Retro-orbital Tissue Research Articles

12231 PAPP-A As A Potential Target In Thyroid Eye Disease

Abstract Disclosure: C.A. Conover: None. L.K. Bale: None. D. Hamadi: None. M. Stan: ; Tourmaline, Genentech, Third Rock Ventures, ArgenX, Septerna, OrthoDi. ; Horizon, Immunovant, Lassen, Sling. Background: Proptosis in Thyroid Eye Disease (TED) can result in facial disfigurement and visual dysfunction. Studies revealed an interaction between thyroid-stimulating hormone receptor (TSHR) and insulin-like growth factor-I receptor (IGF-IR) that is essential in promoting TED pathogenesis. Treatment with Insulin-like growth factor I receptor (IGF-IR) inhibitors has been shown to be effective in reducing proptosis but with side effects. PAPP-A is metalloprotease that can increase pericellular IGF bioavailability through specific cleavage of inhibitory IGF binding proteins, in particular IGFBP-4. We propose that inhibition of IGF-IR indirectly and more selectively with PAPP-A inhibitory antibodies attenuates IGF-IR signaling in TED with fewer side effects. Methods: Informed consent was obtained from TED patients undergoing surgery in Mayo Clinic operating suites in Rochester, MN. Retro-orbital tissue was collected from 19 TED patients and 2 control subjects for fibroblast isolation and culture and was performed in a sterile tissue culture facility. TED and control fibroblasts were treated with pro-inflammatory cytokines, and flow separation of CD34- and CD34+ orbital fibroblasts was done, the latter representing infiltrating fibrocytes into the orbit in TED. Main outcome measured were PAPP-A expression and proteolytic activity, IGF-I stimulation of phosphatidylinositol 3 kinase/Akt pathway and inhibition by immuno-neutralizing antibodies against PAPP-A, CD34+ status and associated PAPP-A and IGF-IR expression. Results: Primary cultured cells showed that PAPP-A is expressed in orbital fibroblasts from TED patients but not in control subject fibroblasts and were markedly increased by pro-inflammatory cytokines stimulation. IGF-IR expression was not affected by cytokine treatment. Inhibition of PAPP-A’s proteolytic activity suppressed IGF-IR activation in orbital fibroblasts from TED patients. CD34+ orbital fibroblasts represent 80% of cells in culture from TED patients, and approximately 70% of these cells were accountable for PAPP-A and IGF-IR expression. Conclusion: These results support a role for PAPP-A in TED pathogenesis and indicate the potential for novel therapeutic targeting of the IGF axis. Presentation: 6/2/2024

Erdheim-chester disease with bilateral proptosis, coated aorta and hairy kidney

Erdheim-Chester disease (ECD) is a rare histiocytic disorder with a spectrum of clinical manifestations, ranging from asymptomatic single-organ involvement to multisystem disease. We present a classic case of ECD with detailed radiographic and histopathologic findings. A 63-year-old Thai female with a history of triple vessel disease post-PCI presented with bilateral proptosis and blurred vision for one year. On admission, she exhibited marked proptosis epiblepharon, lagophthalmos, conjunctival injection, chemosis, limited extraocular movement and cranial nerve II palsy. Imaging showed increased bilateral retro-orbital infiltrative lesions, osteosclerotic changes, and soft tissue thickening along the great vessels and retroperitoneum. A retro-orbital soft tissue biopsy showed foamy histiocytic proliferation with Touton giant cells. EDC was confirmed by next-generation sequencing revealing a BRAF V600E mutation. This patient received pegylated interferon-alpha. At 1-year follow-up visit, the disease remained stable. In this report, we present a classic case of EDC. The rarity of this disease makes it challenging to diagnose. The typical presentation characteristics raise awareness for the diagnosis of EDC, which is based on features such as osteosclerotic lesions in the long bones, soft tissue infiltration in medium to large vessels (coated aorta) and the bilateral pelvicalyceal systems (hairy kidney). These findings were confirmed through tissue pathology and molecular diagnostics.

PAPP-A as a Potential Target in Thyroid Eye Disease.

