Medical treatment in thyroid eye disease in 2020

2020 ◽  
pp. bjophthalmol-2020-316051 ◽  
Author(s):  
Jwu Jin Khong ◽  
Alan McNab
Keyword(s):  
Clinical Trials ◽  
T Cells ◽  
Cell Surface ◽  
Medical Treatment ◽  
Severe Disease ◽  
Thyroid Eye Disease ◽  
Eye Disease ◽  
Molecular Pathways ◽  
Surface Receptors ◽  
Intravenous Corticosteroid

Thyroid eye disease (TED) affects 25% of patients with Graves’ hyperthyroidism, where 1 in 20 patients has active, moderate-to-severe disease that will require medical treatment for reducing TED activity and severity. Intravenous corticosteroid has been the mainstay of treatment for active moderate-to-severe TED. With improved understanding of the pathophysiology of TED, immunotherapy targeting different molecular pathways including T cells, B cells, cytokines and cell surface receptors have been investigated in randomised clinical trials. This review provides an overview of the current advances in medical treatment including teprotumumab, tocilizumab, rituximab and mycophenolate and the indications for their use in the management of active, moderate-to-severe TED.

Recent advances in thyroid eye disease: An overview

2021 ◽  
Vol 7 (2) ◽  
pp. 117-130
Author(s):  
Sahil Agrawal ◽  
Rajendra Prakash Maurya ◽  
Ananya P R ◽  
Syeed Mehbub UL Kadir ◽  
Virendra Pratap Singh ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Medical Management ◽  
Randomized Clinical Trials ◽  
Immunosuppressive Drugs ◽  
Thyroid Eye Disease ◽  
Diagnostic Tools ◽  
Eye Disease ◽  
Management Options ◽  
Surface Receptors ◽  
Recent Advances

Thyroid eye disease (TED) is a chronic debilitating condition which causes physical discomfort, oculo-facial disfigurement and compromised visual function. Around 25% of people with Graves’ hyperthyroidism are affected by TED, where 1 in 20 patients might report with moderate-to-severe, active disease that will require medical management for reducing both TED activity and severity. The mainstay of medical management involves intravenous corticosteroids for active moderate-to-severe TED. After accurate understanding of the mechanism and pathophysiology of this disease, investigations and randomized clinical trials have been conducted. The role of immunotherapy targeting and influencing different biomolecular pathways including that of T cells, B cells, cytokines and cell surface receptors have been investigated in various randomized clinical trials. This review article addresses the epidemiology, associated risk factors, recent advances in pathophysiology, newer diagnostic tools and current management options available for TED which include the use of immunosuppressive drugs like rituximab (RTX), tocilizumab, infliximab (IFX), etanercept ( ETN) and teprotumumab etc.

scholarly journals Polymyositis, Topological Proteomics Technology and Paradigm for Cell Invasion Dynamics

2002 ◽  
Vol 4 (1) ◽  
pp. 75-84 ◽  
Author(s):  
Walter Schubert
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Surface ◽  
Cell Invasion ◽  
Large Scale ◽  
Expression Patterns ◽  
Inflammatory Myopathy ◽  
Protein Profiling ◽  
Cell Surface Receptors ◽  
Surface Receptors

Polymyositis is an inflammatory myopathy characterized by muscle invasion of T-cells penetrating the basal lamina and displacing the plasma membrane of normal muscle fibers. This investigation presents a technology for the direct mapping of protein networks involved in T-cell invasionin situ. Simultaneous localization of 17 adhesive cell surface receptors reveals 18 different combinatorial expression patterns (CEP), which are unique for the T-cell invasion process in muscle tissue. Each invasion step can be assigned to specific CEP on the surface of individual T-cells. This indicates, that the T-cell invasion is enciphered combinatorially in the T-cells' adhesive cell surface proteome fraction. Given 217possible combinations, the T-cell appears to have at its disposal a highly non-random restricted repertoire to specify migratory pathways at the cell surface. These higher-level order functions in the cellular proteome cannot be detected by large-scale protein profiling techniques from tissue homogenates. High-throughput whole cell mapping machines working on structurally intact tissues, as shown here, will allow to measure how cells of different origin (immune cells, tumor cells) combine cell surface receptors to encipher specificity and selectivity for interactions.

scholarly journals Peripheral regulatory CD8+CD28-KLRG1+ T cells as markers of disease and treatment response in rheumatoid arthritis.

