml, P < 0.03). In conclusion, since the results suggested that IgE plays a role in the inflammatory eye signs in Graves' ophthalmopathy, we propose administering antihistamines for medical management.

Adult↗
PubMed1981

Graves' ophthalmopathy.

Graves' ophthalmopathy usually occurs in association with hyperthyroidism. Its occasional occurrence in the absence of thyroid disease suggests, however, that it may be a separate autoimmune disorder. While the evidence supporting an autoimmune pathogenesis is considerable for the ophthalmopathy, it is not so impressive as that for Graves' hyperthyroidism: orbital antibodies have not been convincingly demonstrated and autoantigens have not been identified. On the other hand, in patients with Graves' ophthalmopathy the orbital tissues and eye muscle membranes are infiltrated with lymphoid cells and show evidence of cell-mediated immune reactions. Although there is some evidence that binding of thyroid stimulating hormone fragments and thyroglobulin-antithyroglobulin immune complexes to eye muscle membranes may be important in the pathogenesis of the ophthalmopathy, this needs to be confirmed. The mechanism for the association of hyperthyroidism and ophthalmopathy is unknown, but the association likely reflects an influence of thyroid hormones on the immune system. In view of the autoimmune pathogenesis the logical treatment of Graves' ophthalmopathy appears to be immunosuppression.

Autoantibodies↗
PubMed2002

Epidemiology and prevention of Graves' ophthalmopathy.

Graves' ophthalmopathy is clinically relevant in approximately 50% of patients with Graves' disease, severe forms affecting 3%-5% of patients. Two age peaks of incidence are observed in the fifth and seventh decades of life, with slight differences between women and men. The disease is more frequent in women than in men, although the female-to-male ratio is only 1:4 in severe forms of eye disease. The natural history of Graves' ophthalmopathy is incompletely defined, but in many instances, especially in mild forms, the disease may remit or improve spontaneously. The onset of the ophthalmopathy is in most cases concomitant with the onset of hyperthyroidism, but eye disease may precede or follow hyperthyroidism. Cigarette smoking plays an important role in the occurrence of the ophthalmopathy, and is also associated with a higher degree of disease severity and a lower effectiveness of its medical treatment. Primary prevention (i.e., avoidance of the occurrence of the ophthalmopathy) is presently not feasible, but smoking withdrawal in relatives of patients with Graves' disease might be important. In terms of secondary prevention (i.e., avoidance of progression of subclinical eye disease into overt and severe ophthalmopathy) in addition to refraining from smoking, early and accurate control of thyroid dysfunction (both hyperthyroidism and hypothyroidism), as well as early diagnosis and treatment of mild eye disease are important. As to the role that management of hyperthyroidism may play in the course of Graves' ophthalmopathy, while antithyroid drugs and thyroidectomy are not disease-modifying treatments, radioiodine therapy causes a progression of the ophthalmopathy in approximately 15% of patients, especially high-risk patients, who smoke, have severe hyperthyroidism or uncontrolled hypothyroidism, high levels of thyrotropin (TSH)-receptor antibody, or preexisting eye disease. However, the risk of radioiodine-associated progression of the opthalmopathy can be eliminated by concomitant treatment with middle-dose glucocorticoids. In terms of tertiary prevention (i.e., avoidance of deterioration and complications of overt disease) early immunosuppressive treatment or orbital decompression, as appropriate, are essential tools. Smoking withdrawal may increase the effectiveness of immunosuppressive treatment.

Graves Disease↗
PubMed2001

[Intravenous immunoglobulins treatment of patients with Graves' ophthalmopathy].