Proptosis in Thyroid Eye Disease (TED) can result in facial disfigurement and visual dysfunction. Treatment with Insulin-like growth factor I receptor (IGF-IR) inhibitors has been shown to be effective in reducing proptosis but with side effects. To test the hypothesis that inhibition of IGF-IR indirectly and more selectively with PAPP-A inhibitors attenuates IGF-IR signaling in TED. Informed consent was obtained from TED patients undergoing surgery, and retro-orbital tissue collected for fibroblast isolation and culture. Surgeries were performed in Mayo Clinic operating suites. Cell culture was performed in a sterile tissue culture facility. Retro-orbital tissue was collected from 19 TED patients. Treatment of TED fibroblasts with pro-inflammatory cytokines. Flow separation of CD34- and CD34+ orbital fibroblasts, the latter representing infiltrating fibrocytes into the orbit in TED. PAPP-A expression and proteolytic activity, IGF-I stimulation of phosphatidylinositol 3 kinase/Akt pathway and inhibition by immuno-neutralizing antibodies against PAPP-A, CD34+ status and associated PAPP-A and IGF-IR expression. Pro-inflammatory cytokines markedly increased PAPP-A expression in TED fibroblasts. IGF-IR expression was not affected by cytokine treatment. Inhibition of PAPP-A's proteolytic activity suppressed IGF-IR activation in orbital fibroblasts from TED patients. TED fibroblasts that were CD34+ represented ∼80% of the cells in culture and accounted for ∼70% of PAPP-A and IGF-IR expressing cells. These results support a role for PAPP-A in TED pathogenesis and indicate the potential for novel therapeutic targeting of the IGF axis.

Intestinal permeability is associated with aggravated inflammation and myofibroblast accumulation in Graves' orbitopathy: the MicroGO study.

Graves' disease (GD) and Graves' orbitopathy (GO) result from ongoing stimulation of the TSH receptor due to autoantibodies acting as persistent agonists. Orbital pre-adipocytes and fibroblasts also express the TSH receptor, resulting in expanded retro-orbital tissue and causing exophthalmos and limited eye movement. Recent studies have shown that GD/GO patients have a disturbed gut microbiome composition, which has been associated with increased intestinal permeability. This study hypothesizes that enhanced intestinal permeability may aggravate orbital inflammation and, thus, increase myofibroblast differentiation and the degree of fibrosis. Two distinct cohorts of GO patients were studied, one of which was a unique cohort consisting of blood, fecal, and retro-orbital tissue samples. Intestinal permeability was assessed by measuring serum lipopolysaccharide-binding protein (LBP), zonulin, TLR5, and TLR9 ligands. The influx of macrophages and accumulation of T-cells and myofibroblast were quantified in orbital connective tissue. The NanoString immune-oncology RNA targets panel was used to determine the transcriptional profile of active fibrotic areas within orbital sections. GO patients displayed significantly higher LBP serum concentrations than healthy controls. Within the MicroGO cohort, patients with high serum LBP levels also showed higher levels of zonulin and TLR5 and TLR9 ligands in their circulation. The increased intestinal permeability was accompanied by augmented expression of genes marking immune cell infiltration and encoding key proteins for immune cell adhesion, antigen presentation, and cytokine signaling in the orbital tissue. Macrophage influx was positively linked to the extent of T cell influx and fibroblast activation within GO-affected orbital tissues. Moreover, serum LBP levels significantly correlated with the abundance of specific Gram-negative gut bacteria, linking the gut to local orbital inflammation. These results indicate that GO patients have enhanced intestinal permeability. The subsequent translocation of bacterial compounds to the systemic circulation may aggravate inflammatory processes within the orbital tissue and, as a consequence, augment the proportion of activated myofibroblasts, which actively secrete extracellular matrix leading to retro-orbital tissue expansion. These findings warrant further exploration to assess the correlation between specific inflammatory pathways in the orbital tissue and the gut microbiota composition and may pave the way for new microbiota-targeting therapies.

Single-cell transcriptomics in thyroid eye disease

Abstract Thyroid eye disease (TED) is a poorly understood autoimmune condition affecting the retroorbital tissue. Tissue inflammation, expansion, and fibrosis can potentially lead to debilitating sequelae such as vision loss, painful eye movement, proptosis, and eyelid retraction. Current treatment modalities for TED include systemic glucocorticoids, thioamides, methimazole, teprotumumab, beta-blockers, and radioactive iodine; however, it has been reported that up to 10%–20% of TED patients relapse after treatment withdrawal and 20%–30% are unresponsive to mainstay therapy for reasons that have yet to be more clearly elucidated. In the past 4 years, vision researchers have harnessed high-throughput single-cell RNA sequencing to elucidate the diversity of cell types and molecular mechanisms driving the pathogenesis of TED at single-cell resolution. Such studies have provided unprecedented insight regarding novel biomarkers and therapeutic targets in TED. This timely review summarizes recent breakthroughs and emerging opportunities for using single-cell and single-nuclei transcriptomic data to characterize this highly complex disease state. We also provide an overview of current challenges and future applications of this technology to potentially improve patient quality of life and facilitate reversal of disease endpoints.