2020 ◽  
Author(s):  
Charlotte Thompson ◽  
Richard Beatson ◽  
Ruth Davies ◽  
Claire Greenhill ◽  
Simon A Jones ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Flow Cytometry ◽  
T Cells ◽  
Cell Surface ◽  
Treatment Response ◽  
Early Arthritis ◽  
Cell Surface Receptors ◽  
Surface Receptors ◽  
Markers Of Inflammation ◽  
Conventional Dmards

CD3+CD8+CD28- cells are increased in the periphery and tissues of rheumatoid arthritis (RA) patients. The aim of this study was to characterise CD3+CD8+CD28- cells for the presence of cell surface receptors that regulate immune activation and function and to track their presence in a disease model of RA. Cell surface receptors expressed by CD3+CD8+CD28- cells were then related to serological and clinical disease parameters to establish whether these cells are prognostic of a clinical response to conventional DMARDs. Method. Using healthy donor peripheral blood mononuclear (PBMC) cell surface expression of >50 candidate markers were tested using flow cytometry and compared against CD28 expression. The prevalence of cells expressing the most suitable candidate was investigated in the collagen induced arthritis (CIA) and the antigen-induced arthritis (AIA) models. Fifty RA patients were recruited from University Hospital of Wales (UHW) rheumatology outpatient clinic. Clinical and serological markers of inflammation were noted, and PBMC were analysed using flow cytometry +/- in vitro stimulation. Results. CD3+CD8+CD28- T cells express CD244, CD57, CX3CR1 and KLRG1. The strongest inverse correlate of CD28 expression was KLRG1. CD3+CD8+CD28-KLRG1+ cells were elevated in experimental models of RA. Notably, Il-10-deficiency was linked with exacerbated arthritis and an increase in the number of CD3+CD8+CD28-KLRG1+ cells, suggesting a regulatory role for Il-10 in their development or survival. In RA patients, CD3+CD8+CD28-KLRG1+ cells correlate with ACPA, RF and ESR, and produce more IL-10 than controls. Finally, these cells are higher in early arthritis patients that do not respond to treatment with synthetic DMARDs at six months. Conclusion. KLRG1 is a marker for regulatory CD3+CD8+CD28- cells. The presence of CD3+CD8+CD28-KLRG1+ cells increases with certain measures of disease, and is indicative of poor treatment response to DMARDs in early arthritis.

Recent Developments in the Medical Treatment of Thyroid Eye Disease

Orbit ◽  
2006 ◽  
Vol 25 (2) ◽  
pp. 117-122 ◽  
Author(s):  
G. E. Krassas ◽  
K. Boboridis
Keyword(s):  
Medical Treatment ◽  
Thyroid Eye Disease ◽  
Eye Disease ◽  
Recent Developments

scholarly journals Severe Thyroid Eye Disease in the US: A National Perspective

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A843-A843
Author(s):  
Gurkirpal Singh ◽  
Maanek Sehgal ◽  
Alka Mithal ◽  
Chris Alabiad ◽  
Andrea Kossler
Keyword(s):  
Ambulatory Surgery ◽  
Private Insurance ◽  
Severe Disease ◽  
Hospital Setting ◽  
Thyroid Eye Disease ◽  
Eye Disease ◽  
Treatment Pathways ◽  
The Us ◽  
Icd 10 ◽  
Total Charges