Graves' ophthalmopathy is an autoimmune disease manifested as exophthalmus, lid lag and diplopia. As in the accompanying autoimmune thyroid disease, there is an autoimmune homonal and cellular attack on the orbita, mainly the retro-orbital tissues. Steroids are the cornerstone of therapy. We reviewed the evidence for a similar therapeutic effect of i.v., immunoglobulins (IVIGs) and their better side affect profile as compared to steroids. We also described an impressive therapeutic success with IVIG given to a patient with resistant ophthalmopathy. The clinical picture of Graves' ophthalmopathy is attributed to a pathologic hyper--activation of orbital fibroblasts, deposition of collagen and glycosaminoglycans in the extra-cellular matrix and eventually fibrosis. These are mediated by leucoregulin, IL-1, IFN-gamma, and TGF-beta--all secreted by lymphocytes and mast cells in the retorbital space. Another mode of cell activation is by binding of autoantibodies (presumably thyroid stimulating Ab's) to an antigenic determinant on the surface of fibroblasts. I.v. immunoglobulins, known today to be active in a variety of autoimmune processes, exert their effect on autoantibodies, complement, phagocytic cells etc. IVIGs also inhibit orbital lymphocytes and fibroblasts through inhibition of IL-1 or/and TGF-beta.

Aged↗
PubMed2006

Intravenous cyclophosphamide pulse therapy is effective for refractory Graves' ophthalmopathy.

Graves' ophthalmopathy is the most frequent extrathyroidal manifestation of Graves' disease. Although glucocorticoids and orbital radiotherapy have been used and are effective for the disease, we often experience cases refractory to either therapy. We report here a case that did not respond satisfactorily to either therapy and was later successfully treated by intravenous cyclophosphamide (IV-CY) pulse therapy. A 31 year old woman presented with typical Graves' disease and ophthalmopathy. After establishing a euthyroid state, she received intravenous glucocorticoid pulse therapy and orbital radiotherapy. Although this induced the resolution of the ophthalmopathy, it was temporary and thyroid-stimulating antibody (TSAb) increased to high titers, associated with relapse of ophthalmopathy 2 months after the treatment. Four courses of IV-CY pulse therapy were administered, which resulted in complete improvement of the symptoms and normalization of the TSAb titers. We suggest that IV-CY pulse therapy might be useful for Graves' ophthalmopathy, especially for patients refractory to glucocorticoid pulse therapy.

Adult↗
PubMed1997

The full length and splice variant thyrotropin receptor is expressed exclusively in skeletal muscle of extraocular origin: a link to the pathogenesis of Graves' ophthalmopathy.

Graves' ophthalmopathy occurs in up to 90% of patients with Graves' disease, supporting the notion of a common denominator in the development of these two disorders. The thyrotropin receptor has been proposed as the link for this clinical association. In the present study we have investigated whether thyrotropin receptor mRNA species exist in extraocular muscle and non-ocular skeletal muscle by reverse transcription-polymerase chain reaction (RT-PCR). We have, with high stringency RT-PCR, Southern analysis, and direct sequencing of PCR products, identified for the first time the presence of both full length and splice variant thyrotropin receptor mRNA in extraocular but not non-ocular skeletal muscle. This extraocular muscle thyrotropin receptor expression was shared, as expected, with normal thyroid but not other control tissues including brain and kidney. These data demonstrate that the thyrotropin receptor, the autoimmune target of Graves' disease, is exclusively expressed in extraocular muscle as well as the thyroid and lend support to the notion that it is a likely candidate autoantigen in Graves' ophthalmopathy.

Brain↗
PubMed1995

Graves' ophthalmopathy.

Graves' ophthalmopathy is an organ-specific autoimmune process strongly linked to Graves' hyperthyroidism. Although the hyperthyroidism can be successfully treated, it is often the ophthalmopathy that produces the greatest long-term disability for patients suffering from this disease. Eyelid retraction, proptosis, periorbital edema, chemosis, and disturbances of ocular motility have both cosmetic and functional consequences. In some cases, the disease may progress to visual loss by exposure keratopathy or compressive optic neuropathy. This article discusses the manifestations of Graves' ophthalmopathy that require urgent attention and the relationship of the activity of Graves' ophthalmopathy to thyroid function status.

Emergencies↗
PubMed2004

[Radiotherapy for Graves' ophthalmopathy].