GLOKOM HASTALARINDA SHEAR WAVE ELASTOGRAFİ BULGULARI

OBJECTIVE: Our aim is to measure the stiffness values in different regions of the eye with shear wave elastography (SWE) in patients with glaucoma and to compare the results with healthy eyes to investigate whether there is a change in the elasticity of the ocular compartments in glaucoma patients.MATERIAL AND METHODS: In this study, we compared 12 patients with open-angle glaucoma and 32 healthy volunteers using an SWE-equipped ultrasonography device. Only the right eye was evaluated in all patients. First, the eye globe was generally examined in B-mode. Then, the stiffness values of the optic nerve head, retro-orbital nerve, sclera-retina complex and retro-orbital adipose tissue in the posterior segment and the stiffness values of the cornea, lens and anterior chamber in the anterior segment of the eye were measured with SWE in kiloPascal and both groups were compared statistically.RESULTS: No statistically significant differences were found between the patient and control groups in terms of the stiffness values recorded in the measurements performed in different parts of the eye.CONCLUSIONS: Although SWE is an easily applicable method, no significant differences were found between glaucoma and control groups. However, thanks to this study, reference values for different parts of the eye in normal individuals have been determined.

PSAT352 A Case Report: Unilateral Graves’ Ophthalmopathy in Euthyroid Patient

Abstract Introduction Graves’ Ophthalmopathy is an immune mediated inflammation in orbital and retroorbital tissues, occurs mainly with hyperthyroidism,10% with euthyroid and rarely with hypothyroidism, more frequently in females(1). Thyroid-stimulating hormone (TSH) receptor (TSHR) is the main auto-antigen, expressed in the thyroid gland, adipocytes and fibroblasts. It is aligned with insulin-like growth factor 1 (IGF-1) receptor. T cells activate TSHR and IGF-1 receptors and initiating a retro-orbital inflammation and accumulation of hydrophilic glycosaminoglycans (GAG)(2). Case 46 yo, Hispanic obese male with history of type 2 DM and HLD, non-smoker, non- alcoholic, no illicit drugs. Family History of DM, no allergy,Home medications: Alogliptin benzoate 25mg/day, Metformin 1000mg twice/day and atorvastatin 10mg/day. Ophthalmology checkup 2 months before; visual acuity of 20/30, B/L nasal pterygium, no Diabetic retinopathy. Normal TSH (0.56ulU/ml) 6 months before. He presented to the Emergency department with 3 days of progressive redness, puffiness, photophobia and pressure like sensations in left eye, denied palpitations, change in bowel movements, weight loss/gain, heat/cold intolerance, fever, vomiting, headache, motor weakness, sensory loss. General examination alert, orientated x3,ABP 130/60, HR 75BPM, afebrile(98.4 F), BMI 37.56kg/m2, no tremors, no thyromegaly, normal heart, lung, abdomen examinations, no edema. Left eye conjunctival injection, proptosis, decrease visual acuity 20/60 and color vision, restricted eye movements, relative afferent pupillary defect, optic Neuropathy. Right eye nasal Pterygium and normal fundus examination. Laboratory findings; normal TSH 1.4ulU/ml, FT4 1.2ng/dl, FT3121ng/dl, High TSHR antibody4.69IU/L (normal less than 1.75IU/L), Thyroid peroxidase antibody 363IU/ml (normal less than 34.9IU/ml) and Thyroid stimulating immunoglobulin 3.55 IU/L (normal less than 0.55IU/L). Normal CBC, GFR, negative C-ANCA, P-ANCA antibodies. CT orbit showed marked exophthalmoses, prominence of infraorbital fat, thickening of inferior and medial rectus muscles of left eye. He was kept on IV Solumedrol 250mg Q 6hrs for 3 days, artificial tears. Symptoms improved, was discharged on tapering oral steroid starting with prednisone 80mg daily. Follow up after 5 days reported marked improvement of symptoms with slight proptosis, no optic neuropathy. Conclusion Graves’ Ophthalmopathy can occur in euthyroid patients. Presents mainly with bilateral eye affection, few cases have unilateral eye affection. IV or oral Steroid is the Main treatment of Graves’ ophthalmopathy with local eye measures and management of thyroid disease. Other options are teprotumumab (IGF-1 receptor Inhibitor), and rituximab or orbital decompression surgery/external orbital radiation. Close follow up is recommended as orbitopathy precedes hyperthyroidism in 20%of cases(3,4). References 1-Kersten R. American Academy of Ophthalmology Section 7, Orbit, Eyelids and Lacrimal System 2004-2005: 48-56. 2-Bahn RS. Graves’ ophthalmopathy. N Engl J Med 2010; 362: 726. 3-Douglas RS, Kahaly GJ, Patel A, et al. Teprotumumab for the Treatment of Active Thyroid Eye Disease. N Engl J Med 2020; 382: 341. 4-Zang S, Ponto KA, Kahaly GJ. Clinical review: Intravenous glucocorticoids for Graves’ orbitopathy: efficacy and morbidity. J Clin Endocrinol Metab 2011; 96: 320. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