Abstract Background: Thyroid eye disease (TED) is an unpredictable autoimmune inflammatory disease which can be sight-threatening, debilitating, and disfiguring. The majority of patients have mild, self-limited TED, 20-30% of patients experience moderate/severe disease, and 3-5% may develop sight-threatening disease, such as CON or exposure keratopathy. Surgical intervention is commonly necessary for patients with moderate/severe stable disease or sight-threatening disease, however, there is little data on the prevalence of TED requiring surgical interventions. Objective: To document the number of surgical procedures for thyroid eye disease in the US and evaluate the associated costs of these interventions. Methods: National Ambulatory Surgery Sample (NASS) is the largest ambulatory surgery database, representing approximately 14 million ambulatory surgeries performed annually in a hospital setting in the US. Data from 2,699 hospital-owned facilities located in 31 States and the District of Columbia, approximating a 63-percent stratified sample of U.S. hospital-owned facilities performing selected ambulatory surgeries are available for analyses. Data on clinical procedures and diagnoses, disposition of the patient, expected source of payment, and total charges, as well as geographic, hospital-owned facility, and patient characteristics are collected. For the purposes of this study, TED was identified by concomitantly occurring ICD 10 codes of thyroid disease and ICD-10 codes for eye manifestations of thyroid eye disease. CPT codes were used to identify eye surgeries performed in these patients. The coding algorithms were developed by consensus of three ophthalmic surgeons. Results: In 2018, a total of 1,991 patients with TED required eye surgery, with a national prevalence of 0.6 per 100,000 population. Mean age at surgery was 56.2 years (95% Confidence Interval (CI) 55.3-57.2). Women comprised 73% (1455 women and 536 men) of TED patients who underwent surgery. The average charges for each surgical encounter were $21,875 (95% CI $19,066-$24,684). Total charges for TED surgery in the US totaled over 43.5 million annually. While many patients had private insurance (49.7%), Medicare (31%) and Medicaid (13%) were also significant sources of reimbursement. Of all TED-related surgeries, 93% were conducted in teaching hospitals. Only 0.2% of surgeries were conducted in non-urban rural settings. Conclusion: In the US, severe TED requiring surgery, although uncommon, has significant economic impact. Further research is warranted to better understand the natural history of TED that may inform treatment pathways which may prevent complications needing surgery.

scholarly journals Tyrosine phosphorylation of CD6 by stimulation of CD3: augmentation by the CD4 and CD2 coreceptors.

1993 ◽  
Vol 177 (1) ◽  
pp. 219-223 ◽  
Author(s):  
S Wee ◽  
G L Schieven ◽  
J M Kirihara ◽  
T T Tsu ◽  
J A Ledbetter ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Surface ◽  
T Cell Activation ◽  
Intracellular Signaling ◽  
Cell Activation ◽  
Cell Receptor ◽  
Surface Proteins ◽  
Cell Surface Receptors ◽  
Surface Receptors

When T cells are activated via the T cell receptor (TCR) complex a number of cellular substrates, including some cell surface proteins, become phosphorylated on tyrosine (Tyr) residues. Phosphorylation of cytoplasmic Tyr renders these cell surface receptors competent to interact with proteins that link cell surface receptors to protein in the intracellular signaling pathways. Here we show that Tyr residues in the cytoplasmic domain of CD6 become phosphorylated upon T cell activation via the TCR complex. Tyr phosphorylation was observed when the T cells were activated by crosslinking CD3 or by cocrosslinking CD3 with CD2 or CD4, but not when the cells were stimulated by crosslinking CD2, CD4, or CD28 alone. Unlike other Tyr kinase substrates, such as the phospholipase C gamma 1-associated pp35/36 protein, whose level of Tyr phosphorylation is highest when T cells are activated by cocrosslinking CD3 with CD2, the levels of CD6 Tyr phosphorylation are highest when T cells were activated by cocrosslinking CD3 with CD4.

scholarly journals Automatic Recognition of Muscle-Invasive T-Lymphocytes Expressing Dipeptidyl-Peptidase IV (CD26) and Analysis of the Associated Cell Surface Phenotypes

2002 ◽  
Vol 4 (1) ◽  
pp. 67-74 ◽  
Author(s):  
W. Schubert ◽  
M. Friedenberger ◽  
R. Haars ◽  
M. Bode ◽  
L. Philipsen ◽  
...  
Keyword(s):  
T Cells ◽  
T Lymphocytes ◽  
Cell Surface ◽  
Detection System ◽  
Dipeptidyl Peptidase ◽  
Dipeptidyl Peptidase Iv ◽  
Cell Detection ◽  
Surface Receptors ◽  
Dpp Iv ◽  
Muscle Invasive