Graves' ophthalmopathy (GO) is the most frequent extrathyroidal manifestation of Graves' disease, an autoimmune disorder of the thyroid, whereas the precise pathogenesis still remains unclear. In Hashimoto's thyroiditis the occurrence of proptosis is an extremely rare event. The therapy for middle and severe courses of GO shows in partly disappointing results, although several therapy modalities are possible (glucocorticoid therapy, radiotherapy, antithyroid drug treatment, surgery). All these therapies lead in only 40 - 70 % to an improvement of the pathogenic symptoms. An intensive interdisciplinary cooperation is necessary to satisfy the requirements for the treatment of Graves' ophthalmopathy. As a consequence of the very different results of the few of clinical studies that were accomplished with reference to this topic, treatment by radiotherapy in the management of the disease is presently controversially discussed. In the German-speaking countries the radiotherapy is, however, firmly established as a therapy option in the treatment of the moderate disease classes (class 2-5 according to NO SPECS), especially if diplopia is present. This article describes the sequences, dosages and fractionation schemes as well as the risks and side effects of the radiotherapy. Altogether, radiotherapy is assessed as an effective and sure method. The administration of glucocorticoids can take place before the beginning of or during the radiotherapy. For the success of treatment the correct selection of patients who may possibly profit from a radiotherapy is absolutely essential. By realising that GO proceeds normally over a period of 2-5 years, which is followed by a period of fibrotic alteration, the application of the radiotherapy in the early, active phase is indispensable. A precise explanation for the effects of radiotherapy in treatment of the GO does not exist at present. The determination of the most effective irradiation doses was made from retrospectively evaluated collectives. Recently the results of a national survey of all German RT departments were published, initiated by the working group of the DEGRO (German Society of Radiooncology). In the most of the German radiooncology departments irradiation with 8 to 10 x 1.8-2.0 Gy 5 x weekly to 16 or 20 Gy is standard. Two recently published prospective German studies pointed out the equivalence of the effectiveness of a short therapy in low dose ranges up to 2.4 Gy as well as of a low proportioned irradiation during a longer period in relation to a standard therapy with 20 Gy. That is why at the moment it is not possible to give a definite recommendation with reference to dosages or the fractionation schemes. In 2003 the first European group (European Group on Graves ' Orbitopathy Experience -- EUGOGO) was founded for pursuing investigations of GO in multi-centric studies, mainly to improve therapy results.

Diplopia↗
PubMed2005

[Orbital decompression for Graves' ophthalmopathy].

Graves' ophthalmopathy is a complex orbital condition with a controversial pathogenesis. It is the clinical expression of a discordance between the inextensible orbit and hypertrophic muscular and fatty elements within the orbit responding to immunological stimulation. The relationship between the orbital and its content can be improved by surgical expansion which increases the useful volume of the orbit. This procedure can be combined with lipectomy to decrease the volume of the orbital contents. We briefly recall the history of surgical decompression techniques and present our experience with Graves' ophthalmopathy patients.

Decompression, Surgical↗
PubMed2006

CD4+ T cells and the Th1/Th2 imbalance are implicated in the pathogenesis of Graves' ophthalmopathy.