MSR67 Bridging and Validation of a Thyroid Eye Disease (TED) Specific Quality of Life (QOL) Questionnaire to Utility Values Assessed By a Time Trade-Off (TTO) Analysis

TED, an autoimmune, inflammatory disease, is characterized by retro-orbital tissue expansion and devastating changes in facial appearance and visual function. The Graves’ Ophthalmopathy QOL (GO-QOL) questionnaire is TED specific but has not been mapped to health state utility (HSU) scores. Recently, mean score for moderate-severe TED was assessed as 0.44. To quantify QALY improvements with teprotumumab, we correlated and bridged GO-QOL values with TTO-derived utility scores.

Multiple Drug Regimen-Refractory Rosai-Dorfman-Destombes Disease Mimicking Relapsing Polychondritis Successfully Treated with Cobimetinib.

Rosai–Dorfman–Destombes disease (RDD) or sinus histiocytosis with massive lymphadenopathy is a rare non-Langerhans cell histiocytosis of unknown cause. The disease often manifests as painless bilateral cervical lymphadenopathy associated with systemic symptoms such as fever and weight loss. Extranodal disease is also frequent and can involve any organ, mostly the skin, nasal cavity, bone, and retro-orbital tissue. Swelling of cartilaginous tissues, such as the helix of the ear or laryngeal structures, may mimic the entity known as relapsing polychondritis. Although spontaneous remission is the most expected evolution, some cases require systemic treatment with prednisone, methotrexate or cytotoxic agents, with variable rates of success. In this respect, since somatic variants in the genes involved in the mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinases (ERK) pathway have been observed to play a pathogenic role in RDD. Therefore, the use of therapies targeting these pathogenic variants appears to be a reasonable strategy. Here we present the case of a 37-year-old woman with RDD and extensive extranodal involvement that showed a rapid and complete response to the MEK inhibitor cobimetinib.LEARNING POINTSRosai–Dorfman–Destombes disease (RDD) may mimic the entity known as relapsing polychondritis but should be treated with drug therapy for the underlying disease.Mutations in MAPK/ERK pathway components should be determined in RDD with systemic involvement, although testing to determine every somatic mutation responsible for the disease is not available in all healthcare centres.MEK inhibitors like cobimetinib could be effective in RDD cases with severe and refractory systemic disease, even if molecular analysis has not been possible.

ORBITAL Ultrasonography a diagnosis tool in early cellulitis

The term cellulitis in general parlance refers to non-suppurative invasive infection (most commonly bacterial) of subcutaneous tissue. Spreading infection, poor localization in addition to cardinal signs of inflammation are the hallmark of cellulitis. Cellulitis can be complicated by spread of infection to the underlying deeper structures with progressive tissue destruction & ulceration with release of bacterial toxins. (1) Orbital cellulitis is an infection of the fat and ocular muscles of the orbit posterior to the orbital septum. It is classically distinguished clinically from pre-septal cellulitis by the presence of pain with eye movement and proptosis on physical examination (1, 2). What makes cellulitis in the preseptal, orbital & retro-orbital soft tissue regions different from generalized cellulitis are the transitional anatomical differences from preseptal (Eyelid skin) to adnexal/orbital to intracranial structures and the presence of well recognized anatomical/surgical sub-compartments. Preseptal cellulitis follows pattern similarities to generalized cellulitis characterized by eyelid edema, eyelid erythema, local rise of temperature and tenderness. Unlike pre-septal cellulitis, orbital cellulitis is considered a medical emergency. If left untreated, it can lead to permanent vision loss, brain abscesses, meningitis, and cavernous sinus thrombosis (3). Though the diagnosis of orbital cellulitis can be made clinically, imaging modalities such as computed tomography (CT) and Orbital Ultrasonography are commonly used to confirm the diagnosis. (4) The present study was designed to provide sequential imaging to visualize the disease progression.

