Not All Orbitopathy Is Graves': Discussion of Cases and Review of Literature.
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ABSTRACT:
SUBMITTER: Boddu N
PROVIDER: S-EPMC5534452 | biostudies-other | 2017
REPOSITORIES: biostudies-other
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Project description:IntroductionGraves' disease (GD) and Graves' orbitopathy (GO) development were suspected to be HLA-related in both Asian and Caucasian populations. However, most studies were performed with application of serological methods or low resolution genetic typing, which led to inconsistent results even among the same population. The present review is intended to summarize the state-of-art knowledge on the HLA significance in GD and GO in Asians and Caucasians, as well as to find the most significant alleles for each of the populations.MethodsPubMed was searched for relevant articles using the following search terms: HLA plus thyroid-associated ophthalmopathy or Graves' disease or Graves' orbitopathy or thyroid eye disease or thyroid-associated orbitopathy.ResultsIn Asian population GD was found to be associated mostly with B*46:01, DPB1*05:01, DRB1*08:02/03, DRB1*16:02, DRB1*14:03, DRB1*04:05, DQB1*05:02 and DQB1*03:03, while DRB1*07:01, DRB1*01:01, DRB1*13:02, DRB1*12:02 are potentially protective. HLA-B*38:02, DRB1*16:02, DQA1*01:02, DQB1*05:02 can be considered associated with increased risk of GO in Asians, while HLA-B*54:01 may play protective role. In Caucasians, C*07:01, DQA1*05:01, DRB1*03, DQB1*02:01 are associated with GD risk while DRB1*07:01, DQA1*02:01 may be protective. Significance of HLA in the course of GD and novel aspects of HLA amino acid variants and potential HLA-based treatment modalities were also discussed.
| S-EPMC10568027 | biostudies-literature
Project description:The most important of the extra-thyroidal manifestations of Graves' disease, Graves' orbitopathy (GO), remains a vexing clinical problem. Treatment of severe active disease has been limited to steroids or radiotherapy. In the relatively rare case where vision is threatened, emergent decompression surgery can be performed. The proptosis, motility, or cosmetic concerns associated with stable GO are commonly remedied with surgical intervention. Substantial obstacles have prevented the development of specific medical therapies for GO, in large part resulting from poor understanding of disease pathogenesis and the absence of preclinical animal models. Fundamental aspects of GO's etiology have been uncovered from studies based in cell culture, extensive analysis of blood constituents, and detailed examination of orbital contents collected at the time of surgical intervention. Many of the published reports resulting from these studies are descriptive and all have failed to yield unifying concepts that integrate the anatomically divergent manifestations of Graves' disease. This brief review covers recent findings of several research groups. While major breakthroughs continue to occur in closely related autoimmune diseases, progress in identifying the pathogenic mechanisms relevant to GO has been limited. As emerging insights into human autoimmunity becomes applied to the study of Graves' disease, we anticipate that improved therapeutic strategies will find their way to our patients with GO.
| S-EPMC6779038 | biostudies-literature
Project description:Background:On 21st January 2020, the FDA approved Tepezza (teprotumumab-trbw) for the treatment of active Graves' orbitopathy (GO) in adults. This approval was based on positive results from two multinational randomised double-blind placebo-controlled clinical trials. Discussion:This article discusses the outcomes of those trials and the potential role of teprotumumab in altering current treatment paradigms in Graves' orbitopathy. Future challenges are explored, including the need to confirm its disease-modifying effect, to establish its optimal position in the treatment pathway, and to define the appropriate subset of patients who would benefit from its use. Conclusions:The results from these two large clinical trials have shown teprotumumab to have remarkable effects on multiple clinical outcomes in GO, particularly in its ability to reverse proptosis. It may herald a new era in the treatment of thyroid eye disease and could offer an alternative to surgery and its associated complications. Additional studies will continue to shape the treatment of GO and define the role of teprotumumab within the treatment paradigm.
| S-EPMC7334856 | biostudies-literature
Project description:Graves' orbitopathy (GO), also known as thyroid-associated ophthalmopathy, is the most common ocular abnormality of Graves' disease. It is a disfiguring, invalidating, and potentially blinding orbital disease mediated by an interlocking and complicated immune network. Self-reactive T cells directly against thyroid-stimulating hormone receptor-bearing orbital fibroblasts contribute to autoimmune inflammation and tissue remodeling in GO orbital connective tissues. To date, T helper (Th) 1 (cytotoxic leaning) and Th2 (antibody leaning) cell subsets and an emerging role of Th17 (fibrotic leaning) cells have been implicated in GO pathogenesis. The potential feedback loops between orbital native residential CD34- fibroblasts, CD34+ infiltrating fibrocytes, and effector T cells may affect the T cell subset bias and the skewed pattern of cytokine production in the orbit, thereby determining the outcomes of GO autoimmune reactions. Characterization of the T cell subsets that drive GO and the cytokines they express may significantly advance our understanding of orbital autoimmunity and the development of promising therapeutic strategies against pathological T cells.