Graves' ophthalmopathy (GO) is considered to be an organ-specific autoimmune disease. However, the pathogenesis of GO is incompletely understood at the present time. To clarify the immunological differences between newly diagnosed GO and Graves' disease (GD) without ophthalmopathy or healthy controls (HC), we examined T-cell profile and the Th1/Th2 profile cell balance in GO (n=20), GD (n=20) and HC (n=20) using flow cytometry. We also assessed the influence of methimazole on the immunocyte profiles in patients with GO and GD and analyzed the relationship of the immunologic changes with CAS, FT3, FT4, TRAb, TMA and TGA among the three investigated groups. We report in this study that: 1) The percentage of CD4+ T cells and the ratio of CD4+/CD8+ cells were higher, but the population of CD8+ T cells was lower in both GO and GD than those of HC (P<0.05); 2) The percentage of CD8-/IFNgamma+ T cells (Th1) and the ratio of CD8-/IFNgamma+ to CD8-/IL-4+ T cells (Th1/Th2) in GO were considerably higher as compared to those in GD and HC (P<0.05). On the contrary, the population of Th1 cells, as well as the ratio of Th1/Th2 cells, was lower in GD than that of GO and HC (P<0.05); 3) There were no significant differences in T-cell profile and the Th1/Th2 cell balance in either GO or GD patients before and after methimazole treatment; 4) There was a positive correlation of Th1 cell percentage and the Th1/Th2 cell ratio with the clinical activity score (CAS) in GO (P<0.05), whereas CAS in GO had no correlation with the T-cell profile, the percentage of Th2 cells, and TRAb (P>0.05); 5) T-cell subset and the ratio of Th1/Th2 cells did not correlate significantly with FT3, FT4, TRAb, TMA, or TGA in GO and GD (P>0.05). Finally, 6) there were no statistical differences in TRAb, TMA, and TGA between early GO and GD without ophthalmopathy (P>0.05). Collectively, these results indicate that the balance of Th1/Th2 in GO shifts to Th1 dominance and that the cellular immune responses mediated by the Th1-type CD4+ cells might play a dominant role in the pathogenesis of GO, and thus suggest that the Th1 cell percentage and the ratio of Th1/Th2 cell subsets may be potentially utilized as clinical parameters for disease activity, for monitoring the effectiveness of immunosuppressive treatment, or for developing immunospecific forms of therapy for Graves' ophthalmopathy.

Adolescent↗
PubMed1996

The role of radiation therapy in Graves' ophthalmopathy.

Graves' ophthalmopathy can occur in 25-30% of patients with hyperthyroidism. This condition can result in serious visual disturbance and disfigurement. The treatment options for symptomatic disease are oral corticosteroids or orbital irradiation. Ten patients with Graves' ophthalmopathy were treated with external beam radiotherapy at Saint Lukes Hospital from March 1991 to February 1994. Eight of these patients had excellent response with minimal morbidity. We believe that orbital radiotherapy is effective and well tolerated, and should replace corticosteroid therapy as the initial treatment modality in these patients.

Aged↗
PubMed1993

Orbital decompression for preservation of vision in Graves' ophthalmopathy.

Graves' ophthalmopathy (thyroid eye disease) can result in progressive visual loss. The University of Washington (Seattle) experience in orbital decompression was reviewed for the years 1983 through 1990 to determine overall safety and outcome. Twenty patients underwent transantral decompression of 36 orbits for either steroid therapy failure, steroid therapy intolerance, or recurrence of optic neuropathy with tapering of the steroid therapy. Decompression successfully improved visual function in 33 of the orbits (92%) and a second decompression procedure was successful in another two (5%) of the orbits (6%). There were no major complications or cases of decreased visual function. Diplopia, present preoperatively in 17 patients (85%), was improved in eight patients (47%) and unchanged in nine patients (53%). However, of the three patients without preoperative diplopia (15%), one had development of new-onset diplopia postoperatively. Transantral decompression of the orbit offers a safe and effective therapeutic modality for vision-threatening Graves' ophthalmopathy.

Adrenal Cortex Hormones↗
PubMed1994

Molecular cloning and characterization of genes for antibodies generated by orbital tissue-infiltrating B-cells in Graves' ophthalmopathy.

Graves' ophthalmopathy is a distressing autoimmune disease of unknown etiology. Analysis of the genes for antibodies secreted by orbital tissue-infiltrating plasma cells might provide insight into the pathogenesis of this disease. We, therefore, constructed an immunoglobulin heavy (H) chain and an immunoglobulin kappa light (L) chain cDNA library from the orbital tissue of a patient with active Graves' ophthalmopathy. Analysis of 15 H (IgG1) and 15 L (kappa) chains revealed a restricted spectrum of variable region genes. Fourteen of 15 variable kappa genes were about 94% homologous to the closest known germline gene, KL012. Thirteen of 15 H chain genes were 91% and 90% homologous to the closest germline genes, DP10 and hv1263, respectively. Remarkably, these germline genes also code for other autoantibodies to striated muscle (KL012) and thyroid peroxidase (KL012 and hv1263). These studies raise the possibility that particular germline genes may be associated with autoimmunity in humans. Further, the present study opens the way to identifying ocular autoantigens that may be the target of an humoral immune response.