Mechanisms in Graves Eye Disease: Apoptosis as the End Point of Insulin-Like Growth Factor 1 Receptor Inhibition.

Background: Graves' eye disease, also called Graves' orbitopathy (GO), is a potentially debilitating autoimmune disease associated with retro-orbital inflammation and tissue expansion, involving both fibroblasts and adipocytes, resulting in periorbital edema, worsening proptosis, and muscle dysfunction with diplopia and may ultimately threaten sight. Accumulating evidence has indicated that autoantibodies to the thyrotropin receptor (TSHR), which induce the hyperthyroidism of Graves' disease, also help mediate the pathogenesis of the eye disease in susceptible individuals through TSHR expression on retro-orbital cells. Since it has long been known that the effects of insulin-like growth factor 1 (IGF-1) and thyrotropin are additive, recent clinical trials with a human monoclonal IGF-1 receptor blocking antibody (teprotumumab; IGF-1R-B-monoclonal antibody [mAb]) have demonstrated its ability to induce significant reductions in proptosis, diplopia, and clinical activity scores in patients with GO. However, the molecular mechanisms by which such an antibody achieves this result is unclear. Methods: We have used Li-Cor In-Cell Western, Western blot, and immunohistochemistry to define levels of different proteins in mouse and human fibroblast cells. Proteomic array was also used to define pathway signaling molecules. Using CCK-8 and BrdU cell proliferation ELISA, we have analyzed proliferative response of these cells to different antibodies. Results: We now show that a stimulating TSHR antibody was able to induce phosphorylation of the IGF-1R and initiate both TSHR and IGF-1R signaling in mouse and human fibroblasts. IGF-1R-B-mAb (1H7) inhibited all major IGF-1R signaling cascades and also reduced TSHR signaling. This resulted in the antibody-induced suppression of autophagy as shown by inhibition of multiple autophagy-related proteins (Beclin1, LC3a, LC3b, p62, and ULK1) and the induction of cell death by apoptosis as evidenced by activation of cleaved caspase 3, FADD, and caspase 8. Furthermore, this IGF-1R-blocking mAb suppressed serum-induced perkin and pink mitophagic proteins. Conclusions: Our observations clearly indicated that stimulating TSHR antibodies were able to enhance IGF-1R activity and contribute to retro-orbital cellular proliferation and inflammation. In contrast, an IGF-1R-B-mAb was capable of suppressing IGF-1R signaling leading to retro-orbital fibroblast/adipocyte death through the cell-extrinsic pathway of apoptosis. This is likely the major mechanism involved in proptosis reduction in patients with Graves' eye disease treated by IGF-1R inhibition.

Immunoglobulin G4-Related Disease: What an Allergist Should Know.

Immunoglobulin G4-related disease (IgG4-RD) is a fibroinflammatory disorder that begins in 1 or more organs as inflammatory tumors that progress toward fibrosis. It is often accompanied by elevated serum IgG4. IgG4-RD was first described in 2003 as a new concept encompassing a number of immunoallergic diseases that had previously been considered unrelated. IgG4-RD mainly affects middleaged and older men. It consists of upregulation and expansion of CD4+ cytotoxic T lymphocytes, oligoclonal plasmablasts, and other inflammatory cells that infiltrate affected tissues and induce inflammation, organ dysfunction, and fibrosis. Symptoms depend on the location, severity, and extent of the disease. Virtually any organ can be affected, including the pancreas, salivary glands, lacrimal glands, thyroid gland, retro-orbital tissue, lymph nodes, retroperitoneum, mediastinum, lung, kidney, aorta, serosal surfaces, and meninges. Patients with widespread disease may present general symptoms. At least 30%-40% of patients are atopic or display atopic traits such as eosinophilia and elevated serum IgE levels. Additional laboratory features include increased serum IgG4 concentrations, increased blood IgG4-plasmablasts, hypergammaglobulinemia, and hypocomplementemia. Diagnosis of IgG4-RD is based on a clinicopathological correlation. Lymphoplasmacytic infiltrate with abundant IgG4-positive plasma cells, storiform-type fibrosis, obliterative phlebitis, and tissue eosinophilia are the pathological hallmarks. Therapy for IgG4-RD is based primarily on corticosteroids but may include additional immunomodulatory drugs and monoclonal antibodies such as rituximab. In individuals with allergic features, IgG4-RD should be suspected when a history of unexplained swelling is observed in 1 or more organs, particularly if they respond to corticosteroids and the patients are men in the sixth decade of life and beyond.