| S-EPMC8049604 | biostudies-literature
Project description:ObjectivesA beneficial effect of sirolimus in Graves' orbitopathy (GO) was reported, suggesting a possible use in clinical practice. We conducted an observational, single-centre, no-profit, clinical study to investigate the efficacy of sirolimus as a second-line treatment for moderate-to-severe, active GO compared with methylprednisolone.MethodsData from consecutive patients given sirolimus (2 mg orally on first day, followed by 0.5 mg/day for 12 weeks) or methylprednisolone [500 mg iv/weekly (6 weeks), 250 mg/weekly (6 weeks)] as a second-line treatment were collected and compared.Primary objectiveoverall GO outcome at 24 weeks, based on a composite evaluation. Secondary objectives at 24 weeks: (1) improvement in quality of life, evaluated using a specific uestionnaire (GO-QoL); (2) reduction in proptosis; (3) reduction in the clinical activity score (CAS); (4) improvement of eye ductions; and (5) reduction in eyelid aperture.ResultsData from 30 patients (15 per group) treated between January 15, 2020, and June 15, 2021, were analysed. Proportion of GO responders (primary outcome) at 24 weeks was significantly greater in sirolimus group compared with methylprednisolone group (86.6% vs 26.6%; OR: 17.8; 95% CI from 2.7 to 116.8; P = 0.0026). GO-quality of life (GO-QoL) score was greater in sirolimus group. Proportion of proptosis responders was greater in sirolimus group, as well as proportion of clinical activity score (CAS) responders. No serious adverse events were observed, with no differences between groups.ConclusionsSirolimus seems to be an effective second-line treatment for GO. Further randomized clinical trials are needed to confirm our observations.
| S-EPMC9525329 | biostudies-literature
Project description:Graves' disease (GD), similarly to most autoimmune disease, is triggered by environmental factors in genetically predisposed individuals. Particular HLA alleles increase or decrease GD risk. No such correlation was demonstrated for Graves' orbitopathy (GO) in Caucasian population. HLA-A, -B, -C, -DQB1 and -DRB1 genotyping was performed using a high-resolution method in a total number of 2378 persons including 70 patients with GO, 91 patients with non-GO GD and 2217 healthy controls to compare allele frequencies between GO, non-GO and controls. Significant associations between GO and HLA profile were demonstrated, with HLA-A*01:01, -A*32:01, -B*37:01, -B*39:01, -B*42:01, -C*08:02, C*03:02, DRB1*03:01, DRB1*14:01 and DQB1*02:01 being genetic markers of increased risk of GO, and HLA-C*04:01, -C*03:04, -C*07:02 and -DRB1*15:02 being protective alleles. Moreover, correlations between HLA alleles and increased or decreased risk of non-GO GD, but with no impact on risk of GO development, were revealed. Identification of these groups of GO-related and GO-protective alleles, as well as the alleles strongly related to non-GO GD, constitutes an important step in a development of personalized medicine, with individual risk assessment and patient-tailored treatment.
| S-EPMC9935388 | biostudies-literature
Project description:CONTEXT:Graves' orbitopathy (GO) is a potentially sight-threatening disease for which available medical therapy is not uniformly successful. Multiple case series suggest that rituximab (RTX) may be effective therapy for GO patients. OBJECTIVE:To determine the efficacy of RTX in GO. DESIGN:It is a prospective, randomized, double-masked, placebo-controlled trial. SETTING:The study was conducted at a large academic private practice. PATIENTS:Twenty five patients with active moderate to severe GO were enrolled, and 21 completed the study to the primary endpoint. INTERVENTIONS:Two RTX infusions (1000 mg each) or two saline infusions were given 2 weeks apart. MAIN OUTCOME MEASURES:The primary endpoint was a reduction in clinical activity score (CAS) assessed as a continuum and separately as improvement by ? 2 points at 24 weeks. Secondary endpoints included success and failure rates, proportions showing clinically significant improvement in proptosis, lid fissure width, diplopia score, lagophthalmos and disease severity, and changes in those parameters, orbital fat/ muscle volume and quality-of-life. RESULTS:The treatment groups were similar in all parameters at baseline. The last observation was carried forward if the patient discontinued prematurely. No differences were found in the proportions of patients showing CAS improvement at 24 weeks (25% placebo; 31% RTX, P = .75) or in CAS decrease from baseline to 24 or 52 weeks [mean 1.5 points (1.8 SD) placebo; 1.2 (2 SD) RTX at 24 weeks, P = .73]. Similarly, there were no differences between groups in any of the secondary endpoints at either 24 or 52 weeks. There were four adverse events (AE) in 3/12 placebo patients and 11 AE in 8/13 RTX-treated patients; 5/6 moderate or severe AE occurred in the RTX group. CONCLUSION:RTX offered no additional benefit over placebo to our patients with active and moderate to severe GO and carried with it non-negligible adverse effects.