A neural cell detection system (NCDS) for the automatic quantitation of fluorescent lymphocytes in tissue sections was used to analyze CD26 expression in muscle-invasive T-cells. CD26 is a cell surface dipeptidyl-peptidase IV (DPP IV) involved in co-stimulatory activation of T-cells and also in adhesive events. The NCDS system acquires visual knowledge from a set of training cell image patches selected by a user. The trained system evaluates an image in 2 min calculating (i) the number, (ii) the positions and (iii) the phenotypes of the fluorescent cells. In the present study we have used the NCDS to identity DPP IV (CD26) expressing invasive lymphocytes in sarcoid myopathy and to analyze the associated cell surface phenotypes. We find highly unusual phenotypes characterized by differential combination of seven cell surface receptors usually involved in co-stimulatory events in T-lymphocytes. The data support a differential adhesive rather than a co-stimulatory role of CD26 in muscle-invasive cells. The adaptability of the NCDS algorithm to diverse types of cells should enable us to approach any invasion process, including invasion of malignant cells.

scholarly journals Transgenic mice demonstrate that epithelial homing of gamma/delta T cells is determined by cell lineages independent of T cell receptor specificity.

1990 ◽  
Vol 171 (4) ◽  
pp. 1015-1026 ◽  
Author(s):  
M Bonneville ◽  
S Itohara ◽  
E G Krecko ◽  
P Mombaerts ◽  
I Ishida ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Surface ◽  
Transgenic Mice ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Gamma Delta T Cells ◽  
Gamma Delta ◽  
Receptor Specificity ◽  
Surface Receptors ◽  
Cell Lineages

gamma/delta T cells with different TCR repertoires are compartmentalized in different epithelia. This raises the possibility that the TCR-gamma/delta directs homing of T cells to these epithelia. Alternatively, the signals that induce TCR-gamma/delta expression in developing T cells may also induce homing properties in such cells, presumably in the form of cell surface receptors. We have examined this issue by studying the homing of gamma/delta T cells in transgenic mice constructed with specific pairs of rearranged gamma and delta genes. In such mice, most gamma/delta T cells express the transgene-encoded TCR. We find that homing to both skin and gut epithelia is a property of T cells and is not determined by the type of gamma and delta genes used to encode their TCR. We also studied the effect of TCR replacement on the expression of Thy-1 and CD8 proteins on the gamma/delta T cells associated with gut epithelia. Our results show that the expression of the appropriate type of TCR-gamma/delta is not required for the Thy-1 expression by these T cells, suggesting that Thy-1 is not an activation marker. In contrast, CD8 expression by gut gamma/delta T cells seems to depend on the expression of the appropriate type of TCR.

scholarly journals The Efficacy of Teprotumumab for Chronic, Progressive Thyroid Eye Disease Greater Than 9 Months

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A844-A845
Author(s):  
Connie Martin Sears ◽  
Julia Y Kang ◽  
Kimberly Cockerham ◽  
Andrea L Kossler
Keyword(s):  
Clinical Trials ◽  
Smoking Status ◽  
Oral Prednisone ◽  
Visual Fields ◽  
Case Series ◽  
Thyroid Eye Disease ◽  
Muscle Size ◽  
Eye Disease ◽  
Clinical Activity ◽  
Ocular Involvement