Point-of-Care Ultrasound Findings in a Case of Orbital Cellulitis: A Case Report

Ophthalmologic complaints are common in the emergency department. The utility of point-of-care ultrasound (POCUS) as an accessible, noninvasive modality to evaluate ocular pathology is of great value-particularly in settings where resources are limited or where ophthalmologic consultation may not be readily available. A 21-year-old woman presented to the emergency department with periorbital edema, erythema, and drainage that was worsening despite topical and oral antimicrobial therapy. Mild proptosis was present on examination. POCUS was performed to investigate her symptoms further. A modified ocular ultrasound revealed prominence and edema of the retro-orbital soft tissue with echogenic fat, consistent with the diagnosis of orbital cellulitis. These findings were corroborated with computed tomography imaging. Why Should an Emergency Physician Be Aware of This?: Few reports describe the utility of POCUS in evaluating patients for orbital cellulitis. This case emphasizes the value of POCUS in assessing patients presenting to the emergency department with ocular complaints and demonstrates ultrasound-specific findings that may lead the clinician toward the diagnosis of orbital cellulitis. © 2021 Elsevier Inc.

A Case of Thyroid Eye Disease Revealed During Secondary Adrenal Insufficiency

Introduction: Thyroid eye disease (TED) or Graves’ orbitopathy (GO) is an autoimmune disease of the retro-orbital tissues. GO is mostly associated with hyperthyroidism in 90% of patients; however, it may coexist with hypothyroid conditions in 5% of cases. Clinical Case: A 56-year-old male with a past medical history of autoimmune diseases including hypothyroidism and Ulcerative Colitis on chronic steroid therapy presented to the emergency department with nausea, fatigue, weight loss, and muscle weakness. The patient stated that his glucocorticoids were abruptly discontinued a month prior to his current presentation. On examination, vitals were stable. The patient was somnolent with a depressed mood. He had bilateral periorbital edema and bilateral eyeball protrusion, left more pronounced than right. Extraocular muscle movement revealed a delay in the lateral movement of the left eye causing double vision on exam. He had no starring look or lid lag. The thyroid gland was normal in size and contour. Initial Laboratories revealed a white blood cell count of 6.7 K/mcL (4-10 K/mcL) with 18% eosinophil count (0-5%). Cortisol at 8 AM was 2.9 mcg/dL (4.3 -22.4 mcg/dl). The patient was managed for secondary adrenal insufficiency and restarted immediately on Prednisone. A review of a recent CT scan of the head revealed bilateral proptosis with no signs of compressing lesions. Further thyroid studies revealed TSH of 2.9 mcIU/mL (0.3-3.7 mcIU/mL), free T4 of 0.8 ng/dL (0.75-2.0 ng/dL), free T3 of 1.6 ng/dL (2.4-4.2 ng/dL), TPO antibodies <0.3 IU/mL (0.0-9.0 IU/mL) and TSH receptor antibodies 0.90 IU/L (reference range <1.75 IU/L). The patient was then diagnosed with Hypothyroid Grave’s ophthalmopathy with negative antibodies given the evidence of proptosis on CT and exam revealing extraocular muscle movement restriction causing diplopia. The patient had a unique presentation of TED with hypothyroidism and asymmetric ophthalmic signs that were only manifested after the patient discontinued the prednisone and therefore unmasking the underlying disorder. Fortunately, in June of 2020, the US Food and Drug Administration (FDA) approved Teprotumumab (an insulin-like growth factor 1 [IGF-1] receptor inhibitor) for the treatment of Graves’ orbitopathy based on the findings from two 24-week trials comparing teprotumumab with placebo in 171 patients with active, moderate-to-severe orbitopathy. (1) Our patient was started on Levothyroxine along with Prednisone and referred for ophthalmology evaluation for possible qualification for Teprotumumab treatment. Conclusion: Clinician awareness of the unusual presentations of TED would allow for early recognition and prevention of progression, especially with the recently approved treatment modality.