| S-EPMC4318907 | biostudies-literature
Project description:BackgroundGraves' orbitopathy (GO) as well as Graves' disease (GD) hyperthyroidism originate from an autoimmune reaction against the common auto-antigen, thyroid-stimulating hormone receptor (TSHR). GO phenotype is associated with environmental risk factors, mainly nicotinism, as well as genetic risk factors which initiate an immunologic reaction. In some patients GO is observed before diagnosis of GD hyperthyroidism, while it can also be observed far after diagnosis. The intensity of GO symptoms varies greatly in these patients. Thus, the pathogenesis of GD and GO may correlate with different genetic backgrounds, which has been confirmed by studies of correlations between GO and polymorphisms in cytokines involved in orbit inflammation. The aim of our analysis was to assess genetic predisposition to GO in young patients (age of diagnosis ?30 years of age), for whom environmental effects had less time to influence outcomes than in adults.Methods768 GD patients were included in the study. 359 of them had clinically evident orbitopathy (NOSPECS ?2). Patients were stratified by age at diagnosis. Association analyses were performed for genes with a known influence on development of GD - TSHR, HLA-DRB1, cytotoxic T-lymphocyte antigen 4 (CTLA4) and lymphoid protein tyrosine phosphatase (PTPN22).ResultsThe rs179247 TSHR polymorphism was associated with GO in young patients only. In young GO-free patients, allele A was statistically more frequent and homozygous carriers had a considerable lower risk of disease incidence than patients with AG or GG genotypes. Those differences were not found in either elderly patients or the group analyzed as a whole.ConclusionsAllele A of the rs179247 polymorphism in the TSHR gene is associated with lower risk of GO in young GD patients.
| S-EPMC4111286 | biostudies-literature
Project description:PurposeCurrently, therapeutic management of patients with Graves' orbitopathy (GO) relies on clinical assessments and MRI. However, monitoring of inflammation remains difficult since external inflammatory signs do not necessarily represent the orbital disease activity. Therefore, we aimed to evaluate the diagnostic value of 18F-FDG-PET/MRI to assess the inflammation of GO patients.MethodsEnrolled patients with new onset of GO underwent ophthalmological examinations to evaluate the activity (CAS) and severity of GO (NOSPECS), as well as an 18F-FDG-PET/MRI (Siemens Biograph mMR) with dual time point imaging (immediately post-injection and 60 min p.i.). A subset of PET parameters including maximum standardized uptake value (SUVmax), metabolic target volume (MTV), and total lesion glycolysis (TLG) were obtained separately per eye and per extraocular eye muscle (EOM). EOM thickness was measured on the co-registered MRI.ResultsOf 14 enrolled patients, three showed mild, seven moderate-to-severe, and four sight-threatening GO. Patients with severe GO showed statistically significant higher TLG than patients with mild GO (p = 0.02) and higher MTV than patients with mild (p = 0.03) and moderate (p = 0.04) GO. Correlation between NOSPECS on one hand and MTV and TLG on the other was significant (R2 = 0.49-0.61).ConclusionTLG and MTV derived from FDG-PET appear to be good discriminators for severe vs. mild-to-moderate GO and show a significant correlation with NOSPECS. As expected, PET parameters of individual eye muscles were not correlated with associated eye motility, since fibrosis, and not inflammation, is mainly responsible for restricted motility. In conclusion, 18F-FDG-PET/MRI can be used for assessment of GO inflammation.
| S-EPMC8478760 | biostudies-literature
Project description:BackgroundBoth Graves' hyperthyroidism (GH) and Graves' orbitopathy (GO) are associated with significant adverse health consequences. All conventional treatment options have limitations regarding efficacy and safety. Most importantly, they do not specifically address the underlying immunological mechanisms. We aim to review the latest development of treatment approaches in these two closely related disorders.SummaryImmunotherapies of GH have recently demonstrated clinical efficacy in preliminary studies. They include ATX-GD-59, an antigen-specific immunotherapy which restores immune tolerance to the thyrotropin receptor; iscalimab, an anti-CD40 monoclonal antibody which blocks the CD40-CD154 costimulatory pathway in B-T cell interaction; and K1-70, a thyrotropin receptor-blocking monoclonal antibody. Novel treatment strategies have also become available in GO. Mycophenolate significantly increased the overall response rate combined with standard glucocorticoid (GC) treatment compared to GC monotherapy. Tocilizumab, an anti-interleukin 6 receptor monoclonal antibody, displayed strong anti-inflammatory action in GC-resistant cases. Teprotumumab, an anti-insulin-like growth factor 1 receptor monoclonal antibody, resulted in remarkable improvement in terms of disease activity, proptosis, and diplopia. Further, rituximab appears to be useful in active disease of recent onset without impending dysthyroid optic neuropathy.Key messagesTherapeutic advances will continue to optimize our management of GH and associated orbitopathy in an effective and safe manner.
| S-EPMC7802437 | biostudies-literature