Amino Acid Sequence↗
PubMed2001

Rationale of treatment in Graves ophthalmopathy.

Graves ophthalmopathy is a chronic and multisystem disorder caused by an autoimmune process, characterized by the presence of antibodies that stimulate a general fibroblastic reaction (thyroid gland and lower extremities), and involves orbital fat tissue and muscles. The clinical findings and therapy for the treatment of the exophthalmos, such as changes in extrinsic eye motility, diplopia, optic nerve involvement, and lid retraction, were analyzed, and the various types of surgical treatment currently available for Graves ophthalmopathy were evaluated. The aim was to choose the best option to treat each case. The surgical techniques were transpalpebral decompression by removal of intraorbital fat, three-wall osseous expansion, and zygomatic osteotomy. Adjunctive procedures were lengthening of the levator muscle of the upper eyelid, lengthening of the retractor of the lower eyelid (if necessary), and surgery of the extrinsic muscles to correct diplopia. All these techniques were useful in treating the disease, which is characterized by chronic evolution and, at times, a "malignant" outcome. A total of 39 orbits were treated using different techniques of decompression and secondary adjunctive procedures. Results were analyzed after a minimum 6-month follow-up. It was evident that surgery greatly reduced the degree of exophthalmos and improved eye motility, diplopia, and visual acuity. Close cooperation among a team of specialists, including an endocrinologist, ophthalmologist, neuroradiologist, surgeon, anesthesiologist, and radiotherapist, is essential to manage and to quantify the postoperative results of this complex disorder. The authors' experience and application of different surgical strategies, as based on clinical data and histopathological classification, are presented.

Adult↗
PubMed1997

The "triple technique" for treating stable Graves' ophthalmopathy.

Graves' ophthalmopathy may range from mild eyelid retraction to a devastating process that involves the entire orbit and culminates in gross ocular congestion, massive proptosis, and even blindness. Whether the ophthalmopathy is mild or severe, patients are managed on an individual basis according to the predominant clinical findings, which may include congestion, myopathy, lid retraction, proptosis, and optic neuropathy. The process usually becomes quiescent after 6 months to 3 years; however, the changes caused by fibrosis (lid retraction and ocular muscle enlargement) are permanent. The cornerstone of surgical treatment for severe cases is bony orbital decompression; however, in our experience, mild to moderate Graves' ophthalmopathy is better treated by combining eyelid surgery and orbital lipectomy. Our approach consists of a conservative orbital lipectomy, the lengthening of the levator-Müller complex by means of marginal myotomies, and a limited lateral tarsal apposition. These three different surgical steps, which have been described previously as isolated procedures, are undertaken on both eyes at the same time and modulated according to the deformity of the patient. The operation can be performed under local anesthesia with sedation, thus allowing intraoperative monitoring of the correction; the patient can be discharged after a few hours. The results in 32 operated eyes of 16 patients have been a marked aesthetic and functional improvement, with no complications after 6 to 18 months of follow-up. The relative simplicity and very low morbidity of this procedure, as well as its reliability, make it ideal in patients with mild to moderate aesthetic and functional impairment who are looking for a substantial improvement but are unwilling to undergo a relatively major procedure such as a transosseous decompression, which, in our opinion, is the operation of choice only when the patient presents with optic neuropathy or major proptosis.

Adult↗
PubMed1981

The clinical immunology of Graves' ophthalmopathy.

Graves' ophthalmopathy is frequently a diagnostic and therapeutic dilemma for practicing ophthalmologists. We have reviewed the clinical immunology of this disorder with regard to clinical manifestations, humoral immunity, and cellular immunity. Special emphasis with applicable clinical and laboratory data is given to the hypothesis that Graves' thyrotoxicosis and ophthalmopathy may be frequently associated diseases rather than disorders caused by a common pathogenetic mechanism. Dysthyroidism may be the substrate for the development of the ophthalmopathy, but the two disorders probably are caused by different immunopathogenetic mechanisms.

Autoimmune Diseases↗