Serum thyroglobulin is associated with orbitopathy in Graves\u2019 disease

PurposeSerum thyroglobulin levels are often elevated in Graves’ disease (GD) and in most cases decrease during treatment. Its relation to Graves’ orbitopathy (GO) has not been clarified. Previously, a risk of GO has been linked to smoking, TSH receptor stimulation, high TSH-receptor antibodies (TRAb), low thyroid peroxidase and thyroglobulin antibodies (TPOAb, TgAb).MethodsWe examined Tg levels in 30 consecutive patients with GD were given drug therapy (methimazole + thyroxine) for up to 24 months. GO was identified by clinical signs and symptoms. 17 patients had GO, 11 of whom had it at diagnosis while 6 developed GO during treatment. During the study, 5 subjects were referred to radioiodine treatment, 3 to surgery. The remaining 22 subjects (GO n = 12, non-GO n = 10) completed the drug regimen.ResultsAt diagnosis, Tg levels in GO patients (n = 11) were higher (84, 30–555 µg/L, median, range) than in non-GO patients (n = 19) (38, 3.5–287 µg/L), p = 0.042. Adding the 6 subjects who developed eye symptoms during treatment to the GO group (n = 17), yielded p = 0.001 vs. non-GO (n = 13). TRAb tended to be higher, while TPOAb and TgAb tended to be lower in the GO group. For the 22 patients who completed the drug regimen, Tg levels were higher in GO (n = 12) vs. non-GO (n = 10), p = 0.004, whereas TRAb levels did not differ.ConclusionThe data may suggest that evaluation of thyroglobulin levels in GD could contribute to identify patients at increased risk of developing GO. Possibly, thyroidal release of Tg in GD reflects a disturbance that also impacts retroorbital tissues.

Graves' disease.

Graves' disease (GD) is an autoimmune disease that primarily affects the thyroid gland. It is the most common cause of hyperthyroidism and occurs at all ages but especially in women of reproductive age. Graves' hyperthyroidism is caused by autoantibodies to the thyroid-stimulating hormone receptor (TSHR) that act as agonists and induce excessive thyroid hormone secretion, releasing the thyroid gland from pituitary control. TSHR autoantibodies also underlie Graves' orbitopathy (GO) and pretibial myxoedema. Additionally, the pathophysiology of GO (and likely pretibial myxoedema) involves the synergism of insulin-like growth factor 1 receptor (IGF1R) with TSHR autoantibodies, causing retro-orbital tissue expansion and inflammation. Although the aetiology of GD remains unknown, evidence indicates a strong genetic component combined with random potential environmental insults in an immunologically susceptible individual. The treatment of GD has not changed substantially for many years and remains a choice between antithyroid drugs, radioiodine or surgery. However, antithyroid drug use can cause drug-induced embryopathy in pregnancy, radioiodine therapy can exacerbate GO and surgery can result in hypoparathyroidism or laryngeal nerve damage. Therefore, future studies should focus on improved drug management, and a number of important advances are on the horizon.

Evidence for Associations Between Th1/Th17 "Hybrid" Phenotype and Altered Lipometabolism in Very Severe Graves Orbitopathy.

The purpose of this article is to investigate the characteristics of Th1-cell and Th17-cell lineages for very severe Graves orbitopathy (GO) development. Flow cytometry was performed with blood samples from GO and Graves disease (GD) patients and healthy controls, to explore effector T-cell phenotypes. Lipidomics was conducted with serum from very severe GO patients before and after glucocorticoid (GC) therapy. Immunohistochemistry and Western blotting were used to examine orbital-infiltrating Th17 cells or in vitro models of Th17 polarization. In GD, Th1 cells predominated in peripheral effector T-cell subsets, whereas in GO, Th17-cell lineage predominated. In moderate-to-severe GO, Th17.1 cells expressed retinoic acid receptor-related orphan receptor-γt (RORγt) independently and produced interleukin-17A (IL-17A), whereas in very severe GO, Th17.1 cells co-expressed RORγt and Tbet and produced interferon-γ (IFN-γ). Increased IFN-γ-producing Th17.1 cells positively correlated with GO activity and were associated with the development of very severe GO. Additionally, GC therapy inhibited both Th1-cell and Th17-cell lineages and modulated a lipid panel consisting of 79 serum metabolites. However, in GC-resistant, very severe GO, IFN-γ-producing Th17.1 cells remained at a high level, correlating with increased serum triglycerides. Further, retro-orbital tissues from GC-resistant, very severe GO were shown to be infiltrated by CXCR3+ Th17 cells expressing Tbet and STAT4 and rich in triglycerides that promoted Th1 phenotype in Th17 cells in vitro. Our findings address the importance of Th17.1 cells in GO pathogenesis, possibly promoting our understanding of the association between Th17-cell plasticity and disease severity of GO.

Determining residual adipose tissue characteristics with MRI in patients with various subtypes of lipodystrophy.