Abstract Purpose: To evaluate the efficacy of teprotumumab for the treatment of patients with chronic, progressive Thyroid Eye Disease (TED) who do not meet the inclusion and exclusion criteria used in prior clinical trials. Methods: This is a prospective case series of patients with chronic, progressive TED, defined as ocular symptoms of more than 9 months prior to treatment initiation with teprotumumab, an insulin-like growth factor I receptor inhibitor (10 mg/kg for the first infusion then 20 mg/kg for subsequent infusions, every three weeks for a total 8 infusions). This study included patients with a Clinical Activity Score (CAS) greater than or equal to 4. Data collected included patients’ age, sex, race, baseline thyroid status, thyroid stimulating immunoglobulin, CAS, smoking status, best corrected visual acuity, intraocular pressure, Schirmer’s, pupil exam, extraocular motility, Gorman diplopia score, and exophthalmometer measurements. Pre-infusion and post-infusion external photos in all 9 gazes, orbital imaging (CT or MRI), Humphrey visual fields and optical coherence tomography were obtained when possible. Results: Ten patients with chronic TED were treated with teprotumumab either as a primary treatment or following other interventions including oral prednisone, intravenous methylprednisolone, orbital radiation, orbital decompression and/or eyelid surgery. The age range was 55 to 79, with 5 female patients and 5 male patients. Four of the patients were African American and 6 of the patients were White/Non-Hispanic. The number of years the patients had been diagnosed with Graves’ disease ranged from 4 to 33 years, with ocular involvement spanning 4 to 15 years. Patients had CT scans of the orbits to document muscle size prior to initiation, and external photos were taken at each visit. All patients improved subjectively after the first infusion and objectively by the fourth infusion. We will report the long-term follow-up after 8 infusions at ENDO2021. Discussion: Teprotumumab is a fully human monoclonal IgG1 antibody that blocks the IGF-1 receptor, disrupting the cell-to-cell signaling of the immunologic cascade and is independent of the duration or severity of TED. At this time, FDA approval for teprotumumab is for the treatment of TED without any specific restrictions. However, our teprotumumab-treated patients included those who would have been excluded in the phase 2 and 3 clinical trials due to: (1) poor thyroid control, (2) previous orbital surgery, (3) previous therapeutic interventions including steroids and radiation, (4) visual loss due to compressive optic neuropathy or exposure keratopathy and (5) chronic TED greater than 9 months. In our series, we found that teprotumumab was as effective in a wider population of chronic TED patients than included in the clinical trials.

scholarly journals The cellular immune response to COVID-19 deciphered by single cell multi-omics across three UK centres

2021 ◽  
Author(s):  
Emily Stephenson ◽  
Gary Reynolds ◽  
Rachel A Botting ◽  
Fernando J Calero-Nieto ◽  
Michael Morgan ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Cell Surface ◽  
Single Cell ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Severe Disease ◽  
Surface Proteins ◽  
Peripheral Blood Mononuclear ◽  
Cell Surface Proteins

AbstractThe COVID-19 pandemic, caused by SARS coronavirus 2 (SARS-CoV-2), has resulted in excess morbidity and mortality as well as economic decline. To characterise the systemic host immune response to SARS-CoV-2, we performed single-cell RNA-sequencing coupled with analysis of cell surface proteins, providing molecular profiling of over 800,000 peripheral blood mononuclear cells from a cohort of 130 patients with COVID-19. Our cohort, from three UK centres, spans the spectrum of clinical presentations and disease severities ranging from asymptomatic to critical. Three control groups were included: healthy volunteers, patients suffering from a non-COVID-19 severe respiratory illness and healthy individuals administered with intravenous lipopolysaccharide to model an acute inflammatory response. Full single cell transcriptomes coupled with quantification of 188 cell surface proteins, and T and B lymphocyte antigen receptor repertoires have provided several insights into COVID-19: 1. a new non-classical monocyte state that sequesters platelets and replenishes the alveolar macrophage pool; 2. platelet activation accompanied by early priming towards megakaryopoiesis in immature haematopoietic stem/progenitor cells and expansion of megakaryocyte-primed progenitors; 3. increased clonally expanded CD8+ effector:effector memory T cells, and proliferating CD4+ and CD8+ T cells in patients with more severe disease; and 4. relative increase of IgA plasmablasts in asymptomatic stages that switches to expansion of IgG plasmablasts and plasma cells, accompanied with higher incidence of BCR sharing, as disease severity increases. All data and analysis results are available for interrogation and data mining through an intuitive web portal. Together, these data detail the cellular processes present in peripheral blood during an acute immune response to COVID-19, and serve as a template for multi-omic single cell data integration across multiple centers to rapidly build powerful resources to help combat diseases such as COVID-19.

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