We aimed to investigate residual adipose tissue with whole-body magnetic resonance imaging to differentiate between subtypes of lipodystrophy. A total of 32 patients (12 with congenital generalized lipodystrophy [CGL], 1 with acquired generalized lipodystrophy [AGL], 12 with familial partial lipodystrophy [FPLD], and 7 with acquired partial lipodystrophy [APL]) were included. Despite generalized loss of metabolically active adipose tissue, patients with CGL1 caused by AGPAT2 mutations had a significant amount of residual adipose tissue in the scalp, earlobes, retro-orbital region, and palms and soles. No residual adipose tissue was noted particularly in the head and neck, palms and soles in CGL2 caused by BSCL2 mutations. CGL4 caused by mutations in the PTRF gene was characterized with well-preserved retro-orbital and bone marrow fat in the absence of any visible residual adipose tissue in other areas. No residual adipose tissue was observed in AGL. Despite loss of subcutaneous fat, periarticular adipose tissue was preserved in the lower limbs of patients with FPLD. Retro-orbital adipose tissue was surprisingly preserved in APL, although they lacked head and neck fat. Lipodystrophies are a heterogeneous group of disorders characterized by generalized or partial loss of adipose tissue, which can be congenital or acquired. Our results suggest that residual adipose tissue characteristics can help distinguish different subtypes of lipodystrophy.

Icariin Inhibits AMPK-Dependent Autophagy and Adipogenesis in Adipocytes In vitro and in a Model of Graves' Orbitopathy In vivo

Graves' orbitopathy (GO), an extrathyroidal manifestation of Graves' disease, is an inflammatory autoimmune disorder of the orbit that involves the differentiation of precursor cells into mature adipocytes and retro-orbital adipose tissue accumulation. Here, we examined the involvement of autophagy in adipogenesis and explored the effects of icariin, a flavonoid isolated from the genus Epimedium with a wide range of biological and pharmacological effects, on autophagy and adipogenesis in 3T3-L1 preadipocytes and in a mouse model of GO. Microscopic examination of autophagosome formation and lipid droplet accumulation by Oil Red O staining, and western blot assessment of autophagic markers in the presence of the autophagy inhibitors Asn and 3-MA showed that autophagy is essential for adipogenesis. Icariin inhibited the differentiation of preadipocytes into mature adipocytes by suppressing autophagy, and these effects were mediated by the inhibition of AMPK/mTOR pathway activation. In a mouse model of thyroid stimulating hormone receptor induced GO, icariin reduced orbital muscle adipose tissue expansion and lipid droplet accumulation by inhibiting AMPK/mTOR mediated autophagy. Collectively, these results reveal a potential mechanism underlying the protective effects of icariin against autophagy induced adipogenesis and suggest that icariin could be developed as a new therapeutic candidate for the prevention and treatment of GO.

The role of thyrotropin receptor antibodies in Grave’s Ophthalmopathy treatment

Background. Graves' ophthalmopathy (GO) is an autoimmune inflammatory disorder affecting the retroorbital tissues. Although the role of TRAb in GO is now accepted by many researchers and clinicians, their use in the disease management of GO is less well studied than the role of TRAb for the diagnosis and therapy monitoring of Graves’ disease.Aim: to evaluate the relation between TRAb level and the activity of GO, the course of GO and the effectiveness of the treatment.Materials and methods. We have studied 26 patients with GO and Grave’s Disease. Activity of GO was measured with the clinical activity score (CAS), we defined active GO as a CAS≥3. TSH, FT4 and TRAb were evaluated. All patients had received intravenous methylprednisolone (ivMP) pulse therapy in cumulative dose 6000 mg. We observed patients for 1 year after pulse therapy. TRAb level was evaluated before, 3, 6 and 12 months after pulse therapy.Results: At the time of initial treatment all patients had active GO, 60% with CAS 3-4 and 40% with CAS 5-7. On year after the pulse therapy of GO, all patients were classified into responders (69,2%) and non-responders (30,8%) according to their clinical manifestations. Pulse therapy considered as effective if GO activity decreased with CAS ≤ 2. Serum TRAb level was significantly higher in patients who non-responded to therapy – 34,8 U/L vs 17,5 U/L (p≤0,01). This level was significantly decreased in patients responded to treatment – 1,6 U/L vs 12,4 U/L (p≤0,01). TRAb level above 28,8 U/L before treatment (p≤0,01), 10,1 U/L after 3 months of treatment (p≤0,01), 5,1 U/L after 6 months of treatment (p≤0,01) and 8,2 U/L after 3 months of treatment (p≤0.01) was associated with higher risk of non-responding.Conclusion: We conclude, that TRAb level may serve not only as predictor of GO activity and severity, but changes in the level of antibodies could be of additional help for the disease management with ivMP.